Katia K. Mattis, Nicole A. J. Krentz, Christoph Metzendorf, Fernando Abaitua, Aliya F. Spigelman, Han Sun, Jennifer M. Ikle, Swaraj Thaman, Antje K. Rottner, Austin Bautista, Eugenia Mazzaferro, Marta Perez-Alcantara, Jocelyn E. Manning Fox, Jason M. Torres, Agata Wesolowska-Andersen, Grace Z. Yu, Anubha Mahajan, Anders Larsson, Patrick E. MacDonald, Benjamin Davies, Marcel den Hoed, Anna L. Gloyn

Genome-wide association studies have identified multiple independent signals at the RREB1 locus associated with type 2 diabetes. However, how altered expression or function of the transcription factor Ras-responsive element binding protein 1 (RREB1) influences diabetes risk was previously unknown. In this issue, Mattis and Krentz et al (https://doi.org/10.1007/s00125-022-05856-6) describe how a combination of zebrafish and human cellular models was used to identify disease-causing mechanisms at the RREB1 locus. The authors show how RREB1 loss-of-function reduced insulin gene expression and insulin content in zebrafish as well as in human beta cell models. Transcriptomic analysis identified RREB1 as a regulator of several genes involved in beta cell development and function, including the RFX family of transcription factors. Consistent with these findings, the authors show how isolated islets from human carriers of RREB1 diabetes-risk alleles exhibited altered glucose-stimulated insulin secretion. The authors conclude that the genetic association of RREB1 with type 2 diabetes is mediated, in part, by a transcriptional role for RREB1 in normal beta cell development and function.

Suping Ling, Francesco Zaccardi, Eyad Issa, Melanie J Davies, Kamlesh Khunti, Karen Brown

Owing to improvements in cardiovascular disease prevention and treatment in the past few decades, mortality rates in people with type 2 diabetes have declined substantially in some high-income countries. Given the increased incidence and mortality for some cancers associated with diabetes, it is unclear whether cancer has overtaken cardiovascular disease as the key cause of death in this population and whether inequalities exist in cancer mortality trends. In this issue, Ling et al (https://doi.org/10.1007/s00125-022-05854-8) report that, in contrast to declining all-cause mortality rates in people with type 2 diabetes at all ages between 1998 and 2018, there were decreasing trends in all-cancer mortality rates at younger ages but increasing trends at older ages (75+). In addition, they show that there were persistent inequalities in cancer mortality rates by gender and socioeconomic status and widening disparities by smoking status. The authors conclude that these findings highlight that cancer deserves a similar level of attention as other diabetes-related complications, such as cardiovascular disease, and that public health policies are needed to address persistent and widening inequalities.

Jedidiah I. Morton, Clara Marquina, Jonathan E. Shaw, Danny Liew, Kevan R. Polkinghorne, Zanfina Ademi and Dianna J. Magliano

Sodium–glucose co-transporter 2 inhibitors (SGLT2is) and glucagon-like peptide‑1 receptor agonists (GLP-1 Ras) reduce the incidence of cardiovascular and kidney disease in addition to their effects on blood glucose. However, it is unclear if they are cost-effective on the basis of their cardiovascular and kidney benefits alone, which may be why many payers/governments have HbA_1c-based restrictions on their use. In this issue, Morton et al (https://doi.org/10.1007/s00125-022-05832-0) report that, based solely on their cardiovascular benefits at current prices, SGLT2is are cost-effective for anyone with type 2 diabetes from the Australian healthcare perspective, while GLP-1 RAs are unlikely to be cost-effective, even in a population with pre-existing cardiovascular disease. The authors conclude that these findings suggest that existing HbA_1c-based restrictions on SGLT2i use may not be justified from a health economic perspective.

Deirdre K. Tobias

Systematic reviews and meta-analyses are respectable research tools when used correctly. In this issue, Deirdre Tobias (https://doi.org/10.1007/s00125-022-05862-8) describes, however, that the quality of systematic reviews today is highly variable, despite standard operating procedures and best practices, warranting serious concerns about over-reliance on their findings without paying careful attention to potential bias. She discusses how this has undoubtedly led to some arguments against their use and value to the scientific community (see the counter-debate by Enzo Bonora in this issue). However, she goes on to highlight that dismissing this critical and growing evidence base altogether would be a disservice to rigorous scientific progress. She concludes that researchers should instead be encouraged to improve their proficiency in reading, conducting and interpreting systematic review research so that these reviews better serve their intended role as efficient synthesisers of accumulating evidence and gatekeepers of redundant original research.

Enzo Bonora

Progress in medicine relies on scientific literature because journals are the main peer-reviewed medium of discoveries, achievements, concepts and ideas, inspiring further research as well as establishing best clinical practices. In this issue, Enzo Bonora (https://doi.org/10.1007/s00125-022-05808-0) illustrates the huge increase in diabetes-related literature over the last few decades but highlights what he believes is an excess of ‘nothing-to-add’ papers and, in particular, redundant meta-analyses and repetitive narrative reviews. He also emphasises the enthusiasm that meta-analyses and reviews receive from some journals and some scientists, anxious to improve their own metrics. He concludes that the scientific relevance of papers and the scientific achievements of investigators and journals are more important for medical progress than their respective metrics. See the counter-debate by Deirdre Tobias in this issue.

Aicha Saadane, Alexander A. Veenstra, Martin S. Minns, Jie Tang, Yunpeng Du, Fatima Abubakr Elghazali, Emma M. Lessieur, Eric Pearlman, Timothy S. Kern

Inflammation has been implicated in the pathogenesis of the early stages of diabetic retinopathy but the molecular mechanisms are unclear. In this issue, Saadane et al (https://doi.org/ 10.1007/s00125-022-05860-w) that deletion of CC chemokine receptor 2 (CCR2)-positive cells (largely monocytes) in a mouse model of diabetes or generation of chimeric mice lacking Ccr2 only from myeloid cells significantly inhibited the diabetes-induced increase in retinal capillary degeneration. The authors highlight how these results in monocytes reflect previous studies that have shown that neutrophils have direct cytotoxic effects on retinal endothelial cells, thus providing at least one mechanism by which leucocytes contribute to diabetes-induced vascular damage in diabetes. They conclude that abnormalities in multiple cell types in the innate immune system contribute to the development of the early stages of diabetic retinopathy, providing potential therapeutic targets for inhibiting retinopathy.

Hyunkyung Kim, Kenneth E. Westerman, Kirk Smith, Joshua Chiou, Joanne B. Cole, Timothy Majarian, Marcin von Grotthuss, Soo Heon Kwak, Jaegil Kim, Josep M. Mercader, Jose C. Florez, Kyle Gaulton, Alisa K. Manning, Miriam S. Udler

Genome-wide association studies (GWAS) have identified hundreds of loci associated with type 2 diabetes; however, clinical translation of findings has been challenging. In this issue, Kim et al (https://doi.org/10.1007/s00125-022-05848-6) describe a high-throughput pipeline using GWAS summary statistics to perform physiologically informed clustering of 323 independent type 2 diabetes loci and identified ten genetic clusters. These clusters represent subsets of diabetes risk variants that are most similar to each other based on their associations with disease-related traits. The ten clusters included both previously captured and novel clusters, and displayed tissue-specific enrichment of epigenomic marks. Cluster-based polygenic scores were associated with distinct clinical outcomes. The authors also demonstrated application of the pipeline to two other metabolic diseases. They conclude that their high-throughput clustering approach can produce robust findings and identify potential genetic subtypes of disease.

Alexandra Coomans de Brachène, Corentin Scoubeau, Anyïshai E. Musuaya, Jose Maria Costa-Junior, Angela Castela, Julie Carpentier, Vitalie Faoro, Malgorzata Klass, Miriam Cnop, Decio L. Eizirik

Exercise training is known to reduce diabetes risk. In this issue, Coomans de Brachène et al (https://doi.org/10.1007/s00125-022-05837-9) report that serum obtained from 82 individuals after 8–12 weeks of exercise training protects human pancreatic beta cells against apoptosis induced by the endoplasmic reticulum stressor thapsigargin, compared with serum obtained from the same individuals before training. The protective effect was observed regardless of the type of exercise training, or sex, age, BMI, ancestry or diabetes status (type 1, type 2 or non-diabetic) of the individuals. The study points to a role for muscle-released clusterin in this protective effect, and other exerkines may also be involved. The authors highlight the unexpected potential to preserve beta cell health by exercise training and suggest that exercise could be tested as a non-pharmacological approach to preserve beta cell mass in the early stages of diabetes.

Annika Rosengren, Pigi Dikaiou

A typical adult with type 1 diabetes is different from adults with type 2 diabetes, with respect to mean age, duration of diabetes and body size. While individuals with type 2 diabetes are generally older and have higher levels of other cardiometabolic risk factors, those with type 1 typically have longer exposure to high plasma glucose levels. In this issue, Rosengren and Dikaiou (https://doi.org/10.1007/s00125-022-05857-5) discuss why both types of diabetes face increased risk of cardiovascular disease. The authors highlight that in each type of diabetes, absolute risk and excess risk, compared with the general population, vary depending on the control of other factors. However, few studies have formally compared the two types, and those studies that have done so have reached different conclusions. Accordingly, there is as yet no consensus on which type of diabetes fares worse with respect to cardiovascular disease. The authors conclude that future studies in large, unselected populations are needed, taking other risk factors into account. The figures from this review are available as a downloadable slideset.

T. J. P. Jansen, M. Brom, M. Boss, M. Buitinga, C. J. Tack, L. A. van Meijel, B. E. de Galan, M. Gotthardt

The importance of residual beta cells for glucose control in people with type 1 diabetes is not yet fully understood and measurement of human beta cell mass is challenging. In this issue, Jansen et al (https://doi.org/10.1007/s00125-022-05830-2) report the novel use of an imaging method, exendin PET, to measure beta cell mass in a non-invasive manner. The authors demonstrate that beta cell mass was markedly increased in people with type 1 diabetes and relatively stable glycaemic control than in people with type 1 diabetes and high glucose variability. They suggest that residual beta cells may therefore play an important role in glycaemic stability in people with type 1 diabetes. The authors highlight that their finding indicates the need for effective therapies aimed at preserving viable beta cells and therapies that can restore or improve beta cell functionality. They conclude that exendin PET may have a role to play in the detection of these residual beta cells and could aid in the selection of the most suitable treatments.

Ruizhi Zheng, Zhuojun Xin, Mian Li, Tiange Wang, Min Xu, Jieli Lu, Meng Dai, Di Zhang, Yuhong Chen, Shuangyuan Wang, Hong Lin, Weiqing Wang, Guang Ning, Yufang Bi, Zhiyun Zhao, Yu Xu

Artificial lighting has increased significantly during recent decades and detrimental effects of artificial light at night (LAN) exposure on metabolic health have been reported. However, it is unclear whether exposure to outdoor artificial LAN is associated with glucose homoeostasis and diabetes. In this issue, Zheng and Xin et al (https://doi.org/10.1007/s00125-022-05819-x) used data from a national survey of the general population in China and report that chronic exposure to outdoor LAN was positively associated with blood glucose levels, insulin resistance and diabetes prevalence and inversely associated with beta cell function. The authors highlight that, considering the acceleration in urbanisation and growing number of domestic migrants arriving in large cities, the number of people with light pollution-related diabetes is projected to increase. They conclude that effective prevention and intervention policies should be developed to protect people from the adverse health effects of light pollution at night.

Peter A. Lazzarini, Susanna M. Cramb, Jonathan Golledge, Jedidiah I. Morton, Dianna J. Magliano, Jaap J. Van Netten

Diabetic foot disease is a leading cause of hospitalisation and amputation. In this issue, Lazzarini et al (https://doi.org/10.1007/s00125-022-05845-9) review published data to determine the latest trends in global hospitalisation and amputation rates for diabetic foot disease. The authors provide evidence that global trends in hospitalisation rates for major amputations are largely decreasing but trends in minor amputations and diabetic foot disease are inconsistent. Further, they highlight that hospitalisation rates for diabetic foot disease without amputation are substantially higher than rates for diabetic foot disease with amputation and higher than rates for most other major diabetes complications. However, they suggest the need for caution in the ‘global’ interpretation of these findings because of the high heterogeneity of published data and limited data from low- and middle-income countries. The authors conclude that global reporting standards are needed to better interpret, monitor and address the large global burden of hospitalisation and amputation caused by diabetic foot disease.

Kamlesh Khunti, Jonathan Valabhji, Shivani Misra

People living with diabetes are at greater risk of hospitalisation and death following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In addition, the coronavirus disease-2019 (COVID-19) pandemic has disrupted healthcare delivery for people living with diabetes. In this issue, Khunti et al (https://doi.org/10.1007/s00125-022-05833-z) summarise the evidence on the acute impact of COVID-19 on people with diabetes, including data on the occurrence of new-onset diabetes and diabetic ketoacidosis, and the wider impact of the pandemic on healthcare services. The authors conclude by presenting recommendations for prioritising patients with diabetes during the pandemic recovery phase. The figures from this review are available as a downloadable slideset

Amy E. Mendham, Lisa K. Micklesfield, Fredrik Karpe, Andre Pascal Kengne, Tinashe Chikowore, Clement N. Kufe, Maphoko Masemola, Nigel J. Crowther, Shane A. Norris, Tommy Olsson, Sölve Elmståhl, Tove Fall, Lars Lind, Julia H. Goedecke

The pathogenesis of type 2 diabetes appears to differ between Black Africans and Europeans, but the diagnostic criteria are the same. In this issue, Mendham et al (https://doi.org/10.1007/s00125-022-05788-1) highlight biomarkers that are both similar and different between Black African and European cohorts who have different lifestyles and sociodemographic profiles. The authors identified 73 proteins associated with impaired glucose metabolism and/or type 2 diabetes in a cohort of middle-aged Black South African men and women, of which 34 proteins were validated in a European cohort. Among the validated proteins, 11 were associated with components of type 2 diabetes pathophysiology such as fasting insulin resistance, peripheral insulin sensitivity and beta cell function. The African-specific biomarkers identified require validation in independent African cohorts to not only identify unique risk markers, but also to increase our understanding of the pathophysiology of type 2 diabetes in African populations.

Roger E. Henriksen, Roy M. Nilsen, Ragnhild B. Strandberg

A growing body of research has pointed to an association between psychological stress and an individual’s risk of developing type 2 diabetes. In this issue, Henriksen et al (https://doi.org/10.1007/s00125-022-05791-6) report from their 20 year follow-up study showing that participants who recorded a high level of loneliness were twice as likely to develop type 2 diabetes than those who did not feel lonely. Although their study did not examine the exact mechanisms involved, the researchers suggest that loneliness may activate the body’s physiological stress response and that this response may play a central role in the development of type 2 diabetes through different pathways. The authors recommend healthcare providers to be open to dialogue about an individual’s concerns during clinical consultations, including loneliness and social relationships.

Gernot Desoye, Lene Ringholm, Peter Damm, Elisabeth R. Mathiesen, Mireille N. M. van Poppel

In pregnant women with type 1 diabetes, whenever metabolism is disturbed, the fetus is at risk of growing too large. This may lead to complications during delivery and also has long term consequences for the child’s health, including childhood obesity. As such, normalising metabolism during pregnancy would be expected to reduce fetal overgrowth. Paradoxically, however, in the past few decades, improved healthcare and blood glucose control in women with type 1 diabetes, especially in the periconception period, have had the opposite effect, i.e. an increase in birthweight. In this review, Desoye et al (https://doi.org/10.1007/s00125-022-05820-4) discuss that improved blood glucose control may lead to better placentation in women with type 1 diabetes, which exposes the fetus to changes in metabolism more than in earlier decades. The resulting fetal overgrowth may then result in excess fat, independent of birthweight. The authors highlight that this calls for even stricter glucose control during the whole pregnancy period and suggest taking advantage of new diabetes technology. They conclude that evaluation of diabetes management should focus on neonatal fat, rather than birthweight. The figures from this review are available as a downloadable slideset.

Beatrice C. Lupsa, Richard G. Kibbey, Silvio E. Inzucchi

Sodium−glucose cotransporter 2 (SGLT2) inhibitors are a relatively recent class of glucose-lowering medication, originally approved for treating individuals with type 2 diabetes, that have been found to have cardiovascular and renal benefits, independent of their glucose-lowering effect. The mechanisms underlying these salutary effects remain unclear. In this issue, Lupsa et al (https://doi.org/10.1007/s00125-022-05815-1) provide a comprehensive review of the advantages of SGLT2 inhibitors on cardiac and kidney outcomes and the potential role of elevated plasma ketone levels in mediating these benefits. The impact of SGLT2 inhibitors on ketone physiology is reviewed and the risk of ‘euglycaemic’ diabetic ketoacidosis is additionally explored. The topic of ketogenesis and SGLT2 inhibitors is of both scientific and clinical significance.

Jennifer L. Sherr, Lutz Heinemann, G. Alexander Fleming, Richard M. Bergenstal, Daniela Bruttomesso, Hélène Hanaire, Reinhard W. Holl, John R. Petrie, Anne L. Peters, Mark Evans

Both clinical studies and real-world experience show that insulin pumps that link to glucose sensors to allow automated insulin delivery (AID) carry great benefits, both in terms of glucose metrics (with lower average blood glucose and increased time in target range) and user experience. However, as with all powerful and effective tools, potential pitfalls exist. In this issue, Sherr et al (https://doi.org/10.1007/s00125-022-05744-z), on behalf of the joint Diabetes Technology Working Group of the European Association for the Study of Diabetes and American Diabetes Association, describe some of these challenges and limitations. Several recommendations are listed for regulators, device companies, diabetes societies, research funders, health care professionals and users of technology. In particular, the authors highlight that AID is not a cure for diabetes, and clinicians need to understand how individual systems work and ensure that people with diabetes using AID are aware of the limitations of current systems.

Josca M. Schoonejans, Heather L. Blackmore, Thomas J. Ashmore, Lucas C. Pantaleão, Luciana Pellegrini Pisani, Laura Dearden, John A. Tadross, Catherine E. Aiken, Denise S. Fernandez-Twinn, Susan E. Ozanne

Metformin is used to treat gestational diabetes in many countries. Although beneficial for the mother and safe for the neonate, the long-term effects on exposed offspring remain unknown. In this issue, Schoonejans et al (https://doi.org/10.1007/s00125-022-05789-0) report that maternal metformin treatment in a mouse model of obese glucose-intolerant pregnancy leads to sex- and age-specific increases in metabolic risk factors in exposed offspring. The authors propose that fetal metformin exposure can adversely influence adipose tissue development, leading to a postnatal phenotype characterised by adiposity, adipose tissue inflammation and ectopic lipid deposition in tissues such as the liver. The authors conclude that the findings highlight the complexity of balancing short-term beneficial maternal or fetal effects and long-term offspring consequences of placenta-crossing therapies such as metformin, and stress the importance of following up offspring of both sexes throughout life.

Lars Krogvold, Angelo Genoni, Anna Puggioni, Daniela Campani, Sarah J. Richardson, Christine S. Flaxman, Bjørn Edwin, Trond Buanes, Knut Dahl-Jørgensen, Antonio Toniolo

The team behind the DiViD study previously reported the presence of enterovirus (EV) genome and proteins in pancreatic sections from six live newly diagnosed patients with type 1 diabetes. In this issue, Krogvold et al (https://doi.org/10.1007/s00125-022-05779-2) confirm the presence of EVs and also demonstrate that no other common human viruses are present in the pancreases of the six DiViD cases. The authors demonstrate that the EV strains detected represent live infectious viruses capable of establishing a persistent pancreatic infection. As previously shown in persistent EV infection of the heart, persistent EV infection of the pancreas could lead to progressive tissue-specific dysfunction. The authors conclude that the early phase of type 1 diabetes is associated with low-grade EV infection. They go on to suggest that the findings strengthen the need for studies exploring the potential benefits of enteroviral vaccines for individuals at high risk of developing type 1 diabetes and antiviral treatment for individuals in the early phase of type 1 diabetes.

Ryan J. Jalleh, Karen L. Jones, Christopher K. Rayner, Chinmay S. Marathe, Tongzhi Wu, Michael Horowitz

Gastric emptying is central to the pathogenesis and rational management of type 1 and type 2 diabetes. In this issue, Jalleh et al (https://doi.org/10.1007/s00125-022-05796-1) review the effects of diabetes and its treatment on gastric emptying. The authors discuss how gastric emptying is delayed (i.e. gastroparesis) in 30–50% of people with longstanding, complicated type 1 or type 2 diabetes. In contrast, in well-controlled type 2 diabetes, gastric emptying is often abnormally rapid. Upper gastrointestinal symptoms, which should be assessed routinely using a validated instrument, occur frequently, but the relationship of symptoms with disordered gastric emptying is not simply ‘cause-and-effect’. The longstanding therapeutic approach of making the stomach ‘pump’ better has, predictably, proven unsuccessful. The authors go on to outline how gastric emptying, even when normal, is a key determinant of postprandial blood glucose levels. In insulin-treated diabetes, disordered gastric emptying may predispose an individual to hypoglycaemia/increased blood glucose variability. Both short- and long-acting glucagon-like peptide-1 receptor agonists slow gastric emptying to diminish postprandial glycaemic excursions. The authors conclude that measurement of gastric emptying, using a precise technique, should be incorporated in clinical trials of novel therapies that lower postprandial glucose. The figures from this review are available as a downloadable slideset.

Julia H. Goedecke, Amy E. Mendham

Sub-Saharan Africa (SSA) is the region that is projected to have the greatest rate of increase in type 2 diabetes (129% by 2045). In this issue, Goedecke and Mendham (https://doi.org/10.1007/s00125-022-05795-2) summarise known mechanisms relating to the pathophysiology of type 2 diabetes in sub-Saharan Africans and highlight factors that may influence the pathogenesis of type 2 diabetes in SSA, such as social determinants, infectious diseases and genetic and epigenetic influences. They propose that, among Black Africans from SSA, hyperinsulinaemia due to a combination of both increased insulin secretion and reduced hepatic insulin clearance is the primary defect, which promotes obesity and insulin resistance, exacerbating the hyperinsulinaemia and eventually leading to beta cell failure and type 2 diabetes. The authors conclude that future research on dietary interventions that reduce hyperinsulinaemia and obesity is warranted to gain insights into the mechanistic underpinnings of type 2 diabetes in this population. The figures from this review are available as a downloadable slideset.

Melanie J. Davies, Vanita R. Aroda, Billy S. Collins, Robert A. Gabbay, Jennifer Green, Nisa M. Maruthur, Sylvia E. Rosas, Stefano Del Prato, Chantal Mathieu, Geltrude Mingrone, Peter Rossing, Tsvetalina Tankova, Apostolos Tsapas, John B. Buse

In 2022, the ADA/EASD updated their consensus report on the management of hyperglycaemia in type 2 diabetes. In this issue, Davies et al (https://doi.org/10.1007/s00125-022-05787-2) present important changes to the 2019 consensus, reflecting new evidence generated in the last 3 years, such as that from cardiovascular and renal outcome trials of sodium–glucose cotransporter-1 inhibitors and glucagon-like peptide-1 receptor agonists, including assessment of subgroups. Recommendations for cardiorenal protection in those with diabetes and at high risk of cardiorenal disease are also presented. The authors focus on holistic management, weight management and consideration of physical behaviours, including sleep, over a 24 h period. The authors also outline that social determinants of health must be addressed if we are to aspire to improve health outcomes. The consensus concludes with a ‘Call to Action’ stating that we must establish and refine quality improvement efforts in diabetes care at local level to equitably implement evidence-based interventions for the benefit of all people living with type 2 diabetes.

Jayron J. Habibe, Maria P. Clemente-Olivo, Torsten P. M. Scheithauer, Elena Rampanelli, Hilde Herrema, Mariska Vos, Arnout Mieremet, Max Nieuwdorp, Daniel H. van Raalte, Etto C. Eringa, Carlie J. M. de Vries

FHL2, the gene encoding the four and a half LIM domains 2 (FHL2) protein, contains DNA methylation marks, which forensic studies have consistently found to be correlated with the age of an individual. Hypermethylation of these CpG loci causes an increase in FHL2 expression. In this issue, Habibe and Clemente-Olivo et al (https://doi.org/10.1007/s00125-022-05750-1) show that individuals with type 2 diabetes also express higher FHL2 levels in their pancreatic islets compared with healthy individuals. Furthermore, the authors demonstrate that, compared with their wild-type littermates, Fhl2-deficient mice clear glucose faster, whereas insulin sensitivity is similar for both strains of mice. Isolated pancreatic islets from mice that are deficient for Fhl2 show increased glucose-induced insulin secretion, which the authors suggest may be explained, at least partially, by enhanced expression of the glucose-transporter GLUT2. In line with this, FHL2 gain of function is detrimental to insulin secretion of cultured beta cells due to a reduced uptake of glucose and enhanced levels of reactive oxygen species. The authors conclude that inhibition of FHL2 in human transplant islets may improve transplant function in vivo.

Charlotte Andriessen, Ciarán E. Fealy, Anna Veelen, Sten M. M. van Beek, Kay H. M. Roumans, Niels J. Connell, Julian Mevenkamp, Esther Moonen-Kornips, Bas Havekes, Vera B. Schrauwen-Hinderling, Joris Hoeks, Patrick Schrauwen

Time-restricted eating (TRE) is a form of intermittent fasting whereby food intake is limited to a pre-defined time window during the day. Previous studies in healthy, overweight/obese adults showed that 6–8 h TRE regimes were successful in improving metabolic health. In this issue, Andriessen et al (https://doi.org/10.1007/s00125-022-05752-z) investigated the effect of a more accessible 10 h TRE intervention in adults with type 2 diabetes. Three weeks of TRE resulted in lower fasting glucose and 24 h glucose levels, as well as more time spent in the normal glucose range as compared with spreading habitual food intake over at least 14 h per day. The study did not find changes in insulin sensitivity, hepatic glycogen or substrate oxidation. The authors conclude that these findings highlight the therapeutic potential of TRE in adults with type 2 diabetes. They recommend that more studies are conducted to investigate the underlying mechanisms and long-term effects of TRE.

Joseph J. Castillo, Alfred C. Aplin, Daryl J. Hackney, Meghan F. Hogan, Nathalie Esser, Andrew T. Templin, Rehana Akter, Steven E. Kahn, Daniel P. Raleigh, Sakeneh Zraika, Rebecca L. Hull

Aggregation of islet amyloid polypeptide (IAPP) is a pathologic feature of several forms of diabetes, including type 2 diabetes. Aggregated IAPP accumulates in the islet extracellular matrix between beta cells and the islet vasculature and is well known to be cytotoxic to islet beta cells. However, whether IAPP aggregation is also detrimental to the islet vasculature, an important modulator of beta cell function/survival, has not previously been examined. In this issue, Castillo et al (https://doi.org/10.1007/s00125-022-05756-9) use cell- and animal models to show that IAPP elicits a cytotoxic and pro-inflammatory response from cultured islet microvascular endothelial cells. In pancreases from transgenic mice, the authors found that aggregated IAPP (amyloid deposits) exerts specific, localised effects to increase capillary diameter and increase the number of neuron-glial antigen 2 (NG2)-positive islet pericytal structures. The authors conclude that, together, these findings demonstrate that the islet vasculature is a target of the cytotoxic and proinflammatory effects of IAPP, which is likely to contribute to beta cell failure in diabetes.

Bruno Vergès

The intestine plays an important role in the dyslipidaemia observed in type 2 diabetes and particularly in postprandial hyperlipidaemia, which is known to promote atherosclerosis and increase the incidence of cardiovascular disease. In this issue, Bruno Vergès (https://doi.org/10.1007/s00125-022-05765-8) reviews disorders of intestinal lipid metabolism in type 2 diabetes, which include increased chylomicron production by enterocytes and delayed catabolism of chylomicrons and chylomicron remnants. He outlines how overproduction of chylomicrons is secondary to increased expression of microsomal triglyceride transfer proteins, higher stability and availability of apolipoprotein B-48 and increased de novo lipogenesis. He goes on to discuss how reduced activity of lipoprotein lipase is a major factor responsible for reduced catabolism of chylomicrons in type 2 diabetes. Interestingly, some glucose-lowering treatments significantly influence intestinal lipid metabolism, particularly glucagon-like peptide-1 agonists. Vergès concludes that a better understanding of intestinal lipid metabolism should help to define interesting therapeutic targets for improving postprandial lipid metabolism in type 2 diabetes. The figures from this review are available as a downloadable slideset.

Jan W. Eriksson, Björn Eliasson, Louise Bennet, Johan Sundström

Over recent years, registry-based randomised clinical trials (RRCT) have been used in some clinical conditions, for example within cardiology and orthopaedic surgery. In both type 1 and type 2 diabetes, there are several examples of observational studies based on registries or established cohorts that evaluate treatment effects; however, to date, no RRCTs have been performed. In this issue, Eriksson et al (https://doi.org/10.1007/s00125-022-05762-x) review how pragmatic large-scale clinical trials could be applied in the diabetes area. The authors propose that both academic and industry sponsors should consider this highly cost-effective and robust design for future large-scale diabetes trials. Following allocation to randomised treatment, the participants’ outcome data are collected from established healthcare registries or potentially from other well-defined cohort databases. The authors outline the pros and cons of RRCTs compared with traditional RCTs. The first RRCT in diabetes is briefly described, namely the ongoing SMARTEST trial, which is evaluating the effects of monotherapy with a sodium–glucose cotransporter 2 (SGLT2) inhibitor vs metformin to prevent macro- and microvascular events and premature death in patients with early-stage type 2 diabetes. The authors conclude that RRCTs in diabetes could enable the rapid recruitment of large cohorts with broad coverage of both geographical and disease subgroups and provide robust endpoint data at very low cost. The figures from this review are available as a downloadable slideset.

Ji Soo Yoon, Shugo Sasaki, Jane Velghe, Michelle Y. Y. Lee, Helena Winata, Cuilan Nian, Francis C. Lynn

Intracellular calcium is an important secondary messenger that can rapidly couple islet cell electrical activity to gene expression changes. However, the identities of calcium-regulated genes in human islets remain largely unknown. In this issue, Yoon et al (https://doi.org/10.1007/s00125-022-05718-1) profile calcium-regulated genes in human islets by comparing the single-cell transcriptomes of islet cells in the presence or absence of extracellular calcium influx. The authors show that alpha, beta, delta and polyhormonal cell types express calcium-regulated genes that are specific to each cell type. The authors also demonstrate that PCDH7 mRNA is present in beta cells that express the highest number of calcium-regulated genes and that cell surface PCDH7 protein can be used to purify beta cells with enhanced glucose-stimulated insulin secretion. The authors conclude that calcium-regulated transcriptional changes can be used to retrospectively identify different human islet cell subtypes or functional states.

Niina Sandholm, Joanne B. Cole, Viji Nair, Xin Sheng, Hongbo Liu, Emma Ahlqvist, Natalie van Zuydam, Emma H. Dahlström, Damian Fermin, Laura J. Smyth, Rany M. Salem, Carol Forsblom, Erkka Valo, Valma Harjutsalo, Eoin P. Brennan, Gareth J. McKay, Darrell Andrews, Ross Doyle, Helen C. Looker, Robert G. Nelson, Colin Palmer, Amy Jayne McKnight, Catherine Godson, Alexander P. Maxwell, Leif Groop, Mark I. McCarthy, Matthias Kretzler, Katalin Susztak, Joel N. Hirschhorn, Jose C. Florez

Diabetic kidney disease is the leading cause of kidney disease. In this issue, Sandholm, Cole et al (https://doi.org/10.1007/s00125-022-05735-0) analysed genetic data from nearly 27,000 individuals with diabetes. These were combined with multiple omics datasets including gene expression, chromatin accessibility and DNA methylation as well as careful morphological characterisation of kidney tissue from nephrectomies and biopsies to identify novel genetic factors and genes that contribute to the risk of diabetic kidney disease. The authors report that several genes—TENM2, DCLK1, AKIRIN2, SNX30 and LSM14A in particular—contribute to the biological processes that lead to diabetic kidney disease and suggest that these genes could be putative therapeutic targets. They also provide evidence that genetic factors for chronic kidney disease in the general population are correlated with those for diabetic kidney disease in type 2 diabetes, but less in type 1 diabetes. The authors also report that the data further confirms the role of obesity in the pathogenesis of diabetic kidney disease.

Inbar Zucker, Yair Zloof, Aya Bardugo, Avishai M. Tsur, Miri Lutski, Yaron Cohen, Tali Cukierman-Yaffe, Noga Minsky, Estela Derazne, Dorit Tzur, Cheli Melzer Cohen, Orit Pinhas-Hamiel, Gabriel Chodick, Itamar Raz, Arnon Afek, Hertzel C. Gerstein, Amir Tirosh, Gilad Twig

Excessive weight at birth or in early childhood is linked to an increased risk for type 1 diabetes later in childhood. However, among adolescents who are overweight or with obesity, the future risk for incident type 1 diabetes is less clear. In this issue, Zucker et al (https://doi.org/10.1007/s00125-022-05722-5) report that higher adolescent BMI was related in a severity-dependent manner to an increased risk for type 1 diabetes in young adulthood in a nationwide cohort of 1.4 million Israeli adolescents. The authors suggest that adolescent obesity may double the risk for incident type 1 diabetes even in the absence of other comorbidities, possibly through various cellular pathophysiological processes. The authors conclude that excessive adolescent weight is a potentially modifiable risk factor for incident type 1 diabetes.

Regina Prigge, Sarah H. Wild, Caroline A. Jackson

Despite the substantial burden of both depression and diabetes, and the potential impact on the prognosis of patients affected by both disorders, limited knowledge exists about the individual and joint effects of depression and diabetes on cause-specific mortality. In this issue, Prigge et al (https://doi.org/10.1007/s00125-022-05723-4) report that individuals with either or both depression and diabetes were generally at higher risk of all-cause mortality and mortality due to cancer, circulatory disease and causes other than circulatory disease or cancer than people with neither condition. The authors show that the association between depression and diabetes was additive for circulatory disease mortality, with synergistic effects observed for cancer mortality and mortality due to causes other than circulatory disease and cancer beyond those expected from their individual effects (i.e. supra-additive effects). The authors conclude that cost-effective interventions for primary and secondary prevention of the individual and joint effects of depression and diabetes are needed.

Jakob Grauslund

Using screening for the early detection of sight-threatening diabetic retinopathy is a pivotal step towards the reduction of visual loss in diabetes. In this issue, Jakob Grauslund (https://doi.org/10.1007/s00125-022-05727-0) presents the current state-of-the-art in diabetic retinopathy screening and outlines the start of the journey towards the adoption of new technologies and initiatives. These include handheld mobile devices, ocular telehealth programmes and automated image analysis using artificial intelligence. The author focuses on the clinical rationale and scientific evidence for deep learning, which has become the state-of-the-art in computer-based classification and segmentation in medical imaging. The author discusses how first regulatory approvals have been obtained for algorithms trained to detect sight-threatening diabetic retinopathy. He concludes that full-scale implementation in local and national screening programmes can be expected in the upcoming years, once ongoing challenges have been addressed in the transition from in silico experiments to clinical care. The figures from this review are available as a downloadable slideset.

James A. Pearson, Heyuan Ding, Changyun Hu, Jian Peng, Brittany Galuppo, F. Susan Wong, Sonia Caprio, Nicola Santoro, Li Wen

B cells secrete different immunoglobulins, which can target bacteria. IgA-deficiency promotes obesity through changes to the composition of gut bacteria; however, IgA deficiency often increases IgM. In this issue, Pearson, Ding and Hu et al (https://doi.org/10.1007/s00125-022-05711-8) used activation-induced cytidine deaminase (AID)-deficient mice (which produce only IgM) fed on a high fat diet to investigate the role of IgM in obesity. They show that increased IgM promoted weight gain and impaired glucose- and insulin tolerance by altering the composition of the intestinal bacteria in the mice. Administration of intravenous IgG, but not IgA, abolished the obesogenic profile of AID-deficient mice. The authors also showed that in obese children with impaired glucose tolerance and type 2 diabetes, IgM-bound stool bacteria are increased compared with normoglycaemic children without type 2 diabetes. Additionally, gut bacteria derived from either AID-deficient obese mice or obese children with impaired glucose tolerance and type 2 diabetes induced similar metabolic changes in germ-free mice. The authors conclude that these findings indicate that IgM may be important in the development of obesity and type 2 diabetes.

Beatriz Merino, Elena Casanueva-Álvarez, Iván Quesada, Carlos M. González-Casimiro, Cristina M. Fernández-Díaz, Tamara Postigo-Casado, Malcolm A. Leissring, Klaus H. Kaestner, Germán Perdomo, Irene Cózar-Castellano

Hyperglucagonaemia is a hallmark of type 2 diabetes, although its underlying mechanisms are poorly elucidated. Insulin-degrading enzyme (IDE) is a protease of insulin and glucagon which is highly expressed in human and mouse pancreatic alpha cells, although its expression levels are decreased in the pancreatic islet cells of individuals with type 2 diabetes. In this issue, Merino et al (https://doi.org/10.1007/s00125-022-05729-y) report that deletion of IDE in adult mouse alpha cells leads to increased proliferation, hyperplasia and constitutively elevated glucagon secretion, with lack of inhibition by insulin or high-glucose levels, leading to hyperglucagonaemia. Furthermore, they demonstrate that IDE deficiency triggers cytoskeletal perturbations, including increased α-synuclein aggregation and decreased tubulin levels, in parallel to impaired ciliogenesis in alpha cells. The authors conclude that these findings highlight novel molecular mechanisms of glucagon secretion regulation in pancreatic alpha cells, which may represent a future therapeutic target to treat hyperglucagonaemia in type 2 diabetes.

Jia Zhang, Zekai Chen, Katri Pärna, Sander K. R. van Zon, Harold Snieder, Chris H. L. Thio

Higher educational attainment protects against type 2 diabetes, but the underlying mechanisms are uncertain. In this issue, Zhang et al (https://doi.org/10.1007/s00125-022-05705-6) report the results of a Mendelian randomisation study, in which they used genetic instruments to minimise bias due to confounding. Using a multivariable extension of this method, they estimated mediation between educational attainment and type 2 diabetes by the modifiable risk factors BMI, sedentary behaviour, smoking and blood pressure. They estimate that up to 84% of the protective effect of higher educational attainment is mediated by lower levels of these risk factors. The two largest mediating factors were BMI and sedentary behaviour, each individually mediating 50% of the protective effect, with partially overlapping effects. The authors conclude that these findings might inform future trials and preventive policies to reduce the burden of type 2 diabetes due to educational inequalities.

Tim Woelfle, Birgit Linkohr, Tim Waterboer, Barbara Thorand, Jochen Seissler, Marc Chadeau-Hyam, Annette Peters

During the COVID-19 pandemic, the link between viral infections and non-communicable diseases has once again become apparent. In this issue, Woelfle et al (https://doi.org/10.1007/s00125-022-05704-7) investigate the link between herpesvirus seroprevalence and the development of type 2 diabetes. The authors applied multiplex antibody assays and saw high co-occurrence of herpesviruses in this population-based study, where individuals exhibited antibodies against an average of four out of seven examined herpesviruses. Herpes simplex virus 2 increased the risk of (pre)diabetes incidence by more than 50% and cytomegalovirus by more than 30%. Many other factors such as age increase both the risk for viral infection and the risk for (pre)diabetes development. However, the authors report that the results were robust when they adjusted for potential confounders. The authors conclude that these findings highlight the need to better understand the link between asymptomatic viral infections and metabolic diseases and call for viral prevention strategies, potentially including the development of effective vaccines against herpesviruses.

Mtaki Ngara, Nils Wierup

Islet dysfunction is a key component of type 2 diabetes but due to the complex cell composition of the islets it has not been easy to understand how each of the five islet cell types is affected by or contributes to disease development. In this issue Ngara and Wierup (https://doi.org/10.1007/s00125-022-05699-1) summarise recent advances in islet biology enabled by single-cell RNA sequencing (scRNAseq). The authors discuss how scRNAseq has generated unprecedented insight into important aspects of islet biology, foremost by uncovering cell-type-specific gene expression in all islet cell populations. The technique has also proven highly useful in the stem cell and development fields. When it comes to identifying type 2 diabetes disease mechanisms, we have not yet seen a major breakthrough. However, the authors conclude that advances in computational methods in combination with larger studies will most likely lead to a leap forward in this area within the near future. The figure from this review is available as a downloadable slide.

Svenja Meyhöfer, Katharina Dembinski, Bernd Schultes, Jan Born, Britta Wilms, Hendrik Lehnert, Manfred Hallschmid, Sebastian M. Meyhöfer

Hypoglycaemia unawareness syndrome due to recurrent hypoglycaemic episodes is a major complication of diabetes treatment. Adaptation of the counterregulatory response to recurrent hypoglycaemia may be considered as a learning process that implicates the formation of neurometabolic memory. Recent epidemiological and experimental findings describe sleep as a relevant factor for metabolic control and may be essential for glucose homeostasis. In this issue, Meyhöfer et al (https://doi.org/10.1007/s00125-022-05702-9) report that, compared with regular sleep, sleep deprivation dampens the adaptation to recurrent hypoglycaemia. They also show that neuroglycopenic symptoms during hypoglycaemia are preserved upon sleep deprivation. The authors conclude that sleep may be a potential modulator of metabolic memory.

Mouna El Mehdi, Saloua Takhlidjt, Mélodie Devère, Arnaud Arabo, Marie-Anne Le Solliec, Julie Maucotel, Alexandre Bénani, Emmanuelle Nedelec, Céline Duparc, Benjamin Lefranc, Jérôme Leprince, Youssef Anouar, Gaëtan Prévost, Nicolas Chartrel, Marie Picot

The last two decades provided evidence that the central nervous system contributes significantly to the maintenance of glucose homeostasis in the body. However, the molecular mechanisms and neuronal networks involved in this regulation remain largely unknown. In this issue, El Mehdi et al (https://doi.org/10.1007/s00125-022-05706-5) report that 26RFa (also referred to as pyroglutamilated RFamide peptide [QRFP]), a neuropeptide previously found to be involved in the peripheral regulation of glycaemia and the control of feeding behaviour, improves glucose tolerance in mice when administrated centrally. The authors also show that insulin targets the hypothalamic 26RFa-expressing neurons, increasing the peripheral secretion of insulin in a hyperglycaemic context. The authors conclude that these findings have identified a key relay for the central regulation of glucose metabolism by insulin and an entirely new mechanism contributing to overall glucose homeostasis in the body, which may represent a new target for the treatment of diabetes.

Fenglei Wang, Megu Y. Baden, Marta Guasch-Ferré, Clemens Wittenbecher, Jun Li, Yanping Li, Yi Wan, Shilpa N. Bhupathiraju, Deirdre K. Tobias, Clary B. Clish, Lorelei A. Mucci, A. Heather Eliassen, Karen H. Costenbader, Elizabeth W. Karlson, Alberto Ascherio, Eric B. Rimm, JoAnn E. Manson, Liming Liang, Frank B. Hu

Plant-based diets, especially healthy plant-based diets that are rich in whole grains, fruits and vegetables, have been associated with a lower risk of type 2 diabetes. However, the plasma metabolite profile underlying this association is not clear. In this issue, Wang and Baden et al (https://doi.org/10.1007/s00125-022-05692-8) report that the plasma metabolite profile of healthy plant-based diets is associated with lower type 2 diabetes risk and could explain part of the beneficial association of the healthy plant-based diet. Furthermore, several plasma metabolites (such as trigonelline, hippurate, isoleucine and a small set of triacylglycerols) were identified as potential mediators of the association between plant-based diets and type 2 diabetes. The authors conclude that the identified plasma metabolite profile could be used to assess the adherence of and metabolic response to a healthy plant-based diet for type 2 diabetes prevention.

Simke W. Waijer, Priya Vart, David Z. I. Cherney, Glenn M. Chertow, Niels Jongs, Anna Maria Langkilde, Johannes F. E. Mann, Ofri Mosenzon, John J. V. McMurray, Peter Rossing, Ricardo Correa-Rotter, Bergur V. Stefansson, Robert D. Toto, David C. Wheeler, Hiddo J. L. Heerspink

Higher albuminuria and lower estimated glomerular filtration rate (eGFR) are predictors of kidney failure and cardiovascular events, and are the basis of Kidney Disease Improving Global Outcomes (KDIGO) risk categorisation. It is unknown if dapagliflozin’s clinical benefits are generalisable to different chronic kidney disease (CKD) stages, defined by baseline KDIGO risk. In this issue, Waijer et al (https://doi.org/10.1007/s00125-022-05694-6) report the effect of dapagliflozin versus placebo on kidney and cardiovascular outcomes in patients with CKD categorised by KDIGO risk. Dapagliflozin consistently reduced the risk of kidney and cardiovascular events compared with placebo, across all KDIGO risk categories, in patients with or without type 2 diabetes. The benefit of dapagliflozin in slowing eGFR decline was also similar across KDIGO risk categories, as was dapagliflozin safety. The authors conclude that these findings support use of dapagliflozin in a broad range of patients with CKD who are at risk of progressive kidney and cardiovascular disease, to prevent clinically important outcomes.

Rollie F. Hampton, Maria Jimenez-Gonzales, Sarah A. Stanley

Recent innovations in 3D imaging and targeted neuromodulation have advanced our understanding of pancreatic innervation. In this issue, Hampton and Jimenez-Gonzalez et al (https://doi.org/10.1007/s00125-022-05691-9) summarise recent advances that provide insights into the complex anatomy of pancreatic nerves and their roles in modulating islet hormone release and regulation of glucose metabolism. New imaging technologies provide detailed 3D analyses of pancreatic islet innervation in multiple species and suggest rapid changes in islet nerve structure with metabolic disease. Transgenic and viral approaches now allow unprecedented organ-specific and pathway-specific neuromodulation to assess the functional roles of pancreatic nerves. The authors discuss how these technologies provide an opportunity to advance our understanding of pancreatic innervation, which may identify new approaches to treat metabolic disease. The figures from this review are available as a downloadable slideset.

Ronan Bergin, David Kinlen, Nidhi Kedia-Mehta, Eadaoin Hayes, Féaron C. Cassidy, Declan Cody, Donal O’Shea, Andrew E. Hogan

Insulin resistance is one of the first signs of metabolic dysregulation to manifest in childhood obesity, long before the development of overt metabolic disease. However, the primary drivers of insulin resistance in childhood obesity remain to be elucidated. In this issue, Bergin and Kinlen et al (https://doi.org/10.1007/s00125-022-05682-w) report that an innate T cell subset, the mucosal-associated invariant T (MAIT) cell, is strongly associated with insulin resistance in children with obesity. Furthermore, the authors demonstrate that the production of IL-17 by MAIT cells in particular is associated with insulin resistance. The authors then provide evidence from cell-based models that IL-17 can directly disrupt insulin-mediated glucose uptake. The authors conclude that these findings highlight a novel cellular driver of insulin resistance, which may represent a future therapeutic target.

Kailun Lee, Jeng Yie Chan, Cassandra Liang, Chi Kin Ip, Yan-Chuan Shi, Herbert Herzog, William E. Hughes, Mohammed Bensellam, Viviane Delghingaro-Augusto, Mark E. Koina, Christopher J. Nolan, D. Ross Laybutt

Islet beta cell dedifferentiation has been implicated in beta cell failure in type 2 diabetes, although the mechanisms are poorly defined. The endoplasmic reticulum stress response factor X-box binding protein 1 (XBP1) is a major regulator of the unfolded protein response. Reduced XBP1 expression has been observed in islets of people with type 2 diabetes. In this issue, Lee et al (https://doi.org/10.1007/s00125-022-05669-7) report that XBP1 is crucial for the maintenance of beta cell identity and repression of beta-to-alpha transdifferentiation in mice. The authors show that deletion of Xbp1 in adult mouse beta cells deactivates beta cell identity genes and derepresses beta cell dedifferentiation and alpha cell genes. They also demonstrate that XBP1 is required for beta cell compensation and protection against diabetes in insulin-resistant states. It is proposed that XBP1 protects against beta cell apoptosis during metabolic stress by promoting the beta cell’s antioxidant response. The authors conclude that targeting XBP1 might help to reverse the process of beta cell dedifferentiation and restore functional beta cell mass in type 2 diabetes.

Moneeza K. Siddiqui, Ranjit Mohan Anjana, Adem Y. Dawed, Cyrielle Martoeau, Sundararajan Srinivasan, Jebarani Saravanan, Sathish K. Madanagopal, Alasdair Taylor, Samira Bell, Abirami Veluchamy, Rajendra Pradeepa, Naveed Sattar, Radha Venkatesan, Colin N. A. Palmer, Ewan R. Pearson, Viswanathan Mohan

South Asians in general, and Asian Indians in particular, are at greater risk of early onset type 2 diabetes than white Europeans. This contributes to the higher prevalence of diabetes in people of South Asian descent and the increasing burden of diabetes in South Asia. In this issue, Siddiqui and Anjana et al (https://doi.org/10.1007/s00125-022-05671-z) use data from non-migrant populations and show that the prevalence of lean young-onset type 2 diabetes is two to four times higher in Asian Indians compared with white Europeans. This phenotype highlights the potential role of poor insulin secretion due to impaired beta cell function in South Asians. The authors applied partitioned polygenic scores (pPS) for poor beta cell function to genetic data from India, Scotland and the UK Biobank, and report that South Asians have a greater genetic burden of beta cell dysfunction. They find that this genetic risk explains, in part, the higher risk of young-onset type 2 diabetes in lean South Asians. The authors conclude that these findings highlight the inter-ethnic differences in the genetics of diabetes and have implications for diabetes care for South Asians.

Wolfgang Rathmann, Oliver Kuss, Karel Kostev

Inflammation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may result in insulin resistance. It is unclear whether these metabolic changes are temporary, or if coronavirus disease-2019 (Covid-19) may increase the risk of developing diabetes. In this issue, Rathmann et al (https://link.springer.com/article/10.1007/s00125-022-05670-0) report that adults who recovered from mild Covid-19 had a higher risk of developing type 2 diabetes than a matched control group who had other types of respiratory infections. New cases of type 2 diabetes were more common in individuals who tested positive for Covid-19 in primary care compared with those diagnosed with an acute upper respiratory infection (15.8 vs 12.3 per 1000 people per year, giving an incidence rate ratio of 1.28). The authors conclude that although type 2 diabetes is not likely to be a problem for the majority of people with mild Covid-19, anyone who has recovered from Covid-19 should be aware of symptoms such as fatigue, frequent urination and increased thirst, and promptly seek medical advice.

Tom Barsby, Timo Otonkoski

Many recent studies have uncovered novel molecular insights into the functional maturation of beta cells following postnatal development and throughout stem cell-derived islet differentiation. In this issue, Barsby and Otonkoski (https://doi.org/10.1007/s00125-022-05672-y) draw together recent findings in the regulatory and metabolic mechanisms underlying this maturation. The authors discuss how the interplay of nutrient sensitivity, metabolic signatures and circadian regulation are all important facets of functional maturation that regulate (and are regulated by) the transcriptomic state of the beta cell. This review further highlights that beta cell maturation is not a binary process and encompasses processes beyond the acquisition of a beta cell identity and the expression of a subset of particular single marker genes. The figures from this review are available as a downloadable slideset.

Yan Qiu, Stanley Buffonge, Raina Ramnath, Sophie Jenner, Sarah Fawaz, Kenton P. Arkill, Chris Neal, Paul Verkade, Stephen J. White, Melanie Hezzell, Andrew H. J. Salmon, M.-Saadeh Suleiman, Gavin I. Welsh, Rebecca R. Foster, Paolo Madeddu, Simon C. Satchell

Diabetic cardiomyopathy is a serious and under-recognised complication of diabetes. The first sign is diastolic dysfunction, which progresses to heart failure. Endothelial glycocalyx plays multiple vital roles in the microcirculation and whilst it is known to be compromised in diabetes, it has not previously been studied in the coronary microcirculation in diabetes. In this issue, Qiu et al (https://doi.org/10.1007/s00125-022-05650-4) report that, in mouse models of diabetes, diastolic dysfunction is associated with glycocalyx loss from coronary microvascular endothelial cells and increased microvascular permeability. The authors also show that endothelial glycocalyx damage is sufficient to impair cardiac function. They provide evidence for increased matrix metalloproteinase activity as a potential mechanism of endothelial glycocalyx damage. They go on to demonstrate that angiopoietin 1 restores the endothelial glycocalyx and ameliorates diastolic dysfunction in diabetes. The authors conclude that these findings identify coronary microvascular endothelial glycocalyx damage as a contributor to the development of diabetic cardiomyopathy and, therefore, as a therapeutic target for heart failure in people with diabetes.

Inna Starskaia, Essi Laajala, Toni Grönroos, Taina Härkönen, Sini Junttila, Roosa Kattelus, Henna Kallionpää, Asta Laiho, Veronika Suni, Vallo Tillmann, Riikka Lund, Laura L. Elo, Harri Lähdesmäki, Mikael Knip, Ubaid Ullah Kalim, Riitta Lahesmaa

DNA methylation changes associated with type 1 diabetes were previously detected in individuals clinically diagnosed with the disease. Recently, using array-based methods, these changes were also detected in whole blood samples from individuals before they developed diabetes. In this issue, Starskaia et al (https://doi.org/10.1007/s00125-022-05657-x) use genome-wide reduced representation bisulphite sequencing to detect cell type-specific DNA methylation changes associated with type 1 diabetes before clinical diagnosis, and even before the appearance of autoantibodies. The authors conclude that the early epigenetic changes associated with type 1 diabetes identified in this study may contribute to pathogenesis and provide basis for the early detection of diabetes.

Shugo Sasaki, Michelle Y. Y. Lee, Yuka Wakabayashi, Luka Suzuki, Helena Winata, Miwa Himuro, Taka-aki Matsuoka, Iichiro Shimomura, Hirotaka Watada, Francis C. Lynn, Takeshi Miyatsuka

Although endocrine pancreas development has been investigated by many researchers, the beta cell developmental niche, or precisely where and when beta cells arise in vivo, remains less well described. Part of the reason for this is that there have been no methods to readily detect newly generated beta cells in situ. In this issue, Sasaki et al (https://doi.org/10.1007/s00125-022-05662-0) describe a novel time-resolved mouse model, which was developed to distinguish newborn beta cells from more differentiated beta cells. The authors report that this model provides the first in vivo evidence that beta cells arise from two distinct regions: ductal or blood vessel niches. Using this model, the authors also show that single-cell transcriptional heterogeneity during beta cell genesis correlates with the spatial heterogeneity. Furthermore, single-cell mRNA profiles of human embryonic stem cell-derived beta-like cells demonstrated a transcriptional similarity with the data from newborn beta cells in mice. The authors conclude that this work provides insight for the future development of regenerative therapies for diabetes.

Eliza Fraszczyk, Annemieke M. W. Spijkerman, Yan Zhang, Stefan Brandmaier, Felix R. Day, Li Zhou, Paul Wackers, Martijn E. T. Dollé, Vincent W. Bloks, Xīn Gào, Christian Gieger, Jaspal Kooner, Jennifer Kriebel, H. Susan J. Picavet, Wolfgang Rathmann, Ben Schöttker, Marie Loh, W. M. Monique Verschuren, Jana V. van Vliet-Ostaptchouk, Nicholas J. Wareham, John C. Chambers, Ken K. Ong, Harald Grallert, Hermann Brenner, Mirjam Luijten, Harold Snieder

Epigenetics may play a role in the development of type 2 diabetes, and predictive DNA methylation markers have been identified in single-cohort epigenome-wide association studies. Combining results from several prospective cohorts may identify additional markers. In this issue, Fraszczyk et al (https://doi.org/10.1007/s00125-022-05652-2) report 76 DNA methylation markers from the meta-analysis of five European cohorts, of which 63 were novel for incident type 2 diabetes. The authors suggest that epigenetics has the potential to elucidate new biological pathways underlying the development of type 2 diabetes, and predictive DNA methylation markers could ultimately be useful in type 2 diabetes prevention efforts.

Bruno Fève and André J. Scheen

Drug-induced diabetes is not a novel concern, and this is examined in this issue by Fève and Scheen (https://doi.org/10.1007/s00125-022-05666-w). The archetype of this iatrogenic complication is glucocorticoid-induced diabetes, which remains the most frequently encountered one in clinical practice. However, we should not overlook the high prevalence of diabetes caused by antipsychotics, in particular by second generation compounds. The pharmacopoeia of antiretrovirals has greatly improved since the first classes of these drugs became available at the end of the 1980s; however, there is still a residual metabolic toxicity of several new generation molecules. Even more recently, the advent of immunotherapies in oncology has been accompanied by the emergence of diabetes cases that are reminiscent of the phenotype of type 1 diabetes. This short review is focused on these four families of diabetogenic drugs, and will provide information on the prevalence of this complication, the main clinical presentations and the key pathophysiological mechanisms, before addressing the management and prevention of these chemically induced forms of diabetes. The figure from this review is available as a downloadable slide.

Jan-Frieder Harmsen, Jakob Wefers, Daniel Doligkeit, Luc Schlangen, Bas Dautzenberg, Pascal Rense, Dirk van Moorsel, Joris Hoeks, Esther Moonen-Kornips, Marijke C. M. Gordijn, Wouter D. van Marken Lichtenbelt, Patrick Schrauwen

We spend most of our time indoors under light conditions that are either not as bright as natural daylight or too bright in the evening after sunset. Such suboptimal light conditions are considered to be risk factors for metabolic diseases, with detrimental effects of light exposure at night on sleep quality and glucose metabolism. In this issue, Harmsen and Wefers et al (https://doi.org/10.1007/s00125-021-05643-9) investigate the metabolic impact in insulin-resistant men and women of a 24h light scheme resembling the natural light/dark cycle, with bright light during daytime and dim light during the evening. They report that the optimised light scheme was beneficial for plasma glucose levels preceding dinner, energy expenditure during the night, and diurnal rhythms in peripheral skin temperature. The authors conclude that these findings provide the rationale to further explore indoor lighting designs to prevent or treat metabolic diseases.

Lucie Oberhauser, Cecilia Jiménez-Sánchez, Jesper Grud Skat Madsen, Dominique Duhamel, Susanne Mandrup, Thierry Brun, Pierre Maechler

About three decades ago, in the context of type 2 diabetes, the concept of lipotoxicity, and later of glucolipotoxicity, was applied to pancreatic beta cells. However, after all these years it remains debated whether essential components of the organ’s chemistry, namely fat and sugar, could be qualified as genuine toxic molecules. In this issue, Oberhauser et al (https://doi.org/10.1007/s00125-021-05633-x) report results from a study in which they exposed pancreatic islets to various so-called glucolipotoxic culture conditions before analysing their response to standard conditions of glucose-stimulated insulin secretion. The authors report that high glucose, rather than glucose per se, is detrimental for beta cell function. Cells exposed to fatty acids and high glucose exhibited massive fat storage, which was rapidly mobilised upon return to normal conditions. Such fat turnover was instrumental for the preservation of the secretory response in cells experiencing glucotoxicity. The authors conclude that these findings advocate against continuous energy-rich snacking without fasting periods for the preservation of beta cell function.

Davis Kibirige, Isaac Sekitoleko, William Lumu, Angus G. Jones, Andrew T. Hattersley, Liam Smeeth, Moffat J. Nyirenda

Atypical diabetes has been described in sub-Saharan Africa, with non-insulin-requiring apparent type 2 diabetes seen in lean and sometimes young individuals. However, robust data on the clinical and metabolic characterisation of these lean individuals with diabetes are lacking. In this issue, Kibirige et al (https://doi.org/10.1007/s00125-021-05644-8) investigated the phenotype of newly diagnosed adult-onset diabetes in Uganda. The authors report that individuals with a lean type 2 diabetes phenotype were predominantly male, exhibiting significant pancreatic beta cell dysfunction but no evidence of the metabolic syndrome or insulin resistance. This study further adds to evidence of differences in the pathogenesis of type 2 diabetes across populations. The authors suggest that due to the observed differences in underlying pathophysiological defects of type 2 diabetes, there is a need for interventional studies to investigate the optimal individualised therapies for individuals with a lean type 2 diabetes phenotype in sub-Saharan Africa.

Evelyn Teo, Norasyikin Hassan, Wilson Tam, Serena Koh

Glucose monitoring is a key method for individuals with type 1 diabetes to maintain adequate glycaemic control and delay the onset of diabetic complications. The limitations of traditional self-monitoring of blood glucose (SMBG) can be overcome by using continuous glucose monitoring (CGM). Current reviews regarding the effectiveness of CGM and SMBG on glycaemic control revealed several research gaps. In this issue, Teo et al (https://doi.org/10.1007/s00125-021-05648-4) report that CGM significantly reduces HbA_1c levels compared with SMBG, with larger effects observed among those with higher baseline HbA_1c. However, their results show that CGM has no effect on severe hypoglycaemia and diabetic ketoacidosis. The authors conclude that CGM is superior to SMBG in improving glycaemic control, especially among those with poorly controlled glycaemia. They also suggest that individuals with poorly controlled glycaemia would benefit most from CGM compared with SMBG in the community.

Alicia J. Jenkins, Maria B. Grant, Julia V. Busik

 The highly metabolically active retina obtains essential lipids through both endogenous biosynthesis and via the systemic circulation. Both quantitative and qualitative changes in lipids have been associated with diabetic retinopathy. Whilst the role of lipids and lipid-modifying drugs in cardiovascular disease in people with diabetes is well-studied, their roles in diabetic retinopathy are currently less well known. In this issue, Jenkins et al (https://doi.org/10.1007/s00125-022-05655-z) review the potential role of lipids and lipid-lowering drugs in diabetic retinopathy, examining results from retinal tissue analyses, clinical observational studies, clinical trials and meta-analyses. The authors discuss several statin and fibrate trials that were designed to predominantly address cardiovascular outcomes, but which have also reported potential retinal benefits. They outline the many challenges in this clinically important field, but also highlight that ongoing research in this area. This includes several in-progress trials of lipid drugs that have diabetic retinopathy-related primary endpoints, which may further elucidate the potential mechanisms by which lipid-modifying therapies could impact diabetic retinopathy. The figures from this review are available as a downloadable slideset.

Karin M. Kirschner, Anna Foryst-Ludwig, Sabrina Gohlke, Chen Li, Roberto E. Flores, Ulrich Kintscher, Michael Schupp, Tim J. Schulz, Holger Scholz

The induction of thermogenically active beige adipocytes in white adipose tissue (WAT) is a key feature of WAT browning. Browning has recently gained interest for its potential use to enhance energy expenditure. Beige adipocytes can be readily induced in subcutaneous WAT of mice, whereas visceral WAT is more resistant to browning. In this issue, Kirschner et al (https://doi.org/10.1007/s00125-021-05621-1) show that otherwise healthy mice, heterozygous for the Wilms tumour gene, Wt1, display morphological and genetic signs of browning in their visceral WAT. Strikingly, Wt1 heterozygosity improved whole-body glucose tolerance and prevented severe hepatic steatosis under a high-fat diet. Mechanistically, the authors identified WT1 as an upstream regulator of Aldh1a1 and Zfp423, key suppressors of the thermogenic programme in adipocytes. Their data provide evidence that WT1 downregulates thermogenic genes and functions as a white adipocyte determination factor in visceral WAT. The authors conclude that targeting Wt1 expression in visceral fat may offer a promising novel approach to fight metabolic disorders.

Mads N. Thomsen, Mads J. Skytte, Amirsalar Samkani, Martin H. Carl, Philip Weber, Arne Astrup, Elizaveta Chabanova, Mogens Fenger, Jan Frystyk, Bolette Hartmann, Jens J. Holst, Thomas M. Larsen, Sten Madsbad, Faidon Magkos, Henrik S. Thomsen, Steen B. Haugaard, Thure Krarup

Weight loss is the cornerstone of management of type 2 diabetes. Whether a diet reduced in carbohydrate and increased in protein and fat can augment the beneficial effects of weight loss, compared with a conventional diabetes diet, is not known. In this issue, Thomsen et al (https://doi.org/10.1007/s00125-021-05628-8) present the results of a randomised study that evaluated the metabolic effects of matched 6% weight loss, induced after 6 weeks of a fully-provided carbohydrate-reduced diet (30% of energy from carbohydrate) or a conventional diabetes diet (50% of energy from carbohydrate) in individuals with type 2 diabetes. The authors show that the experimental diet was well tolerated and, for the same amount of weight loss as that induced by the control diet, augmented the reduction in HbA_1c by 1.9 mmol/mol, in liver fat by 26%, in plasma triacylglycerol by 18% and in diurnal blood glucose by 0.8 mmol/l. The authors conclude that carbohydrate reduction has weight loss-independent beneficial metabolic effects and should be considered in the treatment of type 2 diabetes.

Carolina G. Downie, Sofia F. Dimos, Stephanie A. Bien, Yao Hu, Burcu F. Darst, Linda M. Polfus, Yujie Wang, Genevieve L. Wojcik, Ran Tao, Laura M. Raffield, Nicole D. Armstrong, Hannah G. Polikowsky, Jennifer E. Below, Adolfo Correa, Marguerite R. Irvin, Laura J. F. Rasmussen-Torvik, Christopher S. Carlson, Lawrence S. Phillips, Simin Liu, James S. Pankow, Stephen S. Rich, Jerome I. Rotter, Steven Buyske, Tara C. Matise, Kari E. North, Christy L. Avery, Christopher A. Haiman, Ruth J. F. Loos, Charles Kooperberg, Mariaelisa Graff, Heather M. Highland

Previous genome-wide association studies (GWAS) have identified over 500 loci associated with type 2 diabetes and glycaemic-related traits. However, most of these studies were conducted in populations of European ancestry. This lack of ancestral diversity hinders efforts to identify novel loci, refine causal signals through fine-mapping, and develop equitable genetic approaches for precision medicine and risk prediction. In this issue, Downie et al (https://doi.org/10.1007/s00125-021-05635-9) identify novel glycaemic trait loci in the ancestrally diverse Population Architecture using Genomics and Epidemiology (PAGE) Study. Specifically, the authors identify three fasting insulin novel loci in a transethnic meta-analysis, one novel low-frequency fasting glucose locus in an African American-specific analysis, and novel independent secondary signals at known fasting glucose and insulin loci. The authors conclude that these findings highlight the continued importance of conducting genetic studies in diverse populations and provide new insights into the genetic architecture of glycaemic traits.

Frank G. Preston, Yanda Meng, Jamie Burgess, Maryam Ferdousi, Shazli Azmi, Ioannis N. Petropoulos, Stephen Kaye, Rayaz A. Malik, Yalin Zheng, Uazman Alam

The accurate detection of diabetic neuropathy in routine clinical practice remains a major unmet clinical need. Current screening practices largely rely on insensitive tests which only primarily detect the insensate foot. It has been demonstrated that artificial intelligence (AI) trained using annotated corneal confocal microscopy images can provide accurate segmentation of corneal nerve images, allowing the detection of peripheral neuropathy. In this issue, Preston and Meng et al (https://doi.org/10.1007/s00125-021-05617-x) report that AI utilising corneal nerve images can accurately classify peripheral neuropathy in people with prediabetes and diabetes, without the need for underlying nerve segmentation. This was achieved by use of a single corneal confocal microscope image. The authors discuss that, as annotation of the image/dataset was not required, larger sets of unannotated images may be leveraged in providing a more robust model. The authors conclude that with validation in a larger real-world study, the AI algorithm has considerable potential for adoption into screening programmes for diabetic neuropathy.

Kim L. Ho, Qutuba G. Karwi, David Connolly, Simran Pherwani, Ezra B. Ketema, John R. Ussher, Gary D. Lopaschuk

Diabetes increases the risk of heart failure by over two-fold, and the need to improve our understanding of the way in which this occurs is becoming ever important. In this issue, Ho et al (https://doi.org/10.1007/s00125-021-05637-7) summarise the cardiac metabolic, structural, and biochemical changes that occur in diabetes. The authors discuss how hyperlipidaemia and hyperglycaemia contribute to changes in fatty acid and glucose metabolism, and that structural remodelling of the heart occurs in the form of hypertrophy and fibrosis.  They go on to explore how, biochemically, impairments in calcium handling, glucotoxicity, lipotoxicity, and transcriptional and translational modifications all contribute to cardiac dysfunction in diabetes. The authors conclude by highlighting that with the increasing amount of research going into the mechanisms by which certain diabetes drugs improve cardiovascular outcomes, new therapeutic strategies are emerging to treat diabetes and heart failure. The figures from this review are available as a downloadable slideset.

Estefania Quesada-Masachs, Samuel Zilberman, Sakthi Rajendran, Tiffany Chu, Sara McArdle, William B. Kiosses, Jae-Hyun M. Lee, Burcak Yesildag, Mehdi A. Benkahla, Agnieszka Pawlowska, Madeleine Graef, Susanne Pfeiffer, Zbigniew Mikulski, Matthias von Herrath

For many decades, the question of whether HLA class II can be expressed by pancreatic beta cells has been controversial. In this issue, Quesada-Masachs et al (https://doi.org/10.1007/s00125-021-05619-9) report that HLA class II is upregulated in islets of pancreatic tissue sections from organ donors with type 1 diabetes: 28% of the beta cells from the patients with type 1 diabetes expressed HLA class II. Immunofluorescence microscopy was used to thoroughly quantify HLA class II in situ, using a machine learning approach. Furthermore, the authors report that healthy human islets stimulated with proinflammatory cytokines upregulate HLA class I and class II, as measured by quantitative fluorescent microscopy and RNA sequencing. The authors suggest that a crosstalk could exist between beta cells and CD4⁺ T cells in type 1 diabetes, although further research is necessary to demonstrate this cellular communication and elucidate its biological role in disease initiation and progression.

Feifei Cheng, Andrea O. Luk, Hongjiang Wu, Claudia H. T. Tam, Cadmon K. P. Lim, Baoqi Fan, Guozhi Jiang, Luke Carroll, Aimin Yang, Eric S. H. Lau, Alex C. W. Ng, Heung Man Lee, Elaine Chow, Alice P. S. Kong, Anthony C. Keech, Mugdha V. Joglekar, Wing Yee So, Anandwardhan A. Hardikar, Juliana C. N. Chan, Alicia J. Jenkins, Ronald C. W. Ma

Telomere length shortening, representing reduction in the protective caps at the ends of our chromosomes, is known to be associated with biological ageing and different cardiometabolic diseases, although it is unclear whether it has prognostic significance for predicting kidney disease in diabetes. In this issue, Cheng et al (https://doi.org/10.1007/s00125-021-05613-1) report that in a large cohort of people with type 2 diabetes from Hong Kong, reduced telomere length in white blood cells was an independent predictor for decline in kidney function and future risk of kidney failure. The authors suggest that this effect was independent of other established risk factors for kidney dysfunction, and improves prediction beyond that provided by clinical factors alone. The authors conclude that these findings indicate telomere length shortening may be helpful in stratifying the future risk of kidney disease in people with diabetes.

Neli Tsereteli, Raphael Vallat, Juan Fernandez-Tajes, Linda M. Delahanty, Jose M. Ordovas, David A. Drew, Ana M. Valdes, Nicola Segata, Andrew T. Chan, Jonathan Wolf, Sarah E. Berry, Matthew P. Walker, Timothy D. Spector, Paul W. Franks

Small in-patient studies and larger observational studies suggest that features of how we sleep may affect our metabolic health. In this issue, Tsereteli et al (https://doi.org/10.1007/s00125-021-05608-y) report data from the largest experimental study to date focusing on objectively assessed sleep and its impact on postprandial blood glucose following standardised breakfast meals. The authors show that poor sleep efficiency and later bedtime routines worsen blood glucose responses overall. The authors also show that at an individual level, sleep matters, as person-specific deviations from normal sleep patterns also impact the blood glucose response to breakfast. This was especially true when an oral glucose load was given as the breakfast meal, suggesting that the popular practice of consuming energy drinks after a poor night’s sleep may be particularly detrimental for blood glucose regulation. The authors conclude that these findings underscore the importance of sleep in the optimal regulation of human metabolic health.

Sabrina Schlesinger, Manuela Neuenschwander, Janett Barbaresko, Alexander Lang, Haifa Maalmi, Wolfgang Rathmann, Michael Roden, Christian Herder

The number of people with prediabetes is increasing. Prediabetes is defined here as a condition in which glucose metabolism is impaired but the diagnostic criteria for type 2 diabetes are not currently met. However, it is often a precursor for the development of type 2 diabetes. Whilst it does not usually exhibit symptoms, studies have reported that prediabetes is associated with comorbidities that are traditionally considered as diabetes-related complications. In this issue, Schlesinger et al (https://doi.org/10.1007/s00125-021-05592-3) summarised and evaluated the existing evidence on prediabetes and health outcomes in an umbrella review of meta-analyses. The authors found that prediabetes is associated with an increased risk for all-cause mortality, cardiovascular diseases, chronic kidney disease, different types of cancer, and dementia, compared with people without prediabetes. They conclude that these observations emphasise the need for early prevention and management of prediabetes, for example by lifestyle interventions, to prevent diabetes-related complications.

Joline W. J. Beulens, Maria G. M. Pinho, Taymara C. Abreu, Nicole R. den Braver, Thao M. Lam, Anke Huss, Jelle Vlaanderen, Tabea Sonnenschein, Noreen Z. Siddiqui, Zhendong Yuan, Jules Kerckhoffs, Alexandra Zhernakova, Milla F. Brandao Gois, Roel C. H. Vermeulen

A major part of the burden of type 2 diabetes is attributed to environmental risks and modifiable risk factors such as lifestyle. The environment we live in, and changes to it, can therefore contribute substantially to the prevention of type 2 diabetes at a population level. In this issue, Beulens et al (https://doi.org/10.1007/s00125-021-05618-w) summarise the evidence on the role of the food-, built-, physico-chemical- and social environment in the development of type 2 diabetes. The authors discuss the established associations of air pollution, residential noise and area-level socioeconomic deprivation with an increased risk of type 2 diabetes, and highlight that neighbourhood walkability and green space are associated with a reduced risk of type 2 diabetes. The contribution of the food environment, along with other aspects of the social environment and outdoor temperature are less clear. The authors suggest that these environmental factors affect type 2 diabetes risk mainly through mechanisms that incorporate lifestyle factors, the microbiome, inflammation or chronic stress. The figures from this review are available as a downloadable slideset

Aaron Jesuthasan, Sviatlana Zhyzhneuskaya, Carl Peters, Alison C. Barnes, Kieren G. Hollingsworth, Naveed Sattar, Michael E. J. Lean, Roy Taylor, Ahmad H. Al-Mrabeh

The cardiovascular risks associated with type 2 diabetes are increased to a greater extent in women compared with men. The metabolic basis for this sex difference is not known. In this issue, Jesuthasan et al (https://doi.org/10.1007/s00125-021-05583-4) report that women without diabetes have lower levels of triacylglycerol in their liver compared with men, but this difference is lost in individuals with diabetes. The authors also report levels of plasma insulin, a driver of hepatic de novo lipogenesis, which are normally lower in women than men, were as high in women with diabetes as in men with diabetes. Higher levels of fat in the liver leads to higher rates of VLDL secretion. As the most atherogenic lipid particles (small dense LDL) are derived from VLDL particles after release of triacylglycerol, the authors propose that the relatively greater cardiovascular risk in women is directly linked to the greater increase in intrahepatic fat during type 2 diabetes. The authors conclude that management of type 2 diabetes by substantial weight loss is particularly important for cardiovascular health in women.

Ryan D. Russell, Katherine M. Roberts-Thomson, Donghua Hu, Timothy Greenaway, Andrew C. Betik, Lewan Parker, James E. Sharman, Stephen M. Richards, Stephen Rattigan, Dino Premilovac, Glenn D. Wadley, Michelle A. Keske

Blood flow increases in skeletal muscle after a mixed nutrient meal to promote nutrient storage. In individuals who are obese or have type 2 diabetes, this vascular response is impaired. However, it is unclear if this vascular impairment is present in apparently healthy people at risk of type 2 diabetes. In this issue, Russell and Roberts-Thomson et al (https://doi.org/10.1007/s00125-021-05572-7) reported that people with normal glucose tolerance but with at least one first-degree relative with type 2 diabetes have impaired skeletal muscle vascular responses to a mixed nutrient meal compared with individuals without a family history. The authors suggest that the impaired postprandial skeletal muscle vascular response is an early feature of insulin resistance. The authors conclude that these findings indicate that the skeletal muscle vasculature may be a therapeutic target for early intervention to prevent development of type 2 diabetes.

Li Xiong, Li Chen, Liting Wu, Weiman He, Dubo Chen, Zishan Peng, Jin Li, Xiaonan Zhu, Lei Su, Yanbing Li, Yingying Gong, Haipeng Xiao

Circular RNAs (circRNAs) play important roles in regulating beta cell function, and exosomes are essential mediators of intercellular communication. However, the role of exosomal circRNAs in type 2 diabetes is poorly understood. In this issue, Xiong et al (https://doi.org/10.1007/s00125-021-05591-4) report that circGlis3 (Gli-similar 3) participates in the development of type 2 diabetes in two different ways. In a conventional way, circGlis3 exerts deleterious effects on beta cells by inhibiting cell survival and insulin secretion. In an unconventional way, by acting as a mediator of intercellular crosstalk, beta cell-derived exosomal circGlis3 promotes islet endothelial cell dysfunction through the glucocorticoid modulatory element-binding protein 1 (GMEB1)/ heat shock protein 27 (HSP27) signalling pathway. They also demonstrate that exosomal circGlis3 is upregulated by lipotoxicity and is found at higher levels in mouse models of diabetes and in the serum of participants with type 2 diabetes. The authors conclude that this study provides new insights into the pathogenesis of type 2 diabetes and suggests the significance of circGlis3 as a potential biomarker and therapeutic target for the disease.

Mohammed K. Ali, Jonathan Pearson-Stuttard, Elizabeth Selvin, Edward W. Gregg

Trends in diabetes complications and mortality rates convey the health impacts of diabetes and serve as a barometer of whether clinical practice, intervention programmes and policies are achieving their intended goals. In this issue, Ali et al (https://doi.org/10.1007/s00125-021-05585-2) review recent published data to characterise patterns in type 2 diabetes complications and mortality in adults since 2015, noting stark disparities between different populations. For example, while the burden of diabetes in high-income countries is declining, complications and mortality rates are increasing in low- and middle-income countries. Ali and colleagues discuss how data sources and definitions may be influencing rates and trends observed, and recommend four critical areas of investment to harmonise and bridge the data divide: (1) increasing investments in data collection systems; (2) standardising case definitions and approaches to ascertainment; (3) strengthening analytical capacity; and (4) developing and implementing structured guidelines for reporting of data.

Carlijn M. E. Remie, Georges E. Janssens, Lena Bilet, Michel van Weeghel, Bernard M. F. M. Duvivier, Vera H. W. de Wit, Niels J. Connell, Johanna A. Jörgensen, Bauke V. Schomakers, Vera B. Schrauwen-Hinderling, Joris Hoeks, Matthijs K. C. Hesselink, Esther Phielix, Riekelt H. Houtkooper, Patrick Schrauwen

An effective strategy to improve health is to replace sitting time with standing and walking. However, how this compares to exercise, and the underlying molecular mechanism, remain unknown. In this issue, Remie and Janssens et al (https://doi.org/10.1007/s00125-021-05558-5) describe the results of a randomised crossover intervention study in which three 4-day activity regimens were evaluated. These included: (1) a sitting regimen; (2) an exercise regimen where 1 h of sitting was replaced by a 1 h bout of exercise; and (3) a sitting less regimen that replaced several hours of sitting with standing and walking. The authors found an improvement in insulin sensitivity in the sitting less (~13%) and the exercise (~20%) regimens. Evaluating over a hundred metabolites in muscle biopsies, the authors found that sitting less showed similar global molecular changes to exercise. The authors conclude that a sitting-less regimen can be a viable strategy for metabolic health.

Takahiro Fukaishi, Yuko Nakagawa, Ayako Fukunaka, Takashi Sato, Akemi Hara, Keiko Nakao, Michiko Saito, Kenji Kohno, Takeshi Miyatsuka, Motoyuki Tamaki, Munehide Matsuhisa, Taka-aki Matsuoka, Tetsuya Yamada, Hirotaka Watada, Yoshio Fujitani

The islets of Langerhans, which are composed of four main types of endocrine cells (alpha, beta, delta and pancreatic polypeptide [PP] cells), play an important role in maintaining blood glucose levels. In this issue, Fukaishi et al (https://doi.org/10.1007/s00125-021-05560-x) report that insulin-producing beta cells in mice are composed of several subpopulations with different gene expression profiles. Among them, they found a novel subpopulation of beta cells with a gene expression profile similar to that of PP cells and named them ‘Ppy-lineage beta cells’. Ppy-lineage beta cells showed a reduced glucose-stimulated calcium response compared with non-Ppy-lineage beta cells and were resistant to cellular injury. Consequently, the percentage of Ppy-lineage beta cells remaining in mouse models of diabetes was significantly higher than the other types of beta cells. The authors conclude that this study provides new insights into the functional heterogeneity of beta cells, helping to elucidate mechanisms underlying the onset and progression of diabetes, and may lead to the development of new therapies for diabetes.

Inês Barroso

Genetic studies of type 2 diabetes and related traits (e.g. glucose, insulin or HbA_1c levels) have revealed hundreds of trait-associated loci and increased knowledge of related biological pathways. However, expanding genetic studies to reflect the diversity of individuals with type 2 diabetes has been much slower. In this issue, Inês Barroso (https://doi.org/10.1007/s00125-021-05575-4) summarises the key advances made by genome-wide association studies of type 2 diabetes and related glycaemic traits that have included populations of diverse ancestry. Four main areas that benefit from population diversity are discussed: trait-associated locus discovery, improved understanding of the genetic architecture of these traits across populations, refinement of association signals for causal variant identification, and genetic approaches for precision medicine. The author states that expansion of genetic and genomic studies to encompass more diverse populations promises to deliver more equitable precision medicine. However, she also highlights that it is essential that these studies are conducted in ways that build local research capacity and scientific leadership. The figures from this review are available as a downloadable slideset.

Richard I. G. Holt, J. Hans DeVries, Amy Hess-Fischl, Irl B. Hirsch, M. Sue Kirkman, Tomasz Klupa, Barbara Ludwig, Kirsten Nørgaard, Jeremy Pettus, Eric Renard, Jay S. Skyler, Frank J. Snoek, Ruth S. Weinstock, Anne L. Peters

This is the first ADA/EASD guideline devoted solely to the management of adults with type 1 diabetes. The 14 members of the committee, half from the USA and half from Europe, discuss all aspects of the management of people with type 1 diabetes (https://doi.org/10.1007/s00125-021-05568-3). Of particular note are the recommendations for the diagnosis of adult-onset type 1 diabetes and the universal adoption of continuous glucose monitoring. Throughout, the need for psychosocial support and diabetes education is stressed, given the challenges associated with living with type 1 diabetes for the individual, their families and, in some cases, caregivers.

Chao Huang, Robert F. Rosencrans, Raluca Bugescu, Cristiano P. Vieira, Ping Hu, Yvonne Adu-Agyeiwaah, Karen L. Gamble, Ana Leda F. Longhini, Patrick M. Fuller, Gina M. Leinninger, Maria B. Grant

Low grade inflammation and an increased number of circulating monocytes are key features of diabetes that exacerbate many diabetic complications, including diabetic retinopathy. In this issue, Huang and Rosencrans, et al (https://doi.org/10.1007/s00125-021-05549-6) report that, in mice, a type 2 diabetes-associated loss of hypothalamic somatostatin is sufficient to induce neuroinflammation and bias haematopoiesis towards a proinflammatory monocyte phenotype without overtly altering glucose homeostasis. The authors conclude that these findings provide evidence that neuroinflammation is sufficient to initiate several diabetic complications. This supports the repurposing of somatostatin analogues, such as octreotide, for management of neuroinflammation in diabetes.

Jiangbo Du, Jiong Li, Xiaoqin Liu, Hu Liu, Carsten Obel, Hongbing Shen, Zhibin Hu, Yongfu Yu

Intrauterine exposure to high levels of glucose may lead to vision impairment in offspring. However, whether, or to what extent, prenatal exposure to maternal diabetes increases the risk of refractive error (RE) in offspring is still unknown. In this issue, Du and Li, et al (https://doi.org/10.1007/s00125-021-05526-z) report that children of mothers with diabetes, especially those mothers with diabetic compilations, have increased risk of developing high RE in general, as well as specific types of high RE, persisting from the neonatal period to early adulthood. The authors conclude that these findings highlight the importance of early ophthalmological screening in children of mothers with diabetes diagnosed before or during pregnancy.

Yi-Xin Wang, Siwen Wang, Makiko Mitsunami, JoAnn E. Manson, Janet W. Rich-Edwards, Liang Wang, Cuilin Zhang, Jorge E. Chavarro

Long or irregular menstrual cycles have been associated with many endocrine-related diseases, but evidence linking menstrual cycle dysfunction with gestational diabetes mellitus is scant. In this issue, Wang et al (https://doi.org/10.1007/s00125-021-05531-2) report that, among 10,906 premenopausal women participating in the Nurses’ Health Study II, both irregular and long menstrual cycles during mid-adulthood (age 29–46 years) are associated with a greater risk of gestational diabetes mellitus . These associations are independent of BMI determined across the reproductive lifespan, as well as other well-known risk factors for gestational diabetes mellitus (e.g. advanced maternal age, greater parity and unhealthy lifestyles). The authors conclude that these findings indicate that menstrual cycle characteristics before pregnancy may serve as early markers for subsequent risk of gestational diabetes mellitus.

Matthew A. Budd, Mahdis Monajemi, Sarah J. Colpitts, Sarah Q. Crome, C. Bruce Verchere, Megan K. Levings

Regulatory immune cells are known to control both innate and adaptive immunity, mitigating autoreactivity in type 1 diabetes. However, simply preventing autoimmune attack may not be sufficient to restore the function of damaged or destroyed islet beta cells. In this issue, Budd, Monajemi and Colpitts, et al (https://doi.org/10.1007/s00125-021-05565-6) summarise evidence suggesting that regulatory immune cells may also mediate tissue repair and regeneration, thus working to restore beta cell function. Focussing on macrophages, innate lymphoid cells and regulatory T cells, the authors discuss possible regenerative mechanisms of action and how networks of regulatory cells may work together to enhance beta cell function. They also highlight how technological advances will further knowledge in this area, potentially enabling new therapeutic avenues for type 1 diabetes.  The figure from this review is available as a downloadable slide.

Samantha B. J. Schipper, Maaike M. Van Veen, Petra J. M. Elders, Annemieke van Straten, Ysbrand D. Van Der Werf, Kristen L. Knutson, Femke Rutters

Sleep disorders are linked to type 2 diabetes and diabetes complications. In this issue, Schipper et al (https://doi.org/10.1007/s00125-021-05541-0) summarise the evidence demonstrating a high prevalence of sleep disorders in type 2 diabetes compared with the general population. They also discuss the association between sleep disorders and health outcomes, such as glycaemic control, microvascular and macrovascular complications, depression, mortality and quality of life. Additionally, they show that treating sleep disorders in people with type 2 diabetes improves these aforementioned health outcomes. The authors conclude that efforts should, therefore, be made to diagnose and treat sleep disorders in people with type 2 diabetes in order to ultimately improve their health and quality of life. The figures from this review are available as a downloadable slideset.

Helmut Hiller, Changjun Yang, Dawn E. Beachy, Irina Kusmartseva, Eduardo Candelario-Jalil, Amanda L. Posgai, Harry S. Nick, Desmond Schatz, Mark A. Atkinson, Clive H. Wasserfall

The expression of the non-neurodegenerative, normal isoform of cellular prion protein (PrP^C) within pancreatic islets can affect glucose homeostasis in rodents. In this issue, Hiller et al (https://doi.org/10.1007/s00125-021-05501-8) evaluated PrP^C expression and localisation in human pancreas samples from the Network for Pancreatic Organ donors with Diabetes. Compared with control tissues from individuals without diabetes, PRNP gene expression was reduced in pancreases from islet-autoantibody-positive donors but increased in pancreases from donors with type 1 diabetes. For all donor groups, PrP^C localised specifically to the pancreatic islets. However, within pancreases from donors with type 1 diabetes, PrP^C localised to beta cells of insulin-positive islets and alpha cells of insulin-negative islets. PrP^C was detected in the endoplasmic reticulum and on the cell surface but not in the Golgi apparatus, suggesting unconventional trafficking in islet endocrine cells. PrP^C co-localised with stress-inducible phosphoprotein 1 (STI1), which the authors suggest has potential implications for islet cell protection during type 1 diabetes pathogenesis. The authors conclude that these findings provide new insights into the role that PrP^C may play in the pathogenesis of type 1 diabetes and speculate that intervention through PrP^C protein–ligand interactions could be therapeutic in type 1 diabetes. However, they note that further studies are required.

Jeffrey P. Krischer, Xiang Liu, Åke Lernmark, William A. Hagopian, Marian J. Rewers, Jin-Xiong She, Jorma Toppari, Anette-G. Ziegler, Beena Akolkar, on behalf of the TEDDY Study Group

In this issue, Krischer et al (https://doi.org/10.1007/s00125-021-05514-3) compared the prognostic factors and characteristics of children diagnosed with type 1 diabetes before 6 years of age with those diagnosed at 6–13 years of age, using participants enrolled in The Environmental Determinants of Diabetes in the Young (TEDDY) study. They found that children who developed type 1 diabetes at 0–6 years of age developed a persistent confirmed autoantibody at a younger age than those who were diagnosed with diabetes at 6–12 years of age. Specifically, diabetes diagnosed before 6 years of age was likely to be preceded by insulin autoantibodies, which developed earlier than GAD autoantibodies in this group. In contrast, autoantibodies first appearing against insulinoma antigen-2 were found only in those who developed diabetes at 6–13 years of age. Children who developed diabetes at a younger age also progressed to diabetes more rapidly than children who developed diabetes at 6–13 years of age (mean duration of time between the first-appearing autoantibody and diabetes diagnosis: 1.9 years vs 5.4 years). Among those who developed diabetes at 6–13 years of age, once multiple autoantibodies had been observed, there was not a statistically significant association between progression to type 1 diabetes and the age of the child or family history of type 1 diabetes. Diabetes risk associated with HLA genotypes was statistically significant in those who developed diabetes in both age groups. The authors conclude that these findings suggest that factors associated with diabetes risk need to be conditioned on age to be properly understood.

An Tran-Duy, Josh Knight, Philip M. Clarke, Ann-Marie Svensson, Björn Eliasson, Andrew J. Palmer

Currently, communication between physicians and patients with diabetes about the health benefits of therapeutic strategies are predominantly based on reduced risks of complications and mortality. While the information obtained from a risk chart is useful for prescribing medications, the benefits of risk reduction (e.g. a 2% reduction in 10 year cardiovascular risk) may not be well perceived by the patients. In this issue, Tran-Duy, Knight et al (https://doi.org/10.1007/s00125-021-05503-6) developed a life expectancy table to show how changes in combined levels of age, sex, smoking status, BMI, eGFR and HbA_1c affect the average remaining lifetime of an individual with type 1 diabetes. This table showed a substantial variation in life expectancy across patients with different risk factor levels (see the interactive version of the table at https://antranduy.shinyapps.io/le-t1d/). For example, the life expectancy of 20-year-old men varied from 29.3 years to 50.6 years, constituting a gap of 21.3 years between those with worst and best risk factor levels. The authors conclude that these findings indicate a strong incentive to increase life expectancy via optimisation of risk factors. They suggest that this table may support clinicians in their discussions with patients with type 1 diabetes about the benefits of improving risk factors in terms of life-years gained, an important and easily understood outcome measure

Rachel Brandt, Minsun Park, Kristen Wroblewski, Lauretta Quinn, Esra Tasali, Ali Cinar 

Reducing glycaemic variability is a key objective in glycaemic management. Suboptimal subjective sleep quality is common in adults with type 1 diabetes. In this issue, Brandt et al (https://doi.org/10.1007/s00125-021-05500-9) explore the relationships between overnight glycaemic variability measures and objective sleep quality in a real-life setting. The authors report that during nights with poor sleep quality glycaemic variability was greater, while nights with good sleep quality showed less variability after accounting for age, sex, BMI and overnight insulin dose. While the directionality of this relationship is unknown, the authors state that these findings provide a strong incentive for both healthcare providers and patients to consider sleep quality in personalised diabetes management plans.

Rachel Folz, Neda Laiteerapong

Over the last two decades, a large number of landmark clinical trials and observational and translational research studies have advanced the understanding of how glycaemic control affects diabetes outcomes over time. In this issue, Folz and Laiteerapong (https://doi.org/10.1007/s00125-021-05539-8) summarise the evidence on the glycaemic legacy effect. Studies among individuals with early diabetes suggest that there is a long-term effect of early glycaemic control, although long-term follow-up of trials in participants with established diabetes does not corroborate this. In general, the findings of a legacy effect are more conclusive for microvascular than for macrovascular complications. Two main hypotheses exist for the pathophysiological mechanisms of the legacy effect: epigenetic modifications of the endothelium and intracellular production of superoxide anions. This summary suggests that the glycaemic legacy effect largely applies to individuals in the early stages of diabetes, and that those with established diabetes and diabetic complications may no longer benefit from early intensive glycaemic control. The figure from this review is available as a downloadable slide.

Rasmus J. O. Sjögren, David Rizo-Roca, Alexander V. Chibalin, Elin Chorell, Regula Furrer, Shintaro Katayama, Jun Harada, Håkan K. R. Karlsson, Christoph Handschin, Thomas Moritz, Anna Krook, Erik Näslund, Juleen R. Zierath

Branched-chain amino acid (BCAA) metabolism is impaired in type 2 diabetes, as reflected by elevated circulating levels of leucine, isoleucine and valine. Since skeletal muscle is the largest contributor to systemic BCAA oxidation, perturbations in myocyte BCAA metabolism may impact whole-body metabolic homeostasis. In this issue, Sjögren, Rizo-Roca et al (https://doi.org/10.1007/s00125-021-05481-9) demonstrate that skeletal muscle BCAA catabolism in response to glucose loading is attenuated in type 2 diabetes, revealing that the metabolic inflexibility that characterises type 2 diabetes encompasses BCAA catabolism. Moreover, the authors identify oestrogen-related receptor α (ERRα) as an essential transcriptional partner of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) in the regulation of the expression of the BCAA gene set in primary human myotubes. The authors state that these findings highlight the utility of an oral glucose tolerance test to unravel disturbances in both BCAA and glucose metabolism and provide insight into the development of new therapeutic strategies for the treatment of type 2 diabetes.

Ziyi Zhou, John Macpherson, Stuart R. Gray, Jason M. R. Gill, Paul Welsh, Carlos Celis-Morales, Naveed Sattar, Jill P. Pell, Frederick K. Ho

People who are obese and with a normal metabolic profile are sometimes referred to as having ‘metabolically healthy obesity’ (MHO). In this issue, Zhou et al (https://doi.org/10.1007/s00125-021-05484-6) present findings from a prospective cohort study of 381,363 UK Biobank participants. They found that those with MHO had higher risk of incident diabetes, atherosclerotic cardiovascular disease, heart failure, respiratory disease and all-cause mortality, compared with those who were not obese and had a normal metabolic profile. The results were similar in an analysis excluding participants with incident outcomes in the first 5 years of follow-up, indicating minimal reverse causation. There were weak or non-significant interactions between obesity and metabolic health factors with health outcomes, suggesting MHO is not a distinctive phenotype. The authors conclude that the use of the label ‘metabolically healthy’ is misleading and should be avoided. Weight management could be beneficial for all people with obesity, irrespective of metabolic profile.

Wilma S. Leslie, Eman Ali, Leanne Harris, C. Martina Messow, Naomi T. Brosnahan, George Thom, E. Louise McCombie, Alison C. Barnes, Naveed Sattar, Roy Taylor, Michael E. J. Lean

A diagnosis of type 2 diabetes carries a life-expectancy reduction ranking alongside major cancers, with several weight-related cardiometabolic factors (the metabolic syndrome) contributing to this. For example, over half of individuals with type 2 diabetes are also hypertensive. In this issue, Leslie et al (https://doi.org/10.1007/s00125-021-05471-x) present a secondary analysis of the Diabetes Remission Clinical Trial (DiRECT), in which they aimed to evaluate the safety and efficacy of the planned therapeutic withdrawal of all antihypertensive and diuretic medications, upon commencement of a formula low-energy diet replacement, targeting remission of type 2 diabetes.  The authors report that the DiRECT protocol led to remission of diabetes (i.e. HbA_1c values that were not in the diabetic range, without glucose-lowering medications) after 2 years for about one-third of all participants who commenced a dietary weight management programme. Over 80% of those who lost over 15 kg of weight achieved remission.  To avoid postural hypotension, the trial protocol included a therapeutic trial of withdrawing antihypertensive medications upon starting 12–20 weeks of a 3470 kJ/day (830 kcal/day) formula diet; no rebound hypertension was observed.  Overall, blood pressures fell, with 28% needing to resume antihypertensives before 20 weeks. The weight-loss maintenance protocol maintained normal blood pressure at 24 months, without medication, for 28% of those who stopped antihypertensives at baseline, and for 44% of those who sustained remission of diabetes (mean weight loss: 11.4 kg). The authors conclude that weight loss is a safe and effective antihypertensive treatment.

Eva Xepapadaki, Ioanna Nikdima, Eleftheria C. Sagiadinou, Evangelia Zvintzou, Kyriakos E. Kypreos

Clinical and epidemiological evidence suggests an optimal range of plasma HDL-cholesterol concentrations, while very low and very high HDL-cholesterol levels are equally associated with high risk of mortality. In addition to plasma HDL-cholesterol levels, the recent observation that the HDL proteome dictates its lipidome, and subsequently HDL particle functionality, indicates that alterations in the HDL metabolic pathway may substantially influence its properties. In this issue, Xepapadaki et al (https://doi.org/10.1007/s00125-021-05509-0) review the accumulating evidence that suggests a bidirectional correlation between HDL dysfunction and type 2 diabetes, leading to a perpetual cycle. Although not all HDL disturbances are causatively associated with the development and progression of type 2 diabetes, many contribute to reduced secretory performance of beta cells in pancreatic islets and skeletal muscle insulin sensitivity. The interrelation between HDL lipidome, proteome and particle functionality remains a missing part of the puzzle that needs to be solved. The authors conclude that understanding HDL functionality and the factors affecting it in individuals with diabetes will be a crucial step towards better glucose homeostasis. The figure from this review is available as a downloadable slide.

Miranda T. Schram, Willem J. J. Assendelft, Theo G. van Tilburg, Nicole H. T. M. Dukers-Muijrers

Social networks are important determinants for well-being and general health in type 2 diabetes. In this issue, Schram et al (https://doi.org/10.1007/s00125-021-05496-2) review the state-of-the-art evidence on the role of social networks on type 2 diabetes risk, diabetes management and the risk for diabetes complications. Despite the heterogeneity of social networks and study designs, the authors reveal that valuable conclusions can be drawn from previous research. For example, living alone and lack of social support have been identified as risk factors for type 2 diabetes. In addition, a smaller network size and less social support increase the risk for diabetes complications, such as chronic kidney disease and CHD. Moreover, the authors highlight that some evidence was found that social support may have a beneficial effect on diabetes self-management. The authors conclude that these findings support the idea that engaging the social network in prevention and treatment strategies for type 2 diabetes may be helpful to improve their effectiveness. The figures from this review are available as a downloadable slideset.

Éva Korpos, Nadir Kadri, Sophie Loismann, Clais R. Findeisen, Frank Arfuso, George W. Burke III, Sarah J. Richardson, Noel G. Morgan, Marika Bogdani, Alberto Pugliese, Lydia Sorokin

Tertiary lymphoid organs (TLOs) show structural and functional similarities to secondary lymphoid organs. They form in non-lymphoid tissues to generate local immune responses during chronic infection, autoimmunity and cancer. In this issue, Korpos et al (https://doi.org/10.1007/s00125-021-05453-z) show the presence of TLOs in the pancreas of individuals with ongoing islet autoimmunity in three distinct clinical settings of type 1 diabetes: (1) at risk of diabetes (autoantibody positive); (2) at/after diagnosis; and (3) in the transplanted pancreas with recurrent diabetes. The authors report that pancreatic TLOs in humans with type 1 diabetes and mouse models of type 1 diabetes are structurally and molecularly similar, exhibiting high endothelial venule formation, a biochemically similar reticular fibre network, fibroblastic reticular cells and T and B cells. TLOs were mostly associated with insulin-positive islets containing immune cell aggregates. Based on these findings, the authors suggest that TLOs are potential sites of autoreactive effector T cell generation in islet autoimmunity and may contribute to the progression of disease.

Amalia Gastaldelli, Norbert Stefan, Hans-Ulrich Häring

The global epidemic of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) and the high prevalence of these diseases among individuals with type 2 diabetes have caught the attention of researchers and clinicians treating patients with diabetes affecting the liver. Many drugs are in the pipeline for the treatment of NAFLD/NASH and several glucose-lowering drugs have now been tested specifically for the treatment of liver disease. In this issue, Gastaldelli et al (https://doi.org/10.1007/s00125-021-05442-2) review and appraise the various pharmacological treatment approaches predominantly targeting the liver that have been approved or are in development for the treatment of diabetes and NAFLD/NASH. The authors conclude that the improvement of hyperglycaemia and/or insulin resistance, as well as lipid metabolism, in response to many of these drugs is beneficial for the liver in both type 2 diabetes and NAFLD/NASH. The figure from this review is available as a downloadable slide.

David Nathanson, Ann-Marie Svensson, Mervete Miftaraj, Stefan Franzén, Jan Bolinder, Katarina Eeg-Olofsson

The increasing use of glucose-sensor technologies makes it difficult to design long-term randomised controlled trials with conventional self-monitoring of blood glucose (SMBG) as a comparator. Instead, the evidence regarding the effectiveness of flash glucose monitoring (FM) is largely derived from observational data lacking well-matched non-FM-using control participants. In this issue, Nathanson et al (https://doi.org/10.1007/s00125-021-05437-z) used data from the Swedish National Diabetes Registry (NDR) to investigate long-term changes in glucose control after initiation of FM in comparison with conventional SMBG. The authors also assessed the efficacy of FM in alleviating the incidence of severe hypoglycaemic events. Nathanson and colleagues identified all adults with type 1 diabetes using FM for 2 years, as well as continuous glucose monitoring (CGM)/FM-naive individuals. Propensity scores and inverse probability of treatment weighting were used to balance the groups. The analyses showed a small and lasting decrease in HbA_1c in FM users compared with control individuals and a 21% reduction in severe hypoglycaemic events. The authors conclude that FM is associated with improvements in HbA_1c and alleviation of severe hypoglycaemia, which supports the use of FM in adults with type 1 diabetes. However, the long-term clinical significance of the modest lowering of HbA_1c achieved by FM use remains to be elucidated.

Sandra S. Hammer, Cristiano P. Vieira, Delaney McFarland, Maximilian Sandler, Yan Levitsky, Tim F. Dorweiler, Todd A. Lydic, Bright Asare-Bediako, Yvonne Adu-Agyeiwaah, Micheli S. Sielski, Mariana Dupont, Ana Leda Longhini, Sergio Li Calzi, Dibyendu Chakraborty, Gail M. Seigel, Denis A. Proshlyakov, Maria B. Grant, Julia V. Busik

Intermittent fasting has been shown to exert beneficial effects by improving metabolic health. It has also been shown to prevent the development of diabetic retinopathy in mouse models of diabetes. The mechanism(s) responsible for these advantageous effects, however, remains undefined. Sirtuin 1 (SIRT1) is a nutrient-sensing deacetylase that is activated in low-nutrient environments (such as intermittent fasting) and downregulated in diabetes. In this issue, Hammer et al (https://doi.org/10.1007/s00125-021-05431-5) demonstrate that activation of SIRT1/liver X receptor alpha (LXRα) signalling prevents diabetes-induced retinal damage in both cell culture and animal models of diabetes. Specifically, the authors show prevention of inflammation and cell death in neurovascular retinal cells in diabetes, as well as improvement of bone marrow health in diabetic mice via SIRT1 activation. Pharmacological SIRT1 activation also prevented diabetes-induced visual function impairment in mouse models of type 2 diabetes. The authors conclude that these findings suggest that activation of SIRT1 signalling can provide a mechanistic link between the advantageous effects associated with fasting regimens and improvements in metabolic health in diabetes.

Felicia Gerst, Elisabeth Kemter, Estela Lorza-Gil, Gabriele Kaiser, Ann-Kathrin Fritz, Rita Nano, Lorenzo Piemonti, Marie Gauder, Andreas Dahl, Silvio Nadalin, Alfred Königsrainer, Falko Fend, Andreas L. Birkenfeld, Robert Wagner, Martin Heni, Norbert Stefan, Eckhard Wolf, Hans-Ulrich Häring, Susanne Ullrich

There is accumulating evidence that beta cells acquire a neonatal-like phenotype in type 2 diabetes, i.e. increased basal secretion and reduced glucose responsiveness. The loss of functional maturity occurs early during disease development and hepatic steatosis could be a driver of this process. Fetuin-A is a fetal glycoprotein that is downregulated post-partum, but the secretion of which is increased by hepatocytes of the fatty liver. This glycoprotein is also a marker of insulin resistance and a risk factor for type 2 diabetes. In this issue, Gerst et al (https://doi.org/10.1007/s00125-021-05435-1) report that fetuin-A restrains functional maturity of both neonatal and adult beta cells. They show that fetuin-A impairs TGFβ receptor (TGFBR)–SMAD2/3 signalling, thereby curtailing expression of genes governing beta cell identity. It is also shown to reduce adaptive proliferation via downregulation of forkhead box M1 (FOXM1) targets. By doing so, fetuin-A impairs glucose responsiveness and decreases beta cells mass. Indeed, the authors found a negative correlation between plasma fetuin-A level and beta cell area in individuals without diabetes. The authors conclude that their findings suggest that therapies effectively counteracting hepatic steatosis may also prevent beta cell failure and the onset of type 2 diabetes.

Mugdha V. Joglekar, Wilson K. M. Wong, Fahmida K. Ema, Harry M. Georgiou, Alexis Shub, Anandwardhan A. Hardikar, Martha Lappas

Women with diabetes during pregnancy are at higher risk of developing type 2 diabetes in later life than mothers without any history of gestational diabetes. Although clinical tests enable the identification of mothers at risk of type 2 diabetes, more accurate methodologies for early diabetes prediction are needed. In this issue, Joglekar et al (https://doi.org/10.1007/s00125-021-05429-z) used supervised learning methods to identify circulating microRNAs associated with future type 2 diabetes risk in women with gestational diabetes, post-delivery.  They found that levels of specific microRNAs at 12 weeks after delivery predicted diabetes progression over the next 10 years and enhanced current clinical risk-stratification methods. Their results demonstrate the potential of using circulating microRNA biomarkers in the early prediction of future diabetes. The authors conclude that these findings may help to facilitate more accurate identification of mothers at risk of diabetes and make way to interventions that could prevent diabetes in later life.

Anita Jeyam, Fraser W. Gibb, John A. McKnight, Brian Kennon, Joseph E. O’Reilly, Thomas M. Caparrotta, Andreas Höhn, Stuart J. McGurnaghan, Luke A. K. Blackbourn, Sara Hatam, Rory J. McCrimmon, Graham Leese, Robert S. Lindsay, John Petrie, John Chalmers, Sam Philip, Sarah H. Wild, Naveed Sattar, Paul M. McKeigue, Helen M. Colhoun, On behalf of the Scottish Diabetes Research Network (SDRN) Epidemiology Group

As the use of continuous subcutaneous insulin infusion (CSII) to aid diabetes management becomes more widespread, there is still uncertainty regarding its effectiveness and safety. In this issue, Jeyam et al (https://doi.org/10.1007/s00125-021-05413-7) report that, among the Scottish population with type 1 diabetes, CSII initiation is associated with reductions in HbA_1c in both adults and children, with the largest improvements being observed in those with the highest starting HbA_1c levels. They also report CSII initiation to be associated with an overall reduction in the incidence of severe hospitalised hypoglycaemia and diabetic ketoacidosis, though directions of associations varied across age groups for the latter. Finally, they highlight the existing socioeconomic disparities in CSII usage between least and most deprived areas. The authors conclude that CSII is a promising option for improving glycaemic control, especially for those with high HbA_1c levels.

Bruce A. Perkins, Leif Erik Lovblom, Sebastien O. Lanctôt, Krista Lamb, David Z. I. Cherney

Award programmes that acknowledge the remarkable accomplishments of long-term survivors with type 1 diabetes have naturally evolved into research programmes to determine the factors associated with survivorship and resistance to chronic complications. These have led to the discovery that many individuals retain insulin production and, other than for diabetic neuropathy, appear to resist the development of microvascular and macrovascular complications. In this issue, Perkins and colleagues (https://doi.org/10.1007/s00125-021-05403-9) consider the putative mechanisms underlying this phenomenon. They also discuss mechanisms that may result in the maintenance or recovery of beta cells and their function, which include: activation of specific glycolytic enzymes, such as pyruvate kinase M2; modification of AGE production and processing; novel mechanisms for modification of renin–angiotensin–aldosterone system activation, in particular those that may normalise afferent rather than efferent renal arteriolar resistance; and activation and modification of processes such as retinol binding and DNA damage checkpoint pathways. The authors conclude that these mechanisms may, in the future, serve as therapeutic targets. The figures from this review are available as a downloadable slideset.

Nima Purvis, Sweta Kumari, Dhananjie Chandrasekera, Jayanthi Bellae Papannarao, Sophie Gandhi, Isabelle van Hout, Sean Coffey, Richard Bunton, Ramanen Sugunesegran, Dominic Parry, Philip Davis, Michael J. A. Williams, Andrew Bahn, Rajesh Katare

Stem cell therapies promise to regenerate the diseased heart by replacing dead cardiac cells and stimulating new blood vessels. However, this approach is limited in individuals with diabetes due to a marked reduction in the number and functional efficacy of cardiac progenitor cells (CPC). In this issue, Purvis et al (https://doi.org/10.1007/s00125-021-05405-7) identified the dysregulation of microRNAs associated with survival, proliferation and self-renewal of CPCs in the diabetic heart. In addition, they demonstrated that therapeutic restoration of microRNA-30c-5p, one of the downregulated microRNAs in diabetic CPCs, activated endogenous stem cells in the diabetic heart and improved their survival by inhibiting pro-apoptotic voltage-dependent anion-selective channel 1 (VDAC1), the direct target of microRNA-30c-5p. The authors conclude that these findings emphasise the need for an understanding of the nature and condition of progenitor/stem cells of diabetic individuals before microRNA-targeted therapy can be used to activate endogenous stem cells in the heart, thereby eliminating the need for stem cell transplantation.

Wolfgang Rathmann, Brenda Bongaerts

Pharmacogenetics is still an emerging field, and there remains a lack of studies on the role of gene variants in treatment responses to novel glucose-lowering drugs (e.g. dipeptidyl peptidase-4 inhibitors [DPP-4i], glucagon-like peptide-1 receptor agonists [GLP-1 RA] and sodium–glucose cotransporter 2 inhibitors [SGLT2i]). In this issue, Rathmann and Bongaerts (https://doi.org/10.1007/s00125-021-05402-w) discuss gene variants related to metabolic responses to these novel agents, including glycaemic effects, diabetes-related metabolic traits and body-weight changes. For  example, some studies have indicated a reduced glycaemic response to DPP-4i in individuals carrying GLP1R variants. On the other hand, greater weight reductions with GLP-1 RA were reported in carriers of certain GLP1R variants. For type 2 diabetes risk genes, the authors highlight that the magnitude of HbA_1c reductions under DPP-4i therapy is dependent on genotype: HbA_1c reductions were larger in those carrying a CDKAL1 variant vs those carrying two copies of the common alleles, whilst it was smaller in individuals carrying a specific TCF7L2 variant (rs7903146 TT genotype). Meanwhile, studies on SGLT2i have focused on genes affecting renal glucose reabsorption (e.g. SLC5A2), but the few pieces of data available indicate no effects. The authors suggest that further identification of type 2 diabetes subtypes will be necessary before pharmacogenetic insights can be used for stratified prescription of novel glucose-lowering drugs.

Andrew P. McGovern, Nick J. Thomas, Sebastian J. Vollmer, Andrew T. Hattersley, Bilal A. Mateen, John M. Dennis

In this issue, McGovern et al (https://doi.org/10.1007/s00125-021-05404-8) investigate the combined effects of age and diabetes on Coronavirus disease-2019 (COVID-19) mortality. Triangulating published data from large UK population-based (OpenSAFELY [n=17,278,392] and QCOVID [n=6,083,102]) and critical care-based (COVID-19 Hospitalisation in England Surveillance System [CHESS] cohort [n=19,256]) studies, the authors describe a disproportionate excess relative mortality risk in younger people with diabetes compared with older people with diabetes. For example, a person aged 40 years with diabetes has the equivalent COVID-19 mortality risk of a 60-year-old person without diabetes: an additional risk of 20 years. This difference reduces significantly with increasing age, so that a person aged 70 with diabetes has the equivalent COVID-19 mortality risk of a 78-year-old person without diabetes: an additional risk of just 8 years. The authors suggest that country-level strategies to define priority groups for vaccination should consider the disproportionate relative risk of COVID-19 mortality in middle-aged people with diabetes.

Mu Zhang, Chunjie Yang, Meng Zhu, Li Qian, Yan Luo, Huimin Cheng, Rong Geng, Xiaojun Xu, Cheng Qian, Yu Liu

Failure of pancreatic and duodenal homeobox factor 1 (PDX1) to localise in the nucleus of islet beta cells under high-fat-diet conditions may contribute to beta cell failure in type 2 diabetes; however, the mechanism of PDX1 intracellular mislocalisation is unclear. Saturated fatty acids (SFAs) are known to be adverse factors in blood glucose regulation, but the underlying mechanisms for this are unknown. Owing to their biochemical features, SFAs are involved in liquid–liquid phase separation, whilst stress granules (SGs) are cytoplasmic structures that form by phase separation and impair nucleocytoplasmic transport. In this issue, Zhang et al (https://doi.org/10.1007/s00125-021-05389-4) investigated whether SG formation contributes to PDX1 mislocalisation and beta cell dysfunction under SFA-induced stress conditions. They found that SGs assembled in cells after they were exposed to SFAs, and that this was dependent on the phosphoinositide 3-kinase (PI3K)/eukaryotic translation initiation factor 2α (eIF2α) axis. They also demonstrated that PDX1 was entrapped in SGs after SFA treatment. The authors suggest that modulation of SG formation may ameliorate the impairment of pancreatic beta cell function and may be a potential therapeutic strategy for obesity and type 2 diabetes.

Mengliu Yang, Sheng Qiu, Yirui He, Ling Li, Tong Wu, Ning Ding, Fanghong Li, Allan Z. Zhao, Gangyi Yang

Besides serving as a traditional inflammatory marker in the clinic, C-reactive protein (CRP) is positively associated with the development of obesity, diabetes and cardiovascular diseases. However, genetic evidence is needed to definitively conclude whether CRP directly participates in the regulation of energy and glucose metabolism rather than just being a surrogate marker for these. In this issue, Yang, Qiu et al (https://doi.org/10.1007/s00125-021-05384-9) report on a Crp knockout rat model generated to investigate this question. They found that CRP-deficiency led to a significant reduction in weight gain and food intake, elevated energy expenditure and improved insulin sensitivity after exposure to a high-fat diet. Importantly, it also significantly enhanced the weight-reducing effect of leptin. The authors state that this study represents the first line of genetic evidence that CRP is not merely a surrogate blood marker for inflammation and metabolic syndromes, but that it also directly regulates adiposity and insulin sensitivity. They conclude that, clinically, elevated blood CRP levels will negate leptin’s actions. Hence, reduction of CRP-induced leptin resistance may be a promising therapeutic strategy for the treatment of obesity and type 2 diabetes.

Rachel B. Forster, Emmanuel Sandoval Garcia, Anniek J. Sluiman, Sheila M. Grecian, Stela McLachlan, Tom J. MacGillivray, Mark W. J. Strachan, Jackie F. Price, on behalf of the Edinburgh Type 2 Diabetes Study (ET2DS) investigators

Diabetic retinopathy is a common complication of diabetes and can have a major impact on quality of life. In this issue, Forster et al (https://doi.org/10.1007/s00125-021-05388-5) report that recent developments have allowed for detailed analysis of the retinal vessels in the back of the eye. This gives hope of identifying early changes that can predetermine local vascular disease. Through follow-up of the Edinburgh Type 2 Diabetes Study, the authors aimed to identify associations between several retinal vessel measurements and the development of diabetic retinopathy. They identified that increased venular tortuosity (curvature of the small veins and how much the vessels twist) and decreased fractal dimension (complexity of the vessel system) were both associated with later development of diabetic retinopathy. Further analysis found venular tortuosity to be a possible biomarker candidate for future risk prediction models, which, according to the authors, could be used to help identify risk of diabetic retinopathy prior to disease onset.

As summarised in an Editorial by our Guest Editor and previous Editor-in-Chief, Sally Marshall (https://doi.org/10.1007/s00125-021-05417-3), our 2021 special issue (https://diabetologia-journal.org/collections/insulin-100/) celebrates 100 years since the discovery of insulin. Fralick and Zinman (https://doi.org/10.1007/s00125-020-05371-6) begin by recounting the story of insulin’s discovery in Toronto, Canada, in 1921/1922. This discovery meant that type 1 diabetes went from being a death sentence to a chronic condition. Despite this, globally, only one in two people currently have access to the insulin they require; Mbanya and colleagues (https://doi.org/10.1007/s00125-020-05375-2) outline the barriers to insulin access and suggest ways to overcome these. For those fortunate enough to have insulin access, hypoglycaemia remains a frequent complication of insulin therapy. Stephanie Amiel (https://doi.org/10.1007/s00125-020-05366-3) describes the immediate and cumulative consequences of hypoglycaemia, whilst Rory McCrimmon (https://doi.org/10.1007/s00125-020-05369-0) summarises the impact of recurrent hypoglycaemia on brain function. Chantal Mathieu (https://doi.org/10.1007/s00125-020-05354-7) suggests options for minimising hypoglycaemia risk, including patient education, insulin analogues, novel technologies and adjunct therapies. To help us understand how insulin therapies work, Yoon and Diano (https://doi.org/10.1007/s00125-021-05395-6) describe the central glucose-sensing mechanisms involved in the regulation of glucose metabolism, whilst Kahn et al (https://doi.org/10.1007/s00125-021-05415-5) outline current and evolving concepts of insulin action/resistance in type 2 diabetes. The authors state that understanding the primary source of metabolic disturbances and drivers of disease will offer important new avenues for the development of novel therapies. Boughton and Hovorka (https://doi.org/10.1007/s00125-021-05391-w) outline an excellent example of a novel therapeutic approach for diabetes, the closed-loop insulin-delivery system, summarising the supporting evidence and limitations of these devices. On a similar note, Weiss and colleagues (https://doi.org/10.1007/s00125-021-05422-6) introduce us to ‘smart’ insulin-delivery devices and molecular technologies designed to exploit feedback regulation. As an alternative approach, Douglas Melton (https://doi.org/10.1007/s00125-020-05367-2) explores the promise of stem cell-derived islet replacement therapy, whilst von Herrath and colleagues (https://doi.org/10.1007/s00125-021-05398-3) give an overview of therapeutics that may help to prevent the destruction of beta cells in the first place. Turning to diabetes complications, David Nathan (https://doi.org/10.1007/s00125-021-05397-4) demonstrates that insulin therapy ameliorates the long-term complications of type 1 diabetes, using findings from the DCCT and Epidemiology of Diabetes Interventions and Complications (EDIC) study. To complete this special series, Daniel Drucker (https://doi.org/10.1007/s00125-021-05396-5) looks to the future, highlighting the potential of smart insulins, fully automated insulin delivery, reprogramming of the immune system and stem cell-derived islets to alter the natural history and treatment of type 1 diabetes. This special series is in collaboration with the University of Toronto’s Insulin 100 Scientific Symposium (https://insulin100.com/).

Marie M. Henriksen, Henrik U. Andersen, Birger Thorsteinsson, Ulrik Pedersen-Bjergaard

Symptomatic hypoglycaemia has been reported to reduce quality of life in type 1 diabetes; however, it remains unclear if nocturnal hypoglycaemia (recorded by continuous glucose monitoring [CGM]) affects daily reported quality of life. In this issue, Henriksen et al (https://doi.org/10.1007/s00125-020-05360-9) investigate the impact of CGM-recorded nocturnal hypoglycaemia on quality of life the following day in people with type 1 diabetes. The authors report that, in individuals with hypoglycaemia unawareness, who generally report lower quality of life, unrecognised nocturnal asymptomatic hypoglycaemia was associated with improved self-estimated quality of life the subsequent day (as assessed by the EuroQol-5D visual analogue scale [EQ-5D VAS] but not the WHO Well-Being Index) . The authors suggest that this may be driven by a different biological brain response to hypoglycaemia in people with hypoglycaemia unawareness, in accordance with patterns reported by previous neuroimaging studies. They state that these findings may help to explain differences in perception and attitudes towards hypoglycaemia among people with type 1 diabetes and emphasise the need for reducing the risk of both symptomatic and asymptomatic nocturnal hypoglycaemia.

Charanya Muralidharan, Abass M. Conteh, Michelle R. Marasco, Justin J. Crowder, Jeroen Kuipers, Pascal de Boer, Amelia K. Linnemann

Autophagy is a degradation process in which excessive or damaged cellular materials are degraded and recycled. This degradative process has been shown to promote beta cell homeostasis and proliferation and, also, to protect against apoptosis. Crinophagy is a specialised form of autophagy where secretory granules directly fuse with lysosomes and get degraded. Prior studies have reported impaired autophagy in the context of type 2 diabetes; however, it is unknown if islet autophagy is impaired in type 1 diabetes. In this issue, Muralidharan et al (https://doi.org/10.1007/s00125-021-05387-6) provide evidence of impairment in autophagy in the islets of diabetic NOD mice, as well as impairment of both autophagy and crinophagy in the beta cells of human organ donors with type 1 diabetes. Additionally, the authors report an accumulation of telolysosomes in the beta cells of autoantibody-positive donors, suggesting that lysosomal defects are present prior to the onset of clinical hyperglycaemia. The authors conclude that these findings indicate that the beta cell autophagy and crinophagy impairments observed in type 1 diabetes could be, at least in part, due to defective lysosomes in the prediabetic phase of disease development.

Anita M. Nucci, Suvi M. Virtanen, David Cuthbertson, Johnny Ludvigsson, Ulle Einberg, Celine Huot, Luis Castano, Bärbel Aschemeier, Dorothy J. Becker, Mikael Knip, Jeffrey P. Krischer, The TRIGR Investigators

Accelerated growth during childhood has been considered as a cause for the increasing incidence of type 1 diabetes, either by initiating or accelerating islet autoimmunity (IA).  However, the relationship between the occurrence of being overweight and obese during childhood and the development of IA and type 1 diabetes is unknown.  In this issue, Nucci, Virtanen et al (https://doi.org/10.1007/s00125-020-05358-3) examined growth measures annually and over time (up to 10 years of age) and the risk of development of IA and type 1 diabetes in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) population, who have at least one first-degree relative with type 1 diabetes and carry HLA-conferred susceptibility. The authors reported that the occurrence of being overweight at 2–10 years of age was associated with an increased risk of developing type 1 diabetes, but not with the development of IA. This is the first study to examine the relationship between weight status and the development of IA and type 1 diabetes using the standardised definitions of being overweight and obese that guide clinical practice.  The authors state that the findings provide further support for existing recommendations to aid with the prevention and treatment of being overweight in childhood.

Alice E. Hughes, Andrew T. Hattersley, Sarah E. Flanagan, Rachel M. Freathy

In 1998, the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. In this issue, Hughes et al (https://doi.org/10.1007/s00125-021-05386-7) review evidence from recent genetics research relevant to the fetal insulin hypothesis. People with monogenic diabetes not only have early-onset diabetes that results from reduced insulin secretion, but also usually have low birthweight. The authors highlight that genome-wide association studies have established overlap between common genetic variants associated with lower birthweight and higher risk of type 2 diabetes. There is strong evidence that certain risk alleles associated with reduced pancreatic beta cell function or metabolically unfavourable patterns of adiposity are associated with lower birthweight when inherited, but fetal risk alleles associated with obesity do not alter birthweight. The authors conclude that it is likely that further advances in genetics research will help us better understand the complex relationship between fetal growth and type 2 diabetes risk, which has both genetic and epigenetic components. The figures from this review are available as a downloadable slideset.

Sergiu-Bogdan Catrina, Xiaowei Zheng

Hypoxia-inducible factors (HIFs) sense oxygen changes and coordinate a multitude of processes that enable cells to cope with hypoxia, such as angiogenesis, mitochondrial respiration, glycolysis, proliferation, differentiation and apoptosis. HIF signalling is tightly controlled and its disturbed activity is involved in several pathologies (such as cancer and ischaemic diseases). In this issue, Catrina and Zheng (https://doi.org/10.1007/s00125-021-05380-z) summarise the role of hypoxia and HIFs in diabetes and its complications. They explain that, while multiple tissues are hypoxic in diabetes, the appropriate reaction of HIF signalling is inhibited by hyperglycaemia and fatty acids. The dysregulated HIF signalling impairs the adaptive responses of tissues to hypoxia and, thus, plays an important pathogenic role in the development of diabetes and its complications. The authors also discuss the potential of specific HIF-targeting therapies for the prevention and treatment of diabetes and its related complications. The figures from this review are available as a downloadable slideset.

Väinö Lithovius, Jonna Saarimäki-Vire, Diego Balboa, Hazem Ibrahim, Hossam Montaser, Tom Barsby, Timo Otonkoski

Congenital hyperinsulinism caused by mutations in the K_ATP-channel-encoding genes often leads to life-threatening hypoglycaemia. Current treatment options are inadequate and many patients have to undergo radical pancreatic surgery. The development of new pharmacological treatment options is hindered by the lack of disease-specific beta cell models. In this issue, Lithovius et al (https://doi.org/10.1007/s00125-020-05346-7) set out to create a new disease model of congenital hyperinsulinism due to loss-of-function of the K_ATP channel (K_ATPHI) to circumvent the issue of limited patient material. They used induced pluripotent stem cells (iPSCs), derived from an individual with  K_ATPHI, as well as CRISPR-Cas9 mutation-corrected iPSCs for control purposes. iPSCs were differentiated into pancreatic islet-like cells, allowing comparison of mutated and corrected cells, which are isogenic, both in vitro and after transplantation into mice. The authors observed insulin hypersecretion in vitro and in vivo, along with increased beta cell proliferation and mass, thus highlighting the relevance of their model for K_ATPHI research. They concluded that this model could serve as a platform for developing new treatment options for K_ATPHI.

Louise Cottle, Wan Jun Gan, Ian Gilroy, Jaswinder S. Samra, Anthony J. Gill, Thomas Loudovaris, Helen E. Thomas, Wayne J. Hawthorne, Melkam A. Kebede, Peter Thorn

Accumulating evidence demonstrates that rodent beta cells are structurally and functional polarised. In this issue, Cottle et al (https://doi.org/10.1007/s00125-020-05345-8) investigated whether human beta cells are also polarised. This is an important question given the anatomical differences between rodent and human islets. The authors used pancreatic slices to preserve islet structure and 3D immunostaining to show that human beta cells are polarised with an apical–basal orientation, locating the basal pole of each cell at the capillary interface. Presynaptic scaffold proteins were enriched in this basal region, suggesting local specialisation for insulin granule exocytosis. The authors provide functional evidence indicating that the orientation of human beta cells is a focal adhesion-mediated response to extracellular matrix proteins secreted by capillary endothelial cells. They conclude that this evidence—that human beta cells are polarised—advances our understanding of normal islet function. They state that, clinically, these findings are relevant for understanding type 2 diabetes, in which islet capillary structure changes, and for cell-based treatments for type 1 diabetes.

Inna Y. Gong, Matthew C. Cheung, Stephanie Read, Yingbo Na, Iliana C. Lega, Lorraine L. Lipscombe 

While diabetes has been implicated as a risk factor for cancer, much of the data to date have focused on solid malignancies, while less conclusive data exist for diabetes and haematological malignancies. In this issue, Gong et al (https://doi.org/10.1007/s00125-020-05338-7) used Canadian population-based data to evaluate the incidence and prognosis of haematological malignancies among individuals with diabetes. They showed that diabetes is associated with a higher likelihood of developing a haematological malignancy. The authors also demonstrated that individuals with diabetes and haematological malignancy have higher all-cause mortality and cancer-specific mortality than those without diabetes. Importantly, these associations were seen even beyond 1 year after a diabetes diagnosis, which argues against a detection bias due to enhanced health contact. These findings suggest that diabetes adversely affects risk and prognosis of haematological malignancy , and that diabetes prevention strategies may not only reduce diabetes burden but may also potentially improve the risk of haematological malignancy.

Rongrong Yang, Hui Xu, Nancy L. Pedersen, Xuerui Li, Jing Yu, Cuiping Bao, Xiuying Qi, Weili Xu

To date, epidemiological studies have shown that type 2 diabetes increases the risk of cardiovascular disease, which includes coronary heart disease and stroke. However, it is still unclear whether type 2 diabetes is specifically associated with the risk of heart disease and its subtypes, and whether a healthy lifestyle could reduce the risk of heart disease related to type 2 diabetes. In this issue, Yang, Xu et al (https://doi.org/10.1007/s00125-020-05324-z) report that type 2 diabetes is associated with a more than fourfold increased risk of heart disease, including coronary heart disease, cardiac arrhythmias and heart failure. Genetic and early-life familial environmental background did not account for the association between type 2 diabetes and heart disease. However, findings suggested that adulthood lifestyle factors were important in this association: patients with type 2 diabetes who maintained a healthy lifestyle (consisting of being a non-smoker, no/mild alcohol consumption, regular physical activity and not being overweight) had a significantly lower risk of heart disease than those with an unfavourable lifestyle. The authors concluded that these findings highlight the importance of a healthy lifestyle in the prevention of heart disease among individuals with type 2 diabetes.

Katherine A. Sauder, Natalie D. Ritchie

Strategies promoting the health of women of reproductive age are urgently needed to reduce intergenerational transmission of obesity and diabetes risk. In this issue, Sauder and Ritchie (https://doi.org/10.1007/s00125-020-05341-y) summarise findings and gaps arising from published studies of prenatal and preconception lifestyle interventions. They demonstrate that prenatal interventions have shown some success in limiting gestational weight gain and reducing risk of gestational diabetes but have had little impact on offspring outcomes at birth or beyond. Preconception interventions have been successful in reducing weight and improving glucose metabolism by the end of intervention, but whether effects were sustained to conception or whether the interventions had an impact on offspring outcomes is unclear. The authors conclude that future clinical trials should include interventions with high potential for dissemination, diverse populations, thorough maternal phenotyping from enrolment through to conception and pregnancy, and rigorous assessment of offspring obesity and diabetes risks from birth onwards, including into the third generation. The figure from this review is available as a downloadable slide

Christine P. Limonte, Leila R. Zelnick, John Ruzinski, Andrew N. Hoofnagle, Ravi Thadhani, Michal L. Melamed, I-Min Lee, Julie E. Buring, Howard D. Sesso, JoAnn E. Manson, Ian H. de Boer

Immune system activation contributes to the development of diabetes complications. Vitamin D and n-3 fatty acids have been recognised for their anti-inflammatory effects in laboratory models, with mixed evidence from trials in diabetes populations. In this issue, Limonte et al (https://doi.org/10.1007/s00125-020-05300-7) report results of changes in serum concentrations of inflammatory and cardiovascular biomarkers from the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease (VITAL-DKD), in which 1312 adults with type 2 diabetes were randomised to supplementation with vitamin D₃ (2000 IU/day) and/or n-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid; 1 g/day) or placebo and followed for 5 years. The authors found that supplementation did not lead to a decline in serum levels of IL-6, high-sensitivity C-reactive protein or N-terminal pro-B-type natriuretic peptide. They conclude that this study tilts the balance of available evidence to favour no benefit of these interventions on inflammation and suggests that supplementation is unlikely to have a positive impact on diabetes complications for which inflammation is an underlying cause.

Luiz Sérgio F. Carvalho, Isabela M. Benseñor, Ana C. C. Nogueira, Bruce B. Duncan, Maria I. Schmidt, Michael J. Blaha, Peter P. Toth, Steven R. Jones, Raul D. Santos, Paulo A. Lotufo, Andrei C. Sposito, on behalf of the ELSA-Brasil study

Little is known regarding risk prediction of type 2 diabetes before the detection of glucose abnormalities; however, up to 3% of individuals in the general population who are not in the impaired fasting glucose range develop diabetes each year. In this issue, Carvalho et al (https://doi.org/10.1007/s00125-020-05322-1) hypothesise that, among the pathophysiological processes that play a role in type 2 diabetes, the loading of triacylglycerol-enriched remnant lipoproteins (TRLs) with lipids (resulting in large particles) could be useful for risk prediction. The authors report that, when included in a risk prediction model, TRL particle diameter improved the risk prediction of diabetes after 3.7 years of follow-up as compared with a model that did not include this variable, particularly in individuals with normal HbA_1c levels at baseline. These data support TRL particle size as a risk factor that is changed early in the pathophysiological processes that lead to the development of type 2 diabetes, even before glucose abnormalities are established.

Christopher Rohde, Jakob S. Knudsen, Norbert Schmitz, Søren Dinesen Østergaard, Reimar W. Thomsen

Incident depression in type 2 diabetes is associated with poor self-care and suboptimal treatment adherence. However, it is not known how pre-existing depression treatment relates to quality of care for individuals with newly diagnosed type 2 diabetes. In this issue, Rohde et al (https://doi.org/10.1007/s00125-020-05303-4) report that individuals with newly diagnosed type 2 diabetes who already receive treatment for depression are more likely than others to initiate and be adherent to glucose-lowering and lipid-modifying treatment. Pre-existing depression treatment was also associated with successful attainment of LDL-cholesterol and HbA_1c treatment targets among individuals with type 2 diabetes. The authors suggest that these findings may be driven by the fact that individuals with ongoing depression treatment are already familiar with the healthcare system and drug treatment, and that effective treatment of depression, in itself, may improve diabetes care.

Natalie Nanayakkara, Andrea J. Curtis, Stephane Heritier, Adelle M. Gadowski, Meda E. Pavkov, Timothy Kenealy, David R. Owens, Rebecca L. Thomas, Soon Song, Jencia Wong, Juliana C.-N. Chan, Andrea O.-Y. Luk, Giuseppe Penno, Linong Ji, Viswanathan Mohan, Anandakumar Amutha, Pedro Romero-Aroca, Danijela Gasevic, Dianna J. Magliano, Helena J. Teede, John Chalmers, Sophia Zoungas

Type 2 diabetes is increasingly diagnosed in younger adults; however, the relationship between age at diagnosis and diabetes complications is unclear. In this issue, Nanayakkara et al (https://doi.org/10.1007/s00125-020-05319-w) integrate data from 1.3 million individuals from 30 countries to conduct the first systematic review and meta-analyses exploring associations between age at diabetes diagnosis and subsequent complications. Each 1 year increase in age at diabetes diagnosis was associated with a 4%, 3% and 5% decreased risk of all-cause mortality, macrovascular disease and microvascular disease, respectively, adjusted for current age. The authors propose that, over time, the effects of both ageing and diabetes duration may be compounded, resulting in premature complications and death in people diagnosed with type 2 diabetes at a younger age. Early and sustained interventions to optimise glycaemic control and cardiovascular risk profiles in those with established type 2 diabetes, and measures to delay the onset of type 2 diabetes in high-risk groups are crucial to reduce future diabetes-related morbidity and mortality.