Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide 1.
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.
de Heer
Jocelyn
J
Department of Medical Physiology, The Panum Institute, University of Copenhagen, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark.
Holst
Jens J
JJ
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005934:Glucagon / Q000187:drug effects / Q000378:metabolism*; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology* / Q000502:physiology; D005947:Glucose / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D015221:Potassium Channels / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013004:Somatostatin / Q000187:drug effects / Q000378:metabolism*; D014044:Tolbutamide / Q000494:pharmacology*
D007004:Hypoglycemic Agents; D007328:Insulin; D015221:Potassium Channels; D013004:Somatostatin; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D014044:Tolbutamide; D005947:Glucose