Novel insights into the regulation of insulin secretion by GLP-1, GIP and glucagon

Sammanfattning: There are many contributing factors to the development of type 2 diabetes, however, failure of beta-cells to sufficiently secrete insulin is the key component. The underlying mechanism of beta-cell failure is not fully established. In this thesis, we examined the role of high glucagon levels, i.e. hyperglucagonemia, for the development of beta-cell dysfunction in pre-diabetic mice. We found that induction of 2 week hyperglucagonemia leads to defective insulin secretion. To enhance beta-cell function, there are several therapeutic strategies. One important strategy is based on the gut incretin hormone glucagon-like peptide 1 (GLP-1), which potently stimulates insulin secretion. In the clinic, GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase 4 (DPP-4), the enzyme responsible for degradation of GLP-1, are currently used. A new concept of GLP-1 based therapies is to increase also endogenous GLP-1 secretion. In this thesis, we explored the importance of meal macronutrient composition for GLP-1 and insulin responses in healthy mice. We found that intake of mixed macronutrients compared to isocaloric glucose leads to a synergistic increase in GLP-1 and insulin levels. We also explored the effects of a novel GPR119 receptor agonist on GLP-1 and insulin levels after meal intake in healthy and glucose intolerant mice. GPR119 activation markedly increased GLP-1 and insulin responses to meal intake, however, only in glucose intolerant mice. Furthermore, we examined the mechanisms behind the effects of DPP-4 inhibition and found that vagal nerve signaling is important for the insulinotropic effects of DPP-4 inhibition. To conclude, the work in this thesis shed new light on possible ways to increase GLP-1 and insulin secretion, on the mechanism behind the effects of DPP-inhibition and on glucagon as a possible factor that may contribute to beta-cell failure.