METABOLIC AND HORMONAL FACTORS CONTRIBUTING TO THE DEVELOPMENT OF TYPE 2 DIABETES IN YOUNG ADULTS

Abstract

The recent rapid increase in the incidence of type 2 diabetes (T2D) in the young individuals and the youth is a burning health issue of the population and the onset of T2D in the youth is more virulent than the onset of T2D in adults where the complication starts at a younger age and the dysfunction of beta-cells progresses. The pathophysiological processes leading to such a quick process of development are not well known. This prospective mixed-method study was used to thoroughly describe the metabolic, hormonal and genetic predictors of youth-onset T2D and to establish the independent predictors of swift beta-cell loss in high-risk (low, moderate and high) and in normal T2D adolescents. Serial metabolic phenotyping using oral glucose tolerance test, genetic phenotyping using beta-cell specific single nucleotide polymorphism and lipotoxicity and inflammation. The overall conclusion was the decrease in the rate of Disposition Index (DI) which has been approximated with the assistance of mixed-effects linear regression and Cox proportional hazards models. High-risk youth exhibited a significantly lower baseline DI (4.31 ± 1.06) compared to controls (11.90 ± 2.14, p < 0.001), with an annual DI decline of 1.57 ± 0.33 units/year, accelerating to 2.41 ± 0.45 units/year post-diagnosis—a rate 3.5-fold faster than adult-onset T2D (p < 0.001). The parameters of metabolism were greatly influenced by the pubertal stage as well as Tanner IV DI. The GH/IGF-1 proportion carried out a strong negative association with DI (r = -0.62, p < 0.001) and turned out to be an independent predictor of speedy beta-cell deterioration (HR: 1.32, 95% CI: 1.15-1.51). Children with diabetes were also more susceptible to having high total genetic risk score of beta-cell dysfunction ( z-score: 1.52 -0.35 vs. -0.31 - 0.21 in controls, p < 0.001) and lipotoxicity and inflammatory substances. They were all found to have developed a non-alcoholic fatty liver disease one in every five years and 26% of them developed micro albuminuria. Multivariate analysis. Poor baseline DI, high GH/IGF-1 ratio, high glucagon and high genetic risk score were found to be the independent predictors of fast beta-cell loss. T2D youth-onset disease is a severe disease with a complex dynamics of excessive insulin resistance, peaks of pubertal hormones, genetic predisposition and metabolic stress causing the beta-cell mass loss to be accelerated by 3.5 times of that with adult-onset disease. The results suggest the level of urgency of developmentally-specific, early interventions that would help to insulin sensitize and keep the beta-cell at the pre-diabetic stage.