The hearts noninsulin-dependent diabetes mellitus are highly susceptible to ischemic and hypertensive damage, respond poorly to stress 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 exhibit abnormal carbohydrate metabolism, reduced mechanical function and impaired calcium movement. In this proposal, the effect of NIDDM on calcium transport and one of the factors which regulate calcium transport, membrane phosphorylation, will be examined. Isolated sarcolemmal and sarcoplasmic reticular studies will focus on differences in membrane phosphorylation resulting from diabetes-mediated alterations in intrinsic protein phosphatase and kinase activities, as well as changes in the properties of certain phosphorylatable protein substrates. In vivo phosphorylation of isolated NIDDM and nondiabetic hearts will be carried out. In some experiments the heart will be stimulated by the introduction of certain protein kinase activators. Sarcolemma and sarcoplasmic reticulum from unstimulated and stimulated hearts will be isolated and their calcium transport properties and phosphorylation patterns examined. Also examined will be the effect of the protein kinase activators on mechanical function of the diabetic and nondiabetic heart. These studies will provide information on the physiological significance of some of the diabetes-linked defects. The relevance of these changes will also be explored by examining the effect of diabetes on kinase-mediated changes in calcium transients of isolated myocytes using fura 2 as the calcium probe.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK036440-06
Application #
3234840
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1986-01-01
Project End
1994-06-30
Budget Start
1991-07-01
Budget End
1994-06-30
Support Year
6
Fiscal Year
1991
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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