Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide 1.

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Jocelyn de Heer, Jens J Holst

Glucagon-like peptide (GLP)-1 mimetics have been reported to cause hypoglycemia when combined with sulfonylureas. This study investigated the impact of tolbutamide on the glucose dependence of the GLP-1-mediated effects on insulin, glucagon, and somatostatin secretion in the in situ perfused rat pancreas. At 3 mmol/l glucose, GLP-1 alone did not augment insulin secretion, whereas tolbutamide alone caused a rapid increase in insulin secretion. However, when GLP-1 and tolbutamide were administered simultaneously, insulin secretion increased significantly to 43.7 +/- 6.2 pmol/min (means +/- SE), exceeding the sum of the responses to GLP-1 (2.0 +/- 0.6 pmol/min; P = 0.019) and tolbutamide (11.3 +/- 3.8; P = 0.005) alone by a factor of 3.3. At 11 mmol/l glucose, co-infusion of GLP-1 and tolbutamide augmented insulin secretion to 141.7 +/- 10.3 vs. 115.36 +/- 14.1 (GLP-1) and 42.5 +/- 7.3 pmol/min (tolbutamide). Interestingly, increases in somatostatin secretion, both by glucose and GLP-1, were consistently paralleled by suppression of glucagon release. In conclusion, we demonstrate uncoupling of GLP-1 from its glucose dependence by tolbutamide. This uncoupling probably explains the tendency of GLP-1 to provoke hypoglycemia in combination with sulfonylureas. The results suggest that closure of ATP-sensitive K(+) channels by glucose might be involved in the glucose dependence of GLP-1's insulinotropic effect and that somatostatin acts as a paracrine regulator of glucagon release.
Original languageEnglish
JournalDiabetes
Volume56
Issue number2
Pages (from-to)438-43
Number of pages5
ISSN0012-1797
DOIs
Publication statusPublished - 2007

Bibliographical note

Keywords: Animals; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glucagon; Glucagon-Like Peptide 1; Glucose; Hypoglycemic Agents; Insulin; Male; Potassium Channels; Rats; Rats, Wistar; Somatostatin; Tolbutamide

ID: 8463172