7 DAYS OF EUGLYCEMIC HYPERINSULINEMIA INDUCES INSULIN-RESISTANCE FOR GLUCOSE-METABOLISM BUT NOT HYPERTENSION, ELEVATED CATECHOLAMINE LEVELS, OR INCREASED SODIUM RETENTION IN CONSCIOUS NORMAL RATS

Epidemiological studies have suggested an association among chronic hy perinsulinemia, insulin resistance, and hypertension. However, the cau sality of this relationship remains uncertain, In this study, chronica lly catheterized conscious rats were made hyperinsulinemic for 7 days (similar to 90 mU/l, i.e., threefold over basal), while strict euglyce mia was maintained (similar to 130 mg/dl, coefficient of variation <10 %) by using a modification of the insulin/glucose clamp technique, Con trol rats received vehicle infusion, Baseline mean arterial pressure a nd heart rate were 125 +/- 5 mmHg and 427 +/- 12 beats/min and remaine d unchanged during the 7-day infusion of insulin (127 +/- 7 mmHg; 401 +/- 12 beats/min) or vehicle (133 +/- 4 mmHg; 411 +/- 10 beats/min). B aseline plasma epinephrine (88 +/- 15 pg/ml), norepinephrine (205 +/- 31 pg/ml), and sodium balance (0.34 +/- 0.09 mmol) remained constant d uring the 7-day insulin or vehicle infusion, After 7 days of insulin o r vehicle infusion, in vivo insulin action was determined in all rats using a 2-h hyperinsulinemic (1 mU/min) euglycemic clamp with [3-H-3]g lucose infusion to quantitate whole-body glucose uptake, glycolysis, g lucose storage (total glucose uptake minus glycolysis), and hepatic gl ucose production. Compared with vehicle-treated rats, 7 days of sustai ned hyperinsulinemia resulted ins a reduction (P < 0.01) in insulin-me diated 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 u ptake nor glucose storage correlated with blood pressure or heart rate , in conclusion, 7 days of englycemic hyperinsulinemia induces severe insulin resistance with respect to whole-body glucose metabolism but d oes not increase blood pressure, catecholamine levels, or sodium reten tion, 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 hyperinsul inemia was initiated in normal rats under euglycemic conditions, addit ional (inherited off acquired) factors may be necessary to observe an effect of hyperinsulinemia and/or insulin resistance to increase blood pressure.