Angiotensin II induces insulin resistance independent of changes in interstitial insulin

Abstract

We set out to examine whether angiotensin-driven hypertension can alter insulin action and whether these changes are reflected as changes in interstitial insulin (the signal to which insulin-sensitive cells respond to increase glucose uptake). To this end, we measured hemodynamic parameters, glucose turnover, and insulin dynamics in both plasma and interstitial fluid (lymph) during hyperinsulinemic euglycemic clamps in anesthetized dogs, with or without simultaneous infusions of angiotensin II (ANG II). Hyperinsulinemia per se failed to alter mean arterial pressure, heart rate, or femoral blood flow. ANG II infusion resulted in increased mean arterial pressure (68 +/- 16 to 94 +/- 14 mmHg, P < 0. 001) with a compensatory decrease in heart rate (110 +/- 7 vs. 86 +/- 4 mmHg, P < 0.05). Peripheral resistance was significantly increased by ANG II from 0.434 to 0.507 mmHg. ml(-1). min (P < 0.05). ANG II infusion increased femoral artery blood flow (176 +/- 4 to 187 +/- 5 ml/min, P < 0.05) and resulted in additional increases in both plasma and lymph insulin (93 +/- 20 to 122 +/- 13 microU/ml and 30 +/- 4 to 45 +/- 8 microU/ml, P < 0.05). However, glucose uptake was not significantly altered and actually had a tendency to be lower (5.9 +/- 1.2 vs. 5.4 +/- 0.7 mg. kg(-1). min(-1), P > 0.10). Mimicking of the ANG II-induced hyperinsulinemia resulted in an additional increase in glucose uptake. These data imply that ANG II induces insulin resistance by an effect independent of a reduction in interstitial insulin.

Selective Angiotensin II Receptor Antagonism Reduces Insulin Resistance in Obese Zucker Rats

“…Results of the present investigation are consistent with and complement the findings of Richey et al 23 These investigators demonstrated that acute infusion of Ang II into normal dogs during euglycemic, hyperinsulinemic clamp led to a significant decrease in insulin sensitivity and that this Ang II-induced insulin resistance probably developed because of direct inhibition of glucose transport by the myocyte. Our findings that the acute administration of irbesartan, which would prevent any negative action of Ang II on cellular glucose transport, led to an enhancement of insulinstimulated skeletal-muscle glucose transport (at least in type I muscle), is entirely consistent with this hypothesis.…”

“…Moreover, Rao 22 and Richey et al 23 have reported that acute infusion of Ang II leads to substantial reduction in glucose disposal in normal skeletal muscle, which could not be attributed to hemodynamic alterations. 23 To our knowledge, neither the acute effects of specific Ang II receptor antagonism on insulin-stimulated glucose transport in insulin-resistant type I skeletal muscle (eg, soleus) nor the chronic effects of Ang II receptor antagonism on the skeletal-muscle glucose transport system in conditions of insulin resistance have been investigated.In this context, the purpose of the present study was to assess in an animal model of skeletal-muscle insulin resistance, hyperinsulinemia, glucose intolerance, and dyslipidemia (obese Zucker fa/fa rat) the effects of acute or chronic treatment with a specific Ang II receptor (AT 1 -subtype) …”

“…19 In contrast, chronic administration of Ang II receptor antagonists to insulin-resistant fructose-fed 12 or spontaneously hypertensive 20 rats or to human subjects with essential hypertension 21 leads to significant improvements in whole-body insulin sensitivity. Moreover, Rao 22 and Richey et al 23 have reported that acute infusion of Ang II leads to substantial reduction in glucose disposal in normal skeletal muscle, which could not be attributed to hemodynamic alterations. 23 To our knowledge, neither the acute effects of specific Ang II receptor antagonism on insulin-stimulated glucose transport in insulin-resistant type I skeletal muscle (eg, soleus) nor the chronic effects of Ang II receptor antagonism on the skeletal-muscle glucose transport system in conditions of insulin resistance have been investigated.…”

Role of aldosterone and angiotensin II in insulin resistance: an update

“…reported a significant increase in plasma Ang II concentrations, 38 which is associated with insulin resistance and impaired glucose homeostasis. 41,42 In addition, in these studies MR blockade was also associated with significantly increased plasma cortisol. As glucocorticoids and mineralocorticoids have similar affinity for MR, it is possible that MR blockade decreases clearance of cortisol, leading to impaired insulin action in numerous tissues such as skeletal muscle, adipose, hepatic and cardiovascular tissues, 43 whole-body insulin resistance and impaired glucose homeostasis.…”

TANK-binding kinase 1 mediates phosphorylation of insulin receptor at serine residue 994: a potential link between inflammation and insulin resistance

“…It has been shown that Ang II infusion induces insulin resistance as well as a substantial reduction in glucose disposal in normal skeletal muscle (Rao 1994, Richey et al 1999. Conversely, treatment with AT1R blockers enhances insulin sensitivity (Henriksen et al 2001, Shiuchi et al 2004, Muñoz et al 2006.…”