Insulin Treatment Reverses the Postreceptor Defect in Adipocyte 3-O-Methylglucose Transport in Type II Diabetes Mellitus*

Abstract

The insulin resistance of type II diabetes mellitus is due to both receptor and postreceptor defects of in vivo insulin action, with the postreceptor defect being the predominant abnormality. Diminished glucose transport has been found in adipocytes from patients with type II diabetes, suggesting that decreased cellular glucose transport activity may be responsible in part for the in vivo postreceptor defect observed in these patients. Recent studies have shown that the in vivo postreceptor defect initially present in patients with Type II diabetes is significantly reversed by insulin therapy. For these reasons, we speculated that the defect in adipocyte glucose transport might also be corrected with exogenous insulin therapy. Therefore, we measured adipocyte 3-O-methylglucose transport in cells from five type II diabetic subjects before and after a 2-week period of intensive insulin treatment. Glycemic control was significantly improved by this regimen. The mean (+/- SE) fasting serum glucose level fell from 292 +/- 24 to 135 +/- 29 mg/100 ml (P less than 0.005), and the mean integrated glucose area under a 7-h meal tolerance test curve decreased from 171,212 +/- 20,403 to 72,408 +/- 9,292 mg/min . dl. The mean 3-O-methylglucose transport activity increased after treatment at all insulin concentrations studied, including basal (before, 0.18 +/- 0.05; after, 0.45 +/- 0.09 pmol/2 X 10(5) cells . 10 sec; P less than 0.005) and maximally effective (25 ng/ml) insulin concentrations (before, 0.50 +/- 0.14; after, 1.32 +/- 0.30 pmol/2 X 10(5) cells . 10 sec; P less than 0.025), although the mean maximal glucose transport activity was still 25% decreased compared to normal values, indicating that a residual in vitro postreceptor defect remained. These results corresponded well with the degree of reversal (75%) of the in vivo postreceptor defect, as assessed by the euglycemic glucose clamp technique. These studies demonstrated that the decrease in adipocyte glucose transport activity in type II diabetes is practically reversible by intensive insulin therapy. This closely corresponds to the reversal by insulin therapy of the postreceptor defect expressed in vivo and provides further evidence that a cellular cause of the postreceptor defect in type II diabetes is a decrease in glucose transport system activity in the major insulin target tissues.

Glucosamine induces insulin resistance in vivo by affecting GLUT 4 translocation in skeletal muscle. Implications for glucose toxicity.

“…In NIDDM, insulin resistance can be partially reversed by treatment modalities which lower ambient hyperglycemia (5)(6)(7)(8)(9)(10)(11)48). Therefore, it appears that insulin resistance is multicomponential and comprised of reversible and nonreversible biochemical defects.…”

“…In vivo data have suggested that hyperglycemia per se can induce or worsen insulin resistance. In patients with NIDDM, induction of euglycemia by weight reduction (5), sulfonylureas (6,7), or insulin therapy (8,9) results in significant amelioration of insulin sensitivity, as well as increased glucose transport rates measured in adipocytes (5,10) and skeletal muscle (11) obtained from these patients. Likewise, patients with insulin-dependent diabetes mellitus (IDDM) in poor glycemic control exhibit insulin resistance which can be reversed by intensified insulin therapy designed to achieve near normal glycemia (12, 13).…”

Facilitative glucose transporters: regulatory mechanisms and dysregulation in diabetes.

“…Stimulation of glucose transport by insulin is markedly impaired in adipose cells from humans with non-insulin-dependent diabetes mellitus (NIDDM)' (12) and this defect reverses with insulin treatment (35,58). Recent evidence demonstrates a striking decrease in GLUT4 mRNA and protein levels in adipose cells from obese humans and an even greater reduction in obese NIDDM subjects (12 , Table III).…”

“…Importantly, it is uncommon and other mutations in the coding region ofthe GLUT4 gene are unlikely in the vast majority of cases of NIDDM (72). The impairment in insulin-stimulated glucose transport in NIDDM is probably due in part to hyperglycemia, since it is partially reversed with good glycemic control (35,58) and it is also observed in IDDM and in animal models ofinsulin-deficient diabetes (1 1,12,46) in which restoration ofeuglycemia without insulin therapy results in normalization of insulin-stimulated glucose transport and in vivo glucose disposal (46).…”

A case for glucosamine

“…In patients with noninsulin-dependent diabetes mellitus (NIDDM), induction of euglycemia with weight reduction (5), sulfonylureas (6,7), or insulin therapy (8,9) results in significant amelioration of insulin sensitivity as well as increased glucose transport rates measured in adipocytes (5,10) and skeletal muscle (11). Similarly, patients with insulin-dependent diabetes mellitus (IDDM) in poor glycemic control exhibit insulin resistance which can be reversed by intensified insulin therapy designed to achieve near normal glycemia (12,13).…”