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

Islets from fed and 24-h-fasted rats were studied immediately after collage nase 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 i slets 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 275 mM glucose were not affected if fatty acid-free albumin was used during the perifusion. (5 ) Inclusion of alpha-ketoisocaproate (5 mM), monomethyl succinate (10 mM) o r carbachol (10 mu M) significantly amplified insulin release from fasted i slets in the simultaneous presence of 8 mM glucose. (6) Phospholipase C act ivation by glucose, carbachol or their combination was not adversely affect ed 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 1 1 mM glucose; however, the further addition of 10 mu M carbachol still enha nced release from these islets. The results confirm that caloric restrictio n 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 res tricted animals. These results also demonstrate that free fatty acids are n ot essential for glucose to evoke secretion from isolated islets of fasted donors.