Angiotensin II–Induced Insulin Resistance Is Associated With Enhanced Insulin Signaling

Abstract

Abstract-Angiotensin II (AII) is involved in the pathogenesis of both hypertension and insulin resistance, though few studies have examined the relationship between the two. We therefore investigated the effects of chronic AII infusion on blood pressure and insulin sensitivity in rats fed a normal (0.3% NaCl) or high-salt (8% NaCl) diet. AII infusion for 12 days significantly elevated blood pressure and significant insulin resistance, assessed by a hyperinsulinemic-euglycemic clamp study and glucose uptake into isolated muscle and adipocytes. High-salt loading exacerbated the effects of AII infusion significantly. Despite the insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol (PI) 3-kinase, and phosphorylation of Akt were all enhanced by AII infusion. Subsequently, to investigate whether oxidative stress induced by AII contributes to insulin resistance, the membrane-permeable superoxide dismutase mimetic, tempol, was administered to AII-infused rats. Chronic AII infusion induced an accumulated plasma cholesterylester hydroperoxide levels, indicating the increased oxidative stress, whereas the treatment with tempol normalized plasma cholesterylester hydroperoxide levels in AII-infused rats. In addition, the treatment with tempol normalized insulin resistance in AII-infused rats, shown as a decreased glucose infusion rate in the hyperinsulinemic euglycemic clamp study and a decreased insulin-induced glucose uptake into isolated skeletal muscle, as well as enhanced insulin-induced PI 3-kinase activation to those in the control rats. These results strongly suggest that AII-induced insulin resistance cannot be attributed to impairment of early insulin-signaling steps and that increased oxidative stress, possibly through impaired insulin signaling located downstream from PI 3-kinase activation, is involved in AII-induced insulin resistance. Key Words: angiotensin II Ⅲ insulin resistance Ⅲ oxidative stress Ⅲ glucose clamp technique Ⅲ sodium Ⅲ kinase S everal lines of evidence point to an association between hypertension and insulin resistance, 1,2 eg, hypertensive individuals are more likely to become diabetic than normotensive ones. 3 It is therefore notable that angiotensin II (AII) is reportedly involved in the development of both hypertension and insulin resistance, 4 -7 and agents that inhibit the action of AII, ie, angiotensin-converting enzyme inhibitors and type 1 AII (AT1) receptor antagonists, not only reduce blood pressure but also restore insulin sensitivity. 8 -14 It has been suggested that crosstalk between AII-and insulinsignaling pathways underlies AII-induced insulin resistance. According to that model, AII induces tyrosine phosphorylation of insulin receptor substrate (IRS)-1 by Janus kinase 2 (JAK2) associated with the AT1 receptor, thereby attenuating insulin-induced activation of phosphatidylinositol (PI) 3-kinase associated with IRS-1, which in turn diminishes insulin sensitivity. 15,16 However, ...

Inhibition of PI-3 kinase/Akt/mTOR, but not calcineurin signaling, reverses insulin-like growth factor I-induced protection against glucose toxicity in cardiomyocyte contractile function

“…Two scenarios may be considered for reduced Akt signaling in diabetes including 'resistance' to insulin-stimulated Akt activation and inhibition of Akt by elevated protein kinase C (PKC) activity in diabetes (Shiojima et al 2002). However, recent evidence indicated that glucose-stimulated chronic Akt over-activation may contribute to 'de-sensitization' of Akt phosphorylation en route to insulin resistance (Ogihara et al 2002). Over-phosphorylated Akt has been shown in cardiac tissues under both type 2 diabetes (Huisamen 2003) and hypertension (Ogihara et al 2002).…”

“…However, recent evidence indicated that glucose-stimulated chronic Akt over-activation may contribute to 'de-sensitization' of Akt phosphorylation en route to insulin resistance (Ogihara et al 2002). Over-phosphorylated Akt has been shown in cardiac tissues under both type 2 diabetes (Huisamen 2003) and hypertension (Ogihara et al 2002). Hyperinsulinemia in insulin resistance and type 2 diabetes chronically activates Akt in the hearts, triggering a negative feedback loop to inhibit further Akt activation and excessive IRS-1 degradation (Haq et al 2001).…”

Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence

“…Recent studies have suggested that AII may impair glucose metabolism through its adverse effects on insulin signalling pathways, tissue blood flow, oxidative stress, sympathetic activity and adipogenesis. [45][46][47][48] However, certain ARBs like telmisartan exert their beneficial effects on glucose metabolism independently of the reninangiotensin system. 49, 50 The molecule of telmisartan has a structural similarity to peroxisome proliferator-activated receptor-gamma (PPAR gamma) ligand pioglitazone, which has been approved for the treatment of type II diabetes mellitus.…”

Effect of ID ACE gene polymorphism on dietary composition and obesity-related anthropometric parameters in the Czech adult population

“…Several lines of evidence have previously suggested that angiotensin II, the direct consequence of ACE activity, impairs insulin sensitivity [22,24], and insulin resistance promotes the development of various co-morbidities by upregulating the number and activity of angiotensin II receptors [20]. In several other studies, insulin resistance has been improved in response to treatment with angiotensin I-converting enzyme inhibitors (ACEIs) [12,13].…”