Mechanisms of decreased insulin responsiveness of large adipocytes.

UNLABELLED

We have studied glucose metabolism using large adipocytes isolated from older, fatter rats (greater than 12 months old, greater than 550 g), and smaller cells obtained from younger, leaner animals (4-5 weeks old, 126-160 g). 2-Deoxyglucose uptake was equal in large and small adipocytes, while insulin mediated oxidation of [1(-14)C]glucose was greatly diminished (7-fold) in large cells. Thus, the defect in oxidation of the number one carbon atom of glucose (pentose pathway oxidation) is distal to the 2-deoxyglucose uptake system. However, this intracellular defect is not present in all pathways of glucose oxidation as demonstrated by the finding that [6(-14)C]glucose oxidation was comparable in small and large adipocytes. Thus, the number six carbon atom of glucose is oxidized normally indicating that glycolytic and Krebs cycle activity is intact in the large adipocyte. Furthermore, in large adipocytes conversion of glucose to total lipid was normal in the basal state and moderately decreased at high glucose concentrations in the presence of insulin (up to 35%). When the radioactivity in total lipids was fractionated, a severe decrease in glucose incorporation into fatty acids was found in the large cells. Total glucose uptake was also measured, and found to be 10-50% decreased in large cells, suggesting that the decreases in pentose pathway glucose metabolism and conversion to fatty acids lead to accumulation of free intracellular glucose with glucose efflux and a decrease in net glucose uptake. Comparing the 2-deoxyglucose uptake and glucose oxidation data showed that insulin promotes [6(-14)C]glucose oxidation by stimulating the processes responsible for 2-deoxyglucose uptake whereas insulin promotes [1(-14)C]glucose oxidation both by increasing these processes and by increasing the activity of the C-1 oxidative pathway.

IN CONCLUSION

1. the 2-deoxyglucose uptake system of the large adipocyte is basically intact, 2) [1(-14)C]glucose oxidation is markedly decreased in large adipocytes, while [6(-14)C]glucose oxidation is normal, and 3) in comparing small and large adipocytes, it appears that it is the ability of insulin to enhance glucose oxidation via the pentose pathway and to promote glucose incorporation into fatty acids which is most impaired in large adipocytes.