The Role of Phosphodiesterase 3B in the Regulation of Insulin Secretion

Sammanfattning: Pancreatic beta-cell dysfunction and insulin resistance are the two hallmarks of type 2 diabetes. An early sign of beta-cell dysfunction is impaired nutrient-induced insulin release. Several insulin secretagogues act by increasing the formation of intracellular cAMP. Thus, accurate regulation of cAMP is of vital importance for the ability of the beta-cell to respond properly to these stimuli. The level of cAMP is defined by the activities of adenylyl cyclases and cAMP-degrading phosphodiesterases (PDEs). The aim of this thesis was to study the role of PDE3B in the regulation of insulin secretory processes in pancreatic beta-cells and in the regulation of overall energy homeostasis. Results in this thesis demonstrate that mice with a specific increase in beta-cell PDE3B activity (RIP-PDE3B mice) have, in comparison to control mice, a reduced insulin response to glucose as well as to glucose in combination with GLP-1, glucose intolerance and altered islet morphology. Moreover, when metabolically challenged RIP-PDE3B mice develop severe obesity and insulin resistance. The insulin secretory capacity of isolated islets from RIP-PDE3B mice was studied and a specific reduction in the first phase of glucose-stimulated insulin release was identified. An important role of beta-cell PDE3B for exocytosis and release of insulin was further demonstrated by overexpression of PDE3B and by selective inhibition of the enzyme in both insulinoma cell lines and rat pancreatic islets. Of specific interest was the marked decrease of glucose-stimulated cAMP levels and concomitant decrease in insulin release observed in cells overexpressing PDE3B. In summary, this thesis has contributed to an increased understanding for the role of beta-cell PDE3B in the regulation of insulin secretory processes. Results suggest that PDE3B regulates cAMP pools important for exocytosis of insulin-containing granules responsible for the first phase of insulin release. Also, these studies bring forward the role of cAMP in nutrient-induced insulin release. Finally, the work in this thesis demonstrates for the first time a functional role for beta-cell PDE3B in the maintenance of whole body energy homeostasis in mice.