Role of basal insulin in maintenance of intracellular glucose metabolic pathways in non—insulin-dependent diabetes mellitus

Abstract

Impairments of both basal and insulin-stimulated oxidative (G ox) and nonoxidative (N ox) glucose metabolism are documented to exist in non—insulin-dependent diabetes mellitus (NIDDM). Although these defects have been well characterized during insulin stimulation, little is known about the effects of basal insulin or its deficiency on intracellular glucose metabolism in NIDDM. To determine the physiological significance of basal insulin in the maintenance of glucose metabolism in NIDDM, we studied nine subjects with NIDDM in the basal and insulin-deficient state produced by 3 hours of somatostatin (SRIF) infusion (0.08 pmol/kg/min). Glucose turnover rates were quantified by [3- 3H]glucose turnover, and substrate oxidation was assessed by a combination of indirect calorimetry and urinary nitrogen measurements. Skeletal muscle glycogen synthase (GS) and pyruvate dehydrogenase (PDH) activities were also measured in the basal state and during SRIF infusion. Basal glucose levels were maintained during SRIF infusion by exogenous glucose infusion (12.5 ± 0.9 mmol/L in the basal state v 12.8 ± 0.8 during SRIF infusion, P = NS). During the last hour of SRIF infusion, plasma C-peptide levels declined by 88% from 0.73 ± 0.11 to 0.09 ± 0.02 nmol/L ( P < .001), and serum insulin concentrations were undetectable (<14 pmol/L). During insulinopenic conditions, rates of glucose uptake (GU) were decreased by 12% from basal level of 2.26 ± 0.13 to 1.99 ± 0.12 mg/kg/min ( P < .05), and were entirely accounted for by reduced rates of G ox (1.01 ± 0.10 to 0.65 ± 0.14 mg/kg/min, P < .01). Corresponding measurements of active PDH (PDHa) activity in skeletal muscle were similarly decreased from 0.50 ± 0.14 to 0.31 ± 0.09 nmol/min/mg protein ( P < .05) during insulinopenia, whereas rates of fat oxidation (F ox) were increased from 0.87 ± 0.05 to 1.05 ± 0.07 mg/kg/min ( P < .01). The reduction in energy expenditure (EE) from lower G ox was completely offset by increased energy from enhanced F ox and resulted in unchanged total EE (1.42 ± 0.10 v 1.41 ± 0.11 kcal/min, P = NS). Although skeletal muscle GS activity was significantly decreased (2.6% ± 0.7% to 1.8% ± 0.8%, P < .05), calculated rates of N ox remained unchanged (1.24 ± 0.17 to 1.34 ± 0.21 mg/kg/min, P = NS) and were significantly correlated with non—insulin-mediated GU (NIMGU) during insulinopenia ( r = .76, P < .05). In conclusion, approximately 35% of basal G ox in NIDDM was dependent on basal insulin action. Basal N ox was independent of basal insulin and was determined by the rate of NIMGU. Basal insulin regulates intracellular glucose oxidation by multiple mechanisms that include effects on glucose uptake, free fatty acid (FFA) substrate availability, and PDH enzyme activity.