Etiology of insulin resistance in youth with type 2 diabetes

Abstract

Type 2 diabetes (T2DM), historically an adult disease, is now increasingly prevalent in obese youth. Poor diet and increased sedentary behavior contribute to the increasing rates of obesity in youth, yet not all obese children develop T2DM. In general, T2DM is characterized by both insulin resistance (IR) and pancreatic beta-cell insufficiency. In children, IR is related to elevated body mass index (BMI) and pubertal hormones, along with abnormal fat partitioning, elevated free fatty acids, inflammation, and/or mitochondrial dysfunction. Hyperglycemia and T2DM develop when the pancreas cannot match the increased insulin demands resulting from IR. Unique to youth, IR varies with stage of pubertal development, and some children may have resolution of hyperglycemia post-puberty once the IR of puberty resolves. Further understanding of IR, the progression to T2DM in youth, and later outcomes as adults will help direct future therapies and interventions for youth at risk.

Fig. 1

Patterns of insulin resistance and pancreatic beta-cell function throughout puberty. Proposed patterns of insulin resistance and beta-cell function are shown for different populations of children. ••••• Denotes beta-cell function, and – Insulin resistance in all graphs. a In lean children, there is a modest increase in insulin resistance as they progress through puberty, which is matched by pancreatic insulin secretions. b The same is seen in obese children with NGT, although they are more IR, with matched increases in insulin release. c In obese children who become NGT or IGT, as they progress through puberty, they return to an NGT state, but maybe at risk for redevelopment of IGT/FGT when they face another physiologic stressor. d In obese children who progress to developing diabetes, they develop IGT/FGT first, and then have continued insulin deficiency, and cannot compensate for their degree of IR, even as they progress to adulthood