Glucose Transport Activity in Insulin-Resistant Rat Muscle: Effects of Angiotensin-Converting Enzyme Inhibitors and Bradykinin Antagonism

Abstract

Insulin resistance of skeletal muscle glucose disposal underlies the pathogenesis of NIDDM and is associated with hypertension, obesity, and dyslipidemia. Angiotensin-converting enzyme (ACE) inhibitors are used primarily in antihypertensive therapy but also are known to improve whole-body insulin-mediated glucose disposal. However, the exact site of action is not well characterized. We have used the isolated epitrochlearis muscle from a well-established animal model of skeletal muscle insulin resistance, the obese Zucker rat, to test the effect of oral administration of ACE inhibitors on insulin-sensitive muscle glucose transport activity. Both acute and chronic administration of a sulfhydryl-containing ACE inhibitor (captopril) or a non-sulfhydryl-containing ACE inhibitor (tran-dolapril) significantly enhanced in vitro insulin-mediated muscle glucose transport activity. In addition, the acute effect of oral captopril administration was completely abolished by pretreatment of the animal with a bradykinin B2 receptor antagonist (HOE 140). These findings indicate that ACE inhibitors may improve whole-body glucose metabolism by acting on the insulin-sensitive skeletal muscle glucose transport system. In addition, bradykinin or one of its metabolites may be involved in the action of the ACE inhibitor captopril on insulin-resistant muscle.

Vasopeptidase Inhibitor Omapatrilat Induces Profound Insulin Sensitization and Increases Myocardial Glucose Uptake in Zucker Fatty Rats

“…1 ACE inhibitors (ACEIs), frequently the first line of treatment of hypertension in people with type 2 diabetes, have been shown to improve insulin sensitivity, prevent cardiovascular events, and reduce the number of new cases of type 2 diabetes. [2][3][4][5][6] This effect has been postulated to be a result of the bradykinin (BK)-raising effects of ACEIs. 2,6 The vasopeptidase inhibitor omapatrilat (OMA) inhibits both neutral endopeptidase and ACE with similar potency.…”

“…[2][3][4][5][6] This effect has been postulated to be a result of the bradykinin (BK)-raising effects of ACEIs. 2,6 The vasopeptidase inhibitor omapatrilat (OMA) inhibits both neutral endopeptidase and ACE with similar potency. 7 In addition to decreasing angiotensin II production, OMA also potently inhibits the metabolism of BK to a greater extent than ACEIs.…”

The influence of the kallikrein-kinin system on the characteristics of insulin receptors in rat skeletal muscle during ischemia

“…Trandolapril improves the sensitivity of glycogen synthesis to insulin in the soleus muscle (Leighton et al, 1996). Captopril can improve the glucose transport system in skeletal muscles and this improvement, according to Henriksen and Jacob (1995), involves bradykinin metabolism (Henriksen et al, 1996). Bradykinin, in turn, according to some recent concepts, can influence tyrosine kinase and tyrosine phosphatase activity leading to phosphorylation of MAP kinases and probably activating the Ras GTP/Raf pathway.…”

Retrospective Analysis

“…1 Gurwitz and colleagues also found an increased likelihood of diabetes in the age category of 55-74 years compared to the age category of [35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54] years. 41 However, no significant difference was found between the age groups of '75 years and older' and '35-54 years'.…”

“…ACEIs may reduce insulin resistance in skeletal muscles, resulting in increased glucose disposal, which consequently decreases the need for pancreatic insulin. [33][34][35][36][37] This mechanism is due to increased bradykininmediated nitric oxide production, and not to reduction in angiotensin II production or action; 38 and 5. ACEIs may also reduce insulin resistance in the liver and fat cells, which would reduce hepatic glucose production and lower free fatty acid levels.…”