Pioglitazone Improves Whole Body Insulin Sensitivity and Increases Insulin Signaling in Adipose Tissue of Insulin Resistant Patients with Untreated Obstructive Sleep Apnea

Presentation Number: MON-854
Date of Presentation: June 17th, 2013

Alice Liu*1, Shiming Xu2, James Cardell2, Philip S Tsao1, Clete Kushida2 and Gerald M Reaven3
1Stanford Univ, Stanford, CA, 2Stanford University, 3Stanford University, Stanford, CA

Abstract

Patients with obstructive sleep apnea (OSA) are at increased risk for insulin resistance and type 2 diabetes. While treatment of OSA with positive airway pressure (PAP) has been reported to improve insulin sensitivity, low adherence with PAP therapy may mitigate its metabolic benefits. We tested the hypothesis that pioglitazone treatment can enhance insulin action in insulin resistant patients with untreated OSA. Secondary objectives were to ascertain treatment effect on adipose tissue insulin signaling and insulin suppression of lipolysis in isolated adipocytes in vitro.

The steady-state plasma glucose concentration (SSPG) during the insulin suppression test (IST) was used to identify insulin resistance in non-diabetic, obese patients diagnosed with OSA by overnight polysomnogram. Needle aspiration of peri-umbilical subcutaneous adipose tissue was performed in 9 insulin resistant patients, after which patients were administered pioglitazone for 8 weeks (dosage 30 mg daily for 2 weeks, followed by 45 mg daily). In addition, the ability of insulin to suppress isoproterenol-induced free fatty acid (FFA) release was studied in isolated adipocytes in vitro in 5 patients. IST and biopsies were repeated after completing pioglitazone treatment.

After 8 weeks of pioglitazone therapy, SSPG concentrations during the IST were reduced by 33% (216 ± 23 vs. 145 ± 37 mg/dL, P <0.001) among 9 patients with untreated, moderate OSA (mean Apnea-Hypopnea Index 25 events/hr). Adipose tissue lysates harvested from needle biopsies were subjected to Western blotting and demonstrated 1.68–fold increase (P < 0.01) in Akt phosphorylation post-pioglitazone therapy as compared to baseline. The ability of insulin to suppress isoproterenol-induced release of FFA from isolated adipocytes was also enhanced 2.7-fold (P<0.05) in response to pioglitazone.

In conclusion, insulin sensitivity can be enhanced by relatively short-term treatment with pioglitazone in insulin resistant, obese patients with moderate OSA not being treated with PAP. The improvement in whole body insulin action is associated with increased insulin signaling in adipose tissue and the ability of insulin to regulate lipolysis.

 

Nothing to Disclose: AL, SX, JC, PST, CK, GMR