Seven Days of Euglycemic Hyperinsulinemia Induces Insulin Resistance for Glucose Metabolism but Not Hypertension, Elevated Catecholamine Levels, or Increased Sodium Retention in Conscious Normal Rats

Abstract

Epidemiological studies have suggested an association among chronic hyperinsulinemia, insulin resistance, and hypertension. However, the causality of this relationship remains uncertain. In this study, chronically catheterized conscious rats were made hyperinsulinemic for 7 days (∼90 mU/1, i.e., threefold over basal), while strict euglycemia was maintained (∼130 mg/dl, coefficient of variation <10%) by using a modification of the insulin/glucose clamp technique. Control rats received vehicle infusion. Baseline mean arterial pressure and heart rate were 125 ± 5 mmHg and 427 ± 12 beats/min and remained unchanged during the 7-day infusion of insulin (127 ± 7 mmHg; 401 ± 12 beats/min) or vehicle (133 ± 4 mmHg; 411 ± 10 beats/min). Baseline plasma epinephrine (88 ± 15 pg/ml), norepinephrine (205 ± 31 pg/ml), and sodium balance (0.34 ± 0.09 mmol) remained constant during the 7-day insulin or vehicle infusion. After 7 days of insulin or vehicle infusion, in vivo insulin action was determined in all rats using a 2-h hyperinsulinemic (1 mU/min) euglycemic clamp with [3-³H]glucose infusion to quantitate whole-body glucose uptake, glycolysis, glucose storage (total glucose uptake minus glycolysis), and hepatic glucose production. Compared with vehicle-treated rats, 7 days of sustained hyperinsulinemia resulted in a reduction (P < 0.01) in insulin-mediated glucose uptake, glucose storage, and glycolysis by 39, 62, and 26%, respectively. Hepatic glucose production was normally suppressed after 7 days of hyperinsulinemia. Neither insulin-stimulated glucose uptake nor glucose storage correlated with blood pressure or heart rate. In conclusion, 7 days of euglycemic hyperinsulinemia induces severe insulin resistance with respect to whole-body glucose metabolism but does not increase blood pressure, catecholamine levels, or sodium retention. This indicates that hyperinsulinemia-induced insulin resistance is not associated with the development of hypertension in rats who do not have a genetic predisposition for hypertension. Because hyperinsulinemia was initiated in normal rats under euglycemic conditions, additional (inherited or acquired) factors may be necessary to observe an effect of hyperinsulinemia and/or insulin resistance to increase blood pressure.