Effects of Pioglitazone on High-density Lipoprotein (HDL) Function in Persons With Diabetes

Summary

Metabolic defects contributing to the development of type 2 diabetes (T2D) are relative insulin insufficiency and insulin resistance that are associated with a cluster of abnormalities that increase the risk for cardiovascular disease including dyslipidemia, inflammation, hemodynamic changes and endothelial dysfunction. The dyslipidemia associated with T2D is characterized by elevated triglycerides and decreased high-density lipoprotein-cholesterol (HDL). The ability of the insulin sensitizing agent pioglitazone (ACTOS®) , to improve hyperglycemia in subjects with T2D is now well established. Pioglitazone functions as a PPAR-γ (peroxisome proliferator-activated receptor gamma) agonists and this class of drugs have demonstrated several other potential benefits, beyond glucose homeostasis. Specifically pioglitazone can improve diabetic dyslipidemia by increasing HDL cholesterol and lowing triglycerides. A potential beneficial effect on reverse cholesterol transport may be mediated by the increased HDL levels. This proposal aims to examine the effect of PPAR-γ activation by PIO on various aspects of reverse cholesterol transport by testing the hypothesis that PIO treatment affects key steps in the reverse cholesterol transport pathway either directly, through induction of protein expression, or indirectly, by altering HDL structure and composition leading to increase cholesterol flux through this pathway.

Timeline

Start

2008-04

Primary completion

2010-09

Completion

2010-09

Publications

• Background Mudaliar S, Henry RR. New oral therapies for type 2 diabetes mellitus: The glitazones or insulin sensitizers. Annu Rev Med. 2001;52:239-57. doi: 10.1146/annurev.med.52.1.239.
• Background Campbell IW. Long-term glycaemic control with pioglitazone in patients with type 2 diabetes. Int J Clin Pract. 2004 Feb;58(2):192-200. doi: 10.1111/j.1368-5031.2004.0108.x.
• Background Olansky L, Marchetti A, Lau H. Multicenter retrospective assessment of thiazolidinedione monotherapy and combination therapy in patients with type 2 diabetes: comparative subgroup analyses of glycemic control and blood lipid levels. Clin Ther. 2003;25 Suppl B:B64-80. doi: 10.1016/s0149-2918(03)80243-6.
• Background Charbonnel B, Roden M, Urquhart R, Mariz S, Johns D, Mihm M, Widel M, Tan M. Pioglitazone elicits long-term improvements in insulin sensitivity in patients with type 2 diabetes: comparisons with gliclazide-based regimens. Diabetologia. 2005 Mar;48(3):553-60. doi: 10.1007/s00125-004-1651-9. Epub 2005 Mar 1.
• Background Rasouli N, Raue U, Miles LM, Lu T, Di Gregorio GB, Elbein SC, Kern PA. Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue. Am J Physiol Endocrinol Metab. 2005 May;288(5):E930-4. doi: 10.1152/ajpendo.00522.2004. Epub 2005 Jan 4.

Drugs

Indications