DIET-INDUCED HYPERINSULINEMIA IN OBESE HYPERTENSION

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That primary hypertension constitutes a heterogeneous disorder, particularly in the obese population, is well recognized. Elucidation of the role of hyperinsulinemia and insulin resistance in the etiology of this complex disorder is a primary goal of this proposal. But this goal hinges upon the prior definition of distinct subgroups with respect to sensitivity to the anti-pressor effects of weight loss. Our hypothesis is that hyperinsulinemia and insulin resistance are major factors in the development of "weight sensitive" hypertension due to obesity. This proposal will investigate the relationship between insulin resistance and hypertension in obese patients in a weight loss program (NIH ROL HL 31989), an aim of which is to evaluate sensitivity to the anti-pressor effects of weight loss. Analysis of the change in blood pressure achieved in those subjects whose weight loss was 10% reveals a bimodal distribution with mean (plus or minus SD) decline in diastolic blood pressure of 23 plus or minus 3 mmHg and 3 plus or minus 5 mmHg. The proposed study is designed to demonstrate that the change in Insulin Sensitivity Index (SI) calculated from simultaneous blood glucose and insulin data according to the Minimal Model of Bergman, is a predictor of the response of blood pressure to weight loss. To establish this, each patient will be studied after weight loss; a subset of patients with 30% recidivism and a second weight loss will also be studied. Covariates will include Na+/K+ excretion, catecholamine excretion, plasma renin activity, plasma atrial naturetic factor, body mass index (wt/ht2), age and sex. Concurrent experiments will be conducted in Fischer and Zucker fa/fa obese rats fed high fat or high carbohydrate diets in order to delineate an analogous animal model. The hemodynamic characteristics of these animals will be evaluated using measurements of cardiac output and regional blood flow rates in different tissues. The hypothesis that insulin potentiates vascular autoregulation in response to acute or chronic volume expansion will be tested. Autoregulation (response in vascular resistance) will be measured in the basal insulin state, and at two levels of hyperinsulinemic/euglycemic glucose clamps. Thus, parallel experiments in obese animals and human subjects will be used to test a mechanistic hypothesis about the role of hyperinsulinemia in obesity as it relates to primary hypertension.