Insulin resistance in adipocytes: Novel insights into the pathophysiology of metabolic syndrome

Abstract

Insulin resistance in all major target tissues is present in metabolic syndrome (MetS). The resistance in adipocytes is not well described and was presently examined. In this observational study on isolated abdominal white subcutaneous adipocytes from 419 adults, concentration-response effects of insulin on lipolysis inhibition (glycerol release) and lipogenesis stimulation (glucose conversion to total lipids) were determined. Insights into early and late insulin signaling events were obtained through the determination of insulin sensitivity (half maximum effective concentration) and responsiveness (maximum effect), respectively. In a subgroup of 132 subjects, we analyzed the subcutaneous adipose mRNA expression of genes in the canonical insulin signaling pathway using microarray. These results were validated using quantitative real-time polymerase chain reaction in 74 individuals. While the insulin responsiveness was similar in subjects with or without Mets, the sensitivity to insulin-mediated inhibition of lipolysis and stimulation of lipogenesis was ∼tenfold lower in subjects with MetS (p<0.0001). When age, sex, adipocyte volume, body mass index and body shape were considered, only the antilipolytic resistance was independently associated with MetS. The mRNA expression of several genes in the canonical insulin signaling pathway were altered in MetS (p<0.0006 or better) where the mRNA levels of insulin receptor substrate 2 associated with the antilipolytic effect (Rho=0.34; p=0.0016). The sensitivities of the antilipolytic and lipogenic effects of insulin are decreased in the MetS but only antilipolysis remains significant after multiple regression analysis. This resistance is localized at initial and receptor-near events in hormone signaling involving insulin receptor substrate 2.