Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM

• Published in: Diabetes (New York, N.Y.) Vol. 41; no. 4; pp. 465 - 475
• Main Authors: Garvey, W. T., Maianu, L., Hancock, J. A., Golichowski, A. M., Baron, A.
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01-04-1992
• ISSN: 0012-1797; 1939-327X; 0012-1797
• DOI: 10.2337/diabetes.41.4.465

Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM.
W T Garvey ,
L Maianu ,
J A Hancock ,
A M Golichowski and
A Baron
Section of Endocrinology, Indianapolis Veterans Administration Medical Center, IN.
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.