Low birthweight is independently linked to increased risk of type 2 diabetes, and a particular presentation including lower age at diagnosis

Lower birthweight, genetic susceptibility of type 2 diabetes, and adult adiposity are independent and strong risk factors of type 2 diabetes
Among newly diagnosed patients with type 2 diabetes, lower birthweight is associated with younger age, lower prevalence of obesity, and fewer individuals with a family history of type 2 diabetes
Lower birthweight among newly diagnosed patients with type 2 diabetes is also linked to increased use of diabetes drugs, as well as a larger burden of comorbidity including high blood pressure

Embargo 2301H UK time Monday 12 June

Two studies published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) show that lower birthweight is an independent risk factor for type 2 diabetes (T2D), and is linked to a distinct presentation of T2D at the time of diagnosis – including younger age, a lower prevalence of overweight/obesity, and fewer people in the family with T2D.

T2D patients with lower birthweight also show higher use of diabetes drugs than those with normal birthweight, and a larger number of comorbidities including high blood pressure, at the time of diagnosis.

The first study is by Dr Rasmus Wibaek, Steno Diabetes Center Copenhagen, Herlev, Denmark, and Dr Allan Vaag, Steno Diabetes Center Copenhagen, and also Lund University, Malmö, Sweden, and colleagues.

This study included adults aged 30–60 years enrolled in the Danish Inter99 cohort in 1999–2001 (baseline examination), with information on birthweight from original birth records from 1939–1971 and without diabetes at baseline. Birth records were linked with individual-level data on age at diabetes diagnosis. Incidence rates of T2D by age, sex and birthweight were estimated using statistical modelling, adjusting for prematurity status at birth, birth order (position in the birth order among any sibilings), genetic risk scores for birthweight and type 2 diabetes, maternal and paternal diabetes history, socioeconomic status and adult body mass index (BMI).

The authors found that, among 4590 participants, there were 492 incident T2D cases during an average follow-up of 19 years. T2D incidence rate increased with age, was higher in male participants, and decreased linearly with increasing birthweight, with each extra kg of birthweight linked to a 40% reduced risk of T2D, which continued into the highest birthweights. Notably, the absolute rate of increase in T2D incidence across age was markedly steeper in persons born with lower birth weights compared with higher birth weights.

The findings suggest that the effect of birth weight on type 2 diabetes risk is distinct and independent of genetic susceptibility to T2D and adult adiposity, and that low birth weight as a proxy of an adverse fetal environment is of similar aetiological importance to that of genotype.

The second study, also by Dr Vaag and first author Dr Aleksander L. Hansen of the Steno Diabetes Center Copenhagen, and colleagues, analysed midwife records for 6866 individuals with T2D in the Danish Centre for Strategic Research in type 2 diabetes cohort.

They assessed age at diagnosis, anthropomorphic measures (body dimensions), comorbidities, medications, metabolic variables, and family history of T2D in individuals with the lowest 25% of birthweight (<3000 g) and highest 25% of birthweight (>3700 g), compared with a birthweight of 3000–3700 g as reference (the middle 50% of birthweights 25%-75%), using statistical modelling. Continuous relationships across the entire birthweight spectrum were also assessed. Weighted polygenic scores (PS) for type 2 diabetes and birthweight were calculated to assess the impact of genetic predispositions.

Each 1 kg decrease in birthweight was associated with a 3.3 year younger age of diabetes onset, 1.5 kg/m² lower BMI and 3.9 cm smaller waist circumference. Compared with the reference birthweight, a birthweight of <3000 g was associated with more overall comorbidity, with a 36% higher chance of having 3 or more comorbidities and a 26% higher chance of having a systolic blood pressure above 155 mm Hg (severe hypertension).

Compared with birthweight 3000–3700 g (the average birthweight in Denmark being around 3.4kg), birthweight <3000 g was associated with younger age at type 2 diabetes diagnosis. The authors found those with low birthweight had a 28% increased risk of being diagnosed with T2D aged under 45 years (more likely to be diagnosed younger), and a 30% lower risk of being diagnosed aged over 75 years (less likely to be diagnosed older).

Birthweight under 3kg was associated with reporting fewer individuals with a family history of type 2 diabetes, with a slight (7%) increased chance of reporting no type 2 diabetes-affected relatives, but a 33% reduced risk of reporting three or more relatives with type 2 diabetes. Similarly, birthweight under 3kg was associated with a lower BMI, with a 12% increased chance of being in the normal weigh category (BMI <25 kg/m²), decreasing to a 43% reduced risk of having severe obesity (BMI above 40). The associations between birthweight and adult BMI, were completely linear across the entire birthweight spectrum.

Other factors linked to a lower birthweight were a lower prevalence of diabetes-associated neurological disease and a 33% increased risk of using of three or more glucose-lowering drugs.

Clinically defined low birthweight (below 2.5kg) yielded stronger associations, and a higher birthweight was associated with characteristics mirroring lower birthweight in opposite directions. This in full agreement with the observed linear associations between birthweights and most relevant clinical outcomes.

The authors say: “Taken together, the two studies collectively provide strong support for the following conclusions: an adverse fetal environment reflected by low birthweight is a strong and non-genetic risk factor not only of developing type 2 diabetes per se, but in addition for the development of a relatively more severe subtype of type 2 diabetes – with earlier disease onset, more complications, and co-morbidities, as well as with an increased need for clinical care and medical treatments.

“The impact of low birthweight appears independent to that of genetics and obesity, which is why people with low birthweight are at a relatively increased risk for type 2 diabetes for any given increase in BMI. This, in turn, explains the finding of a lower BMI in low birthweight subjects at the time of type 2 diabetes onset. Low birthweight should therefore be considered as a criteria for screening for type 2 diabetes with same importance as that of a positive family history of diabetes. Notably, as the study by Wibaek et al. indicates, neither people with a lower birth weight, nor those with a high genetic risk of type 2 diabetes are actually at a particularly very high absolute risk of developing type 2 diabetes if they are able to keep a normal BMI throughout their lives. Finally, within the era of precision medicine, low birthweight holds the potential to be used as a marker to guide clinical care and treatment in type 2 diabetes.”

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