Studies of pancreatic islet microcirculation and insulin secretion in normal and diabetic rats

Abstract: Type 2 diabetes is increasing globally. The disease is characterized not only by hyperglycemia, but also by insulin resistance with attendant dyslipidemia, hypertension and endothelial dysfunction. These aberrations may result in macrovascular disease, and deeply impact the longevity and quality of life in diabetic patients. Gender differences also exist with more pronounced negative effects of diabetes on the lipid profile and blood pressure in women compared with men. To well control all of these risk factors, diabetic patients frequently need to be treated with a lipid lowering statin, and an ACE inhibitor or angiotensin receptor antagonist against hypertension and/or albuminuria. Such drugs reportedly also decrease the risk of incident diabetes in clinical trials, by unknown mechanisms. The aim of the present work was to characterize the effects of vasoactive drugs, free fatty acids and ethanol on islet microcirculation, in vivo insulin secretion and glucose tolerance in normal and diabetic rats of both genders. To this end, a microsphere technique was evaluated and applied for measurements of islet blood flow in rats. Vasoactive drugs that are frequently given to diabetic patients were found to increase islet blood flow (IBF), augment insulin secretion and improve glycemia. This suggests that a local pancreatic RAS plays a substantial role in the regulation of islet microcirculation, thereby impacting insulin secretion and glucose tolerance. Qualitative and quantitative gender-specific differences in responses to such drugs were noted, which may be due to the vasoactive features of sex hormones or other influences conferred by gender. Free fatty acids lowered IBF and may thus worsen hyperglycemia by limiting the supply of insulin needed to curb hyperglycemia. Alternatively, the decreased IBF could represent a protective mechanism by which islet exposure to free fatty acid toxicity can be limited. Ethanol acutely exerted substantial influences on pancreatic microcirculation by evoking a massive redistribution of pancreatic blood flow from the exocrine into the endocrine part via mechanisms mediated by nitric oxide and vagal stimuli, augmenting late phase insulin secretion, and thereby evoking hypoglycemia. This effect may in part underlie the well known hypoglycemic properties of alcohol in diabetic patients or in alcoholics with hepatic failure. Collectively, these direct islet effects of RAS-interfering drugs, statins, fatty acids and ethanol may prove valuable in designing different and gender-specific treatment strategies for diabetic patients or subjects at risk of developing glucose intolerance. Moreover, vasoactive drugs that are frequently given to diabetic patients may confer additional treatment benefits beyond their systemic effects by increasing islet blood flow, augmenting insulin secretion and improving glycemia.