Short-Term Overeating Induces Insulin Resistance in Fat Cells in Lean Human Subjects

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.

Carotid Intima-media thickness in childhood and adolescent obesity relations to abdominal obesity, high triglyceride level and insulin resistance

“…Insulin resistance is a common phenomenon and plays an important role in the cardio-cerebrovascular disease in obese population 17,18. In our study, the obese and MetS group both demonstrated increased fasting insulin than control group rather than fasting blood glucose.…”

Proliferation of nutrition sensing preadipocytes upon short term HFD feeding

“…2,3 Long-and short-term overnutrition has been shown to directly influence adipose tissue and to cause hypertrophy, inflammation, insulin resistance, and changes in plasma parameters in mice and humans. 2,[4][5][6][7][8][9] Conversely, removal of HFD was shown to reverse most of these changes. 2,10,11 For some time it was believed, that the total number of fat cells is set during adolescence and a change of fat mass in adults is exclusively caused by hypertrophy.…”

Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2

“…For example, insulin-stimulated activation of ERK1/2 is normal in obese and type 2 diabetic individuals, whereas PI3K activation is impaired or almost absent [86]. ERK1/2 activation is also sensitised to insulin in adipocytes from humans fed a high-energy diet, potentially contributing to the adaptive expansion of adipose tissue [119]. Compatible with this, mice lacking ERK1 exhibit decreased white adipose mass [86], and greater sensitivity to insulin than control mice during high-fat feeding.…”