Chronic exercise enhances insulin secretion ability of pancreatic islets without change in insulin content in non-diabetic rats.

We evaluated the effect of chronic exercise on insulin secretion in response to high-glucose by using a perifusion method with isolated pancreatic islets from normal rats. Male Wistar rats were assigned to one of two groups: a sedentary group and a trained group. Running exercise was carried out on a treadmill for one hour per day, five days per week, for six, nine, or 12 weeks. The chronic exercise significantly enhanced the insulin secretion ability of pancreatic islets in response to the high-glucose stimulation upon nine and 12 weeks of exercise. The insulin content in the pancreas and the weight of the pancreas did not change upon nine weeks of exercise. Potassium-stimulated insulin secretion was also increased in the islets isolated from rats that trained for nine weeks compared with that in sedentary rats, suggesting that insulin secretion events downstream of membrane depolarization are involved in targets of the exercise effect. These findings suggest that chronic exercise could be a useful strategy not only for the maintenance of peripheral insulin sensitivity but also for the promotion of islet function to secrete insulin in non-diabetics.

Cholesterol biosynthesis pathway intermediates and inhibitors regulate glucose-stimulated insulin secretion and secretory granule formation in pancreatic beta-cells.

Cholesterol is reportedly abundant in the endocrine secretory granule (SG) membrane. In this study, we examined the involvement of cholesterol biosynthesis intermediates and inhibitors in insulin secretion and SG formation mechanisms. There are two routes for the supply of cholesterol to the cells: one via de novo biosynthesis and the other via low-density lipoprotein receptor-mediated endocytosis. We found that insulin secretion and content are diminished by ß-hydroxy-ß-methylglutaryl-coenzyme A inhibitor lovastatin but not by lipoprotein depletion from the culture medium in MIN6 ß-cells. Cholesterol biosynthesis intermediates mevalonate, squalene, and geranylgeranyl pyrophosphate enhanced glucose-stimulated insulin secretion, and the former two increased insulin content. The glucose-stimulated insulin secretion-enhancing effect of geranylgeranyl pyrophosphate was also confirmed in perifusion with rat islets. Morphologically, mevalonate and squalene increased the population of SGs without affecting their size. In contrast, lovastatin increased the SG size with reduction of insulin-accumulating dense cores, leading to a decrease in insulin content. Furthermore, insulin was secreted in a constitutive manner, indicating disruption of regulated insulin secretion. Because secretogranin III, a cholesterol-binding SG-residential granin-family protein, coincides with SG localization based on the cholesterol composition, secretogranin III may be associated with insulin-accumulating mechanisms. Although the SG membrane exhibits a high cholesterol composition, we could not find detergent-resistant membrane regions using a lipid raft-residential protein flotillin and a fluorescent cholesterol-Si-pyrene probe as markers on a sucrose-density gradient fractionation. We suggest that the high cholesterol composition of SG membrane with 40-50 mol% is crucial for insulin secretion and SG formation functions.