title: Clinical proof-of-concept study with MSDC-0160, a prototype mTOT-modulating insulin sensitizer.
abstract: It may be possible to achieve insulin sensitivity through the recently identified mitochondrial target of thiazolidinediones (mTOT), thereby avoiding peroxisome proliferator-activated receptor-γ (PPAR-γ)-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-γ 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-γ agonists.
authors: Metabolic Solutions Development Company, Kalamazoo, Michigan, USA. jcolca@msdrx.com
authors: J R
authors: JR
authors: Colca
authors: J T
authors: JT
authors: VanderLugt
authors: W J
authors: WJ
authors: Adams
authors: A
authors: A
authors: Shashlo
authors: W G
authors: WG
authors: McDonald
authors: J
authors: J
authors: Liang
authors: R
authors: R
authors: Zhou
authors: D G
authors: DG
authors: Orloff
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000097:blood / Q000150:complications; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000187:drug effects*; D000077205:Pioglitazone; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D024101:Mitochondrial Proteins; D000077205:Pioglitazone; D011725:Pyridines; D045162:Thiazolidinediones; C581095:MSDC-0160