Abnormal glucose transport and GLUT1 cell-surface content in fibroblasts and skeletal muscle from NIDDM and obese subjects.
Glucose transport and GLUT1 expression were studied in fibroblasts from 7 lean and 5 obese non-insulin-dependent diabetic (NIDDM) subjects with at least 2 NIDDM first-degree relatives and from 12 lean and 5 obese non-diabetic subjects with no family history of diabetes. The obese individuals also had a strong family history of obesity. Fibroblasts from all of the subjects exhibited no difference in insulin receptor binding, autophosphorylation, and kinase and hexokinase activity. At variance, basal 2-deoxyglucose (2-DG) uptake and 3H-cytochalasin B binding were 50% increased in cells from individuals with NIDDM (p < 0.001) and/or obesity (p < 0.01) as compared to the lean non-diabetic subjects. Insulin-dependent (maximally stimulated-basal) 2-DG uptake and cytochalasin B binding were decreased three-fold in cells from the diabetic and/or obese subjects (p < 0.01). GLUT1 mRNA and total protein levels were comparable in fibroblasts from all the groups. However, basal GLUT1 cell-surface content was 50% greater in fibroblasts from the NIDDM and/or obese subjects as compared to the lean non-diabetic individuals while insulin-dependent GLUT1 recruitment at the cell surface was diminished three-fold. Increased basal GLUT1 content in the plasma membrane was also observed in skeletal muscle of 4 NIDDM and 3 non-diabetic obese individuals (p < 0.05 vs the lean non diabetic subjects). Basal 2-DG uptake in fibroblasts from diabetic/obese individuals and lean control subjects strongly correlated with the in vivo fasting plasma insulin concentration of the donor. A negative correlation was demonstrated between the magnitude of insulin-dependent glucose uptake by the fibroblasts and plasma insulin levels in vivo. We conclude that a primary abnormality in glucose transport and GLUT1 cell-surface content is present in fibroblasts from NIDDM and obese individuals. The abnormal GLUT1 content is also present in skeletal muscle plasma membranes from NIDDM and obese individuals.
Miele
C
C
C.N.R. Center of Experimental Endocrinology and Oncology, Naples, Italy.
Formisano
P
P
Condorelli
G
G
Caruso
M
M
Oriente
F
F
Andreozzi
F
F
Tocchetti
C G
CG
Riccardi
G
G
Beguinot
F
F
D000328:Adult; D000368:Aged; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003847:Deoxyglucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood; D007700:Kinetics; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D011972:Receptor, Insulin / Q000378:metabolism*; D012016:Reference Values; D012044:Regression Analysis; D012867:Skin / Q000378:metabolism*; D013851:Thinness / Q000378:metabolism; D014158:Transcription, Genetic
D001786:Blood Glucose; D051272:Glucose Transporter Type 1; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; C495677:SLC2A1 protein, human; D003847:Deoxyglucose; D006593:Hexokinase; D011972:Receptor, Insulin; D005947:Glucose