MSDC-0160

MSDC-0160 is a prototype mTOT-modulating insulin sensitizer [1].

MSDC-0160 is a thiazolidinedione insulin sensitizer without the peroxisome proliferator–activated receptor-γ (PPAR-γ)-dependent side effects. Co-incubation of islets with MSDC-0160 and IGF-1 reduces the resistance of insulin-signaling pathway and preserves insulin content. MSDC-0160 at 50μM alone also prevents the loss of insulin content significantly. Besides that, treatment of MSDC-0160 increases the phosphorylation of AMPK and reduces mTOR phosphorylation. Moreover, MSDC-0160 is also found to display pro-survival effects in human islets via reducing the level of cleaved caspase-3 and increasing the expression of apoptosis-related genes such as bcl2. In addition, MSDC-0160 exerts prevention of nuclear translocation with β-catenin localized on the cell membrane or cytoplasm in human β-cells [1].

References:
[1] Rohatgi N, Aly H, Marshall C A, et al. Novel insulin sensitizer modulates nutrient sensing pathways and maintains β-cell phenotype in human islets. PloS one, 2013, 8(5): e62012.

An evaluation of MSDC-0160, a prototype mTOT modulating insulin sensitizer, in patients with mild Alzheimer's disease.[Pubmed:24931567]

Curr Alzheimer Res. 2014;11(6):564-73.

Alzheimer's disease (AD) is associated with insulin resistance and specific regional declines in cerebral metabolism. The effects of a novel mTOT modulating insulin sensitizer (MSDC-0160) were explored in non-diabetic patients with mild AD to determine whether treatment would impact glucose metabolism measured by FDG-PET in regions that decline in AD. MSDC-0160 (150 mg once daily; N=16) compared to placebo (N=13) for 12 weeks did not result in a significant difference in glucose metabolism in pre-defined regions when referenced to the pons or whole brain. However, glucose metabolism referenced to cerebellum was maintained in MSDC-0160 treated participants while it significantly declined for placebo patients in anterior and posterior cingulate, and parietal, lateral temporal, medial temporal cortices. Voxel-based analyses showed additional differences in FDG-PET related to MSDC-0160 treatment. These exploratory results suggest central effects of MSDC-0160 and provide a basis for further investigation of mTOT modulating insulin sensitizers in AD patients.

Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer.[Pubmed:23462886]

Clin Pharmacol Ther. 2013 Apr;93(4):352-9.

It may be possible to achieve insulin sensitivity through the recently identified mitochondrial target of thiazolidinediones (mTOT), thereby avoiding peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-dependent side effects. In this phase IIb clinical trial, 258 patients with type 2 diabetes completed a 12-week protocol with 50, 100, or 150 mg of MSDC-0160 (an mTOT modulator), 45 mg pioglitazone HCl (a PPAR-gamma agonist), or a placebo. The two active treatments lowered fasting glucose levels to the same extent. The decreases in glycated hemoglobin (HbA1c) observed with the two higher doses of MSDC-0160 were not different from those associated with pioglitazone. By contrast, fluid retention as evidenced by reduction in hematocrit, red blood cells, and total hemoglobin was 50% less in the MSDC-0160-treated groups. There was also a smaller increase in high-molecular-weight (HMW) adiponectin with MSDC-0160 than with pioglitazone (P < 0.0001), suggesting that MSDC-0160 produces less expansion of white adipose tissue. Thus, mTOT modulators may have glucose-lowering effects similar to those of pioglitazone but without the adverse effects associated with PPAR-gamma agonists.

Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT)--relationship to newly identified mitochondrial pyruvate carrier proteins.[Pubmed:23690925]

PLoS One. 2013 May 15;8(5):e61551.

Thiazolidinedione (TZD) insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARgamma. We have recently shown PPARgamma-independent actions of TZD insulin sensitizers, but the molecular target of these molecules remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44) and BRP44 Like (BRP44L), which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT) cells, MSDC-0602, a PPARgamma-sparing TZD, altered the incorporation of (13)C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT) and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacology.

Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier.[Pubmed:23513224]

Proc Natl Acad Sci U S A. 2013 Apr 2;110(14):5422-7.

Facilitated pyruvate transport across the mitochondrial inner membrane is a critical step in carbohydrate, amino acid, and lipid metabolism. We report that clinically relevant concentrations of thiazolidinediones (TZDs), a widely used class of insulin sensitizers, acutely and specifically inhibit mitochondrial pyruvate carrier (MPC) activity in a variety of cell types. Respiratory inhibition was overcome with methyl pyruvate, localizing the effect to facilitated pyruvate transport, and knockdown of either paralog, MPC1 or MPC2, decreased the EC50 for respiratory inhibition by TZDs. Acute MPC inhibition significantly enhanced glucose uptake in human skeletal muscle myocytes after 2 h. These data (i) report that clinically used TZDs inhibit the MPC, (ii) validate that MPC1 and MPC2 are obligatory components of facilitated pyruvate transport in mammalian cells, (iii) indicate that the acute effect of TZDs may be related to insulin sensitization, and (iv) establish mitochondrial pyruvate uptake as a potential therapeutic target for diseases rooted in metabolic dysfunction.

Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione.[Pubmed:22621923]

J Biol Chem. 2012 Jul 6;287(28):23537-48.

Currently approved thiazolidinediones (TZDs) are effective insulin-sensitizing drugs that may have efficacy for treatment of a variety of metabolic and inflammatory diseases, but their use is limited by side effects that are mediated through ectopic activation of the peroxisome proliferator-activated receptor gamma (PPARgamma). Emerging evidence suggests that the potent anti-diabetic efficacy of TZDs can be separated from the ability to serve as ligands for PPARgamma. A novel TZD analog (MSDC-0602) with very low affinity for binding and activation of PPARgamma was evaluated for its effects on insulin resistance in obese mice. MSDC-0602 treatment markedly improved several measures of multiorgan insulin sensitivity, adipose tissue inflammation, and hepatic metabolic derangements, including suppressing hepatic lipogenesis and gluconeogenesis. These beneficial effects were mediated at least in part via direct actions on hepatocytes and were preserved in hepatocytes from liver-specific PPARgamma(-/-) mice, indicating that PPARgamma was not required to suppress these pathways. In conclusion, the beneficial pharmacology exhibited by MSDC-0602 on insulin sensitivity suggests that PPARgamma-sparing TZDs are effective for treatment of type 2 diabetes with reduced risk of PPARgamma-mediated side effects.

MSDC 0160 (Mitoglitazone) is a mitochondrial target of thiazolidinediones (mTOT)-modulating insulin sensitizer and a modulator of mitochondrial pyruvate carrier (MPC). MSDC 0160 is a thiazolidinedione (TZD) with antidiabetic and neuroprotective activities. MSDC 0160 has the potential for Alzheimer′s disease.

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