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Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
 
J Clin Invest. Jun 1976; 57(6): 1523–1532.
PMCID: PMC436811
Cellular basis of insulin insensitivity in large rat adipocytes.
M P Czech
Abstract
The marked stimulatory effect of insulin on the conversion of 20 mM D-[6-14C]glucose to CO2, glyceride-glycerol, and fatty acid observed in small rat adipocytes was greatly diminished in large cells from older rats. Similarly, total glucose utilization as estimated by summing the total metabolites accumulated intracellularly plus the release of labeled CO2 and lactate was substantially lower in large cells in the presence of insulin and 5 mM labeled glucose. However, under conditions of 0.2 mM medium glucose where transport of the hexose into adipocytes is relatively more rate-limiting for subsequent metabolism, large cells actually utilized slightly greater total amounts of glucose than small cells in the presence of insulin. Increments of total glucose utilization due to both submaximal and maximal doses of insulin were similar in large and small cells incubated with a low glucose concentration. Under these conditions, conversion of labeled glucose to CO2 and fatty acid in response to insulin was somewhat diminished in large cells, while conversion to glyceride-glycerol was enhanced. The activity of the D-glucose transport system in large and small cells was estimated by monitoring initial rates and small cells was estimated by monitoring initial rates of 3-O-[3H]methylglucose uptake by a rapid filtration method. Transport system activity on a per cell basis was actually severalfold higher in large adipocytes in the basal state as well as in the presence of submaximal and maximal concentrations of insulin compared to small cells. However, the percent stimulation by insulin was less in the large cells. Uptake of 2-deoxyglucose under basal conditions and in response to insulin was also higher in large cells compared to small cells. Analysis of the accumulated label in extracts from fat cells incubated with D-[14C]deoxyglucose revealed the presence of free deoxyglucose, deoxyglucose-6-phosphate, and 6-phosphodeoxygluconate. The levels of these metabolites were significantly higher in large cells compared to small cells indicating hexokinase activity appears not to account for the defective glucose utilization in large cells at high glucose concentrations. It is concluded that (a) possible defects in insulin receptor components, the D-glucose transport system, and the coupling mechanism which links these entities do not significantly contribute to the apparent insulin-insensitivity of large fat cells and (b) the principal cellular defect which confers this blunted insulin response to large rat adipocytes involves one or more intracellular enzymes involved in glucose metabolism.
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