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Insulin Sensitizing and Anti-Inflammatory Effects of Thiazolidinediones Are Heightened in Obese Patients
  1. Yonah B. Esterson, BA*,
  2. Kehao Zhang, MD, DDS*,
  3. Sudha Koppaka, MD*,
  4. Sylvia Kehlenbrink, MD*,
  5. Preeti Kishore, MD*,
  6. Pooja Raghavan, MD*,
  7. Sylvan Roger Maginley, MD*,
  8. Michelle Carey, MD*,
  9. Meredith Hawkins, MD*†
  1. From the *Division of Endocrinology, Department of Medicine, and †Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, NY.
  1. Received July 25, 2013.
  2. Accepted for publication September 13, 2013.
  3. Reprints: Meredith Hawkins, MD, 1300 Morris Park Ave, Belfer 709, Bronx, NY 10461. E-mail: meredith.hawkins{at}
  4. Supported by the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH), through grant numbers UL1TR000086, TL1RR000087, KL2TR000088 as well as by an Investigator-Initiated Research Grant from Takeda Pharmaceuticals North America and by research grants from the NIH (DK-069861, and DK-48321) and the American Diabetes Association.
  5. Meredith Hawkins is a Beeson Scholar of the American Federation for Aging Research and an investigator in the Diabetes Research and Training Center (DK-20541) and the Clinical Research Center (RR 12248).
  6. Y.B. Esterson researched data, performed experimental studies, and wrote the manuscript. K. Zhang, S. Koppaka, and S. Kehlenbrink performed experimental studies. P. Kishore developed the study and performed or supervised experimental studies. P. Raghavan, M. Carey, and S.R. Maginley reviewed/edited the manuscript. M. Hawkins developed the study, researched data, edited the manuscript, and is the guarantor of this study.


Objective The American Diabetes Association has called for further research on how patients’ demographics should determine drug choices for individuals with type 2 diabetes mellitus (T2DM). Here, using in-depth physiology studies, we investigate whether obese patients with T2DM are likely to benefit from thiazolidinediones, medications with a known adverse effect of weight gain.

Materials and Methods Eleven obese and 7 nonobese individuals with T2DM participated in this randomized, placebo-controlled, double-blind, crossover study. Each subject underwent a pair of “stepped” pancreatic clamp studies with subcutaneous adipose tissue biopsies after 21 days of pioglitazone (45 mg) or placebo.

Results Obese subjects demonstrated significant decreases in insulin resistance and many adipose inflammatory parameters with pioglitazone relative to placebo. Specifically, significant improvements in glucose infusion rates, suppression of hepatic glucose production, and whole fat expression of certain inflammatory markers (IL-6, IL-1B, and inducible nitric oxide synthase) were observed in the obese subjects but not in the nonobese subjects. Additionally, adipose tissue from the obese subjects demonstrated reduced infiltration of macrophages, dendritic cells, and neutrophils as well as increased expression of factors associated with fat “browning” (peroxisome proliferator–activated receptor gamma coactivator-1α and uncoupling protein-1).

Conclusions These findings support the efficacy of pioglitazone to improve insulin resistance and reduce adipose tissue inflammation in obese patients with T2DM.

Key Words
  • type 2 diabetes
  • obesity
  • pioglitazone
  • adipose tissue inflammation
  • insulin resistance

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