Possible interactions between angiotensin II and insulin: effects on glucose and lipid metabolism in vivo and in vitro

Angiotensin II (ANGII) increases insulin sensitivity in diabetic and non-di abetic subjects, even at subpressor doses, and because there is 'crosstalk' between ANGII and insulin-signaling pathways the underlying mechanism may not be due solely to changes in regional blood flow. A series of experiment al studies was undertaken to evaluate the effects of ANGII on glucose and l ipid metabolism in vivo and in vitro. Groups of fructose-fed, insulin-resis tant Sprague-Dawley (SD) rats were pre-treated with 0.3 mg/kg per day of th e AT(1)-receptor antagonist L-158 809 (n=16), or vehicle (n=16), by oral ga vage. This was prior to all oral glucose tolerance test (day 5) and measure ment of the effects of ANGII infusion (20 ng/kg per min i.v. for 3 h) on wh ole-body insulin sensitivity using the insulin suppression test (day 7). Th e effect of ANGII infusion on total triglyceride secretion rate (TGSR) was evaluated in normal SD rats pretreated for 7 days with L-158 809 (n=12) or vehicle (n=12). AT(1)- and AT(2)- receptor mRNA expression and [H-3]2-deoxy glucose uptake were assessed in cultured L6 myoblasts. Short-tron treatment with L-158 809 had Ilo effect on glucose tolerance or fasting triglyceride levels in fructose-fed rats. ANGII infusion had no effect on insulin sensi tivity in fructose-fed rats pretreated with vehicle (steady-state plasma gl ucose (SSPG) values 8.1 +/- 1.6 vs 8.4 +/- 0.4 mmol/l), but pretreatment wi th L-158 809 resulted in ANGII having a modest insulin antagonist effect in this insulin-resistant model (SSPG values 9.6 +/- 0.3 vs 7.1 +/- 0.6, P<0. 03). ANGII infusion had no significant effect on TGSR (e.g. 24.6 +/- 1.4 vs 28.4 +/- 0.9 mg/100 g per h in vehicle-treated animals). RT-PCR analysis s howed that L6 cells express both AT(1)- and AT(2)-receptor mRNA. Incubation with ANGII (10(-9) and 10(-8) M) had no significant effect on the dose-res ponse curve for insulin-stimulated [H-3]2- deoxyglucose uptake. For example C-1200 values (dose of insulin required to increase glucose uptake by 200% ) were 4.5 x 10(-9) M (control) vs 3.9 x 10(-9) M and 6.2 x 10(-9) M, where as the positive control (glucagon-like peptide-1) increased insulin sensiti vity. Thus, ANGII infusion may have a modest insulin antagonist effect on g lucose disposal in insulin-resistant fructose-fed rats pretreated with an A T(1)-blocker, but ANGII has not effect on TGSR or in vitro glucose uptake i n L6 myoblasts. These findings are relevant to recent clinical discussions about the metabolic effects of ANGII and renin-angiotensin system blockade.