Insulin resistance with enhanced insulin signaling in high-salt diet-fed rats

Previous clinical studies showed an apparent correlation between hypertensi on and insulin resistance, and patients with diabetes are known to have inc reased blood pressure responsiveness to salt loading. To investigate the ef fect of high salt intake on insulin sensitivity and the insulin signaling p athway, a high-salt diet (8% NaCl) or a normal diet was given to 7-week-old SD rats for 2 weeks. High salt-fed rats developed slightly but significant ly higher systolic blood pressure than controls (133 +/- 2 vs. 117 +/- 2 mm Hg, P < 0.001)], with no change in food intake or body weight. High salt-fe d rats were slightly hyperglycemic (108.5 +/- 2.8 vs. 97.8 +/- 2.5 mg/dl, P = 0.01) and slightly hyperinsulinemic (0.86 +/- 0.07 vs. 0.61 +/- 0.06 ng/ ml, P = 0.026) in the fasting condition, as compared with controls. Hyperin sulinemic-euglycemic clamp study revealed a 52.7% decrease in the glucose i nfusion rate and a 196% increase in hepatic glucose production in high salt -fed rats, which also showed a 66.4% decrease in 2-deoxyglucose uptake into isolated skeletal muscle and a 44.5% decrease in insulin-induced glycogen synthase activation in liver, as compared with controls. Interestingly, des pite the presence of insulin resistance, high salt-fed rats showed enhanced insulin-induced tyrosine phosphorylation of insulin receptor substrate (IR S)-1, IRS-2 (liver and muscle), and IRS-3 (liver only). Phosphatidylinosito l (PI) 3-kinase activities associated with IRS and phosphotyrosine in the i nsulin-stimulated condition :increased 2.1- to 4.1-fold, as compared with c ontrols. Insulin-induced phosphorylation of Ser-473 of Akt and Ser-21 of gl ycogen synthase kinase-3 also increased 2.9- and a-fold, respectively, in t he liver of the high salt-fed rats. Therefore, in both the liver and muscle off high salt-fed rats, intracellular insulin signaling leading to PI 3-ki nase activation is enhanced and insulin action is attenuated. The hyperinsu linemic-euglycemic clamp study showed that decreased insulin sensitivity in duced with a high-salt diet was not reversed by administration of pioglitaz one. The following can be concluded: 1) a high-salt diet may be a factor pr omoting insulin resistance, 2) the insulin-signaling step impaired by high salt intake is likely to be downstream from PI 3-kinase or Akt activation, and 3) this unique insulin resistance mechanism may contribute to the devel opment of diabetes in patients with hypertension.