Date of Award

5-1995

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

Michael B. Zemel

Committee Members

Michael Karlstad, Roland Bagby, Mary Ann Handel

Abstract

Obesity, insulin resistance and hypertension are risk factors for cardiovascular disease which occur in association more than individually in the general population; this clustering of symptoms is called Syndrome X. The association between hypertension and insulin resistance in this syndrome has traditionally been attributed to the effect of increased circulating insulin on sympathetic nerve activity and renal sodium retention. However, it has been shown that insulin exerts a direct vasodilatory action on the vasculature, which may be impaired in insulin resistant states. Studies in our laboratory have revealed that this vasodilatory effect is, in part, due to insulin stimulation of calcium pumps involved in extrusion of calcium from the cytosol. It is reported herein that recovery from agonist-induced intracellular calcium transients is impaired in vascular smooth muscle from insulin deficient streptozotocin-induced diabetic rats and insulin resistant obese Zucker rats. The obese Zucker rat is a genetic model of obesity, insulin resistance and hypertension carrying two mutant fatty (fa) alleles. Siblings carrying one or zero copies of the fa allele have been considered lean. However, there appear to be intermediate phenotypes in heterozygous lean animals which may be sensitive to environmental manipulations. The interaction of genetics and environment is an important area for study, as many disease processes are influenced by both. Consequently, studies were conducted to assess the effects of high fat feeding on rats carrying zero, one or two copies of the fa allele. Results indicate the presence of gender, genotype, and diet interactions. The fa allele does not appear to be recessive, and male animals carrying one copy of fa are more susceptible to the deleterious consequences of high fat feeding than female siblings or those carrying zero copy of fa. Hence, the heterozygous lean Zucker rat appears to be an appropriate model to study diet-gene interactions with respect to cardiovascular risk.

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