Clinical Context

Clinicians know that there are different forms of adult-onset diabetes, and a previous study by Ahlqvist and colleagues used age at diagnosis, HbA1c, body mass index (BMI), the presence of glutamate decarboxylase antibodies (GADA), and measures of beta-cell function and insulin resistance to characterize different phenotypes of adult-onset diabetes using diabetes registries in Sweden. Their research was published in the May 2018 issue of Lancet Diabetes and Endocrinology.^[1]

A total of 6.4% of cases of adult-onset diabetes were characterized by early-onset disease, relatively low BMI, insulin deficiency, and the presence of GADA, and another 17.5% had a similar phenotype but were GADA-negative. A total of 15.3% of adults had high insulin resistance and high BMI, whereas 21.6% had obesity but only mild insulin resistance. Finally, 39.1% of cases were older at the time of diabetes diagnosis but had only mild metabolic derangements. The cohort with the highest insulin resistance had the highest prevalence of kidney disease, whereas insulin deficiency was more associated with retinopathy.

Similar to adults, there are different phenotypes of diabetes among pediatric patients. However, there is a lack of research into basic differentiating characteristics of these cases, including obesity. The current study addresses this issue.

Study Synopsis and Perspective

Obesity is not a universal phenotype in children with type 2 diabetes, a global systematic review and meta-analysis reported. In fact, the study found, as many as 1 in 4 children with type 2 diabetes do not have obesity and some have normal reference-range body mass measurements. Further studies should consider other mechanisms beyond obesity in the genesis of pediatric diabetes, the authors of the international analysis concluded, writing for JAMA Network Open.^[2]

“We were aware that some children and adolescents with [type 2 diabetes] did not have obesity, but we didn’t know the scale of obesity in [type 2 diabetes] or what variables may impact the occurrence of diabetes in this group,” endocrinologist M. Constantine Samaan, MD, associate professor of pediatrics at McMaster University in Hamilton, Ontario, Canada, said. “So, the analysis did help us understand the body mass distribution of this group in more detail.”

This appears to be the first article to systematically quantify obesity prevalence in this population. “There is not much known about this small but potentially important group of [type 2 diabetes] patients,” Dr Samaan said.

The international investigators included in their meta-analysis 53 articles with 8,942 participants from multiple world regions and races/ethnicities. The overall prevalence of obesity in pediatric patients with type 2 diabetes was 75.27% (95% CI, 70.47%-79.78%). The prevalence of obesity at time of diagnosis in 4,688 participants was 77.24% (95% CI, 70.55%-83.34%). Male participants had higher odds of obesity than females (odds ratio, 2.10; 95% CI, 1.33-3.31), although girls are generally more likely to develop type 2 diabetes. The highest prevalence of obesity occurred in Whites, at 89.86% (95% CI, 71.50%-99.74%), whereas prevalence was lowest in Asian participants, at 64.50% (95% CI, 53.28%-74.99%).

The authors note that childhood obesity affects approximately 340 million children worldwide and is a major driver of pediatric type 2 diabetes, an aggressive disease with a high treatment failure rate. Understanding the contribution of body mass to the evolution of insulin resistance, glucose intolerance, and type 2 diabetes with its attendant comorbidities and complications, such as nonalcoholic fatty liver disease, remains crucial for developing personalized interventions.

Known risk factors for type 2 diabetes include interactions between genetics and the environment, including lifestyle factors such as diet and low physical activity levels, Dr Samaan noted. Certain ethnic groups have higher type 2 diabetes risks, as do babies exposed in the womb to maternal obesity or diabetes, he said. “And there are likely many other factors that contribute to the risk of type 2 diabetes, though these remain to be defined.”

Is “lean” type 2 diabetes in children without obesity likely then to be hereditary, more severe, and harder to control with lifestyle modification? “That’s a great question, but the answer is we don’t know,” Dr Samaan said.

Commenting on the study but not involved in it, Timothy J. Joos, MD, a pediatrician in Seattle, Washington, who is affiliated with the Swedish Medical Center, said that the findings raise the question of how many patients with pediatric type 2 diabetes are being missed because they do not meet current screening criteria. “In nonobese type 2 diabetes pediatric patients, genetics (and by proxy family history) obviously play a heavier role. In my practice, I often get parents asking me to screen their skinny teenager for diabetes because of diabetes in a family member. In the past I would begrudgingly comply with a smirk on my face. Now the smirk will be gone.”

Dr Joos said that it would be interesting to see what percentage of these patients with type 2 diabetes without obesity (body mass index <95th percentile) would still meet the criteria for being overweight (BMI >85th percentile), as this is the primary criterion for screening according to the American Diabetes Association guidelines.

Current guidelines generally look for elevated body mass measures as a main screening indication, Dr Samaan’s group note. But in their view, although factors such as ethnicity and in utero exposure to diabetes are already used in combination with BMI-based measures to justify screening, more sophisticated prediabetes and diabetes prediction models are needed to support a more comprehensive screening approach.

“Because being overweight is the initial criterion, children with multiple other criteria are not being screened,” Dr Joos said. He agreed that more research is needed to sort out the other risk factors for pediatric type 2 diabetes without obesity so that these patients may be detected earlier.

New models may need to incorporate lifestyle factors, hormones, puberty, growth, and sex as well, the authors write. Markers of insulin resistance, insulin production capacity, and other markers are needed to refine the identification of those who should be screened.

Dr Samaan’s group is planning to study the findings in more detail to clarify the effect of body mass on the comorbidities and complications of pediatric type 2 diabetes.

In addition to the study limitation of significant interstudy heterogeneity, the authors acknowledged varying degrees of glycemic control and dyslipidemia among participants.

No specific funding was provided for this review and meta-analysis. The authors and Dr Joos have disclosed no relevant financial relationships.

JAMA Netw Open. 2022;5(12):e2247186.

Clinical Implications

• In a previous study, 6.4% of cases of adult-onset diabetes were characterized by early-onset disease, relatively low BMI, insulin deficiency, and the presence of GADA, and another 17.5% had a similar phenotype but were GADA-negative. A total of 15.3% of adults had high insulin resistance and high BMI, whereas 21.6% had obesity but only mild insulin resistance. Finally, 39.1% of cases were older at the time of diabetes diagnosis but had only mild metabolic derangements.
• The overall prevalence of obesity in cases of pediatric type 2 diabetes was 75.3%. The prevalence of obesity among boys and girls was 78.7% and 59.2%, respectively (P<.001). There was a wide range of HbA1c levels across different studies, but obesity did not correlate with HbA1c. Similarly, obesity did not affect levels of dyslipidemia.
• Implications for the healthcare team: The healthcare team should consider variables other than BMI in assessing the risk for type 2 diabetes among pediatric patients.

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