Insulin Resistance and Metabolic Derangements in Obese Mice Are Ameliorated by a Novel Peroxisome Proliferator-activated Receptor γ-sparing Thiazolidinedione

Abstract

Background: Thiazolidinediones may have insulin-sensitizing effects independent of the nuclear receptor PPAR␥. Results: A novel PPAR␥-sparing thiazolidinedione ameliorated insulin resistance and inflammation in obese mice. Conclusion:The insulin-sensitizing effects of thiazolidinediones are separable from the ability to bind PPAR␥. Significance: Identification of other molecular targets of thiazolidinediones may generate new therapeutics for treatment of insulin resistance and diabetes.

Novel Agents for the Treatment of Type 2 Diabetes

“…94 MSDC-0160 and MSDC-0602 (Metabolic Solutions Development Company) have been shown to improve insulin resistance in multiple tissues, suppress hepatic gluconeogenesis and lipogenesis, reduce plasma glucose and insulin levels, and increase plasma adiponectin concentration in wild-type and PPAR-γ knockout mice.…”

Analysis of Small Molecule Ligands Targeting the HIV-1 Matrix Protein-RNA Binding Site

“…We also tested two glitazones (Fig. 1), pioglitazone and rosiglitazone, that have a similar ring structure to thiadiazolanes and have been used to treat diabetes (73,74). When these compounds were tested at 10 M concentrations, they failed to inhibit MA-RNA binding (Table 1).…”

Treating fatty liver disease by modulating mitochondrial pyruvate metabolism

“…This complex is required for pyruvate to enter the mitochondrial matrix, where it is metabolized, from its site of synthesis in the cytosol. Recent work has suggested the utility of targeting the MPC for treatment of a variety of metabolic and inflammatory diseases, including diabetes,1, 6, 7 Parkinson's and other neurodegenerative diseases,8, 9 and now nonalcoholic fatty liver disease (NAFLD) 10…”

“…Based on this rationale and efficacy in rodent models,6, 10 a phase 2 clinical trial has been initiated to evaluate the efficacy of MSDC‐0602K. This study is a 12‐month, double‐blind, placebo‐controlled evaluation of three exposures of MSDC‐0602K to determine the potential of this PPARγ‐sparing mTOT modulator to resolve NASH (EMMINENCE; NCT02784444; https://clinicaltrials.gov/ct2/show/NCT02784444).…”

“…Current drug development is trained on several specific targets directed at specific symptoms along the natural history of the disease, including lipid synthesis, inflammation, and fibrosis 32, 33. The new data suggest that modification of the usage of pyruvate could be useful at several steps along the progression of the disease from insulin resistance6, 7 to reduction of ballooning and fibrosis 10. Such a treatment modality could be useful on its own or as a component of combination therapy.…”