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The aim of this study was to investigate whether high glucose and/or high insulin produces cellular insulin resistance in human adipocytes and, if so, to evaluate the time course and content of key proteins in the insulin signaling pathway. Subcutaneous fat biopsies were taken from 27 nondiabetic subjects. Insulin action in vitro was studied by measurement of glucose uptake after incubation at a physiologic glucose level (6 mmol/L) for 24 hours or with the last 2, 6, or 24 hours at a high glucose level (20 mmol/L) with or without high insulin (10(4)microU/mL). High glucose alone for 24 hours produced a small but significant impairment (by approximately 20%, P < .05) of insulin's effect to stimulate glucose transport, whereas nonstimulated glucose uptake was left intact. In contrast, the combination of high glucose and high insulin for 6 hours or more reduced basal glucose uptake by approximately 40% (P < .05). In addition, insulin-stimulated glucose uptake capacity was reduced by approximately 40% already after 2 hours (P < .05) and reached a maximal decline (by approximately 50%, P < .05) after a 6-hour culture in high glucose and high insulin. Treatment with high glucose and high insulin in combination for at least 6 hours reduced cellular insulin receptor substrate (IRS)-1, but not IRS-2, protein content by approximately 45% or more (P < .05). Moreover, after 24 hours, the ability of insulin to activate protein kinase B (ie, the phosphorylated protein kinase B [pPKB]-protein kinase B ratio) was decreased by approximately 50% (P < .05). No significant effects were seen on insulin signaling proteins or glucose transporter 4 after a long-term high-glucose culture. Culture with high insulin alone (and low glucose, 6 mmol/L) decreased basal and insulin-stimulated glucose uptake in conformity with the high-glucose/high-insulin setting. However, IRS-1 protein content remained unchanged. We conclude that, in adipocytes from healthy humans, high insulin alone for 2 hours or more decrease glucose uptake capacity. Likewise, high glucose and high insulin in combination for 2 hours or more decrease glucose uptake to the same extent as when cells were cultured with high insulin alone but, in addition, with a diminishment in IRS-1 protein lagging behind. Thus, IRS-1 depletion appears to be a secondary phenomenon in this model of insulin resistance. High glucose alone induces only a minor insulin resistance in human fat cells.