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Review
. 2014 Oct 7;20(4):573-91.
doi: 10.1016/j.cmet.2014.08.005. Epub 2014 Sep 18.

Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes

Raymond E Soccio  1 , Eric R Chen  1 , Mitchell A Lazar  2
Affiliations
Review

Thiazolidinediones and the promise of insulin sensitization in type 2 diabetes

Raymond E Soccio et al. Cell Metab. .

Abstract

Type 2 diabetes is caused by insulin resistance coupled with an inability to produce enough insulin to control blood glucose, and thiazolidinediones (TZDs) are the only current antidiabetic agents that function primarily by increasing insulin sensitivity. However, despite clear benefits in glycemic control, this class of drugs has recently fallen into disuse due to concerns over side effects and adverse events. Here we review the clinical data and attempt to balance the benefits and risks of TZD therapy. We also examine potential mechanisms of action for the beneficial and harmful effects of TZDs, mainly via agonism of the nuclear receptor PPARγ. Based on critical appraisal of both preclinical and clinical studies, we discuss the prospect of harnessing the insulin sensitizing effects of PPARγ for more effective, safe, and potentially personalized treatments of type 2 diabetes.

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Figures

Figure 1
Figure 1. The History of TZDs
The graph shows the annual number of TZD-related publications, with boxes indicating key events in the rise and fall of this drug class. For 2014, publications through May were adjusted to a full year.
Figure 2
Figure 2. PPARγ Agonist Drugs
TZDs like pioglitazone and rosiglitazone are potent PPARγ agonists (red), but other weaker or partial agonists share the TZD structure with different side chains (blue). There are additional structurally diverse non-TZD PPARγ agoinsts (green and purple), including dual agonists of PPARα and PPARγ (orange). See text for details.
Figure 3
Figure 3. Weighing Mortality Risks and Benefits of Pioglitazone
Age-adjusted mortality rates for the entire U.S. population were derived from published government statistics for 2010–2011. Potential effects of pioglitazone on mortality from cardiometabolic causes or certain cancers were approximated from published analyses. The mortality from hip fracture is more complex to estimate, as it is not a proximal cause of death but clearly carries mortality risk in the elderly. See text for details.
See this image and copyright information in PMC

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