Tolbutamide alters glucose transport and metabolism in the embryonic mouse heart

Abstract

Background: Tolbutamide is a sulfonylurea oral hypoglycemic agent widely used for the treatment of non insulin-dependent diabetes mellitus. Tolbutamide produces dysmorphogenesis in rodent embryos and becomes concentrated in the embryonic heart after maternal oral dosing. Tolbutamide increases glucose metabolism in extra-pancreatic adult tissues, but this has not previously been examined in embryonic heart. Methods: CD-1 mouse embryos were exposed on GD 9.5 to tolbutamide (0, 100, 250, or 500 μg/ml) for 6, 12, or 24 hr in whole-embryo culture. Isolated hearts were evaluated for 3H-2DG uptake and conversion of 14C-glucose to 14C-lactate. Glut-1, HKI, and GRP78 protein levels were determined by Western analysis, and Glut-1 mRNA was measured by RT-PCR. Results: Cardiac 3H-2DG uptake increased after exposure to 500 μg/ml tolbutamide for 6 hr, and 100, 250, or 500 μg/ml tolbutamide for 24 hr, compared to controls. Glycolysis increased after exposure to 500 μg/ml tolbutamide for 6 or 24 hr compared to controls. Glut-1 protein levels increased in hearts exposed to 500 μg/ml tolbutamide for 12 or 24 hr, and Glut-1 mRNA increased in hearts exposed to 500 μg/ml tolbutamide for 24 hr compared to controls. HKI protein levels increased in hearts exposed to 500 μg/ml tolbutamide for 6 hr, but not 12 or 24 hr. There was no effect on GRP78 protein levels in hearts exposed to tolbutamide for 6, 12, or 24 hr. Conclusions: Tolbutamide stimulates glucose uptake and metabolism in the embryonic heart, as occurs in adult extra-pancreatic tissues. Glut-1 and HKI, but not GRP78, are likely involved in tolbutamide-induced cardiac dysmorphogenesis. © 2002 Wiley-Liss, Inc.