Glycemic Control Determines Hepatic and Peripheral Glucose Effectiveness in Type 2 Diabetic Subjects

Abstract

Glucose effectiveness is impaired in type 2 diabetes. We hypothesize that chronic hyperglycemia and hyperlipidemia contribute importantly to this defect. To test this hypothesis, we compared the effect of acute hyperglycemia on glucose turnover in type 2 diabetic subjects in good control (GC) (n = 14, age 51.7 ± 3.7 years, BMI 28.4 ± 1.0 kg/ m², HbA_1c 5.9 ± 0.2%) and poor control (PC) (n = 10, age 50.0 ± 2.5 years, BMI 27.9 ± 1.5 kg/m², HbA_1c 9.9 ± 0.6%) with age- and weight-matched nondiabetic subjects (ND) (n = 11, age 47.0 ± 4.4 years, BMI 28.5 ± 1.0 kg/m², HbA_1c 5.1 ± 0.2%). Fixed hormonal conditions were attained by infusing somatostatin for 6 h with replacement of basal insulin, glucagon, and growth hormone. Glucose fluxes ([3-³H]glucose) were compared during euglycemic (5 mmol/l, t = 180–240 min) and hyperglycemic (Hy) (10 mmol/l, t = 300–360 min, variable glucose infusion) clamp intervals. Acute hyperglycemia suppressed hepatic glucose production (GP) by 43% and increased peripheral glucose uptake (GU) by 86% in the ND subjects. Conversely, GP failed to suppress (−7%) and GU was suboptimally increased (+34%) in response to Hy in the PC group. However, optimal glycemic control was associated with normal glucose effectiveness in GC subjects (GP −38%, GU +72%; P > 0.05 for GC vs. ND). To determine whether short-term correction of hyperglycemia and/or hyperlipidemia is sufficient to reverse the impairment in glucose effectiveness, five PC subjects were restudied after 72 h of normoglycemia (∼100 mg/dl; variable insulin infusions). These subjects regained normal effectiveness of glucose to suppress GP and stimulate GU and in response to Hy (GP −47%, GU + 71%; P > 0.05 vs. baseline studies). Thus, chronic hyperglycemia and/or hyperlipidemia contribute to impaired effectiveness of glucose in regulating glucose fluxes in type 2 diabetes and hence to worsening of the overall metabolic condition. Short-term normalization of plasma glucose might break the vicious cycle of impaired glucose effectiveness in type 2 diabetes.