Losartan modifies glomerular hyperfiltration and insulin sensitivity in type 1 diabetes

AIM: The effect of the angiotensin II receptor antagonist losartan on renal haemodynamics and insulin-mediated glucose disposal was examined in normotensive, normoalbuminuric type 1 diabetic patients using a double-blind, placebo-controlled, cross-over design. METHODS: Diurnal blood pressure, glomerular filtration rate (GFR, determined using 125I-iothalamate), renal plasma flow (RPF, determined using 131I-hippuran) and urinary albumin excretion rate (UAE) were measured, and a hyperinsulinaemic, euglycaemic clamp with indirect calorimetry was performed in nine patients (age 30 +/- 7 years (mean +/- s.d.), HbA1c 8.1 +/- 1.1%) following 6 weeks' administration of either losartan 50 mg/day or placebo. RESULTS: Diurnal blood pressure was significantly reduced after losartan compared with placebo (122/70 +/- 11/8 vs. 130/76 +/- 12/6 mmHg, p < 0.05). A significant decline in GFR (133 +/- 23 vs. 140 +/- 22 ml/min, p < 0.05) and filtration fraction (FF; GFR/RPF) (24.6 +/- 3.5 vs. 26.2 +/- 3.6%, p < 0.05) was observed in the losartan vs. placebo groups. RPF and UAE did not change. Isotopically determined glucose disposal rates were similar after losartan and placebo in the basal (2.61 +/- 0.53 vs. 2.98 +/- 0.93 mg/kg/min) and insulin-stimulated states (6.84 +/- 2.52 vs. 6.97 +/- 3.11 mg/kg/min). However, the glucose oxidation rate increased significantly after losartan vs. placebo in the basal state (1.72 +/- 0.34 vs. 1.33 +/- 0.18, mg/kg/min, p < 0.01) and during insulin stimulation (2.89 +/- 0.75 vs. 2.40 +/- 0.62 mg/kg/min, p < 0.03). Basal and insulin-stimulated non-oxidative glucose disposal tended to decrease after losartan; however, this was not significant. Endogenous glucose production and lipid oxidation were unchanged after treatment and similarly suppressed during hyperinsulinaemia. Glycaemic control, total cholesterol, high-density lipoprotein (HDL)-cholesterol and triglycerides were stable in both losartan and placebo groups. CONCLUSIONS: Losartan reduces blood pressure, glomerular hyperfiltration and FF, and improves basal and insulin-stimulated glucose oxidation in normotensive, normoalbuminuric type 1 diabetic patients.