Short-term overeating induces insulin resistance in fat cells in lean human subjects.
Insulin resistance and type 2 diabetes (T2D) are closely linked to obesity. Numerous prospective studies have reported on weight gain, insulin resistance, and insulin signaling in experimental animals, but not in humans. We examined insulin signaling in adipocytes from lean volunteers, before and at the end of a 4-wk period of consuming a fast-food, high-calorie diet that led to weight gain. We also examined adipocytes from patients with T2D. During the high-calorie diet, subjects gained 10% body weight and 19% total body fat, but stayed lean (body mass index = 24.3 kg/m(2)) and developed moderate systemic insulin resistance. Similarly to the situation in T2D subjects, in subjects on the high-calorie diet, the amount of insulin receptors was reduced and phosphorylation of IRS1 at tyrosine and at serine-307 (human sequence, corresponding to murine serine-302) were impaired. The amount of insulin receptor substrate protein-1 (IRS1) and the phosphorylation of IRS1 at serine-312 (human sequence, corresponding to murine serine-307) were unaffected by the diet. Unlike the T2D subjects, in subjects on the high-calorie diet, likely owing to the ongoing weight-gain, phosphorylation of MAP-kinases ERK1/2 became hyperresponsive to insulin. To our knowledge this study is the first to investigate insulin signaling during overeating in humans, and it demonstrates that T2D effects on intracellular insulin signaling already occur after 4 wks of a high-calorie diet and that the effects in humans differ from those in laboratory animals.
Danielsson
Anna
A
Division of Cell Biology, Department of Clinical and Experimental Medicine, Diabetes Research Centre, University of Linköping,Linköping, Sweden.
Fagerholm
Siri
S
Ost
Anita
A
Franck
Niclas
N
Kjolhede
Preben
P
Nystrom
Fredrik H
FH
Strålfors
Peter
P
D015502:Absorptiometry, Photon; D017667:Adipocytes / Q000378:metabolism*; D000328:Adult; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004032:Diet; D005260:Female; D006801:Humans; D006963:Hyperphagia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction; D013851:Thinness / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D014443:Tyrosine; D012694:Serine; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases