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Mechanism of impaired glucose-potentiated insulin secretion in diabetic 90% pancreatectomy rats. Study using glucagonlike peptide-1 (7-37).

By Y A Hosokawa, H Hosokawa, C Chen and J L Leahy


Chronic hyperglycemia causes a near-total disappearance of glucose-induced insulin secretion. To determine if glucose potentiation of nonglucose secretagogues is impaired, insulin responses to 10(-9) M glucagonlike peptide-1 (GLP-1) (7-37) were measured at 2.8, 8.3, and 16.7 mM glucose with the in vitro perfused pancreas in rats 4-6 wk after 90% pancreatectomy (Px) and sham-operated controls. In the controls, insulin output to GLP-1 was > 100-fold greater at 16.7 mM glucose versus 2.8 mM glucose. In contrast, the increase was less than threefold in Px, reaching an insulin response at 16.7 mM glucose that was 10 +/- 2% of the controls, well below the predicted 35-40% fractional beta-cell mass in these rats. Px and control rats then underwent a 40-h fast followed by pancreas perfusion using a protocol of 20 min at 16.7 mM glucose followed by 15 min at 16.7 mM glucose/10(-9) M GLP-1. In control rats, fasting suppressed insulin release to high glucose (by 90%) and to GLP-1 (by 60%) without changing the pancreatic insulin content. In contrast, in Px the insulin response to GLP-1 tripled in association with a threefold increase of the insulin content, both now being twice normal when stratified for the fractional beta-cell mass. The mechanism of the increased pancreas insulin content was investigated by assessing islet glucose metabolism and proinsulin biosynthesis. In controls with fasting, both fell 30-50%. In Px, the degree of suppression with fasting was similar, but the attained levels both exceeded those of the controls because of higher baseline (nonfasted) values. In summary, chronic hyperglycemia is associated with a fasting-induced paradoxical increase in glucose-potentiated insulin secretion. In Px rats, the mechanism is an increase in the beta-cell insulin stores, which suggests a causative role for a lowered beta-cell insulin content in the impaired glucose-potentiation of insulin secretion

Topics: Research Article
Year: 1996
DOI identifier: 10.1172/jci118387
OAI identifier:
Provided by: PubMed Central
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