THE ROLE OF PHOSPHODIESTERASE 3B IN CAMP-MEDIATED REGULATION OF INSULIN SECRETION

Abstract: Type 2 diabetes mellitus (T2DM) is characterized by various combinations of ?-cell failure and insulin resistance leading to hyperglycemia and glucose intolerance. In order to maintain glucose tolerance in the insulin resistance state, increased insulin secretion is a requirement and it is because of inadequate islet adaptation that glucose intolerance develops in T2DM. The pathophysiology of T2DM is not fully understood and more knowledge is needed concerning both insulin action and ?-cell physiology and adaptation. The general aim of this thesis was to investigate the role of ?-cell cAMP-degrading phosphodiesterase 3B (PDE3B) in the regulation of insulin secretion and whole body energy homeostasis. The specific aims were (i) to study the physiological importance of well-regulated ?-cell-cAMP levels for insulin release and whole body energy homeostasis during a long-term metabolic challenge, (ii) to evaluate the role of PDE3B in biphasic insulin secretion and its intracellular localization, and (iii) to investigate the mechanisms for regulation of PDE3B activity in ?-cells. It was previously shown that PDE3B attenuates glucose-stimulated insulin secretion and glucagon-like peptide-1 (GLP-1) potentiated-insulin secretion. It is shown here that accurate regulation of ?-cell cAMP is necessary for adequate islet adaptation to a perturbed metabolic environment and protective for the development of glucose intolerance and insulin resistance. This finding is coupled to the novel discovery that PDE3B, shown to localize to the exocytotic machinery, functions as a specific attenuator of cAMP-mediated potentiation of depolarization-induced insulin secretion. Further, we have begun to elucidate the details concerning the regulation of PDE3B activity in ?-cells. Data are presented suggesting that PDE3B activity in ?-cells is intricately regulated by phosphorylation and dephosphorylation, probably by the action of several differentially regulated kinases and phosphatases. In conclusion, this thesis contributes to the knowledge regarding the importance and function of cAMP-mediated regulation of stimulus-secretion coupling in pancreatic ?-cells and demonstrates that dysfunction of cAMP-PDE3B signalling results in a substantially increased sensitivity to the adverse effects of a high-fat diet.