Valsartan-induced improvement in insulin sensitivity is not paralleled by changes in microvascular function in individuals with impaired glucose metabolism

BACKGROUND: Individuals with impaired glucose metabolism (IGM) are at high risk of developing type 2 diabetes (T2DM). The renin-angiotensin system (RAS) is activated in insulin-resistant states and its inhibition resulted in delayed onset of T2DM. The underlying mechanisms may include improvement in microvascular structure and function, which may increase glucose and insulin delivery to insulin-sensitive tissues. We hypothesized that functional and structural capillary density is impaired in insulin-resistant individuals with IGM and that treatment with the angiotensin-receptor blocker valsartan (VAL) will improve insulin sensitivity and microvascular function. METHODS: In this randomized controlled trial, individuals with IGM (n = 48) underwent a hyperinsulinaemic-euglycaemic clamp to assess insulin sensitivity (M-value) and capillaroscopy to examine baseline skin capillary density (BCD), capillary density after arterial occlusion (PRH) and capillary density during venous occlusion (VEN) before and after 26 weeks of VAL or placebo (PLB). Sixteen BMI-matched individuals with normal glucose metabolism (NGM) served as controls. RESULTS: Individuals with IGM were more insulin resistant (P < 0.001) and had impaired microvascular function compared with those with NGM (all P < 0.01). Univariate associations were found for microvascular function (BCD, PRH, VEN) and M-value (all P < 0.005). The relations were independent of age, sex and BMI. VAL improved insulin sensitivity (P = 0.034) and lowered blood pressure as compared with PLB, whereas microvascular function remained unchanged. CONCLUSION: In insulin-resistant individuals with IGM, impaired functional and structural capillary density was inversely associated with insulin sensitivity. VAL improved insulin sensitivity without affecting the functional and structural capillary density, indicating that other mechanisms may be stronger determinants in the VAL-mediated insulin-sensitizing effect.