Mechanisms underlying lipotoxicity and glucotoxicity in pancreatic islets

University dissertation from Dep.Clinical Sciences Malmö, Div. of Endocrine Pharmacology, Lund University Diabetes Center, CRC 91-11,UMAS, SE-20502 Malmö

Abstract: Although it has been known for many years that long-term exposure of pancreatic islets to a high level of free fatty acids (FFA) or glucose negatively modulates islet hormone release, the identities of signals mediating these effects are not yet fully clarified. The overall objective of this study was to investigate signal transduction pathways involved in FFA- and glucose-exerted effects on beta-cell function during both short-term as well as long-term exposure. The data presented here confirmed that the G-protein coupled receptor 40 (GPR40) is a functional FFA receptor expressed in pancreatic islets. We now show that both the acute stimulatory action of palmitate on IP3-generation, increased Ca2+i and insulin release as well as the long-term effects of palmitate on the activation of MAPKs (SAPK/JNK and p38), iNOS expression and caspase-3 activity is mediated via activation of GPR40. A modulated expression of GPR40 in the islets i.e. overexpression (fa/fa rats) was accompanied by an exaggerated secretion of insulin, glucagon and marked suppression of somatostatin release in response to palmitate. In contrast, a low expression pattern of islet GPR40 (GK rats) was associated with a negligible hormone response to palmitate. The islet expression of iNOS seems to be, at least in part, a common signalling pathway in both lipotoxicity and glucotoxicity. Rosiglitazone (ROZ) effectively counteracted the deleterious effects of palmitate but not that of high glucose on the islet function. Glucose-induced expression of iNOS with subsequent β-cell dysfunction was markedly counteracted by the imidazoline derivative RX871024. We conclude that, in addition to mediating acute stimulatory effects of FFA on insulin release, GPR40 is also an important mediator of dysfunctional effects of FFA overtime. The adverse effects of FFA and high glucose on the islet function involve different or at least partially different signal systems and the FFA signalling is counteracted by ROZ at GPR40, suggesting the thiazolidinediones are protective against beta-cell lipotoxicity.

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