Factors potentially influencing pathogenetic mechanisms and hyperglycemia in pre-diabetes and type 2 diabetes : clinical studies in humans

Abstract: The pathogenetic mechanisms underlying type 2 diabetes (T2D) and prediabetes involve an interaction between β-cell dysfunction and insulin resistance (IR). The resulting hyperglycemia, as well as other clustered cardiovascular (CV) risk factors in T2D, constitutes a severe hazard for development of complications to the disease. To optimally treat these risk factors, it is vital to antagonize the mechanisms of the metabolic disorder. This thesis presents results from studies aiming to understand the mechanisms and effects of some interesting modes of intervention in subjects with T2D, prediabetes and IR. Study I: The effects of exercise training for twelve weeks, with or without the addition of the α-glucosidase inhibitor acarbose, were examined in 48 subjects with T2D and moderate hyperglycemia. Exercise training augmented insulin sensitivity, and improved body composition and blood pressure, but glycemic control was unchanged. When exercise and acarbose were combined, glycemic control was significantly improved, in addition to similar benefits as with exercise alone. Moreover, the overall CV risk factor profile was probably improved with the combination therapy, suggesting it to be an interesting treatment alternative. Study II: The associations between changes in mRNA expression in skeletal muscle of selected key genes, involved in muscle adaptation to exercise, and individual response to physical training were assessed in 19 individuals from study I. The expression of vascular endothelial growth factor (VEGF) was associated with change in insulin sensitivity and glycemic control. This could constitute a mechanism that contributes to the known variation in the individual adaptation to exercise. Study III: The impact of dual endothelin-1 (ET-1) receptor blockade infusion was investigated in eleven males with IR. The study showed that the dual blockade increased glucose uptake in skeletal muscle, both in the basal and the insulin-stimulated state. The finding supports that endogenous ET-1 is important in regulating muscle glucose uptake in IR. Moreover, in vitro studies in cultured skeletal muscle cells demonstrated that ET-1 inhibits glucose uptake by a receptor dependent mechanism, indicating a direct impact on muscle cells by ET-1. Study IV: Intervention with high-dose vitamin D3 treatment for eight weeks was studied in 43 individuals with prediabetes or drug-naïve T2D, especially with respect to change in β-cell function. No significant effect was seen in first-phase insulin secretion, nor could we detect any effects on second-phase insulin secretion, IR or glycemic control. The study gives no support for treatment with vitamin D in subjects with abnormal glucose homeostasis. In conclusion, combined treatment with exercise and acarbose proved superior to exercise alone. Further, a favorable response to physical training could involve increase in VEGF. In IR, ET-1 seems to be directly involved in muscle glucose uptake. And finally, we found no effect of vitamin D treatment on insulin secretion or IR in prediabetes and mild T2D.