Effects of Angiotensin II on Insulin Sensitivity: A Placebo-Controlled Study

Abstract

1. There is evidence that hyperinsulinaemia increases the aldosterone response to angiotensin II, and that angiotensin-converting enzyme inhibitor drugs enhance peripheral glucose utilization, but the direct effects of angiotensin II on insulin sensitivity have not been reported previously. 2. In a randomized, double-blind, placebo-controlled, cross-over study, 12 healthy male subjects attended on 3 study days for the evaluation of the effects of a subpressor (1 ng min-1kg-1) and pressor (5 ng min-1kg-1) infusion of angiotensin II on whole-body insulin sensitivity using the euglycaemic hyperinsulinaemic clamp. Frequent measurements of blood pressure and heart rate were recorded and blood samples were collected for determination of serum insulin, C-peptide and K+ concentration, plasma renin activity and plasma angiotensin II concentration. 3. Plasma angiotensin II concentrations (means +/- SD) were 11 +/- 5 pg/ml after placebo, and 27 +/- 9 and 125 +/- 28 pg/ml after low and high dose angiotensin II, respectively. The higher dose of angiotensin II was associated with significant increases in blood pressure (e.g. 13 mmHg systolic blood pressure at 150 min) and serum aldosterone concentration. Whole-body insulin sensitivity was 10.5 +/- 2 mg of glucose min-1kg-1 after placebo, and 10.5 +/- 2.2 and 10.9 +/- 3.4 mg of glucose min-1kg-1 after low and high dose angiotensin II (not significant). 4. Angiotensin II had no effect on hyperinsulinaemia-induced reductions in serum potassium and triacylglycerol concentrations. 5. Thus, acute infusion of angiotensin II for 3 h, with or without an increase in blood pressure, has no effect on whole-body insulin sensitivity.

Pressor and Subpressor Doses of Angiotensin II Increase Insulin Sensitivity in NIDDM: Dissociation of Metabolic and Blood Pressure Effects

“…However, these results extend the observations of our own group and others who have recently reported the effects of various doses of ANG II on insulin sensitivity in lean healthy male volunteers (12)(13)(14)(15). In our own hands, using an experimental protocol identical to that described here, 5 ng-kg" 1 -min" 1 of ANG II produced a small, sustained increase in BP (11/9 mmHg), but neither this dose nor 1 ng • kg" 1 • min" 1 of ANG II affected glucose uptake under hyperinsulinemic conditions (12).…”

“…Contrary to general expectations, there was evidence that ANG II in doses sufficient to cause a rise in BP led to an increase in insulin-stimulated glucose transport (14,15). Subpressor and weak-pressor doses of ANG II, although increasing plasma ANG II concentrations more than twofold, had no effect on insulin sensitivity (12,13). The mechanism of this effect has not been clearly resolved, but because ANG II appeared to have parallel dose-dependent effects on glucose uptake and BP, with evidence of redistribution of blood flow to skeletal muscle (14), a hemodynamic mechanism rather than a direct biochemical effect has been proposed (14,15).…”

“…Although activation of the sympathetic nervous system (via release of catecholamines) is diabetogenic (11), the effects of other vasoactive hormones on glucose and lipid metabolism have been poorly documented. Our group and others have recently reported the effects of exogenous angiotensin II (ANG II) infusion on insulin sensitivity in healthy, normotensive males (12)(13)(14)(15). Contrary to general expectations, there was evidence that ANG II in doses sufficient to cause a rise in BP led to an increase in insulin-stimulated glucose transport (14,15).…”

Effects of angiotensin II on insulin receptor binding and mRNA levels in normal and diabetic rats

“…Morris et al [34] and Townsend et al [35] did not observe changes in the rate of glucose disposal in healthy subjects during infusion of low-dose angiotensin II (5 and 10 ng ⋅ kg −1 ⋅ min −1 ). Subsequently, the same authors, using higher doses of angiotensin II (15 ng ⋅ kg −1 ⋅ min −1 ), found that this peptide increases the rate of glucose disposal and therefore insulin sensitivity both in healthy [11] and non-insulin-dependent diabetic subjects [12].…”

Drugs and insulin resistance: clinical methods of evaluation and new pharmacological approaches to metabolism.

“…Theoretically this could explain the effects seen with ACE inhibitors but it is then difficult to explain why other vasodilator drugs have no effect on glucose transport. Although angiotensin II has no effect on insulin sensitivity, at least in normal subjects [47], increased kinin levels following ACE inhibition enhance glucose transport [48].…”