REGULATION OF ENDOGENOUS GLUCOSE-PRODUCTION BY GLUCOSE PER SE IS IMPAIRED IN TYPE-2 DIABETES-MELLITUS

We examined the ability of an equivalent increase in circulating gluco se concentrations to inhibit endogenous glucose production (EGP) and t o stimulate glucose metabolism in patients with Type 2 diabetes mellit us (DM2). Somatostatin was infused in the presence of basal replacemen ts of glucoregulatory hormones and plasma glucose was maintained eithe r at 90 or 180 mg/dl. Overnight low-dose insulin was used to normalize the plasma glucose levels in DM2 before initiation of the study proto col. In the presence of identical and constant plasma insulin, glucago n, and growth hormone concentrations, a doubling of the plasma glucose levels inhibited EGP by 42% and stimulated peripheral glucose uptake by 69% in nondiabetic subjects. However, the same increment in the pla sma glucose concentrations failed to lower EGP, and stimulated glucose uptake by only 49% in patients with DM2. The rate of glucose infusion required to maintain the same hyperglycemic plateau was 58% lower in DM2 than in nondiabetic individuals. Despite diminished rates of total glucose uptake during hyperglycemia, the ability of glucose per se (a t basal insulin) to stimulate whole body glycogen synthesis (glucose u ptake minus glycolysis) was comparable in DM2 and in nondiabetic subje cts. To examine the mechanisms responsible for the lack of inhibition of EGP by hyperglycemia in DM2 we also assessed the rates of total glu cose output (TGO), i.e., flux through glucose-6-phosphatase, and the r ate of glucose cycling in a subgroup of the study subjects. In the non diabetic group, hyperglycemia inhibited TGO by 35%, while glucose cycl ing did not change significantly. In DM2, neither TGO or glucose cycli ng was affected by hyperglycemia. The lack of increase in glucose cycl ing in the face of a doubling in circulating glucose concentrations su ggested that hyperglycemia at basal insulin inhibits glucose-6-phospha tase activity in vivo. Conversely, the lack of increase in glucose cyc ling in the presence of hyperglycemia and unchanged TGO suggest that t he increase in the plasma glucose concentration failed to enhance the flux through glucokinase in DM2. In summary, both lack of inhibition o f EGP and diminished stimulation of glucose uptake contribute to impai red glucose effectiveness in DM2. The abilities of glucose at basal in sulin to both increase the flux through glucokinase and to inhibit the flux through glucose-6-phosphatase are impaired in DM2. Conversely, g lycogen synthesis is exquisitely sensitive to changes in plasma glucos e in patients with DM2.