Gene Expression of GLUT4 in Skeletal Muscle From Insulin-Resistant Patients With Obesity, IGT, GDM, and NIDDM

Abstract

In obesity, impaired glucose tolerance (IGT), non-insulin-dependent diabetes mellitus (NIDDM), and gestational diabetes mellitus (GDM), defects in glucose transport system activity, contribute to insulin resistance in target tissues. In adipocytes from obese and NIDDM patients, we found that pretranslational suppression of the insulin-responsive GLUT4 glucose transporter isoform is a major cause of cellular insulin resistance; however, whether this process is operative in skeletal muscle is not clear. To address this issue, we performed percutaneous biopsies of the vastus lateralis in lean and obese control subjects and in obese patients with IGT and NIDDM and open biopsies of the rectus abdominis at cesarian section in lean and obese gravidas and gravidas with GDM. GLUT4 was measured in total postnuclear membrane fractions from both muscles by immunoblot analyses. The maximally insulin-stimulated rate of in vivo glucose disposal, assessed with euglycemic glucose clamps, decreased 26% in obesity and 74% in NIDDM, reflecting diminished glucose uptake by muscle. However, in vastus lateralis, relative amounts of GLUT4 per milligram membrane protein were similar (NS) among lean (1.0 +/- 0.2) and obese (1.5 +/- 0.3) subjects and patients with IGT (1.4 +/- 0.2) and NIDDM (1.2 +/- 0.2). GLUT4 content was also unchanged when levels were normalized per wet weight, per total protein, and per DNA as an index of cell number. Levels of GLUT4 mRNA were similarly not affected by obesity, IGT, or NIDDM whether normalized per RNA or for the amount of an unrelated constitutive mRNA species. Because muscle fibers (types I and II) exhibit different capacities for insulin-mediated glucose uptake, we tested whether a change in fiber composition could cause insulin resistance without altering overall levels of GLUT4. However, we found that quantities of fiber-specific isoenzymes (phopholamban and types I and II Ca(2+)-ATPase) were similar in all subject groups. In rectus abdominis, GLUT4 content was similar in the lean, obese, and GDM gravidas whether normalized per milligram membrane protein (relative levels were 1.0 +/- 0.2, 1.3 +/- 0.1, and 1.0 +/- 0.2, respectively) or per wet weight, total protein, and DNA. We conclude that in human disease states characterized by insulin resistance, i.e., obesity, IGT, NIDDM, and GDM, GLUT4 gene expression is normal in vastus lateralis or rectus abdominis. To the extent that these muscles are representative of total muscle mass, insulin resistance in skeletal muscle may involve impaired GLUT4 function or translocation and not transporter depletion as observed in adipose tissue.

Muscle GLUT4 in cirrhosis

“…It contrasts the normal values reported in other insulin resistant states such as obesity and type 2 diabetes [33,34]. The decrease was not caused by an overall reduction in mRNA levels since the patients had normal levels of b-actin.…”

The effect of insulin on expression of genes and biochemical pathways in human skeletal muscle

“…Tissues obtained under these conditions have yielded high quality RNA for measurement of gene expression in previous studies [8][9][10].…”

“…Percutaneous needles biopsies of the vastus lateralis were performed as previously described [7,8]. In each subject, one biopsy was performed under basal conditions after an overnight fast prior to the clamp study, and a second was performed in the contralateral leg after 3 h of steady-state hyperinsulinemia.…”

Dangnyohwan improves glucose utilization and reduces insulin resistance by increasing the adipocyte-specific GLUT4 expression in Otsuka Long-Evans Tokushima Fatty rats

“…In addition, decreases in GLUT4 in adipose tissues but not in skeletal muscles have been reported in NIDDM and obese patients (Garvey et al, 1991(Garvey et al, , 1992. Recently, Miura et al revealed that the high-fat diet responsive cis-element (HFRE) located in GLUT4 gene is responsible for the adipocyte-specific down regulation of GLUT4 by high-fat diet.…”