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Adolescents with overweight or obesity had a higher risk of developing type 1 diabetes (T1D) in young adulthood, authors of a large retrospective cohort study reported.

In an analysis that included more than 1.4 million individuals ages 16-19 followed for a median of 11 years, those classified as having obesity were twice as likely to develop type 1 diabetes as those with optimal weight (HR 2.05, 95% CI 1.58-2.66), said Gilad Twig, MD, PhD, of the Sheba Medical Center in Tel Hashomer, Israel, and colleagues.

Adolescents with overweight had a 54% risk increase (HR 1.54, 95% CI 1.23-1.94) of T1D. Furthermore, individuals with a higher BMI in the normal range (75th to 84th percentiles) also had an elevated risk (HR 1.41, 95% CI 1.11-1.78). For each one-increment increase in BMI standard deviation, T1D risk increased by 25% (HR 1.25, 95% CI 1.17-1.32), the study found.

"Our findings have public health implications," Twig and co-authors wrote in . "The prevalence of adolescent obesity is rising worldwide at an alarming rate, with dire projections for the near future. Currently it is estimated that nearly 60% of U.S. children will develop obesity by their early thirties, mostly by adolescence, with half progressing to severe obesity. With rising levels of obesity, we may expect a continued rise in [T1D]."

In addition, "physicians should be aware that adolescent obesity is related to an increased risk for incident type 1 diabetes as well as type 2 diabetes in young adulthood, and attaining a normal weight among adolescents at high risk for developing [T1D] may be important for prevention," the researchers wrote.

They analyzed data collected on all Israeli adolescents undergoing medical evaluations in preparation for mandatory military service from 1996 to 2016. The majority (58.5%) of the cohort were boys.

The researchers linked these data with information from the Israeli National Diabetes Registry on adult-onset T1D. There were 777 incident cases of T1D recorded during the 15,819,750 person-years of the study, for an incidence of 4.9 cases per 100,000 person-years.

The researchers used Cox proportional models to examine the relationship between BMI and T1D, adjusting for demographic factors including age, sex, socioeconomic status, and education level. Individuals in the 95th percentile or higher for BMI were classified as having obesity, and those in the 85th to 94th percentile were classed as having overweight.

In a subset analysis limited to patients with islet autoantibody data as part of their T1D diagnosis, the association was stronger. In this analysis, individuals with obesity had nearly three times the risk for T1D (HR 2.90, 95% CI 1.80-4.68), the researchers reported.

Growing evidence has linked obesity with various autoimmune conditions, and this may explain the association with T1D, Twig and co-authors noted. Elevated levels of adipokines and cytokines associated with obesity may diminish self-tolerance by promoting proinflammatory processes. Additional factors associated with obesity may contribute to autoimmunity, including vitamin D deficiency, a high-fat diet, and changes in gut microbiota, the team added.

"Given that, in our cohort, there was an association between obesity and [T1D] even when excluding those with pre-existing autoimmune conditions, additional factors may link obesity specifically to [T1D]," the investigators wrote. "In fact, several biological mechanisms have been suggested to explain the association between obesity and [T1D]."

The "accelerator hypothesis" suggests that both type 1 and type 2 diabetes are caused by insulin resistance and genetic variations that affect the rate of beta cell loss and disease phenotype, the researchers explained. According to this hypothesis, the increasing demand for insulin renders the beta cells more antigenic, and thus accelerates their loss through autoimmune injury.

Study limitations, the researchers said, included that the Israeli National Diabetes Registry does not distinguish between type 1 and type 2 diabetes. As a result, individuals in the study were determined to have T1D if they were actively treated with short-acting insulin that was started within 1 year of diabetes onset, and only insulin was prescribed -- i.e., there was no history of oral diabetes drugs. Individuals who were prescribed an oral glucose-lowering medication were classified as having type 2 diabetes.

"Due to occasional off-label prescribing, chiefly of metformin or sodium–glucose co-transporter 2 inhibitors, it is assumed that a small proportion of [T1D] cases may have been missed, especially among obese participants who are more likely to be prescribed such medications. As a result, the association between obesity and [T1D] incidence may be underestimated in our study," the researchers wrote.

Another limitation was the lack of information on certain type 1 diabetes risk factors, including maternal BMI and family history of type 1 diabetes. In addition, BMI was based on a single weight measurement, so the study lacked longitudinal data on the trajectories or possible cumulative effects of BMI over time.

"In conclusion, our study adds to the growing evidence regarding the health hazards associated with adolescent obesity," Twig and co-authors said. "Not only is adolescent obesity correlated with adult onset of type 2 diabetes as previously reported, but also with type 1 diabetes. Further work needs to be done to unravel this association so that we can better address the full spectrum of risks posed by the obesity epidemic or identify common environmental factors affecting both weight and type 1 diabetes."

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