Oxidative and non-oxidative glucose metabolism in non-obese Type 2 (non-insulin-dependent) diabetic patients

Abstract

Insulin resistance is a common feature of Type 2 (non-insulin-dependent) diabetes mellitus. This defect in insulin-mediated glucose metabolism could result from a defect in either glucose oxidation or non-oxidative glucose disposal. To examine this question, euglycaemic insulin clamp studies were performed in 16 normal weight Type 2 and 11 age-matched control subjects. In Type 2 diabetic patients the fasting plasma glucose concentration, 8.39 +/- 0.50 mmol/l, was allowed to decline (over 54 +/- 6 min) to 5.33 +/- 0.11 mmol/l before starting the insulin clamp. Total body glucose uptake was significantly decreased in Type 2 diabetic patients vs control subjects (148 +/- 15 vs 264 +/- 25 mg/min.m2, p less than 0.001). Both total glucose oxidation (59 +/- 6 vs 89 +/- 6 mg/min.m2, p less than 0.005) and non-oxidative glucose disposal (89 +/- 15 vs 179 +/- 24 mg/min.m2, p less than 0.005) were significantly reduced in the Type 2 diabetic patients. Basal glucose oxidation was also reduced in the Type 2 diabetic patients (22 +/- 3 vs 38 +/- 5 mg/min.m2, p less than 0.01). In conclusion, during the postabsorptive state and under conditions of euglycaemic hyperinsulinaemia, impairment of glucose oxidation and non-oxidative glucose disposal both contribute to the insulin resistance observed in normal weight Type 2 diabetic patients. Since lipid oxidation was normal in this group of diabetic patients, excessive non-esterified fatty acid oxidation cannot explain the defects in glucose disposal.

Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake.

“…Impaired fat oxidation was not responsible for the defect in glucose oxidation since rates of fat oxidation were identical in the NIDDM and control subjects under both basal and stimulated rates of glucose uptake. The similarity in fat oxidation rates and free fatty acid levels in control and NIDDM subjects despite reduced rates ofglucose oxidation in the NIDDM subjects in our study is supported by the findings of a number of researchers who have shown that fat metabolism in non-obese NIDDM subjects is normal despite impaired insulin-mediated glucose utilization (3)(4)(5)(45)(46)(47). Therefore, in nonobese NIDDM subjects, the defect in glucose oxidation is not associated with increased fat oxidation.…”

“…Many studies have shown that rates of intracellular glucose metabolism are lower in NIDDM subjects than nondiabetic subjects (2,3,5,6). However, reduced rates of glucose oxidation and nonoxidative glucose metabolism in these studies have always been accompanied by reduced rates of glucose uptake, therefore making it impossible to determine whether these reduced rates of glucose metabolism are due to intracellular defects or simply a result of less glucose entering the cell.…”

“…In addition to defects in oxidative glucose metabolism, defects in total nonoxidative glucose metabolism have been reported in NIDDM (2)(3)(4)(5)(6)(7)15). The close correlations found between decreases in nonoxidative glucose metabolism and decreases in insulin-mediated glucose uptake (2-10) have lead several investigators to speculate that defects in nonoxidative glucose metabolism may be the cause of reduced rates of glucose uptake in NIDDM and other states of insulin resistance (7,(10)(11)(12)(13)(14)(15).…”

Effects of acute hyperglycemia on myocardial glycolytic activity in humans.

“…Hyperglycemic or euglycemic insulin clamp techniques have been used to investigate total body glucose uptake and oxidation, and glucose metabolism in skeletal muscle and other organ systems in healthy human subjects (1)(2)(3)(4)(5)(6). However, little is known about the effects of hyperglycemia on glucose utilization in the hearts of intact animals and humans.…”

Whole-Body Glycolysis Measured by the Deuterated-Glucose Disposal Test Correlates Highly With Insulin Resistance In Vivo

“…Most attention has been given to the effects of insulin resistance on glycogen storage in tissues such as skeletal muscle, but glycolytic disposal of glucose shares the steps of glucose transport and phosphorylation, which are likely to play key roles in insulin sensitivity (24), and glycolytic enzymes are sensitive to insulin. Moreover, at serum insulin concentrations in the "dynamic range" between basal and maximal (i.e., between ϳ100 and 1000 pmol/l), glycolytic disposal of glucose closely parallels glycogen storage in clamp studies and is impaired to a similar extent by insulin resistance (25,26). Measurement of glycolysis has a major advantage over glycogen synthesis, however, because tissue glycogen is not readily accessible to sampling, whereas an immediate product of glycolysis (hydrogen atoms released to tissue water) can be tagged, traced, and sampled in body fluids.…”