Glucose-induced insulin secretion from islets of fasted rats: modulation by alternate fuel and neurohumoral agonists

Abstract

Islets from fed and 24-h-fasted rats were studied immediately after collagenase isolation. (1) After a 24-h fast, the insulin secretory responses to 8 mM glucose measured during perifusion were reduced by more than 90% from islets of fasted donors. (2) Increasing glucose to 11 or 27·5 mM resulted in enhanced insulin secretion from islets of fasted animals. (3) Fasting did not reduce islet insulin content. (4) Responses to 8 or 27·5 mM glucose were not affected if fatty acid-free albumin was used during the perifusion. (5) Inclusion of -ketoisocaproate (5 mM), monomethyl succinate (10 mM) or carbachol (10 µM) significantly amplified insulin release from fasted islets in the simultaneous presence of 8 mM glucose. (6) Phospholipase C activation by glucose, carbachol or their combination was not adversely affected by fasting. (7) The response to the protein kinase C activator, phorbol 12-myristate 13-acetate (500 nM), was reduced by about 60% after fasting. (8) Extending the fast to 48 h resulted in a severe decline in response to 11 mM glucose; however, the further addition of 10 µM carbachol still enhanced release from these islets. The results confirm that caloric restriction impairs islet sensitivity to glucose stimulation and that protein kinase C may be involved in the reduction of glucose-induced insulin release from these islets. The activation of phospholipase C by cholinergic stimulation may contribute to the maintenance of insulin secretion from calorically restricted animals. These results also demonstrate that free fatty acids are not essential for glucose to evoke secretion from isolated islets of fasted donors.

Reduced expression of SIRT1 is associated with diminished glucose-induced insulin secretion in islets from calorie-restricted rats

“…As it is known, Cch potentiates secretion, increasing the production of IP3 and DAG [35]. Although we have not addressed this issue in this work, we are tempted to speculated that, due to the calorie restriction, it is possible that in the CR rats there is an exacerbation of the cholinergic systems making the islets more sensitive to Ach and consequently to Cch.…”

Rapamycin-induced glucose intolerance: Hunger or starvation diabetes

“…127 Insulin sensitivity worsens in both type II diabetes and in obese subjects during a 60 h fast. 128 Starvation markedly diminished insulin secretion from β cells in rat, 129,130 which is a reversible condition, 131,132 and inhibition of insulin secretion by rapamycin is also a reversible condition.…”

Class II Phosphoinositide 3-Kinase Regulates Exocytosis of Insulin Granules in Pancreatic β Cells

“…Although the importance of class I PI3Ks in the control of β cell mass and survival is well established, conflicting evidence exists in the literature about their role in insulin secretion. It has been reported that the classical PI3Ks inhibitors wortmannin and LY294002 enhance insulin secretion in rat (5) and mouse islets (6) and pancreatic β cell lines (7) and that wortmannin does not inhibit insulin secretion or synthesis (8). However, knock-out mice for the class I isoform p110γ lack the first phase of insulin secretion (9, 10), and specific blockade of p110γ impairs insulin secretion (11).…”