Improved insulin sensitivity and adipose tissue dysregulation after short-term treatment with pioglitazone in non-diabetic, insulin-resistant subjects

Abstract

Aims/hypothesis: We examined whether shortterm treatment with a thiazolidinedione improves insulin sensitivity in non-obese but insulin-resistant subjects and whether this is associated with an improvement in dysregulated adipose tissue (reduced expression of IRS-1, GLUT4, PPARγ co-activator 1 and markers of terminal differentiation) that we have previously documented to be associated with insulin resistance. Methods: Ten nondiabetic subjects, identified as having low IRS-1 and GLUT-4 protein in adipose cells as markers of insulin resistance, underwent 3 weeks of treatment with pioglitazone. The euglycaemic-hyperinsulinaemic clamp technique was used to measure insulin sensitivity before and after treatment. Serum samples were analysed for glucose, insulin, lipids, total and high-molecular-weight (HMW) adiponectin levels. Biopsies from abdominal subcutaneous adipose tissue were taken, cell size measured, mRNA and protein extracted and quantified using real-time RT-PCR and Western blot. Results: Insulin sensitivity was improved after 3 weeks treatment and circulating total as well as HMW adiponectin increased in all subjects, while no effect was seen on serum lipids. In the adipose cells, gene and protein expression of IRS-1 and PPARγ co-activator 1 remained unchanged, while adiponectin, adipocyte P 2, uncoupling protein 2, GLUT4 and liver X receptor-α increased. Insulin-stimulated tyrosine phosphorylation and p-ser-PKB/Akt increased, while no significant effect of thiazolidinedione treatment was seen on the inflammatory status of the adipose tissue in these non-obese subjects. Conclusions/interpretation: Short-term treatment with pioglitazone improved insulin sensitivity in the absence of any changes in circulating NEFA or lipid levels. Several markers of adipose cell differentiation, previously shown to be reduced in insulin resistance, were augmented, supporting the concept that insulin resistance in these individuals is associated with impaired terminal differentiation of the adipose cells.

Changes in adiponectin receptor expression in muscle and adipose tissue of type 2 diabetic patients during rosiglitazone therapy

“…Hammarstedt and colleagues treated non-diabetic insulin-resistant subjects with pioglitazone for 3 weeks and took adipose tissue biopsies before and after treatment [11]. In contrast to our findings, their study did not find any change in adipoR1 and R2 expressions in adipose tissue.…”

Fat cell enlargement is an independent marker of insulin resistance and ‘hyperleptinaemia’

“…Impaired expression of genes regulating adipogenesis, e.g. PPARG and sterol regulatory element binding transcription factor 1, has been shown to be related to insulin resistance [38] and treatment with thiazolidinediones improves insulin sensitivity in parallel with enhancing the differentiation of new, small adipocytes [11,39]. Other suggested mechanisms linking fat cell size and insulin resistance are alterations in the expression pattern of immune-related genes and an altered cholesterol balance in cellular membranes of enlarged adipocytes [40,41].…”

Post-translational Modifications of the Four Conserved Lysine Residues within the Collagenous Domain of Adiponectin Are Required for the Formation of Its High Molecular Weight Oligomeric Complex

“…Several recent studies have demonstrated that the ratio of HMW to total adiponectin is more closely associated with glucose tolerance and insulin sensitivity than the plasma levels of total adiponectin (30,36,37). The HMW/total adiponectin ratio is decreased in obese subjects and in patients with T2DM and coronary heart disease, and this decrease is reversed following moderate weight reduction and treatment with thiazolidinediones (30,35,44). We (29) and others (26) have found that the sexual dimorphism of adiponectin in both humans and rodents is attributed primarily to the difference in the HMW adiponectin, with females having significantly higher levels of this oligomer compared with males.…”