Insulin‐stimulated cardiac glucose uptake is impaired in spontaneously hypertensive rats: role of early steps of insulin signalling

Objective Although the heart is one of the target organs of insulin, it is still unknown whether the effect of insulin on cardiac muscle is preserved in essential hypertension, where insulin resistance has been observed in skeletal muscle. Methods We evaluated cardiac glucose uptake and the early steps of insulin signalling in spontaneously hypertensive (SHR, 10–12 weeks old) and in age-matched normotensive Wistar–Kyoto (WKY) rats. Cardiac glucose uptake (μmol/100 g per min) was assessed by 2-[14C]deoxyglucose method. After an overnight fast, 16 WKY rats and 17 SHR underwent a hyperinsulinemic euglycemic clamp. In particular, 2-h intravenous (i.v.) infusion of insulin (10 mU/kg per min) or saline (NaCl 0.9%) was administered, followed by an i.v. bolus injection of 2-[14C]deoxyglucose (100 μCi/kg) to measure cardiac glucose uptake. Results During saline infusion, cardiac glucose uptake was significantly higher in SHR compared to WKY rats (85 ± 18 versus 8 ± 3 mg/kg per min, P < 0.01). Furthermore, insulin was able to markedly increase cardiac glucose uptake in WKY rats whereas this insulin action was entirely abolished in SHR; thus, the cardiac glucose uptake became similar in the two rat strains (76 ± 16 versus 82 ± 16 mg/kg per min, not significant). More importantly, during saline infusion SHR showed a significantly higher phosphorylation of insulin receptorz substance-1 (IRS-1) coupled to enhanced association of the p85 subunit of phosphatidylinositol 3-kinase (PI 3- kinase) to IRS-1 and to an increased PI 3-kinase activity compared to WKY rats. As expected, insulin exposure evoked an activation of its signalling cascade in WKY rats. In contrast, in SHR, the hormone failed to activate post-receptor molecular events. Conclusions Our data indicate that the heart of SHR shows an overactivity of the proximal steps of insulin signalling which cannot be further increased by the exposure to the hormone. This abnormality may account for the marked increase of basal cardiac glucose uptake and the loss of insulin-stimulated glucose uptake observed in SHR.