Insulin resistance in children and adolescents : mechanisms and clinical effects

Background: Insulin resistance is a condition in which insulin does not achieve appropriate response in different target tissues, it is associated with obesity and one of the main culprits in the development of type 2 diabetes. An early sign of disturbed glucose-insulin homeostasis is impaired fasting glucose (IFG) where glucose is elevated in the fasting state. The American Diabetes Association (ADA) and the International Society for Pediatric Diabetes (ISPAD) suggest 5.6 mmol/L as a cut-off level for IFG, the World Health Organization supports 6.1 mmol/L. Impaired glucose tolerance (IGT) is defined as elevated glucose after a 2-hour glucose tolerance test, which also is a sign of disturbed glucose-insulin homeostasis. IFG and/or IGT, collectively prediabetes, is associated with a significantly elevated risk of type 2 diabetes development in adults, but the consequences of the prediabetic condition in children is not as evident. In Sweden the prevalence of type 2 diabetes in youth has been low, in spite of an increasing overweight and obesity, which are major risk factors for type 2 diabetes. However, the exact present prevalence of type 2 diabetes in youth is currently not known. Early-onset of type 2 diabetes is associated with a high morbidity already at young age and seems to be more aggressive compared with early-onset type 1 diabetes.

Aim: The aims of this thesis were to investigate the pathogenesis of prediabetes in obese children, to examine the prevalence of prediabetes and type 2 diabetes among severely obese adolescents and to estimate the occurrence of complications related to early-onset type 2 diabetes compared to type 1 diabetes of same duration.

Method: Study I and II in this thesis contain data from the Swedish Childhood Obesity Register (BORIS), which is a national quality registry for obesity treatment in childhood and adolescence. Fasting glucose and glucose levels after an oral glucose tolerance test (OGTT) was made to define normal glucose tolerance or prediabetic stage. A frequently sampled intravenous glucose tolerance test was used to study acute insulin response (AIR), insulin sensitivity (Si), and disposition index (DI) in children with obesity. Study III contains data from the National Diabetes Register (NDR); both from the pediatric register (SWEDIABKIDS) and the adult register (NDR) regarding adolescents and young adults with type 1 and 2 diabetes. Study I and II are cross-sectional observational studies and Study III is a longitudinal, retrospective cohort study.

Results: Among severely obese children the prevalence of isolated IFGADA was 35.8 %, isolated IGT 6% and a combined IFG and IGT in 14.2 %. Combined IFG/IGT was associated with significantly lower AIR compared with subjects who had normal glucose metabolism (p<0.05) and DI was the major determinant of 2-h OGTT glucose levels (β=−0.49, p=0.0126). Comparing IFGADA and IFGWHO in obese children, only IFGWHO was associated with a lower AIR and DI (p<0.001). In total 1413 adolescents and young adults were diagnosed and registered in NDR with type 2 diabetes between 1994-2014. Early-onset type 2 diabetes had, compared with individuals with type 1 diabetes with equivalent diabetes duration, significantly higher risk of developing microalbuminuria with a hazard ratio (HR) of 3.32 (95% CI 2.86-3.85, P < .001), and also retinopathy with a HR of 1.17 (95% CI 1.06-1.30, P 0.04). These differences occurred despite lower HbA1c levels among individuals with type 2 diabetes in comparison with type 1 diabetes.

Conclusion: The prevalence of prediabetes was very high among adolescents with severe obesity. IFGWHO and a combination of IFGADA and IGT is significantly associated with disturbed glucose metabolism. Although both type 1 and 2 diabetes were associated with complications, the prevalence of complications and comorbidities is significantly higher among those with early-onset type 2 diabetes than among those with type 1 diabetes. Our results confirm the findings of previous studies, that type 2 diabetes is a severe disease when young individuals are affected, and an active treatment with a widened focus on cardiometabolic risk factors is required to reduce the risk.

List of scientific papers

I. High prevalence of prediabetes in a Swedish cohort of severely obese children Ek AE, Rössner SM, Hagman E, Marcus C. Pediatric Diabetes. 2015 Mar; 16:117-128.
https://doi.org/10.1111/pedi.12136

II. Insulin function in obese children within the low and high ranges of impaired fasting glycemia. Hagman E, Ek AE, Marcus C. Pediatric Diabetes. 2019 Mar;20:160-165.
https://doi.org/10.1111/pedi.12804

III. Microalbuminuria and retinopathy in adolescents and young adults with type 1 and 2 diabetes. Ek AE, Samuelsson U, Jansson A, Carlsson C, Elimam A, Marcus C. Pediatric Diabetes. 2020 Nov;21:1310-1321.
https://doi.org/10.1111/pedi.13074