Mechanisms of impaired insulin release in type-2 diabetes : studies in the GK rat model
Sammanfattning: Type-2 diabetes is a complex syndrome with a polygenic and multifactorial aetiology. It is characterised by its relatively late appearance in life and its mild progressive course. Glucose intolerance can generally be ascribed to disturbed pancreatic hormonal secretion and/or insulin resistance in the liver and extrahepatic tissues. The current studies were performed in the lean spontaneously diabetic mildly diabetic GK (Goto-Kakizaki) rat and F1 hybrids of GK and normal Wistar rats. As in type-2 diabetes in man, glucose-induced insulin release is markedly decreased in isolated GK rat islets and perfused pancreas. This defect is present both in the K(ATP)-dependent and -independent pathways. In contrast, an intact or even exaggerated responses to non-metabolised stimulators of insulin release are described. The defective insulin release does not appear to be due to a decrease in ß-cell density, insulin biosynthesis or content in GK rat pancreas. ATP synthesis also appears to be preserved in GK islets. An increased islet glucose utilization and oxidation characterize animals from the Stockholm but not other GK rat colonies. Insulin release in response to [alpha]-KIC was decreased in GK rats. However, studies in hybrid rats revealed an impaired glucose- but preserved [alpha]-KIC insulinotropic responses, indicating that an imortant defect may indeed reside in the glycolytic rather than the mitochondrial pathway. Insulin response is exaggerated in GK rat pancreas and islets due to stimulation of adenylyl cyclase (AC) or phospholipase-C (PLC). The enhanced insulinotropic effects of forskolin in GK islet were traced to be due to enhanced cAMP generation associated with overexpression of AC3 mRNA related to the presence of 2 functional point-mutations in the promoter region of AC3 gene. We have also identified distinct AC8 overexpression in GK but not control ß- and [alpha]-cells. Activation of cholinergic pathway by carbachol also elicited strong insulinotropic effects in the diabetic islets both through the K(ATP)-dependent and independent pathways. The signalling pathways mediating carbachol effects in islets are probably propagated through a pathway involving stimulation of PLC -> DAG -> AA -> 4 cytochrome P450 and are modulated by the prevailing hyperglycaemia. The enhanced signalling demonstrated by AC and PLC stimulation in GK rats open the possibility for developing novel therapeutic agents that can capitalize on these pathways and their enhanced signalling activity.
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