Abstract
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.
Highlights
Type 2 diabetes (T2D) is closely linked to obesity [1] and is attributable to reduced sensitivity to insulin in the main target tissues of this hormone, and failure of the insulin-producing β-cells of the pancreas to increase the release of insulin to compensate for the reduced insulin sensitivity
Control of target cells by insulin involves binding to and activating cell-surface receptors via autophosphorylation of tyrosine residues. These are recognized by a set of signal transducers, the insulin receptor substrate protein-1 (IRS1), which in turn is phosphorylated on tyrosine residues
We observed no significant effect of the high-calorie diet on the concentration of IRS1 protein (Table 3), nor did we detect any difference in the concentration of IRS1 in adipocytes from patients with T2D compared with the group of nondiabetic subjects (Table 3)
Summary
Type 2 diabetes (T2D) is closely linked to obesity [1] and is attributable to reduced sensitivity to insulin in the main target tissues of this hormone, and failure of the insulin-producing β-cells of the pancreas to increase the release of insulin to compensate for the reduced insulin sensitivity. Control of target cells by insulin involves binding to and activating cell-surface receptors via autophosphorylation of tyrosine residues. These are recognized by a set of signal transducers, the insulin receptor substrate protein-1 (IRS1), which in turn is phosphorylated on tyrosine residues. Tyrosine-phosphorylated IRS1 can bind Grb, which initiates a Ras-mediated activation of MAPkinases ERK1/2 for mitogenic control via phosphorylation of transcription factors. In T2D, insulininduced phosphorylation of IRS1 on tyrosine residues has been shown to be impaired in both human skeletal muscle [4,5,6,7] and adipose tissue [8,9]. In adipocytes from patients with T2D we have found that a positive feedback control loop, involving phosphorylation of IRS1
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