Role of glucose transporters in the cellular insulin resistance of type II non-insulin-dependent diabetes mellitus.

Abstract

To examine the role of glucose transport proteins in cellular insulin resistance, we studied subcutaneous adipocytes isolated from lean control, obese control (body mass index [BMII 33.4±0.9), and untreated obese non-insulin-dependent diabetes mellitus (NIDDM) patients (BMI 35.2±2.1; fasting glucose 269±20 mg/dl). Glucose transporters were measured in plasma membrane (PM), low-density (LDM), and high-density (HDM) microsomal subfractions from basal and maximally insulin-stimulated cells using the cytochalasin B binding assay, and normalized per milligram of membrane protein. In all subgroups, insulin led to an increase in PM glucose transporters and a corresponding depletion of transporters in the LDM. Insulin recruited 20% fewer transporters to the PM in the obese subgroup when compared with lean controls, and this was associated with a decline in LDM transporters with enlarging cell size in the control subjects. In NIDDM, PM, and LDM, transporters were decreased 50% in both basal and stimulated cells when compared with obese controls having similar mean adipocyte size. Cellular depletion of glucose transporters was not the only cause of insulin resistance, because the decrease in rates of '4Cj-D-glucose transport (basal and insulin-stimulated) was greater than could be explained by reduced numbers of PM transporters in both NIDDM and obesity. In HDM, the number of transporters was not influenced by insulin and was similar in all subgroups. We conclude that (a) in NIDDM and obesity, both reduced numbers and impaired activity of glucose transporters contribute to cellular insulin resistance, and (b) in NIDDM, more profound cellular insulin resistance is associated primarily with a further depletion of cellular transporters.

The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro

“…The reduced maximal insulin responsiveness and sensitivity of glucose transport in these cells may originate from a postinsulin binding and coupling defect between the insulin receptor and the translocation machinery and synthesis of GLUT mole cules, because we observed impaired redistribution of GLUT1 and GLUT4 from LDM to PM and a lowered total number of GLUT1 and GLUT4. Both reduced transloca tion and synthesis of GLUT4 are characteristic features for adipose tissue of obese and nonobese NIDDM pa tients (48,49). This suggests similar mechanisms of fat cell insulin resistance operating in vivo and in vitro.…”

Glucose uptake and insulin action in human adipose tissue—influence of BMI, anatomical depot and body fat distribution

“…Adipose tissue glucose uptake and obesity M Stolic et al glucose uptake in isolated adipocytes in obese subjects 15,16 whereas others have found no changes. 14,17 In our study basal glucose transport was reduced in adipose tissue samples from overweight and obese compared to lean subjects, reaching statistical significance in obese subjects.…”

“…In view of these factors, our results are comparable with the results obtained using isolated human adipocytes. 15,21,22 For example, Garvey et al 15 reported a 1.7-fold increase in glucose uptake in lean subjects and a 1.3 fold increase in obese subjects and Marette et al 22 reported a 1.3 -fold increase in severely obese women. Only a few studies have examined differences in insulinmediated glucose uptake between intra-abdominal and subcutaneous adipose tissue.…”

Prolonged glucose infusion into conscious rats inhibits early steps in insulin signalling and induces translocation of GLUT4 and protein kinase C in skeletal muscle

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Impairment of the glucose transport in the insulinsensitive tissues contributes to the pathogenesis of Type II (non-insulin-dependent) diabetes mellitus [1,2]. Skeletal muscle represents the most important tissue for the maintenance of a balanced postprandial glucose homeostasis; about 80 % of insulin-stimulated glucose uptake is accounted for by muscle [3±5].

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