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Pioglitazone Treatment Enlarges Subcutaneous Adipocytes in Insulin-Resistant Patients

Departments of General Internal Medicine (T.B.K., C.J.T., J.M.K., A.F.H.S., J.d.G., L.J.H.v.T., R.S.), Endocrinology (J.M.K., A.R.H.), Pathology (J.v.d.L.), and Chemical Endocrinology (F.C.G.S.), Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands

Address all correspondence and requests for reprints to: Tim B. Koenen, M.Sc., Radboud University Nijmegen Medical Centre, Department of General Internal Medicine 463, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail: t.koenen{at}aig.umcn.nl.

Context: Obesity-related insulin resistance is associated with an increase in adipocyte size. In rodent models, treatment with the insulin-sensitizers thiazolidinediones (TZDs) leads to the appearance of small, insulin-sensitive adipocytes. Whether such TZD-dependent morphological changes occur in adipose tissue of insulin-resistant patients is unclear.

Objective: The objective of the study was to study the effects of treatment with the TZD pioglitazone on sc adipose tissue morphology and function in insulin-resistant subjects.

Design: This was a placebo-controlled, randomized crossover study.

Setting: The study was conducted at a university medical center.

Patients: Twelve adult patients with congenital adrenal hyperplasia (CAH) characterized by insulin resistance were included in this study.

Intervention: After a 4-wk run-in phase, patients were treated with pioglitazone (45 mg/d) followed by placebo, each for 16 wk or vice versa.

Main Outcome Measures: After both placebo and pioglitazone treatment, insulin sensitivity was determined by hyperinsulinemic euglycemic clamp and abdominal sc adipose tissue was obtained to measure adipocyte cell surface and expression of genes involved in glucose uptake and inflammation.

Results: Pioglitazone treatment significantly improved the insulin sensitivity index (placebo: 0.35 ± 0.16 µmol/kg · min per milliunit per liter; pioglitazone 0.53 ± 0.16 µmol/kg · min per milliunit per liter, P < 0.001) and increased mRNA expression levels of adiponectin and glucose transporter-4 in adipose tissue. The increase in insulin sensitivity was accompanied by a significant enlargement of the sc adipocyte cell surface (placebo: 2323 ± 725 µm²; pioglitazone 2821 ± 885 µm², P = 0.03).

Conclusions: In the human situation, treatment of insulin-resistant subjects with pioglitazone improves insulin sensitivity, whereas at the same time, sc adipocyte cell surface increases.