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Randomized Controlled Trial
. 2013 Dec;61(8):1152-60.
doi: 10.2310/JIM.0000000000000017.

Insulin sensitizing and anti-inflammatory effects of thiazolidinediones are heightened in obese patients

Yonah B Esterson  1 , Kehao Zhang, Sudha Koppaka, Sylvia Kehlenbrink, Preeti Kishore, Pooja Raghavan, Sylvan Roger Maginley, Michelle Carey, Meredith Hawkins
Affiliations
Randomized Controlled Trial

Insulin sensitizing and anti-inflammatory effects of thiazolidinediones are heightened in obese patients

Yonah B Esterson et al. J Investig Med. 2013 Dec.

Abstract

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.

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Figures

Figure 1
Figure 1
(A) “Stepped” euglycemic-hyperinsulinemic pancreatic clamp study time course. (B) Overnight insulin infusion rate required to maintain euglycemia was significantly lower following pioglitazone in the obese group (p=0.04) but not in the non-obese group (p=0.85). (C) Hepatic glucose production (HGP) during the low-step of the clamp was significantly suppressed in the obese group (p=0.02) while suppression of HGP in the non-obese group following pioglitazone failed to reach significance (p=0.09). (D) Glucose infusion rate (GIR) required to maintain euglycemia during the low-insulin step of the clamp was significantly increased with pioglitazone in the obese group (p=0.02) while the GIR in the non-obese group did not significantly differ (p=0.40). (E) GIR required to maintain euglycemia during the high-insulin step of the clamp was significantly increased in the obese group with pioglitazone (p=0.009) while GIR did not significantly differ in the non-obese group (p=0.13).
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