Novel insulin sensitizer MSDC-0602K improves insulinemia and fatty liver disease in mice, alone and in combination with liraglutide.

Insulin sensitizers and incretin mimetics are antidiabetic agents with vastly different mechanisms of action. Thiazolidinedione (TZD) insulin sensitizers are associated with weight gain, whereas glucagon-like peptide-1 receptor agonists can induce weight loss. We hypothesized that combination of a TZD insulin sensitizer and the glucagon-like peptide-1 receptor agonist liraglutide would more significantly improve mouse models of diabetes and nonalcoholic steatohepatitis (NASH). Diabetic db/db and MS-NASH mice were treated with the TZD MSDC-0602K by oral gavage, liraglutide (Lira) by s.c. injection, or combination 0602K+Lira. Lira slightly reduced body weight and modestly improved glycemia in db/db mice. Comparatively, 0602K-treated and 0602K+Lira-treated mice exhibited slight weight gain but completely corrected glycemia and improved glucose tolerance. 0602K reduced plasma insulin, whereas Lira further increased the hyperinsulinemia of db/db mice. Surprisingly, 0602K+Lira treatment reduced plasma insulin and C-peptide to the same extent as mice treated with 0602K alone. 0602K did not reduce glucose-stimulated insulin secretion in vivo, or in isolated islets, indicating the reduced insulinemia was likely compensatory to improved insulin sensitivity. In MS-NASH mice, both 0602K or Lira alone improved plasma alanine aminotransferase and aspartate aminotransferase, as well as liver histology, but more significant improvements were observed with 0602K+Lira treatment. 0602K or 0602K+Lira also increased pancreatic insulin content in both db/db and MS-NASH mice. In conclusion, MSDC-0602K corrected glycemia and reduced insulinemia when given alone, or in combination with Lira. However, 0602K+Lira combination more significantly improved glucose tolerance and liver histology, suggesting that this combination treatment may be an effective therapeutic strategy for diabetes and NASH.

Kamm DR ，Pyles KD ，Sharpe MC ，Healy LN ，Colca JR ，McCommis KS ... -  《-》

Insulin sensitizer MSDC-0602K in non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled phase IIb study.

MSDC-0602K is a novel insulin sensitizer designed to preferentially target the mitochondrial pyruvate carrier while minimizing direct binding to the transcriptional factor PPARγ. Herein, we aimed to assess the efficacy and safety of MSDC-0602K in patients with non-alcoholic steatohepatitis. Patients with biopsy-confirmed NASH and fibrosis (F1-F3) were randomized to daily oral placebo, or 1 of 3 MSDC-0602K doses in a 52-week double-blind study. The primary efficacy endpoint was hepatic histological improvement of ≥2 points in non-alcoholic fatty liver disease activity score (NAS) with a ≥1-point reduction in either ballooning or lobular inflammation and no increase in fibrosis stage at 12 months. Secondary endpoints included NAS improvement without worsening fibrosis, NASH resolution, and fibrosis reduction. Exploratory endpoints included changes in insulin sensitivity, liver injury and liver fibrosis markers. Patients were randomly assigned to placebo (n = 94), or 62.5 mg (n = 99), 125 mg (n = 98), or 250 mg (n = 101) of MSDC-0602K. At baseline, glycated hemoglobin was 6.4 ± 1.0%, 61.5% of patients had fibrosis F2/F3 and the average NAS was 5.3. The primary endpoint was reached in 29.7%, 29.8%, 32.9% and 39.5% of patients in the placebo, 62.5 mg, 125 mg and 250 mg dose arms, respectively, with adjusted odds ratios relative to placebo of 0.89 (95% CI 0.44-1.81), 1.22 (95% CI 0.60-2.48), and 1.64 (95% CI 0.83-3.27). The 2 highest doses of MSDC-0602K led to significant reductions in glucose, glycated hemoglobin, insulin, liver enzymes and NAS compared to placebo. The incidence of hypoglycemia and PPARγ-agonist-associated events such as edema and fractures were similar in the placebo and MSDC-0602K groups. MSDC-0602K did not demonstrate statistically significant effects on primary and secondary liver histology endpoints. However, effects on non-invasive measures of liver cell injury and glucose metabolism support further exploration of MSDC-0602K's safety and potential efficacy in patients with type 2 diabetes and liver injury. [ClinicalTrials.gov Identifier: NCT02784444]. First-generation insulin sensitizers are used to treat type 2 diabetes, but are associated with side effects including edema, bone fractures, and hypoglycemia. MSDC-0602K is a second-generation insulin sensitizer designed to reduce these side effects. We hypothesized that insulin sensitization could improve non-alcoholic steatohepatitis. In the current study of patients with non-alcoholic steatohepatitis, MSDC-0602K did not demonstrate significant effects on liver histology with the biopsy techniques used. However, useful information was gained for the design of future studies and MSDC-0602K significantly decreased fasting glucose, insulin, glycated hemoglobin, and markers of liver injury without dose-limiting side effects.

Harrison SA ，Alkhouri N ，Davison BA ，Sanyal A ，Edwards C ，Colca JR ，Lee BH ，Loomba R ，Cusi K ，Kolterman O ，Cotter G ，Dittrich HC ... -  《-》

MSDC-0602K, a metabolic modulator directed at the core pathology of non-alcoholic steatohepatitis.

Colca JR ，McDonald WG ，Adams WJ 《-》

Novel thiazolidinedione analog reduces a negative impact on bone and mesenchymal stem cell properties in obese mice compared to classical thiazolidinediones.

The use of thiazolidinediones (TZDs) as insulin sensitizers has been shown to have side effects including increased accumulation of bone marrow adipocytes (BMAds) associated with a higher fracture risk and bone loss. A novel TZD analog MSDC-0602K with low affinity to PPARγ has been developed to reduce adverse effects of TZD therapy. However, the effect of MSDC-0602K on bone phenotype and bone marrow mesenchymal stem cells (BM-MSCs) in relation to obesity has not been intensively studied yet. Here, we investigated whether 8-week treatment with MSDC-0602K has a less detrimental effect on bone loss and BM-MSC properties in obese mice in comparison to first generation of TZDs, pioglitazone. Bone parameters (bone microstructure, bone marrow adiposity, bone strength) were examined by μCT and 3-point bending test. Primary BM-MSCs were isolated and measured for osteoblast and adipocyte differentiation. Cellular senescence, bioenergetic profiling, nutrient consumption and insulin signaling were also determined. The findings demonstrate that MSDC-0602K improved bone parameters along with increased proportion of smaller BMAds in tibia of obese mice when compared to pioglitazone. Further, primary BM-MSCs isolated from treated mice and human BM-MSCs revealed decreased adipocyte and higher osteoblast differentiation accompanied with less inflammatory and senescent phenotype induced by MSDC-0602K vs. pioglitazone. These changes were further reflected by increased glycolytic activity differently affecting glutamine and glucose cellular metabolism in MSDC-0602K-treated cells compared to pioglitazone, associated with higher osteogenesis. Our study provides novel insights into the action of MSDC-0602K in obese mice, characterized by the absence of detrimental effects on bone quality and BM-MSC metabolism when compared to classical TZDs and thus suggesting a potential therapeutical use of MSDC-0602K in both metabolic and bone diseases.

Benova A ，Ferencakova M ，Bardova K ，Funda J ，Prochazka J ，Spoutil F ，Cajka T ，Dzubanova M ，Balcaen T ，Kerckhofs G ，Willekens W ，van Lenthe GH ，Alquicer G ，Pecinova A ，Mracek T ，Horakova O ，Rossmeisl M ，Kopecky J ，Tencerova M ... -  《-》

Liraglutide modulates gut microbiome and attenuates nonalcoholic fatty liver in db/db mice.

Liraglutide, a glucagon-like peptide-1(GLP-1) analog, is effective for the treatment of type II diabetes and nonalcoholic fatty liver disease (NAFLD). It was proved that gut microbiome plays a role in the development of NAFLD. This study aims to observe the therapeutic effect of liraglutide on nonalcoholic fatty liver (NAFL) in mice and effect on the gut microbial community. The db/db mice were used as the NAFL model, and lactulose was used as the positive control drug. Hepatic triglyceride, liver histopathology, and indices of glucolipid metabolism, including fasting blood glucose, fasting insulin, insulin resistance index and blood lipids were evaluated after treatment of liraglutide or lactulose for four weeks. The colonic microbiome of the mice was analyzed by 16S rRNA gene sequencing. Liraglutide significantly reduced the hepatic triglyceride (TG) content, alanine aminotransferase (ALT) activity, fasting blood glucose, insulin resistance and serum low density lipoprotein (LDL) in the db/db mice. In terms of hepatic pathologies, hepatic steatosis was significantly improved after liraglutide treating. Microbiome analysis revealed that liraglutide significantly increased the abundance of Akkermansia, Romboutsia, norank_f_Bacteroidales_S24-7_group, and decreased the abundance of Klebsiella, Anaerotruncus, Bacteroides, Lachnospiraceae_UCG-001, Lachnospiraceae_NK4A136_group, Ruminiclostridium, uncultured_f__Ruminococcaceae, and Desulfovibrio. The results of the present study suggested that liraglutide had a certain therapeutic effect on fatty liver in db/db mice and had an impact on the composition of the intestinal microflora, especially some bacteria related to glucolipid metabolism and intestinal inflammation. Affecting gut microbiome might be a potential mechanism of liraglutide in treating NAFL.

Liu Q ，Cai BY ，Zhu LX ，Xin X ，Wang X ，An ZM ，Li S ，Hu YY ，Feng Q ... -  《-》