Insulin signal transduction and glucose transport in human adipocytes: effects of obesity and low calorie diet.
OBJECTIVE
We examined insulin signal transduction at the level of insulin receptor substrates (IRS) 1 and 2, phosphatidylinositol (PI) 3-kinase and glucose transport in isolated subcutaneous adipocytes from obese and lean women.


METHODS
Glucose transport and insulin signalling were investigated in isolated adipocytes from six obese women (BMI 36-43 kg/m(2)) (before and after 11 days of very low calorie diet) and from six lean women (BMI 22-26 kg/m(2)).


RESULTS
Insulin sensitivity of glucose transport was reduced in adipocytes from obese women (p<0.05), with further reductions in basal and maximal insulin-stimulated glucose transport after a very low calorie diet (p<0.05). In obese women, IRS-1 associated PI 3-kinase activity was markedly impaired (p<0.05), whereas, IRS-2 associated PI 3-kinase activity was normal. IRS-1 associated PI 3-kinase activity remained blunted after a very low calorie diet, whereas IRS-2 associated PI 3-kinase activity was increased. GLUT4 protein was reduced by 37% in obese versus lean subjects (p<0.05), and decreased further after a very low calorie diet (from 19+/-4 to 14+/-4 arbitrary units; p<0.05).


CONCLUSIONS
IRS-1 signalling to PI 3-kinase is a site of insulin resistance in adipocytes from obese women, whereas insulin action on IRS-2 is normal. Thus, IRS-1 and IRS-2 undergo differential regulation in adipocytes from obese insulin resistant subjects. Finally, a very low calorie diet is associated with a further impairment in glucose transport in adipose tissue. The defect in glucose transport after a very low calorie diet occurs independent of further defects in insulin signalling at the level of the PI 3-kinase.
Björnholm
M
M
Section of Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
Al-Khalili
L
L
Dicker
A
A
Näslund
E
E
Rössner
S
S
Zierath
J R
JR
Arner
P
P
D017667:Adipocytes / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D001692:Biological Transport / Q000502:physiology; D002457:Cell Extracts / Q000737:chemistry; D002149:Energy Intake; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008875:Middle Aged; D009765:Obesity / Q000178:diet therapy* / Q000378:metabolism*; D009994:Osmolar Concentration; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D002457:Cell Extracts; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011506:Proteins; D019869:Phosphatidylinositol 3-Kinases; D005947:Glucose