Pathophysiology and Treatment of Prediabetes and Type 2 Diabetes in Youth

Abstract

Youth-onset type 2 diabetes is a heterogeneous disease with increasing prevalence in relation to increased rates of obesity in children. It has genetic, epigenetic, social, and environmental determinants. Youth-onset type 2 diabetes is alarming given a rapidly progressive course compared with the course of adult-onset disease, early-onset vascular complications, and long-term exposure to hyperglycemia and associated complications. It is often preceded by prediabetes, a disease phase where defects in β-cell function relative to insulin sensitivity emerge. Herein, we review the current understanding of the pathophysiology of prediabetes and type 2 diabetes in youth. We describe the mechanisms underlying insulin resistance, the precipitous decline of β-cell function, and the role of other hormonal abnormalities in the pathogenesis of the disease. We discuss the critical importance of social determinants of health in the predisposition and progression of these conditions and present current management strategies and the advances in therapeutic approaches. These must adapt to meet the unique needs of the individual patient and family. Significant knowledge gaps remain that need to be addressed in future research.

Graphical abstract

Figure 1

Pathophysiological characteristics along the spectrum of glucose dysregulation: IFG, characterized by greater impairment in insulin secretion; IGT, characterized by a greater defect in glucose disposal (insulin sensitivity); and IFG/IGT, intermediary phenotype, compared with normal glucose tolerance and the extreme phenotype in type 2 diabetes with severe impairment in β-cell function as reflected by the glucose DI (GDI). A: Insulin-stimulated total, oxidative, and nonoxidative glucose disposal in youth with normal glucose tolerance, IGT, IGT, IFG/IGT, and type 2 diabetes. B: First- and second-phase insulin concentrations during the hyperglycemic clamp in normal glucose tolerance (○), IFG (◊), IGT (□), IFG/IGT (*), and type 2 diabetes (■). C: GDI In youth with normal glucose tolerance, IFG, IGT, IFG/IGT, and type 2 diabetes. P values are for trend (ANOVA P values). In A and C, lowercase letters indicate significant post hoc analysis (Bonferroni correction): P < 0.05 (a, type 2 diabetes vs. normal glucose tolerance; b, type 2 diabetes vs. IFG; c, type 2 diabetes vs. IGT; e, normal glucose tolerance vs. IFG/IGT; f, normal glucose tolerance vs. IGT). Data are means ± SD. FFM, fat-free mass; NGT, normal glucose tolerance; T2DM, type 2 diabetes mellitus; ns, not significant. Adapted from Bacha et al. (21).

Figure 2

Proposed management approach for pediatric type 2 diabetes. Basal insulin dose is titrated based on self-monitoring of blood glucose up to 1.5 units/kg/day. Insulin should be used for symptomatic hyperglycemia. With target HbA_1c <7.0% (53 mmol/mol) or <6.5% (47.5 mmol/mol) if no associated hypoglycemia. DKA, diabetic ketoacidosis; HHNK, hyperglycemic hyperosmolar nonketotic syndrome; IV, intravenous; GLP-1 RA, GLP-1 receptor agonist; SGLT2i, SGLT2 inhibitors.