Diabetic cardiomyocyte dysfunction and myocyte insulin resistance: role of glucose-induced PKC activity.
Increased protein kinase C (PKC) activity has been implicated in the pathogenesis of a number of diabetic complications, and high concentrations of glucose have been shown to increase PKC activity. The present study was designed to examine the role of PKC in diabetes-induced (and glucose-induced) cardiomyocyte dysfunction and insulin resistance (measured by glucose uptake). Adult rat ventricular myocytes were isolated from nondiabetic and type 1 diabetic animals (4-5 days post-streptozotocin treatment), and maintained overnight, with/without the nonspecific PKC inhibitor chelerythrine (CHEL = 1 microM). Myocyte mechanical properties were evaluated using a video edge-detection system. Basal and insulin-stimulated glucose uptake was measured with [3H]-2-deoxyglucose. Blunted insulin-stimulated glucose uptake was apparent in diabetic myocytes, and both mechanical dysfunctions (e.g., slowed shortening/relengthening) and insulin resistance were maintained in culture, and normalized by CHEL. Cardiomyocytes isolated from nondiabetic animals were cultured in a high concentration of glucose (HG = 25.5 mM) medium, with/without CHEL. HG myocytes exhibited slowed shortening/relengthening and impaired insulin-stimulated glucose uptake compared to myocytes cultured in normal glucose (5.5 mM), and both impairments were prevented by culturing cells in CHEL. Our data support the view that PKC activation contributes to both diabetes-induced abnormal cardiomyocyte mechanics and insulin resistance, and that elevated glucose is sufficient to induce these effects.
Davidoff
Amy J
AJ
Department of Pharmacology, College of Osteopathic Medicine, University of New England, Biddeford, ME 04005, USA. adavidoff@une.edu
Davidson
Michael B
MB
Carmody
Marybeth W
MW
Davis
Mari-Elena
ME
Ren
Jun
J
D000818:Animals; D001696:Biomechanical Phenomena; D048430:Cell Shape; D002478:Cells, Cultured; D048909:Diabetes Complications / Q000209:etiology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006352:Heart Ventricles / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D007333:Insulin Resistance; D008297:Male; D018715:Microscopy, Video; D032342:Muscle Cells / Q000201:enzymology / Q000473:pathology*; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D011493:Protein Kinase C; D005947:Glucose