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Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1

From the Department of Medical Physiology, The Panum Institute, University of Copenhagen, Copenhagen, Denmark

Address correspondence and reprint requests to Jens J. Holst, Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: holst{at}mfi.ku.dk

Abbreviations: GLP, glucagon-like peptide; K_ATP channel, ATP-sensitive K⁺ channel

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.

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