The hearts of patients with noninsulin-dependent diabetes mellitus are highly susceptible to ischemic and hypertensive damage and are more prone to developing congestive heart failure than the nondiabetic. Since the majority of the 10 million Americans with this type of diabetes die of cardiovascular disease, it is important to begin addressing the causes underlying these cardiovascular complications.
The aim of this proposal is to continue studying the consequences of one of the cardiovascular problems of noninsulin-dependent diabetes mellitus, the development of a cardiomyopathy. An animal model appropriate for the study of noninsulin-dependent diabetes mellitus-induced cardiomyopathy has been developed and partially characterized. Hearts from these animals show depressed glucose utilization, decreased glycogen levels and reduced mechanical function. In this proposal the basis for altered glucose and glycogen metabolism will be examined by measuring the content of glycolytic intermediates and tissue levels of key effectors which regulate the rate-limiting enzymes of glycolysis and glycogenolysis. The effects of chronic diabetes on total activities of these key enzymes will also be measured. The proposal will also focus on defects in lipid metabolism associated with the cardiomyopathy. Of particular interest is the effect of noninsulin-dependent diabetes on tissue content of toxic amphiphiles such as fatty acyl CoA. In a related problem, the effect of diabetes on triglyceride lipolysis and fatty acid uptake and utilization by the diabetic heart will be examined. The importance of altered lipid metabolism in the development of defects in high energy phosphate metabolism will be explored. Rats with noninsulin-dependent diabetes mellitus will be treated chronically with insulin to normalize blood glucose levels. These studies will test the efficacy of insulin therapy in reversing the abnormalities in glucose metabolism and mechanical function associated with the slowly developing cardiomyopathy observed in these animals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK036440-01
Application #
3234831
Study Section
Cardiovascular and Pulmonary Research B Study Section (CVB)
Project Start
1986-01-01
Project End
1988-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of South Alabama
Department
Type
Schools of Medicine
DUNS #
City
Mobile
State
AL
Country
United States
Zip Code
36688
Schaffer, S W; Ballard, C; Mozaffari, M S (1997) Is there a link between impaired glucose metabolism and protein kinase C activity in the diabetic heart? Mol Cell Biochem 176:219-25
Ballard, C; Mozaffari, M; Schaffer, S (1994) Signal transduction mechanism for the stimulation of the sarcolemmal Na(+)-Ca2+ exchanger by insulin. Mol Cell Biochem 135:113-9
Schaffer, S W; Warner, B A; Wilson, G L (1993) Effects of chronic glipizide treatment on the NIDD heart. Horm Metab Res 25:348-52
Schaffer, S W; Punna, S (1993) Regulation of sarcolemmal Ca2+ pump by endogenous protein phosphatases. Basic Res Cardiol 88:103-10
Schaffer, S W; Wilson, G L (1993) Insulin resistance and mechanical dysfunction in hearts of Wistar rats with streptozotocin-induced non-insulin-dependent diabetes mellitus. Diabetologia 36:195-9
Liu, Y; Thornton, J D; Cohen, M V et al. (1993) Streptozotocin-induced non-insulin-dependent diabetes protects the heart from infarction. Circulation 88:1273-8
Schaffer, S W; Allo, S; Punna, S et al. (1991) Defective response to cAMP-dependent protein kinase in non-insulin-dependent diabetic heart. Am J Physiol 261:E369-76
Kaplan, R S; Mayor, J A; Blackwell, R et al. (1991) Functional levels of mitochondrial anion transport proteins in non-insulin-dependent diabetes mellitus. Mol Cell Biochem 107:79-86
Schaffer, S W (1991) Cardiomyopathy associated with noninsulin-dependent diabetes. Mol Cell Biochem 107:1-20
Mozaffari, M S; Allo, S; Schaffer, S W (1989) The effect of sulfonylurea therapy on defective calcium movement associated with diabetic cardiomyopathy. Can J Physiol Pharmacol 67:1431-6

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