(taken from the application) The hemodynamic and metabolic effects of insulin make it an ideal hormone to facilitate the delivery and storage of ingested nutrient. Impaired tissue blood flow can reduce glucose uptake by insulin (insulin resistance) and the compensatory hyperinsulinemia has been implicated in the pathogenesis of hyperlipidemia and atherosclerosis. Insulin resistance is associated with activation of the renin-angiotensin and adrenergic nervous systems which can reduce blood flow. Increasing salt intake suppresses activity of both of these systems and may improve insulin sensitivity, but recent studies of this issue are conflicting since studies used different techniques to evaluate insulin sensitivity, were limited to men, and did not compare responses among diverse ethnic groups. The advice to reduce salt intake has important health consequences if salt restriction has adverse metabolic consequences such as a reduction in insulin sensitivity. I have recently shown a significant negative correlation between plasma renin activity and insulin sensitivity, and I hypothesize that high dietary salt intake increases insulin-sensitive glucose transport when compared to a low salt intake. I will test this single hypothesis through three Specific Aims by examining 1) the effects of 1 week isocaloric Low (20 meq sodium) versus 1 week of a High (230 meq) salt intake in Caucasian and African/American men/women using the euglycemic clamp to assess insulin sensitivity; 2) the effect of insulin infusion on leg blood flow using impedance plethysmography on different salt intakes, and 3) the mechanism by which increased salt intake elevates fatty acid concentration by demonstrating an increase in lipolysis rate on High Salt intake, measured by the stable isotope deuterated glycerol coupled with indirect calorimetry measurements to assess fatty acid oxidation on the Low and High salt intakes. Activity of the renin-angiotensin and (indirectly) the adrenergic nervous systems will be evaluated by determining plasma renin activity and plasma/urinary norepinephrine concentrations at the end of each dietary salt phase. Statistical significance of the insulin sensitivity data will be evaluated by paired t-testing. If increased salt intake improves insulin sensitivity this should prompt a re-evaluation of the benefits of recommending a lower sodium intake in normotensive people.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Midcareer Investigator Award in Patient-Oriented Research (K24)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Townsend, Raymond R; Kapoor, Shiv; McFadden, Christopher B (2007) Salt intake and insulin sensitivity in healthy human volunteers. Clin Sci (Lond) 113:141-8
Townsend, Raymond R; Zhao, Huawei (2002) Differential effect of insulin on saturated and unsaturated fatty acids. Metabolism 51:779-82
Malhotra, Arun; Cohen, Debbie; Syms, Charles et al. (2002) Blood pressure changes in the leg on standing. J Clin Hypertens (Greenwich) 4:350-4
Townsend, R R (2001) The effects of angiotensin-II on lipolysis in humans. Metabolism 50:468-72