Abstract
A marked resistance to the stimulatory action of insulin on glucose metabolism has previously been shown in guinea pig, compared to rat, adipose tissue and isolated adipocytes. The mechanism of insulin resistance in isolated guinea pig adipocytes has, therefore, been examined by measuring 125I-insulin binding, the stimulatory effect of insulin on 3-0-methylglucose transport and on lipogenesis from [3-3H]glucose, the inhibitory effect of insulin on glucagon-stimulated glycerol release, and the translocation of glucose transporters in response to insulin. The translocation of glucose transporters was assessed by measuring the distribution of specific D-glucose-inhibitable [3H]cytochalasin B binding sites among the plasma, and high and low density microsomal membrane fractions prepared by differential centrifugation from basal and insulin-stimulated cells. At a glucose concentration (0.5 mM) where transport is thought to be rate-limiting for metabolism, insulin stimulates lipogenesis from 30 to 80 fmol/cell/90 min in guinea pig cells and from 25 to 380 fmol/cell/90 min in rat cells with half-maximal effects at approximately 100 pM in both cell types. Insulin similarly stimulates 3-O-methylglucose transport from 0.40 to 0.70 fmol/cell/min and from 0.24 to 3.60 fmol/cell/min in guinea pig and rat fat cells, respectively. Nevertheless, guinea pig cells bind more insulin per cell than rat cells, and insulin fully inhibits glucagon-stimulated glycerol release. In addition, the differences between guinea pig and rat cells in the stimulatory effect of insulin on lipogenesis and 3-O-methylglucose transport cannot be explained by the greater cell size of the former compared to the latter (0.18 and 0.09 micrograms of lipid/cell, respectively). However, the number of glucose transporters in the low density microsomal membrane fraction prepared from basal guinea pig cells is markedly reduced compared to that from rat fat cells (12 and 70 pmol/mg of membrane protein, respectively) and the translocation of intracellular glucose transporters to the plasma membrane fraction in response to insulin is correspondingly reduced. These results suggest that guinea pig adipocytes are markedly resistant to the stimulatory action of insulin on glucose transport and that this resistance is the consequence of a relative depletion in the number of intracellular glucose transporters.
Highlights
From the §Laboratory of Cellular and Deuelopmental Biology, and Wellulur Metabolism and Obesity Section, National Znstitute of Arthritis, Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20205
Guinea pig adipose cells may is thought to be rate-limiting for metabolism, insulin be resistant to the stimulatory effect of insulin at the stimulates lipogenesis from 30 to 80 fmol/cell/90 min glucose transport level, a fundamental step in the regulation in guinea pig cells and from25 to 380 fmol/cell/90min of glucose metabolismby insulin [3,4,5]
The differences between guinea pig and rat cells in the stimulatory effect of insulin on lipogenesis and 3-0-methylglucose transport cannot be explained by the greater cell size of the formercompared to the latter(0.18 and 0.09 fig having different properties from the plasma membrane
Summary
From the §Laboratory of Cellular and Deuelopmental Biology, and Wellulur Metabolism and Obesity Section, National Znstitute of Arthritis, Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20205. The differences between guinea pig and rat cells in the stimulatory effect of insulin on lipogenesis and 3-0-methylglucose transport cannot be explained by the greater cell size of the formercompared to the latter(0.18 and 0.09 fig having different properties from the plasma membrane Studies of this insulin-induced “cycling” of glucose transporters have been limited so far to tissues or cells from the rat, in part because of the large magnitude of insulin action on glucose transport in this experimental animal. A major cose transporters to the plasma membrane fraction in defect in animals displaying insulin resistance, at least with response to insulin is correspondingly reduced These respect to glucose utilization, appears to be changes in the results suggest that guinea pig adipocytes are mark- concentration of glucose transporters. Tris and all other reagent grade chemicals were from Sigma
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