Decreased insulin responsiveness of glucose uptake in cultured human skeletal muscle cells from insulin-resistant nondiabetic relatives of type 2 diabetic families.
To investigate the contribution of inherited biochemical defects to the peripheral insulin resistance of type 2 diabetes, we studied cultured skeletal muscle from 10 insulin-resistant nondiabetic first-degree relatives of type 2 diabetic families and 6 control subjects. Insulin stimulation of glucose uptake and glycogen synthesis was maximal in myoblasts. Insulin-stimulated glucose uptake (fold-stimulation over basal uptake) was decreased in relative compared with control myoblasts at 0.001 micromol/l (0.93 +/- 0.05 [mean +/- SE] vs. 1.15 +/- 0.06, P < 0.05) and 0.1 micromol/l (1.38 +/- 0.10 vs. 1.69 +/- 0.08, P = 0.025) insulin. Insulin responsiveness was markedly impaired in 5 of the relative myoblast cultures, and in 4 of these, there was an associated increase in basal glucose uptake (76.7 +/- 7.0 vs. 47.4 +/- 5.5 pmol x min(-1) x mg(-1) protein, relative vs. control; P < 0.02). Expression of insulin receptor substrate 1, phosphatidylinositol 3-kinase, protein kinase B, and glycogen synthase was normal in the relative cultures with impaired insulin responsiveness. Glycogen synthesis was also normal in the relative cultures. We conclude that the persistence of impaired insulin responsiveness in some of the relative cultures supports the role of inherited factors in the insulin resistance of type 2 diabetes and that the association with increased basal glucose uptake suggests that the 2 abnormalities may be linked.
Jackson
S
S
Human Diabetes and Metabolism Research Group, University of Newcastle upon Tyne, UK.
Bagstaff
S M
SM
Lynn
S
S
Yeaman
S J
SJ
Turnbull
D M
DM
Walker
M
M
D000328:Adult; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005060:Europe; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D006003:Glycogen / Q000096:biosynthesis; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D014316:Tritium
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; D014316:Tritium; D006003:Glycogen; D005947:Glucose