A defect in glycogen synthesis characterizes insulin resistance in hypertensive patients with type 2 diabetes

A subgroup of patients with type 2 diabetes shows a clustering of abnormali ties such as peripheral insulin resistance, hypertension, and microalbuminu ria. To evaluate whether these traits reflect intrinsic disorders of cell f unction rather than in vivo environmental effects, we studied a group of 7 nondiabetic hypertensive subjects with an altered albumin excretion rate (A ER) (HyMA+) and 3 groups of patients with type 2 diabetes: 7 with normal bl ood pressure and normal AER (DH-MA-), 7 with high blood pressure and normal AER (DH+MA-), and 7 with both high blood pressure and altered AER (DH+MA+) . Glucose disposal was measured during an hyperinsulinemic clamp (40 mU . m (2-1) . min(-1)) with primed deuterated [6.6 H-2(2)] glucose infusion. In t he same subjects, a skin biopsy was performed and the following parameters were investigated: glucose transport (as determined by [H-3]2-deoxyglucose uptake) glycogen synthase activity (as determined by [C-14] glucose incorpo ration from UDP-[U-C-14] glucose into glycogen); glycogen phosphorylase act ivity (as measured by the incorporation of [U-C-14]glucose I-phosphate into glycogen); and total glycogen content. In vivo glucose disposal was signif icantly reduced in DH+MA- and DH+MA+, with respect to DH-MA-, HyMA+, and co ntrols. Insulin-stimulated glucose transport was similar in the 3 groups of patients with diabetes. A significant reduction of intracellular glycogen content was observed in DH+MA- and DH+MA+ compared with DH-MA- in both basa l and insulin-stimulated conditions, probably because of a major impairment of glycogen synthase activity. Glycogen phosphorylase activity did not sho w differences between the groups. These results suggest that (I) the combin ation of type 2 diabetes with hypertension and altered AER is associated wi th impaired insulin sensitivity, and (2) intrinsic, possibly genetic, facto rs may account for increased peripheral insulin resistance in hypertensive microalbuminuric patients with type 2 diabetes, pointing to the reduction o f glycogen synthase activity as a shared common defect.