Muscle insulin resistance in uremic humans: glucose transport, glucose transporters, and insulin receptors.
To determine the cellular basis for insulin resistance observed in patients with uremia, we investigated insulin action in vivo and in vitro using skeletal muscle obtained from patients with chronic renal failure. Uremic subjects had significantly reduced rates of insulin-stimulated glucose disposal, as determined by a 3-h intravenous glucose tolerance test and using the hyperinsulinemic euglycemic clamp technique. Hepatic glucose production was similar before (control, 76.2 +/- 6.3 vs. uremic, 74.2 +/- 6.9 mg.kg-1.min-1) and during insulin infusion at 40 mU.m-2.min-1 (control, -60.9 +/- 6.6 vs. uremic, -53.9 +/- 6.3 mg.kg-1.min-1). In incubated human skeletal muscle fiber strips, basal 2-deoxy-D-glucose transport was unchanged in uremic subjects compared with controls. However, the increase in insulin-stimulated glucose transport was significantly reduced by 50% in muscles from uremic patients (P = 0.012). In partially purified insulin receptors prepared from skeletal muscle, 125I-labeled insulin binding, beta-subunit receptor autophosphorylation, and tyrosine kinase activity were all unchanged in uremic subjects. The abundance of insulin-sensitive (muscle/fat, GLUT-4) glucose transporter protein measured by Western blot using Mab 1F8 or polyclonal antisera was similar in muscles of control and uremic patients. These findings suggest that the insulin resistance observed in skeletal muscle of uremic patients cannot be attributed to defects in insulin receptor function or depletion of the GLUT-4 glucose transporter protein. An alternative step in insulin-dependent activation of the glucose transport process may be involved.
Friedman
J E
JE
Department of Medicine, School of Medicine, East Carolina University, Greenville, North Carolina 27858-4354.
Dohm
G L
GL
Elton
C W
CW
Rovira
A
A
Chen
J J
JJ
Leggett-Frazier
N
N
Atkinson
S M
SM
Thomas
F T
FT
Long
S D
SD
Caro
J F
JF
D000328:Adult; D000906:Antibodies / Q000276:immunology; D015153:Blotting, Western; D005260:Female; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000276:immunology / Q000378:metabolism*; D009132:Muscles / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction; D014511:Uremia / Q000188:drug therapy / Q000378:metabolism*
D000906:Antibodies; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D011494:Protein Kinases; D011972:Receptor, Insulin; D005947:Glucose