ROLE OF BASAL INSULIN IN MAINTENANCE OF INTRACELLULAR GLUCOSE METABOLIC PATHWAYS IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS

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 h ave been well characterized during insulin stimulation, little is know n about the effects of basal insulin or its deficiency on intracellula r glucose metabolism in NIDDM. To determine the physiological signific ance of basal insulin in the maintenance of glucose metabolism in NIDD M, we studied nine subjects with NIDDM in the basal and insulin-defici ent state produced by 3 hours of somatostatin (SRIF) infusion (0.08 pm ol/kg/min). Glucose turnover rates were quantified by [3-H-3]glucose t urnover, and substrate oxidation was assessed by a combination of indi rect calorimetry and urinary nitrogen measurements. Skeletal muscle gl ycogen synthase (GS) and pyruvate dehydrogenase (PDH) activities were also measured in the basal state and during SRIF infusion. Basal gluco se levels were maintained during SRIF infusion by exogenous glucose in fusion (12.5 +/- 0.9 mmol/L in the basal state v 12.8 +/- 0.8 during S RIF 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 nm ol/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). C orresponding measurements of active PDH (PDHa) activity in skeletal mu scle 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 o xidation (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/mi n, P = NS). Although skeletal muscle GS activity was significantly dec reased (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 (N IMGU) during insulinopenia (r = .76, P < .05). In conclusion, approxim ately 35% of basal G(ox) in NIDDM was dependent on basal insulin actio n. Basal N-ox was independent of basal insulin and was determined by t he rate of NIMGU. Basal insulin regulates intracellular glucose oxidat ion by multiple mechanisms that include effects on glucose uptake, fre e fatty acid (FFA) substrate availability, and PDH enzyme activity. Co pyright (C) 1995 by W.B. Saunders Company