Yael Riahi, Aviram Kogot‑Levin, Liat Kadosh, Bella Agranovich, Assaf Malka, Michael Assa, Ron Piran, Dana Avrahami, Benjamin Glaser, Eyal Gottlieb, Fields Jackson III, Erol Cerasi, Ernesto Bernal‑Mizrachi, Aharon Helman, Gil Leibowitz

Diabetes is characterised by hyperglucagonemia as well as insulin deficiency, making it a dual hormone disease; however, the mechanisms involved in alpha cell dysfunction are unclear. In this issue, Riahi et al (https://doi.org/10.1007/s00125-023-05967-8) highlight the nutrient sensor mammalian target of rapamycin complex 1 (mTORC1) as a key player in diabetes-related hyperglucagonemia. They show that mTORC1 activity was increased in alpha cells from type 1 and type 2 diabetes models, and its inhibition by inducible Rptor knockout in alpha cells from a type 1 diabetes model dampened glucagon secretion and ameliorated diabetes. Metabolomics, metabolic flux and gene expression studies revealed that alpha cell exposure to hyperglycaemia enhanced glucose-derived amino acid synthesis and transport, culminating in increased glutamate, branched-chain amino acid and methionine cycle activity, all contributing to stimulation of mTORC1 activation. The authors highlight that prolonged high glucose exposure therefore alters amino acid metabolism, which may drive persistent mTORC1 activation and subsequent excessive glucagon secretion. They conclude that early normalisation of blood glucose levels is crucial to prevent alpha cell dysfunction in diabetes and suggest targeting nutrient(s) metabolism and mTORC1 signalling in alpha cells as an appealing avenue for diabetes treatment.

Yukari Kobayashi, Jin Long, Shozen Dan, Neil M. Johannsen, Ruth Talamoa, Sonia Raghuram, Sukyung Chung, Kyla Kent, Marina Basina, Cynthia Lamendola, Francois Haddad, Mary B. Leonard, Timothy S. Church, Latha Palaniappan

Previous studies in people with overweight/obesity and type 2 diabetes have shown that a combination of aerobic and resistance training is superior to either type of exercise alone for lowering HbA_1c levels. In this issue, Kobayashi et al (https://doi.org/10.1007/s00125-023-05958-9) describe the STRONG-D study, which aimed to determine the impact of different exercise regimens on glycaemic control in people with ‘normal-weight type 2 diabetes’ (BMI <25 kg/m²). The study compared strength training alone, aerobic training alone, and combined strength and aerobic training. In contrast to previous trials in individuals with overweight/obesity, the authors show that strength training alone was more effective at reducing HbA_1c levels than aerobic training alone, with combination training showing intermediate effects. The authors highlight that increased lean mass relative to fat mass, observed only in the strength training group, independently predicted lower HbA_1c levels. The authors emphasise the significance of strength training for managing type 2 diabetes in normal-weight individuals and highlight the importance of considering body composition in exercise recommendations for this population. They conclude that these findings could contribute to personalised care for different diabetes phenotypes.

Matthew Anson, Sizheng S. Zhao, Philip Austin, Gema H. Ibarburu, Rayaz A. Malik, Uazman Alam

The beneficial extra-glycaemic effects of SGLT2i and GLP-1 RA on weight, renal protection and major adverse cardiovascular events are well established and make them attractive therapies in type 2 diabetes compared with other more traditional glucose-lowering agents. People with type 1 diabetes share many of the same cardiovascular risk factors as those with type 2 diabetes. Such novel agents are not approved for type 1 diabetes but are still prescribed off-label, with a paucity of robust data underpinning their safety and efficacy in this cohort. In this issue, Anson et al (https://doi.org/10.1007/s00125-023-05975-8) undertake a retrospective analysis of individuals with type 1 diabetes adjunctively treated with either an SGLT2i or a GLP-1 RA, with outcomes analysed 5 years after initiation of therapy. The authors show that individuals treated with an SGLT2i had a reduced risk of developing heart failure and chronic kidney disease and of being hospitalised for any cause compared with those adjunctively treated with a GLP-1 RA, despite an increased risk of diabetic ketoacidosis. They conclude that the findings suggest a net overall benefit of SGLT2i in type 1 diabetes compared with GLP-1 RA therapy and that dedicated long-term randomised trials are warranted to validate these findings.

In our October 2023 issue, we feature a series of reviews that focus on incretin-based therapies. These drugs were developed following the discovery of a peptide, exendin-4, in the Gila monster’s venom in the 1990s. Being structurally similar to the incretin hormone glucagon-like peptide-1 (GLP-1), exendin-4 was found to mimic the glucose-regulating effects of incretins. The decades following this discovery have seen the generation of several incretin-based therapies and, in this issue of Diabetologia, we are excited to include eight reviews summarising the state-of-the-art knowledge about these agents. Drucker and Holst (https://doi.org/10.1007/s00125-023-05906-7) start by describing the function of GLP-1, namely glucose-dependent potentiation of insulin secretion and glucoregulatory actions, appetite reduction and cardioprotection. Nauck and Müller (https://doi.org/10.1007/s00125-023-05956-x) go on to discuss another incretin hormone: glucose-dependent insulinotropic polypeptide (GIP). GIP was not initially considered an obvious drug candidate; however, a novel drug, tirzepatide, has demonstrated that dual agonism of GLP-1 and GIP receptors produces more substantial reductions in HbA_1c and body weight than selective GLP-1 receptor agonists (GLP-1RAs). Tirzepatide is but one example of a novel incretin-based therapy, with this and other advances in incretin pharmacology and drug development being summarised in the review by Tschöp et al (https://doi.org/10.1007/s00125-023-05929-0). These therapies, old and new, not only have therapeutic potential in type 2 diabetes, but also may be beneficial in other types of diabetes. In their review, Mathieu and Ahmadzai (https://doi.org/10.1007/s00125-023-05980-x) discuss the evidence for the beneficial effects of incretin-based therapies in type 1 diabetes, monogenic forms of diabetes and other conditions leading to hyperglycaemia. In terms of diabetic complications, Solini et al (https://doi.org/10.1007/s00125-023-05973-w) delve into the cardiovascular protection offered by incretin-based therapies, while Goldney et al (https://doi.org/10.1007/s00125-023-05988-3) discuss their effects on microvascular complications. Andreasen et al (https://doi.org/10.1007/s00125-023-05966-9) highlight the use of these drugs in the treatment of other metabolic diseases, specifically obesity and non-alcoholic fatty liver disease (NAFLD). Thus, the potential benefits of incretin-based therapies are clearly extensive. In contrast, however, as discussed by Karagiannis et al (https://doi.org/10.1007/s00125-023-05962-z), their uptake is restricted due to socioeconomic factors, such as affordability, accessibility, health literacy and provider bias. To extend their benefits at a societal level, a concerted effort must be made to address these issues. Looking ahead, the future holds great promise for incretin-based therapies to expand the treatment options available for individuals with metabolic disorders, offering new avenues for effective management and improved quality of life. This review set is accompanied by an editorial by Krook and Mulder (https://doi.org/10.1007/s00125-023-05987-4).

Sandra S. Hammer, Tim F. Dorweiler, Delaney McFarland, Yvonne Adu‑Agyeiwaah, Natalia Mast, Nicole El‑Darzi, Seth D. Fortmann, Sunil Nooti, Devendra K. Agrawal, Irina A. Pikuleva, George S. Abela, Maria B. Grant, Julia V. Busik

With the advancement of spectral-domain optical coherence tomography imaging, hyperreflective crystalline deposits have been identified in retinal pathologies, including diabetic retinopathy. In this issue, Hammer and Dorweiler et al (https://doi.org/10.1007/s00125-023-05949-w) uncover the nature of crystalline deposits in retina from human donors with diabetes as cholesterol crystals. Using cell culture- and animal model-based studies, cholesterol crystals were shown to recapitulate all major pathogenic mechanisms leading to diabetic retinopathy, including inflammation, cell death and breakdown of the blood–retinal barrier. Fibrates, statins and α-cyclodextrin effectively dissolved cholesterol crystals and prevented endothelial pathology. The authors conclude that the formation of cholesterol crystals represents a unifying pathogenic mechanism in the development of diabetic retinopathy and strategies for removal of cholesterol crystals may have therapeutic value in the treatment of diabetic retinopathy.

Rasmus Wibaek, Gregers S. Andersen, Allan Linneberg, Torben Hansen, Niels Grarup, Anne Cathrine B. Thuesen, Rasmus T. Jensen, Jonathan C. K. Wells, Kasper A. Pilgaard, Charlotte Brøns, Dorte Vistisen, Allan A. Vaag

Over the past three decades, longitudinal studies have consistently found lower birthweight to be associated with higher risk of type 2 diabetes, but prospective data on diabetes incidence are lacking. In this issue, Wibaek et al (https://doi.org/10.1007/s00125-023-05937-0) used data on objectively measured birthweight from original midwife records dating back to 1939−1971, and in a large sample of middle-aged to older adults examined the influence of birthweight on age- and sex-specific incidence of type 2 diabetes over two decades, from 1999−2020. The authors show that type 2 diabetes incidence rate increased with age, was higher in male participants, and that the absolute rate of increase was markedly higher in individuals born with lower birthweight compared with higher birthweight in a dose−response manner. Altogether, birthweight, genetic susceptibility of type 2 diabetes and adult adiposity (BMI) were found to be strong and independent risk factors for type 2 diabetes. The authors conclude that, within the era of precision medicine, birthweight holds strong potential to be used as a feasible marker to guide clinical care and treatment in type 2 diabetes.

Daniela Zanetti, Laurel Stell, Stefan Gustafsson, Fahim Abbasi, Philip S. Tsao, Joshua W. Knowles, RISC Investigators, Björn Zethelius, Johan Ärnlöv, Beverley Balkau, Mark Walker, Laura C. Lazzeroni, Lars Lind, John R. Petrie, Themistocles L. Assimes

The euglycaemic−hyperinsulinaemic clamp (EIC) is a reference standard for directly assessing insulin sensitivity but is invasive and time-consuming. In this issue, Zanetti et al (https://doi.org/10.1007/s00125-023-05946-z) assess the incremental value of high-throughput plasma proteomic profiling, using the proximity extension assay, in developing signatures that correlate with the M value derived from the EIC. The authors use two cohorts, the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) and the Uppsala Longitudinal Study of Adult Men (ULSAM), to show that plasma proteomic signatures of up to 67 proteins substantially improve the cross-sectional estimation of the M value over routinely available clinical variables. A smaller subset of proteins afforded much of this improvement, especially when considering predictive models applied across both cohorts. IGF-binding protein 2 was the single most consistently selected protein across all analyses and models. Zanetti and colleagues state that their approach provides opportunities to improve the identification of individuals at risk of adverse health consequences related to insulin resistance.

Valeriya Lyssenko, Allan Vaag

The diabetes epidemic has resulted in an epidemic of diabetes-associated complications. Systemic monitoring  of individuals with diabetes and new insights into biological mechanisms leading to the progression of complications are necessary to halt this escalation. In this issue, Lyssenko and Vaag (https://doi.org/10.1007/s00125-023-05964-x) summarise state-of-the-art discoveries in the genetic predisposition to kidney, eye and nerve damage in individuals with diabetes. They also provide a critical view on the existing gaps in the current clinical definitions of organ damage that might hinder discovery of genomic factors that trigger or cause associated disease. Knowledge about environmental perinatal exposures may shed light on adaptive changes responsible for the intrauterine programming of metabolic mechanisms that may underlie organ vulnerability. Profiling genetic susceptibility to diabetes-associated metabolic risk factors, including high blood glucose levels, impaired insulin secretion and action, obesity, hypertension, reduced liver function and dysregulated immune system, may aid in pathophysiology-based classification of complications and identification of individuals at high risk for these complications for early prevention in individuals with diabetes. The figure from this review is available as a downloadable slide

Amber M. Luckett, Michael N. Weedon, Gareth Hawkes, R. David Leslie, Richard A. Oram, Struan F. A. Grant

Advances in genetic research have greatly expanded our understanding of the genetic contribution to type 1 diabetes, facilitating the development of genetic risk scores (GRSs) for type 1 diabetes risk. In this review, Luckett et al (https://doi.org/10.1007/s00125-023-05955-y) summarise the utility of type 1 diabetes GRSs, specifically for disease classification and prediction. They highlight how progression from simplistic models to models that incorporate HLA interactions have allowed us to capture disease risk and discriminate type 1 diabetes from other forms of diabetes. Alongside other factors, such as family history and autoantibody status, GRSs have been integrated into combined risk scores for type 1 diabetes onset prediction. Within newborn population screening, type 1 diabetes GRSs have the potential to identify infants at risk of future presentation of the disease so that they can receive additional clinical care. The authors conclude that the integration of GRSs into healthcare has huge potential for identifying and informing treatment in individuals with type 1 diabetes. The figures from this review are available as a downloadable slideset

Karis Little, Aditi Singh, Angel Del Marco, María Llorian‑Salvador, Maria Vargas‑Soria, Mireia Turch‑Anguera, Montse Solé, Noëlle Bakker, Sarah Scullion, Joan X. Comella, Ingeborg Klaassen, Rafael Simó, Monica Garcia‑Alloza, Vijay K. Tiwari, Alan W. Stitt, on behalf of the RECOGNISED consortium

People with type-2 diabetes are at higher risk of cognitive decline and dementia; however, the cellular changes that occur in the brain as type 2 diabetes progresses remain poorly understood. In this issue, Little, Singh and Del Marco et al (https://doi.org/10.1007/s00125-023-05935-2) describe using single-cell RNA sequencing to investigate changes to the neurovascular unit (NVU) within the cerebral cortex in a mouse model of type 2 diabetes. The authors identified distinct transcriptional signatures in a number of key neuronal, glial vascular and immune cells, demonstrating that metabolic and inflammatory processes are dysregulated in the cortical glia of diabetic mice. In parallel, they report that neuronal maturation was significantly affected in the type 2 diabetes cortex, with these changes occurring alongside evident cognitive decline and vascular damage. They further demonstrate that post-mortem cortex from individuals with type 2 diabetes showed comparable changes to what was observed in the mouse model. The authors conclude that altered metabolic function, neuroinflammation and changes to neuronal maturation may play an integral role in NVU damage and thus cognitive decline in type 2 diabetes.

Arturo Roca-Rivada, Sandra Marín-Cañas, Maikel L. Colli, Chiara Vinci, Toshiaki Sawatani, Lorella Marselli, Miriam Cnop, Piero Marchetti, Decio L. Eizirik

TNF-α inhibition delays the progression of type 1 diabetes and circulating TNF-α is associated with aggressive forms of the disease. In this issue, Roca-Rivada et al (https://doi.org/10.1007/s00125-023-05908-5) describe the molecular mechanisms triggered by TNF-α that lead to human beta cell dysfunction and death when the type 1 diabetes candidate gene PTPN2 is silenced. Cells silenced for PTPN2 are more susceptible to the deleterious effect of TNF-α and IFN-α, showing increased beta cell apoptosis. The authors demonstrate that beta cell apoptosis is abolished by the parallel blocking of Bcl-2-like protein 2 (BIM) or c-Jun N-terminal kinase (JNK1), indicating an unexpected common pathway between TNF-α and IFN-α. They further identify JNK1 as a substrate for PTPN2 in beta cells. The authors conclude that people with type 1 diabetes carrying risk-associated PTPN2 polymorphisms may benefit from therapies that inhibit TNF-α.

Per-Ola Carlsson, Daniel Espes, Sofia Sisay, Lindsay C. Davies, C. I. Edvard Smith and Mathias G. Svahn

Mesenchymal stromal cells (MSCs) have been shown to modulate the immune system and dampen inflammatory and autoimmune responses in numerous diseases. In this issue, Carlsson et al (https://doi.org/10.1007/s00125-023-05934-3) report their findings from a Phase I/II dose escalation and double-blind placebo-controlled clinical trial investigating the Wharton’s jelly MSC drug product, ProTrans, for the treatment of new-onset type 1 diabetes. In the dose escalation safety study, the authors demonstrate that ProTrans can be safely administered intravenously with no serious adverse events. A fixed dose of 200 million MSCs preserved the production of endogenous insulin and reduced exogenous insulin replacement compared with placebo 1 year after treatment. The authors conclude that a single treatment with ProTrans could potentially delay type 1 diabetes disease progression, thereby reducing the associated complications and improving quality of life.

Nicolai J. Wewer Albrechtsen, Jens J. Holst, Alan D. Cherrington, Brian Finan, Lise Lotte Gluud, Danielle Dean, Jonathan E. Campbell, Stephen R. Bloom, Tricia M.-M. Tan, Filip K. Knop, Timo D. Müller

More than 100 years ago, scientists were on the path to discovering a central novel metabolic regulator, now known as glucagon. Although the role of glucagon in diabetes has been studied intensively, its place in physiology and pathophysiology is still debated. In this issue, Wewer Albrechtsen et al (https://doi.org/10.1007/s00125-023-05947-y) capture the fundamentals of glucagon biology and its role in metabolic diseases. Key questions on how glucagon secretion is controlled, not only by glucose but also by amino acids and lipids, are addressed. In addition, the authors discuss how a new concept, termed ‘glucagon resistance’, may explain the diabetogenic hyperglucagonaemia observed in metabolic diseases. The authors propose that future glucagon research may help to uncover the molecular backbone of inter-organ dysfunction in individuals with diabetes and liver disease. They conclude that, as well as treating hypoglycaemia, glucagon-based therapies may also provide benefits for weight loss and the treatment of fatty liver disease. The figures from this review are available as a downloadable slideset

Caroline B. Terwee, Petra J. M. Elders, Marieke T. Blom, Joline W. Beulens, Olaf Rolandsson, Alize A. Rogge, Matthias Rose, Nicola Harman, Paula R. Williamson, Frans Pouwer, Lidwine B. Mokkink, Femke Rutters

Patient-reported outcomes (PROs) are important for shared decision making and standardisation of outcomes in research. However, in the field of diabetes, the use of PROs and associated patient-reported outcome measures (PROMs) is heterogeneous. A core outcome set for clinical trials and an International Consortium for Health Outcomes Measurement (ICHOM) standard set for clinical practice have been developed, but they, as well as other initiatives, recommend different PROs and PROMs. Standardisation of relevant outcomes and outcome measures is therefore needed. In this issue, Terwee et al (https://doi.org/10.1007/s00125-023-05926-3) provide recommendations on the selection of relevant PROs and PROMs for use in clinical practice and research in people with diabetes. The figure from this review is available as a downloadable slide

Vyron Gorgogietas, Bahareh Rajaei, Chae Heeyoung, Bruno J. Santacreu, Sandra Marín-Cañas, Paraskevi Salpea, Toshiaki Sawatani, Anyishai Musuaya, María N. Arroyo, Cristina Moreno-Castro, Khadija Benabdallah, Celine Demarez, Sanna Toivonen, Cristina Cosentino, Nathalie Pachera, Maria Lytrivi, Ying Cai, Lode Carnel, Cris Brown, Fumihiko Urano, Piero Marchetti, Patrick Gilon, Decio L. Eizirik, Miriam Cnop, Mariana Igoillo-Esteve

Wolfram syndrome is an autosomal recessive disorder caused by mutations in the WFS1 gene. Individuals affected by Wolfram syndrome develop diabetes mellitus, optic nerve atrophy, hearing loss and other neurological problems. There are currently no treatments to prevent or delay the disease. However, glucagon-like peptide 1 receptor (GLP-1R) agonists have been shown to preserve glucose tolerance and reduce neuroinflammation and vision loss in Wfs1-deficient mice and rats. In this issue, Gorgogietas et al (https://doi.org/10.1007/s00125-023-05905-8) report that GLP-1R agonists also improve the function and survival of WFS1-deficient human pancreatic beta cells and neurons. The authors conclude that these data provide a strong preclinical basis to test GLP-1R agonists in individuals with Wolfram syndrome in clinical trials.

Mi Huang, Melina Claussnitzer, Alham Saadat, Daniel E. Coral, Sebastian Kalamajski, Paul W. Franks

Genetic association studies have correlated hundreds of loci with metabolic disorders, but the functional basis of these loci is rarely explored. A well-known common genetic polymorphism in PPARGC1A (rs8192678, C/T, Gly482Ser) has been reproducibly associated with obesity and type 2 diabetes in various ancestries, highlighting the need to examine its allele-specific effects and pinpoint its clinical relevance. In this issue, Mi Huang et al (https://doi.org/10.1007/s00125-023-05915-6) report the use of a state-of-the-art CRISPR/Cas9 technique to generate isogenic adipose cell lines with different rs8192678 genotypes. They show that the rs8192678 T allele causally enhances adipogenic differentiation and mitochondrial function in an allele dosage-dependent manner. They also demonstrate that the T allele is associated with higher levels of the PPARGC1A-encoded peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) protein and of the adipogenesis master regulator peroxisome proliferator-activated receptor γ (PPARγ). These findings provide experimental insights into adipocyte-specific mechanisms underlying epidemiological correlations between rs8192678 and metabolic disorders. The authors conclude that this may prove useful for the development of genotype-based precision medicine for obesity.

Christian Laugesen, Ajenthen G. Ranjan, Signe Schmidt, Kirsten Nørgaard

Consumption of excess carbohydrate to manage hypoglycaemia can lead to rebound hyperglycaemia and promote weight gain. Previous inpatient studies have demonstrated that s.c. low-dose glucagon can be used to effectively treat non-severe hypoglycaemia in people with type 1 diabetes, but studies in outpatient settings are limited. In this issue, Laugesen et al (https://doi.org/10.1007/s00125-023-05909-4) report the findings of a randomised clinical study comparing the efficacy of pen-administered low-dose dasiglucagon with that of usual care for the prevention and treatment of non-severe hypoglycaemia during free-living conditions. The authors show that use of low-dose dasiglucagon was safe, fast and efficacious while significantly reducing the total daily carbohydrate intake and yielding high treatment satisfaction. The authors conclude that their results add to existing evidence suggesting that pen-administered low-dose dasiglucagon has the potential to become a new and non-caloric method of managing non-severe hypoglycaemia for individuals with type 1 diabetes.

Simon Helleputte, Jane E. Yardley, Sam N. Scott, Jan Stautemas, Laura Jansseune, Joke Marlier, Tine De Backer, Bruno Lapauw, Patrick Calders

In people with type 1 diabetes, blood glucose management around exercise can be very challenging, especially if exercise is performed shortly (within 2 h) after a meal (i.e. in the early postprandial period) when circulating insulin levels are high. In this issue, Helleputte, Yardley et al (https://doi.org/10.1007/s00125-023-05910-x) summarise the available data on the glycaemic effects of postprandial exercise in people with type 1 diabetes. They state that an enhanced understanding of the effects of postprandial exercise on blood glucose can help to improve blood glucose management around physical activity in this population. The studies included in this review show that prandial status is an important determinant of the blood glucose response to exercise in type 1 diabetes, as several modalities of postprandial exercise (walking and continuous and interval exercise) resulted in a decline in blood glucose concentration. The authors suggest that mealtime insulin reductions are needed to provide safe glycaemic profiles during exercise and, thereby, avoid exercise-induced hypoglycaemia. However, they highlight that issues remain concerning hyperglycaemia around exercise and late-onset post-exercise hypoglycaemia. The authors conclude that more research is needed into strategies to improve blood glucose management around postprandial exercise in people with type 1 diabetes. The figure from this review is available as a downloadable slide

Anette-Gabriele Ziegler

The first years of life are characterised by an enormous number of new exposures that challenge and shape our immune system and metabolism. It is during this period that genetically susceptible children have the highest risk of developing autoimmunity against beta cells. In this issue, Anette-Gabriele Ziegler (https://doi.org/10.1007/s00125-023-05927-2) reviews the interplay between the environment, immunity and metabolism in an attempt to explain why this fertile period for the development of islet autoimmunity in early childhood is critical for the development of type 1 diabetes. The figures from this review are available as a downloadable slideset

Paola S. Apaolaza, Diana Balcacean, Jose Zapardiel-Gonzalo, Teresa Rodriguez-Calvo

Immune infiltration in the islets of Langerhans is a hallmark of type 1 diabetes. However, there is a lack of understanding of infiltration dynamics in terms of magnitude (i.e. how many immune cells are present) and extent (i.e. in how many islets). In this issue, Apaolaza et al (https://doi.org/10.1007/s00125-023-05888-6) characterise T cell infiltration by investigating islets with moderate and high levels of infiltration in the human pancreas. The authors show that about a third of islets have moderate infiltration in double autoantibody-positive and type 1 diabetic donors, while islets with high infiltration are less abundant. Likewise, these donors have high islet and exocrine T cell density, suggesting that, as disease progresses, T cell infiltration extends throughout the pancreas, reaching both the islets and exocrine compartment. The authors conclude by presenting new analytical tools with the aim of modelling how T cells infiltrate the pancreas, and estimating pancreatic infiltration in living individuals.

Juliette A. de Klerk, Joline W. J. Beulens, Hailiang Mei, Roel Bijkerk, Anton Jan van Zonneveld, Robert W. Koivula, Petra J. M. Elders, Leen M. ’t Hart, Roderick C. Slieker

Individuals with diabetes are a heterogenous group and therefore further stratification is key. It has previously been shown that individuals with type 2 diabetes can be organised into five clusters based on five clinical variables: age, HbA_1c, BMI, C-peptide level and HDL-cholesterol level. While clusters differ in terms of clinical outcomes, the differences at the molecular level are largely unclear. In this issue, de Klerk et al (https://doi.org/10.1007/s00125-023-05886-8) compare whole blood gene expression profiles between the different clusters of people with diabetes. The authors show that relatively young people with a high BMI have an altered blood transcriptome profile compared with the other clusters. Using Mendelian randomisation, they demonstrate that the differentially expressed mRNAs may have a causal effect on multiple traits, including anthropometric characteristics and lipid metabolism. The authors conclude that the clusters may help to further stratify people with diabetes, highlighting the different underlying pathophysiologies and providing a more holistic view of type 2 diabetes.

Jacqueline M. Ratter-Rieck, Michael Roden, Christian Herder

Climate change and associated environmental risk factors, such as extreme weather events, air pollution and altered host–pathogen interactions, are a threat to human health. In this issue, Ratter-Rieck et al (https://doi.org/10.1007/s00125-023-05901-y) summarise recent evidence on how climate change may affect people with diabetes. The authors discuss how impaired responses to heat stress, diabetes-associated comorbidities and specific clinical characteristics make people with diabetes particularly vulnerable to climate-change-associated health risks, leading to increased risks of morbidity and mortality, for instance during heatwaves or after extreme weather events. They highlight that studies identifying additional predisposing factors and high-risk groups will support the development of targeted interventions. The authors conclude that implementation of climate change adaptation and mitigation strategies at governmental, clinical and individual levels will help to limit the detrimental health effects of climate change on people with diabetes. The figures from this review are available as a downloadable slideset

Alexandra Kautzky-Willer, Michael Leutner, Jürgen Harreiter

Our understanding of the sex and gender differences in type 2 diabetes has increased over the past decade. In this issue, Kautzky-Willer et al (https://doi.org/10.1007/s00125-023-05891-x) summarise recent advances in our knowledge of sex-specific clinical features of type 2 diabetes, and the differences between women and men in risk, diagnosis, management and outcomes of type 2 diabetes. The authors discuss how, overall, men have a slightly higher prevalence of type 2 diabetes diagnosis at a younger age while being less obese. Psychosocial stress is a more prominent diabetes risk factor for women than men, and women have a greater cardiometabolic risk factor burden than men at the time of diagnosis. Pregnancy complications, especially gestational diabetes, and early menopause increase the risk of type 2 diabetes in women, while low testosterone levels are associated with a higher risk in men. The authors conclude that more aggressive risk management needs to be implemented for both men and women who are at increased risk of type 2 diabetes, as well as for those with established diabetes. The figures from this review are available as a downloadable slideset

The Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD)

Diabetes management relies on effective evidence-based guidance to inform individuals and support them to improve their health. In this issue, the Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD) (https://doi.org/10.1007/s00125-023-05894-8) provides an update to its 2004 recommendations on the dietary management of diabetes. These guidelines are primarily for health professionals and consider nutrients, foods, food groups, patterns and some of the broader lifestyle aspects of what we eat. The guidelines draw on a substantial body of published work, much of which was conducted to inform this update, and include recommendations on prevention, management and remission. The guidelines provide effective evidence-based advice to inform the conversation between health professionals and their patients, and empower individuals to manage their health.

Shao-Wen Weng, Jian-Ching Wu, Feng-Chih Shen, Yen-Hsiang Chang, Yu-Jih Su, Wei-Shiung Lian, Ming-Hong Tai, Chia-Hao Su, Jiin-Haur Chuang, Tsu-Kung Lin, Chia-Wei Liou, Tian-Huei Chu, Ying-Hsien Kao, Feng-Sheng Wang, Pei-Wen Wang

Heat shock protein 60 (HSP60) is a mitochondrial chaperonin that plays an important role in escorting unfolded proteins. Mice deficient in HSP60 develop mitochondrial dysfunction and insulin resistance; however, the biological role of this chaperonin in nutrient metabolism and the development of non-alcoholic fatty liver disease (NAFLD) remains unclear. In this issue, Wang et al (https://doi.org/10.1007/s00125-023-05869-9) report that HSP60 deficiency was correlated with severe steatosis in human NAFLD biopsies. In contrast, transgenic mice overexpressing Hsp60 (Hsp60-Tg) developed less body fat, showed amelioration of dyslipidaemia, hepatic steatosis and M1/M2 macrophage dysregulation and exhibited lower levels of insulin resistance than wild-type mice when fed a high-fat diet. The respiratory quotient profile indicated that fat in Hsp60-Tg mice may be metabolised to meet energy demands. The authors demonstrate that, mechanistically, HSP60 promoted fatty acid oxidation by preserving sirtuin 3 (SIRT3)/AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor α (PPARα) signalling. The authors conclude that gain of mitochondrial HSP60 function may be a promising avenue for the development of therapeutic interventions for NAFLD and type 2 diabetes.

René van Tienhoven, Maria J. L. Kracht, Arno R. van der Slik, Sofia Thomaidou, Anouk H. G. Wolters, Ben N. G. Giepmans, Juan Pablo Romero Riojas, Michael S. Nelson, Françoise Carlotti, Eelco J. P. de Koning, Rob C. Hoeben, Arnaud Zaldumbide, Bart O. Roep

In type 1 diabetes, insulin-producing beta cells in the pancreatic islets of Langerhans contribute to their own demise in various ways. Under stress, beta cells can generate so-called neoantigens that result from misreads from insulin mRNA (e.g. insulin defective ribosomal product [INS-DRiP]) and which strongly provoke the immune system. In this issue, van Tienhoven et al (https://doi.org/10.1007/s00125-023-05882-y) report on the surprising finding that an antibody generated against these new beta cell stress proteins selectively stains delta cells. The authors show that the target of this antibody is another insulin gene product, resulting from alternative splicing of insulin mRNA (referred to as INS-splice), that partly overlaps with INS-DRiP. Islet delta cells express this insulin gene product, INS-splice, which contains important targets of diabetes-causing T cells. The authors highlight that this finding may point to some delta cells being potential targets of autoimmunity. The authors conclude that insulin splicing may also play a role in islet development and senescence.

Søren Gullaksen, Liv Vernstrøm, Steffen S. Sørensen, Steffen Ringgaard, Christoffer Laustsen, Kristian L. Funck, Per L. Poulsen, Esben Laugesen

Diabetes mellitus is the leading cause of chronic kidney disease. Kidney hypoxia has been suggested as a unifying pathophysiological pathway in the development of chronic kidney disease in diabetes. Renoprotective effects have been documented for the sodium−glucose cotransporter 2 inhibitor empagliflozin whereas positive effects for the glucagon-like peptide-1 receptor agonist semaglutide await confirmation in dedicated kidney outcome trials. The underlying mechanisms of action of the two drugs are unclear, but it has been suggested that they may improve kidney oxygenation. In this issue, Gullaksen et al (https://doi.org/10.1007/s00125-023-05876-w) report that treatment with empagliflozin for 32 weeks, in contrast to previous assumptions, decreases kidney medullary oxygenation in people with type 2 diabetes. Semaglutide did not affect kidney medullary oxygenation nor was there any additional effect on oxygenation with combination therapy. The authors suggest that empagliflozin-induced medullary hypoxia may stimulate erythropoietin production, leading to kidney protection. They conclude that these findings improve our understanding of the differential kidney protective effects of empagliflozin and semaglutide.

Shuai Yuan, Jordi Merino, Susanna C. Larsson

Exploration of causal factors underlying diabetes is of great importance not only for the development of more effective prevention strategies but also to provide insight into the molecular processes underlying disease risk. Mendelian randomisation is an epidemiological method that can strengthen causal inference based on the use of genetic variation. In this issue, Yuan et al (https://doi.org/10.1007/s00125-023-05879-7) summarise the evidence on potential causal risk factors for diabetes by integrating published Mendelian randomisation studies on type 1 and 2 diabetes, and reflect on future perspectives of Mendelian randomisation studies on diabetes. The authors highlight that, despite the influence of genetics on type 1 diabetes, few Mendelian randomisation studies have been conducted to identify causal exposures or molecular processes leading to increased disease risk. For type 2 diabetes, Mendelian randomisation analyses support causal associations of somatic, mental and lifestyle factors with development of the disease. The authors discuss how studies on circulating protein biomarkers, metabolites and gut microbiota provide valuable data to better understand disease pathophysiology and explore potential therapeutic targets. They conclude that more Mendelian randomisation studies in multi-ancestry cohorts are needed to examine the role of different types of physical activity, dietary components, metabolites, protein biomarkers and gut microbiome in diabetes development The figure from this review is available as a downloadable slide.

Nita G. Forouhi

Diet and nutrition are critical for the prevention and mitigation of type 2 diabetes. However, the research evidence and its implementation have been challenging, partly because of the plethora of information and apparently conflicting dietary strategies. In this issue, Nita Forouhi (https://doi.org/10.1007/s00125-023-05873-z) reviews the evidence on the role of dietary components in the prevention and management of type 2 diabetes and obesity. The review cuts through the complexity of, and challenges of measuring, diet and investigates the impact of diet using robust study designs. The author concludes that it is unhelpful to play off one nutrient against another, such as favouring a low-fat or a low-carbohydrate diet. Instead, the review suggests the importance of nutrient type or quality, nutrient food sources in food-based guidelines and the relevance of overall dietary patterns, as well as taking into account dietary adherence and longer term effects. Important areas of consensus on effective dietary strategies are highlighted and future directions are considered. The figure from this review is available as a downloadable slide.

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