The extrapancreatic effects of sulfonylurea drugs include increased glucose uptake by certain peripheral tissues. To study this effect, we used BC3H1 myocytes, which are reported to respond to these drugs. Within 30 min, tolbutamide and glyburide increased [3H]-2-deoxyglucose uptake in a dose-dependent manner. The inactive analogue carboxytolbutamide had no effect on glucose transport. Because increases in glucose transport may be mediated by activation of the diacylglycerol-protein kinase C signaling system, we examined the effects of these drugs on lipid metabolism and protein kinase C activity. Unlike insulin, tolbutamide and glyburide failed to increase [3H]glycerol labeling of diacylglycerol or labeling of phospholipids by 32P. After 30 min of treatment with tolbutamide or glyburide, however, membraneassociated and cytosolic protein kinase C activity were each increased. When cells were treated with 12-O- tetradecanoylphorbol-13-acetate (TPA) for 48 h to deplete certain isoforms of protein kinase C, glyburide, tolbutamide, and acute TPA treatment failed to increase glucose uptake, suggesting that TPA and sulfonylureas operate through activation of a common pathway. The effect of glyburide was additive to TPA in stimulating glucose uptake at low but not high TPA concentrations. As with insulin and TPA, extracellular Ca2+ was not essential for sulfonylurea-stimulated glucose uptake. Staurosporine, a protein kinase C inhibitor, blocked glyburide-, tolbutamide-, and insulinstimulated glucose uptake. In intact cells, glyburide stimulated the phosphorylation of both 80,000-Mr and 40,000-Mr proteins, which are markers for protein kinase C activation. Addition of sulfonylureas directly to the protein kinase C assay system in vitro provoked dioleinlike effects, in that sensitivity of the enzyme to Ca2+ was increased. Our findings suggest that tolbutamide and glyburide increase glucose uptake in BC3H1 myocytes by a postreceptor mechanism, which may involve direct activation of protein kinase C.
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Original Articles|
November 01 1990
Sulfonylurea-Stimulated Glucose Transport Association With Diacylglycerollike Activation of Protein Kinase C in BC3H1 Myocytes
Denise R Cooper;
Denise R Cooper
Research Service, James A. Haley Veterans Hospital, and the Departments of Internal Medicine and Biochemistry, University of South Florida College of Medicine
Tampa, Florida
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Maria C Vila;
Maria C Vila
Research Service, James A. Haley Veterans Hospital, and the Departments of Internal Medicine and Biochemistry, University of South Florida College of Medicine
Tampa, Florida
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James E Watson;
James E Watson
Research Service, James A. Haley Veterans Hospital, and the Departments of Internal Medicine and Biochemistry, University of South Florida College of Medicine
Tampa, Florida
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Govindan Nair;
Govindan Nair
Research Service, James A. Haley Veterans Hospital, and the Departments of Internal Medicine and Biochemistry, University of South Florida College of Medicine
Tampa, Florida
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Robert J Pollet;
Robert J Pollet
Research Service, James A. Haley Veterans Hospital, and the Departments of Internal Medicine and Biochemistry, University of South Florida College of Medicine
Tampa, Florida
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Mary Standaert;
Mary Standaert
Research Service, James A. Haley Veterans Hospital, and the Departments of Internal Medicine and Biochemistry, University of South Florida College of Medicine
Tampa, Florida
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Robert V Farese
Robert V Farese
Research Service, James A. Haley Veterans Hospital, and the Departments of Internal Medicine and Biochemistry, University of South Florida College of Medicine
Tampa, Florida
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Address correspondence and reprint requests to Denise R. Cooper, PhD, Research Service 151, J.A. Haley Veterans Hospital, 13000 Bruce B. Downs Boulevard, Tampa, FL 33612.
Diabetes 1990;39(11):1399–1407
Article history
Received:
October 04 1989
Revision Received:
June 26 1990
Accepted:
June 26 1990
PubMed:
2121569
Citation
Denise R Cooper, Maria C Vila, James E Watson, Govindan Nair, Robert J Pollet, Mary Standaert, Robert V Farese; Sulfonylurea-Stimulated Glucose Transport Association With Diacylglycerollike Activation of Protein Kinase C in BC3H1 Myocytes. Diabetes 1 November 1990; 39 (11): 1399–1407. https://doi.org/10.2337/diab.39.11.1399
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