Piipari, K.; (2011) Metabolic signalling in pancreatic beta cells. Doctoral thesis , UCL (University College London).

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Abstract

The main function of pancreatic beta cells is to maintain correct glucose homeostasis within the body by secretion of insulin in response to increased blood glucose concentration. Beta cell dysfunction contributes to the pathogenesis of diabetes. Using transgenic mouse models, the work described in this thesis has investigated the role of AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K) in beta cell function and their role in the regulation of glucose-stimulated insulin secretion (GSIS). AMPK is activated by low cellular energy levels. Once activated it acts as a cellular fuel gauge to restore energy levels back to normal. An anti-diabetic drug metformin is thought to achieve its blood glucose lowering effect by activation of AMPK in liver and skeletal muscle. However, the role of AMPK in pancreatic beta cells has remained uncertain and controversial. This thesis shows that transgenic mice, which lack functional AMPK in beta cells are glucose intolerant caused by impaired GSIS. Investigation of islet function in vitro revealed that lack of AMPK in beta cells alters glucose sensing and insulin secretory behaviour, which is associated with down-regulation of mitochondrial uncoupling protein 2. PI3K functions as a lipid kinase downstream of receptor tyrosine kinases such as insulin receptor. Previous studies have shown that it has an important role in the regulation of energy metabolism, but no studies to date have investigated the specific role of PI3K in beta cells using mouse knockout models. The study in this thesis demonstrates that transgenic mice that lack functional PI3K catalytic subunits p110α and p110β in beta cells develop marked glucose intolerance and impaired GSIS. Together these two studies demonstrate that AMPK and PI3K signalling in beta cells is essential for the regulation of whole-body glucose homeostasis and insulin secretion.

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