Jerry Colca - Academia.edu (original) (raw)
Papers by Jerry Colca
The FASEB Journal
The objectives of this study were to determine the mass balance excretion, plasma pharmacokinetic... more The objectives of this study were to determine the mass balance excretion, plasma pharmacokinetics and tissue distribution of radioactivity following PO administration of [14C]MSDC‐0602 in rats. Five groups of male SD rats and 1 group of male LE rats (28 total rats) that weighed approximately 250 g were dosed. All rats were administered a single PO bolus of [14C]MSDC‐0602 as a suspension at a dose of 10 mg/kg (50 μCi/kg). Excretion of radioactivity was rapid, with the majority eliminated within 24 h post‐dose. Biliary excretion was the primary route of elimination in bile duct‐cannulated (BDC) rats. Total recovery in urine and bile in BDC rats suggested the extent of oral absorption was at least 60%. Urinary recovery of radioactivity from intact rats (22.4%) was higher than in BDC rats (12.3%), and total radioactivity recovered in feces (31.7%) and bile (48.1%) was higher in the BDC rats (79.8%) than in the feces of intact rats (67.0%), suggesting enterohepatic recirculation of radi...
Bioorganic & Medicinal Chemistry, Dec 1, 2018
Tetrahedron Letters, Aug 1, 2019
Ketones 2 (MSDC-0160) and 3 (MSDC-0602) had been selected for clinical development, however their... more Ketones 2 (MSDC-0160) and 3 (MSDC-0602) had been selected for clinical development, however their initial syntheses were considered suboptimal for application deep into clinical trials. Difficulties ranging from the nature of the starting material, alcohol oxidation problems, epoxide opening regioisomeric issues, and endgame ketone redox problems had been encountered. Direct ketone introduction/maintenance was desired for maximum efficiency and convergence was found to be critically dependent upon the acidity of the nucleophilic species (13, 18) and the use of pre-or post-alkylative oximino-ether/oxime protection (vide infra). Improvements in overall yield for the syntheses of 2 (MSDC-0160) and 3 (MSDC-0602) from 20% (2) and 31% (3) respectively, to 44% (2) and 59% (3) were realized.
Diabetes, Jun 1, 2021
Mitochondrial pyruvate carrier (MPC) disruption attenuates type 2 diabetes NAFLD in mice. MSDC-06... more Mitochondrial pyruvate carrier (MPC) disruption attenuates type 2 diabetes NAFLD in mice. MSDC-0602, a PPARγ-sparing, TZD-like molecule that inhibits the MPC, was recently tested in a phase 2B trial for treating NASH, which reported beneficial effects on glucose and insulin homeostasis. Yet, the broad, in vivo metabolomic effects of MSDC-0602 treatment have remained undefined. Here, we tested MSDC-062 metabolic mechanisms of action in vitro and in vivo, spanning from mitochondrial pyruvate uptake assays in isolated mouse mitochondria, through cultured mouse liver cells, in vivo in mice, and in humans participating in the EMMINENCE trial. First, we examined MSDC-0602’s effect in isolated mouse liver mitochondria: Pyruvate-oxidation was decreased by MSDC-0602, and 2.5 µM MSDC-0602 was sufficient to decrease mitochondrial pyruvate uptake by >50%. We extended these findings to AML12 mouse liver cells and mouse liver in vivo. In AML12 cells, MSDC-0602 treatment increased pyruvate and lactate and decreased alanine. These results were comparable but not identical to results from parallel testing of the specific MPC inhibitor UK5099. 14-day treatment of NCD and HFD fed mice with MSDC-0602 decreased liver alanine and branched chain amino acids. As we previously observed with MPC liver-specific knockout mice, the HFD-induced liver TCA intermediate pool size expansion was mitigated by MSDC-0602. Accordingly, MSDC-0602-dependent metabolomic changes were more pronounced in HFD- versus NCD-fed mice. Human EMMINENCE trial participants receiving MSDC-0602 showed decreased circulating alanine, ketone bodies, and glucose. Similarly, circulating and liver glucose were decreased in HFD mice treated with MSDC-0602. Together, these data are consistent with MSDC-0602 modulating in vivo metabolism in a partially MPC-dependent manner and by additional mechanisms that remain to be understood. Disclosure A. J. Rauckhorst: None. D. J. Pape: None. J. R. Colca: Board Member; Self; Metabolic Solutions Development Company, LLC, Employee; Self; Cirius Therapeutics. E. B. Taylor: None. Funding American Diabetes Association (1-18-PDF-060 to A.J.R.); National Institute of Diabetes and Digestive and Kidney Diseases (DK104998); Cirius Therapeutics
Journal of Biological Chemistry, 2021
Insulin sensitizers and incretin mimetics are antidiabetic agents with vastly different mechanism... more 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.
Journal of Hepatology, Apr 1, 2020
Background & Aims MSDC-0602K is a novel insulin sensitizer designed to preferentially target ... more Background & Aims 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. Methods 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. Results 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. Conclusions 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]. Lay summary 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.
Methods in Enzymology, 1983
Publisher Summary This chapter describes techniques for the mass isolation of islets of Langerhan... more Publisher Summary This chapter describes techniques for the mass isolation of islets of Langerhans and procedures for obtaining characterized and purified subcellular fractions. Limitations of the quantity of isolated islets of Langerhans make extensive purification of islet-cell fractions difficult. The limited yields of protein from this technique require the use of microassay procedures and of constriction pipettes calibrated to microliter quantities. The chapter discusses the techniques for the evaluation of the functions of the plasma membrane and endoplasmic reticulum in the regulation of cellular Ca 2+ levels. Techniques are also presented to study the effects of Ca 2+ and calmodulin on protein phosphorylation in subcellular fractions obtained from islet cells and the correlation of these events with the secretion of insulin. Intracellular Ca 2+ concentration plays an essential role in insulin secretion from islets of Langerhans. A Ca 2+ extrusion pump associated with the plasma membrane may regulate these Ca 2+ levels. A well-characterized Ca 2+ -stimulated and Mg 2+ -dependent adenosine triphosphatase (ATPase) activity localized in the erythrocyte plasma membrane is considered to represent the enzymic basis for the Ca 2+ extrusion pump.
Journal of Hepatology, Dec 1, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Elsevier eBooks, 1992
Publisher Summary This chapter summarizes the recent advancement in the discovery and development... more Publisher Summary This chapter summarizes the recent advancement in the discovery and development of potential antidiabetic agents. Non-insulin-dependent diabetes mellitus (NIDDM) is a common metabolic disorder. Unlike insulin-dependent diabetes mellitus (IDDM) in which the source of endogenous insulin (pancreatic β-cells) is destroyed via an autoimmune attack on the pancreatic β-cells, NIDDM is not accompanied by an absolute deficiency in circulating insulin. The hallmark of this condition is a reduced responsiveness of the various tissues to the actions of insulin. Potential points of therapeutic intervention include augmentation of pancreatic β-cell secretion or alteration of the target tissue responsiveness to insulin. Several possible mechanisms exist whereby insulin secretion may be augmented, resulting in reduced circulating glucose concentrations. The stimulation of the α-2 adrenoreceptor with a number of agonists has been reported to produce a hyperglycemic response through an inhibition of insulin secretion. Midaglizole and dazoxzan have been reported to be peripherally active α-2 adrenoreceptor antagonists that are antihyperglycemic agents in a variety of models of NIDDM. Glimeperide represents the newest class of sulfonylurea-type compounds that are undergoing development for possible use in the treatment of NIDDM. The insensitivity of the target cells to insulin that occurs in NIDDM is thought to result from a reduced transduction of the insulin signal from the insulin receptor. This transduction can apparently be increased by treatment with such compounds as thiazolidinediones, as well as other insulin sensitizers, and β-3 agonists. The problems associated with the disease and recent observations in the area of drug discovery, particularly with the advent of insulin sensitizing compounds, are facilitating the discovery and development of novel agents. These can likely lead to more diverse therapeutic alternatives.
Biochimica et biophysica acta, Mar 1, 1985
The metabolism of arachidonic acid by pancreatic islets has been studied with purified population... more The metabolism of arachidonic acid by pancreatic islets has been studied with purified populations of large numbers of islets isolated from the rat. Sequential high-performance liquid chromatographic analyses of islet-derived metabolites of 3H-labeled arachidonate in both reversed and normal phases with 14C-labeled internal standards have demonstrated synthesis by the islets of the cyclooxygenase products prostaglandin E2, prostaglandin F2 alpha, thromboxane B2 and 12- hydroxyheptadecatrienoic acid as well as the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE). Islet synthesis of these compounds was suppressed with appropriate inhibitors of arachidonate metabolism. Synthesis of the identified metabolites from endogenous arachidonate has also been quantitated with the use of deuterated internal standards, capillary column gas chromatographic analyses, and negative ion-chemical ionization mass spectrometric measurements. The relative abundances of metabolites derived from exogenous, radiolabeled arachidonate versus endogenous precursor differed considerably, and 12-HETE was by far the most abundant of these metabolites synthesized from endogenous arachidonate. Platelets contaminating the isolated islet preparations have been excluded as the source of the identified arachidonate metabolites. These studies establish that cells intrinsic to pancreatic islets synthesize a clearly characterized profile of arachidonate lipoxygenase and cyclooxygenase products. The sensitive and specific mass spectrometric methods for quantitation of these compounds permit detailed evaluation of their possible participation in insulin secretion from isolated islets.
Diabetes, Jun 1, 2021
The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin... more The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms by which MPC inhibition leads to metabolic improvements are incompletely understood. We evaluated whether MPC inhibitors might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. BCAA concentrations were assessed in plasma collected in EMMINENCE (NCT02784444), a randomized, placebo-controlled trial of the MPC inhibitor MSDC-0602K in people with NASH. MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes endpoints, decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH). BCKDH activity is suppressed by phosphorylation mediated by a kinase (BDK) and activated by the phosphatase (PPM1K). In Huh7 or HepG2 cells, MPC inhibitors markedly reduced BCKDH phosphorylation, suggesting increased BCKDH activity. Chemical inhibition or siRNA-mediated silencing of BDK had no effect on suppression of BCKDH phosphorylation by MPC inhibitors. In contrast, PPM1K knockdown prevented the effects of MPC inhibition on phospho-BCKDH. Lastly, we quantified BCKDH phosphorylation in liver of wild-type and hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice after 20 weeks of high fat diet. LS-Mpc2-/- mice exhibited reduced phosphorylation of BCKDH compared to wild-type mice. Lean LS-Mpc2-/- mice also exhibited reduced plasma BCAA concentrations after an overnight fast. These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation via the phosphatase PPM1K. Disclosure D. Ferguson: None. N. K. H. Yiew: None. K. S. Mccommis: None. J. R. Colca: Board Member; Self; Metabolic Solutions Development Company, LLC, Employee; Self; Cirius Therapeutics. B. N. Finck: Advisory Panel; Self; Cirius Therapeutics, Stock/Shareholder; Self; Cirius Therapeutics. Funding National Institutes of Health (R01DK104735, T32DK007120)
Diabetes, Jun 1, 2020
First generation insulin sensitizers improve both hyperglycemia and hyperinsulinemia and can pres... more First generation insulin sensitizers improve both hyperglycemia and hyperinsulinemia and can preserve beta cell mass and function. GLP-1 receptor agonists work by augmenting glucose-stimulated insulin secretion. Our objective was to assess potential additive effects of the new insulin sensitizer, MSDC-0602K (0602K) when combined with a GLP-1 receptor agonist in db/db mice. Mice were gavaged daily with 30 mg/kg 0602K or vehicle, injected subcutaneously every other day with 200 μg/kg Liraglutide (Lira) or vehicle, or received both drugs. Lira reduced glycemia and plasma fructosamine levels, while 0602K or 0602K+Lira normalized glycemia and fructosamine to lean db/+ mouse levels. Both drugs alone improved glucose tolerance compared to vehicle db/db, while the combination of 0602K+Lira further improved glucose tolerance even compared to lean db/+ mice. Vehicle treated db/db mice displayed elevated insulin and C-peptide levels, which were both reduced by 0602K treatment. C-peptide levels were lowered to a greater degree than insulin, indicating that 0602K treatment exerted a major effect on insulin secretion. In contrast, Lira increased the insulin and C-peptide levels in db/db mice, while the combination of 0602K+Lira displayed reduced levels of insulin and C-peptide similar to 0602K-alone treatment. Pancreas immunohistochemistry of vehicle treated db/db mice showed little islet insulin content, but islet insulin was significantly increased by 0602K or 0602K+Lira treatment. Isolated islets from lean, naïve mice showed no defect in glucose-stimulated insulin secretion with 0602K treatment, suggesting that the lowered insulinemia in vivo is due to corrected insulin resistance rather than direct inhibition of insulin secretion. In conclusion, the new insulin sensitizer MSDC-0602K improves insulinemia and helps to restore islet insulin content when used alone or in combination with Liraglutide. Glucose tolerance displayed additive effects with combined 0602K+Lira treatment. Disclosure K.D. Pyles: None. D. Kamm: None. J.R. Colca: Stock/Shareholder; Self; Cirius Therapeutics, Metabolic Solutions Development Company. K.S. McCommis: None. Funding National Institutes of Health (R01HL136658)
Diabetes, Jun 1, 2020
Use of the first-generation insulin sensitizer pioglitazone is limited by PPARγ-driven side effec... more Use of the first-generation insulin sensitizer pioglitazone is limited by PPARγ-driven side effects. MSDC-0602K was designed to maintain pioglitazone’s effects on the mitochondrial pyruvate carrier (MPC), but with minimal direct PPARγ binding. A 12-month Phase 2b dose-ranging study in NASH (Harrison et al, 2019) demonstrated insulin sensitizing pharmacology without dose-limiting issues. Here we describe ongoing analysis of these data. Steady state exposures of drug and active metabolite at the highest doses averaged 4 to 7 micromolar, 1/10thof the affinity to PPARγ, but within the range for modulation of the MPC in intact cells. The effects on fasting plasma insulin (FPI), fasting plasma glucose, and hemoglobin A1c (HbA1c) plateaued at the mid-dose (125 mg), while adiponectin continued to increase 1.7, 2.5, and 4.1x vs. placebo across the 62.5, 125, and 250 mg doses. Glycemic reductions and the reduction of FPI levels were similar in subjects with or without T2D. The treatment-induced decrease in HbA1c was proportional to the baseline HBA1c and was more than 1% in subjects with a baseline above 7%, including those not well-controlled on GLP-1 agonists. In patients with or without diabetes, baseline mean FPI levels exceeded 20 μU/ml (139 pmol/L), levels in the upper quartile of historical T2D studies, and continued to increase in placebo-treated subjects but decreased on treatment with MSDC-0602K. Treatment with MSDC-0602K decreased FPI more than C-peptide. The ratio of C-peptide/FPI increased vs. placebo at end of study (8.54 ± 0.49, 9.69 ± 0.44, 10.45 ± 0.43, and 10.9 ± 0.53 for placebo and the three dose groups, respectively) suggesting both decreased need for secreted insulin and increased clearance of insulin. These data suggest that the new generation insulin sensitizer MSDC-0602K, focused toward MPC and away from PPAR, may be useful to treat patients suffering from combined fatty liver disease and T2D and highlight the importance of FPI. Disclosure J.R. Colca: Stock/Shareholder; Self; Cirius Therapeutics, Metabolic Solutions Development Company. B. Lee: Employee; Self; Cirius Therapeutics. J.S. Iwashita: Employee; Self; Cirius Therapeutics. H.C. Dittrich: Employee; Self; Cirius Therapeutics. S.A. Harrison: Consultant; Self; Akero, Altimmune, Axcella, Cirius, Cirius Therapeutics, Genentech, Inc., Hightide Bio, HistoIndex, Intercept Pharmaceuticals, Inc., Madrigal.
Endocrinology, Feb 1, 1994
Analogs of thiazolidinedione improve the responsiveness of insulin-resistant animals to insulin. ... more Analogs of thiazolidinedione improve the responsiveness of insulin-resistant animals to insulin. One such analog, pioglitazone (5-(4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl)thiazolidine-2,4-dione hydrochloride), when fed to insulin-resistant animals such as the obese (ob/ob) mouse, reduces blood glucose and lipids and also lowers the plasma insulin level. Because GH can produce insulin resistance in humans and animals such as the ob/ob mouse, the present study was conducted to determine whether feeding pioglitazone can 1) inhibit the ability of GH to induce enhanced insulin resistance in obese mice, 2) ameliorate or reverse GH-induced insulin resistance once it has been induced in ob/ob mice, and 3) alter the ability of GH to promote growth in hypophysectomized rats. Female ob/ob mice were fed a control diet or a diet containing pioglitazone (20 mg/kg animal.day) for 4 days. During the last 3 days of the feeding period, the mice also received a daily sc injection of either saline or 200 micrograms S-carboxymethylated human GH (RCM-hGH), which is a GH derivative having mainly diabetogenic activity. In control-fed mice, RCM-hGH increased blood glucose and plasma insulin levels, which is an expected response to GH-induced insulin resistance. By contrast, the ability of RCM-hGH to increase blood glucose and plasma insulin levels was totally blocked in pioglitazone-fed mice. To determine whether pioglitazone can ameliorate GH-induced insulin resistance once it has been established, ob/ob mice were treated sc with either saline or 200 micrograms RCM-hGH for 3 days. Half of the saline-treated and half of the hormone-treated mice were then fed pioglitazone, whereas the remaining animals were continued on the control diet. After 48 h on the diets, the blood glucose and plasma insulin levels of the RCM-hGH treated mice fed the control diet remained elevated with respect to those in the saline-treated controls. On the other hand, the blood glucose and plasma insulin levels of the RCM-hGH treated mice fed pioglitazone were markedly reduced compared to those of the RCM-hGH-treated control-fed animals. Thus, these results suggest that pioglitazone can ameliorate GH-induced insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)
Canadian Journal of Diabetes, 2009
... of the West Indies, Pathology, Kingston 7, Jamaica 3 University of the West Indies, Basic Med... more ... of the West Indies, Pathology, Kingston 7, Jamaica 3 University of the West Indies, Basic Medical Sciences, Kingston 7, Jamaica 4 University of the West Indies, Medicine, Kingston 7, Jamaica Objective: This study investigated the impact of Hatha yoga and conventional physical ...
Molecular metabolism, Apr 1, 2023
Objective: The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treat... more Objective: The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. Methods: Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n ¼ 94) or 250 mg MSDC-0602K (n ¼ 101). Human hepatoma cell lines and mouse primary hepatocytes were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA metabolism in the liver of obese mice and MSDC-0602K treatment of Zucker diabetic fatty (ZDF) rats. Results: In patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, had decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades in vitro. BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2À/À) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo. Finally, while MSDC-0602K treatment improved glucose homeostasis and increased the concentrations of some BCAA metabolites in ZDF rats, it did not lower plasma BCAA concentrations. Conclusions: These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation by activating the mTOR axis. However, the effects of MPCi on glucose homeostasis may be separable from its effects on BCAA concentrations.
Science immunology, Apr 14, 2023
The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes... more The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, SARS-CoV-2 infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyper-inflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease following influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602 K (MSDC), dampened pulmonary inflammation and promoted lung recovery, while concurrently reducing blood glucose levels and hyperlipidemia following viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized HIF-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development following SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.
bioRxiv (Cold Spring Harbor Laboratory), Jan 20, 2022
Background: A growing body of evidence supports the idea that mitochondrial dysfunction might rep... more Background: A growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinson's disease (PD). Central regulators of energy production, mitochondria are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160. Methods: We investigated behavioral, cellular and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrial related processes through. CC-BY-NC-ND 4.
Expert Opinion on Investigational Drugs, 1995
Expert Opinion on Investigational Drugs, Jun 17, 2015
Introduction: This manuscript describes 21 drug targets in the area of diabetes and related condi... more Introduction: This manuscript describes 21 drug targets in the area of diabetes and related conditions that were discontinued in 2015. Areas covered: The material for this paper was obtained by contacting biopharmaceutical companies, reviewing their pipelines, press releases and annual reports. Additionally, the authors searched clinicaltrials.gov, PubMed and general Internet search engines. Majority of the compounds were in early stages of the development. Expert opinion: Business reasons for termination of the drug projects emerge more and more frequently over the years. Safety signals usually appear early in the development and are often associated with novel drugs. 2015 medicines with inadequate efficacy were unable to compete with existing approved members of the class they represented. List of Abbreviations 11β-HSD1-11β-hydroxysteroid dehydrogenase type ACC-acetyl-CoA carboxylase BIP-basal insulin peglispro CCR-CC Chemokine Receptor DPP-4-dipeptidyl peptidase-4 EMA-European medicines agency FDA-food and drug administration GR-glucagon receptor GLP-1-glucagon-like peptide-1 HbA1c-hemoglobin A1c Article Highlights • Due to national differences in the regulatory requirements for drug approval, it is challenging to develop a drug that can be concurrently approved in multiple countries. • The key reasons for the termination of drug projects are: lack of safety and/or efficacy, business decisions and/or strategic reevaluation. • Basal insulin peglispro was, perhaps, the largest anti-diabetes drug project terminated in 2015. • The risk for termination is very low for new members of existing classes. This has resulted in five glucagon-like peptide-1receptor agonists, four dipeptidyl peptidase-4 inhibitors, three sodium/glucose cotransporter 2 inhibitors and four different types of insulin glargine currently on the market. • For capital efficiency it is critical to identify a dug project that carries a high risk of imminent failure as early in the development as possible. • Opportunities for anti-diabetes drug development include an easy to take regimen that could reduce HbA1c without compromising safety, preserve/improve β cell function, and produce clinically significant cardiovascular risk reduction and weight loss. • Development of an oral glucagon-like peptide-1 receptor agonist would further advance therapeutic and commercial success of the class.
The FASEB Journal
The objectives of this study were to determine the mass balance excretion, plasma pharmacokinetic... more The objectives of this study were to determine the mass balance excretion, plasma pharmacokinetics and tissue distribution of radioactivity following PO administration of [14C]MSDC‐0602 in rats. Five groups of male SD rats and 1 group of male LE rats (28 total rats) that weighed approximately 250 g were dosed. All rats were administered a single PO bolus of [14C]MSDC‐0602 as a suspension at a dose of 10 mg/kg (50 μCi/kg). Excretion of radioactivity was rapid, with the majority eliminated within 24 h post‐dose. Biliary excretion was the primary route of elimination in bile duct‐cannulated (BDC) rats. Total recovery in urine and bile in BDC rats suggested the extent of oral absorption was at least 60%. Urinary recovery of radioactivity from intact rats (22.4%) was higher than in BDC rats (12.3%), and total radioactivity recovered in feces (31.7%) and bile (48.1%) was higher in the BDC rats (79.8%) than in the feces of intact rats (67.0%), suggesting enterohepatic recirculation of radi...
Bioorganic & Medicinal Chemistry, Dec 1, 2018
Tetrahedron Letters, Aug 1, 2019
Ketones 2 (MSDC-0160) and 3 (MSDC-0602) had been selected for clinical development, however their... more Ketones 2 (MSDC-0160) and 3 (MSDC-0602) had been selected for clinical development, however their initial syntheses were considered suboptimal for application deep into clinical trials. Difficulties ranging from the nature of the starting material, alcohol oxidation problems, epoxide opening regioisomeric issues, and endgame ketone redox problems had been encountered. Direct ketone introduction/maintenance was desired for maximum efficiency and convergence was found to be critically dependent upon the acidity of the nucleophilic species (13, 18) and the use of pre-or post-alkylative oximino-ether/oxime protection (vide infra). Improvements in overall yield for the syntheses of 2 (MSDC-0160) and 3 (MSDC-0602) from 20% (2) and 31% (3) respectively, to 44% (2) and 59% (3) were realized.
Diabetes, Jun 1, 2021
Mitochondrial pyruvate carrier (MPC) disruption attenuates type 2 diabetes NAFLD in mice. MSDC-06... more Mitochondrial pyruvate carrier (MPC) disruption attenuates type 2 diabetes NAFLD in mice. MSDC-0602, a PPARγ-sparing, TZD-like molecule that inhibits the MPC, was recently tested in a phase 2B trial for treating NASH, which reported beneficial effects on glucose and insulin homeostasis. Yet, the broad, in vivo metabolomic effects of MSDC-0602 treatment have remained undefined. Here, we tested MSDC-062 metabolic mechanisms of action in vitro and in vivo, spanning from mitochondrial pyruvate uptake assays in isolated mouse mitochondria, through cultured mouse liver cells, in vivo in mice, and in humans participating in the EMMINENCE trial. First, we examined MSDC-0602’s effect in isolated mouse liver mitochondria: Pyruvate-oxidation was decreased by MSDC-0602, and 2.5 µM MSDC-0602 was sufficient to decrease mitochondrial pyruvate uptake by >50%. We extended these findings to AML12 mouse liver cells and mouse liver in vivo. In AML12 cells, MSDC-0602 treatment increased pyruvate and lactate and decreased alanine. These results were comparable but not identical to results from parallel testing of the specific MPC inhibitor UK5099. 14-day treatment of NCD and HFD fed mice with MSDC-0602 decreased liver alanine and branched chain amino acids. As we previously observed with MPC liver-specific knockout mice, the HFD-induced liver TCA intermediate pool size expansion was mitigated by MSDC-0602. Accordingly, MSDC-0602-dependent metabolomic changes were more pronounced in HFD- versus NCD-fed mice. Human EMMINENCE trial participants receiving MSDC-0602 showed decreased circulating alanine, ketone bodies, and glucose. Similarly, circulating and liver glucose were decreased in HFD mice treated with MSDC-0602. Together, these data are consistent with MSDC-0602 modulating in vivo metabolism in a partially MPC-dependent manner and by additional mechanisms that remain to be understood. Disclosure A. J. Rauckhorst: None. D. J. Pape: None. J. R. Colca: Board Member; Self; Metabolic Solutions Development Company, LLC, Employee; Self; Cirius Therapeutics. E. B. Taylor: None. Funding American Diabetes Association (1-18-PDF-060 to A.J.R.); National Institute of Diabetes and Digestive and Kidney Diseases (DK104998); Cirius Therapeutics
Journal of Biological Chemistry, 2021
Insulin sensitizers and incretin mimetics are antidiabetic agents with vastly different mechanism... more 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.
Journal of Hepatology, Apr 1, 2020
Background & Aims MSDC-0602K is a novel insulin sensitizer designed to preferentially target ... more Background & Aims 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. Methods 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. Results 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. Conclusions 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]. Lay summary 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.
Methods in Enzymology, 1983
Publisher Summary This chapter describes techniques for the mass isolation of islets of Langerhan... more Publisher Summary This chapter describes techniques for the mass isolation of islets of Langerhans and procedures for obtaining characterized and purified subcellular fractions. Limitations of the quantity of isolated islets of Langerhans make extensive purification of islet-cell fractions difficult. The limited yields of protein from this technique require the use of microassay procedures and of constriction pipettes calibrated to microliter quantities. The chapter discusses the techniques for the evaluation of the functions of the plasma membrane and endoplasmic reticulum in the regulation of cellular Ca 2+ levels. Techniques are also presented to study the effects of Ca 2+ and calmodulin on protein phosphorylation in subcellular fractions obtained from islet cells and the correlation of these events with the secretion of insulin. Intracellular Ca 2+ concentration plays an essential role in insulin secretion from islets of Langerhans. A Ca 2+ extrusion pump associated with the plasma membrane may regulate these Ca 2+ levels. A well-characterized Ca 2+ -stimulated and Mg 2+ -dependent adenosine triphosphatase (ATPase) activity localized in the erythrocyte plasma membrane is considered to represent the enzymic basis for the Ca 2+ extrusion pump.
Journal of Hepatology, Dec 1, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Elsevier eBooks, 1992
Publisher Summary This chapter summarizes the recent advancement in the discovery and development... more Publisher Summary This chapter summarizes the recent advancement in the discovery and development of potential antidiabetic agents. Non-insulin-dependent diabetes mellitus (NIDDM) is a common metabolic disorder. Unlike insulin-dependent diabetes mellitus (IDDM) in which the source of endogenous insulin (pancreatic β-cells) is destroyed via an autoimmune attack on the pancreatic β-cells, NIDDM is not accompanied by an absolute deficiency in circulating insulin. The hallmark of this condition is a reduced responsiveness of the various tissues to the actions of insulin. Potential points of therapeutic intervention include augmentation of pancreatic β-cell secretion or alteration of the target tissue responsiveness to insulin. Several possible mechanisms exist whereby insulin secretion may be augmented, resulting in reduced circulating glucose concentrations. The stimulation of the α-2 adrenoreceptor with a number of agonists has been reported to produce a hyperglycemic response through an inhibition of insulin secretion. Midaglizole and dazoxzan have been reported to be peripherally active α-2 adrenoreceptor antagonists that are antihyperglycemic agents in a variety of models of NIDDM. Glimeperide represents the newest class of sulfonylurea-type compounds that are undergoing development for possible use in the treatment of NIDDM. The insensitivity of the target cells to insulin that occurs in NIDDM is thought to result from a reduced transduction of the insulin signal from the insulin receptor. This transduction can apparently be increased by treatment with such compounds as thiazolidinediones, as well as other insulin sensitizers, and β-3 agonists. The problems associated with the disease and recent observations in the area of drug discovery, particularly with the advent of insulin sensitizing compounds, are facilitating the discovery and development of novel agents. These can likely lead to more diverse therapeutic alternatives.
Biochimica et biophysica acta, Mar 1, 1985
The metabolism of arachidonic acid by pancreatic islets has been studied with purified population... more The metabolism of arachidonic acid by pancreatic islets has been studied with purified populations of large numbers of islets isolated from the rat. Sequential high-performance liquid chromatographic analyses of islet-derived metabolites of 3H-labeled arachidonate in both reversed and normal phases with 14C-labeled internal standards have demonstrated synthesis by the islets of the cyclooxygenase products prostaglandin E2, prostaglandin F2 alpha, thromboxane B2 and 12- hydroxyheptadecatrienoic acid as well as the lipoxygenase product 12-hydroxyeicosatetraenoic acid (12-HETE). Islet synthesis of these compounds was suppressed with appropriate inhibitors of arachidonate metabolism. Synthesis of the identified metabolites from endogenous arachidonate has also been quantitated with the use of deuterated internal standards, capillary column gas chromatographic analyses, and negative ion-chemical ionization mass spectrometric measurements. The relative abundances of metabolites derived from exogenous, radiolabeled arachidonate versus endogenous precursor differed considerably, and 12-HETE was by far the most abundant of these metabolites synthesized from endogenous arachidonate. Platelets contaminating the isolated islet preparations have been excluded as the source of the identified arachidonate metabolites. These studies establish that cells intrinsic to pancreatic islets synthesize a clearly characterized profile of arachidonate lipoxygenase and cyclooxygenase products. The sensitive and specific mass spectrometric methods for quantitation of these compounds permit detailed evaluation of their possible participation in insulin secretion from isolated islets.
Diabetes, Jun 1, 2021
The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin... more The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms by which MPC inhibition leads to metabolic improvements are incompletely understood. We evaluated whether MPC inhibitors might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. BCAA concentrations were assessed in plasma collected in EMMINENCE (NCT02784444), a randomized, placebo-controlled trial of the MPC inhibitor MSDC-0602K in people with NASH. MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes endpoints, decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH). BCKDH activity is suppressed by phosphorylation mediated by a kinase (BDK) and activated by the phosphatase (PPM1K). In Huh7 or HepG2 cells, MPC inhibitors markedly reduced BCKDH phosphorylation, suggesting increased BCKDH activity. Chemical inhibition or siRNA-mediated silencing of BDK had no effect on suppression of BCKDH phosphorylation by MPC inhibitors. In contrast, PPM1K knockdown prevented the effects of MPC inhibition on phospho-BCKDH. Lastly, we quantified BCKDH phosphorylation in liver of wild-type and hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice after 20 weeks of high fat diet. LS-Mpc2-/- mice exhibited reduced phosphorylation of BCKDH compared to wild-type mice. Lean LS-Mpc2-/- mice also exhibited reduced plasma BCAA concentrations after an overnight fast. These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation via the phosphatase PPM1K. Disclosure D. Ferguson: None. N. K. H. Yiew: None. K. S. Mccommis: None. J. R. Colca: Board Member; Self; Metabolic Solutions Development Company, LLC, Employee; Self; Cirius Therapeutics. B. N. Finck: Advisory Panel; Self; Cirius Therapeutics, Stock/Shareholder; Self; Cirius Therapeutics. Funding National Institutes of Health (R01DK104735, T32DK007120)
Diabetes, Jun 1, 2020
First generation insulin sensitizers improve both hyperglycemia and hyperinsulinemia and can pres... more First generation insulin sensitizers improve both hyperglycemia and hyperinsulinemia and can preserve beta cell mass and function. GLP-1 receptor agonists work by augmenting glucose-stimulated insulin secretion. Our objective was to assess potential additive effects of the new insulin sensitizer, MSDC-0602K (0602K) when combined with a GLP-1 receptor agonist in db/db mice. Mice were gavaged daily with 30 mg/kg 0602K or vehicle, injected subcutaneously every other day with 200 μg/kg Liraglutide (Lira) or vehicle, or received both drugs. Lira reduced glycemia and plasma fructosamine levels, while 0602K or 0602K+Lira normalized glycemia and fructosamine to lean db/+ mouse levels. Both drugs alone improved glucose tolerance compared to vehicle db/db, while the combination of 0602K+Lira further improved glucose tolerance even compared to lean db/+ mice. Vehicle treated db/db mice displayed elevated insulin and C-peptide levels, which were both reduced by 0602K treatment. C-peptide levels were lowered to a greater degree than insulin, indicating that 0602K treatment exerted a major effect on insulin secretion. In contrast, Lira increased the insulin and C-peptide levels in db/db mice, while the combination of 0602K+Lira displayed reduced levels of insulin and C-peptide similar to 0602K-alone treatment. Pancreas immunohistochemistry of vehicle treated db/db mice showed little islet insulin content, but islet insulin was significantly increased by 0602K or 0602K+Lira treatment. Isolated islets from lean, naïve mice showed no defect in glucose-stimulated insulin secretion with 0602K treatment, suggesting that the lowered insulinemia in vivo is due to corrected insulin resistance rather than direct inhibition of insulin secretion. In conclusion, the new insulin sensitizer MSDC-0602K improves insulinemia and helps to restore islet insulin content when used alone or in combination with Liraglutide. Glucose tolerance displayed additive effects with combined 0602K+Lira treatment. Disclosure K.D. Pyles: None. D. Kamm: None. J.R. Colca: Stock/Shareholder; Self; Cirius Therapeutics, Metabolic Solutions Development Company. K.S. McCommis: None. Funding National Institutes of Health (R01HL136658)
Diabetes, Jun 1, 2020
Use of the first-generation insulin sensitizer pioglitazone is limited by PPARγ-driven side effec... more Use of the first-generation insulin sensitizer pioglitazone is limited by PPARγ-driven side effects. MSDC-0602K was designed to maintain pioglitazone’s effects on the mitochondrial pyruvate carrier (MPC), but with minimal direct PPARγ binding. A 12-month Phase 2b dose-ranging study in NASH (Harrison et al, 2019) demonstrated insulin sensitizing pharmacology without dose-limiting issues. Here we describe ongoing analysis of these data. Steady state exposures of drug and active metabolite at the highest doses averaged 4 to 7 micromolar, 1/10thof the affinity to PPARγ, but within the range for modulation of the MPC in intact cells. The effects on fasting plasma insulin (FPI), fasting plasma glucose, and hemoglobin A1c (HbA1c) plateaued at the mid-dose (125 mg), while adiponectin continued to increase 1.7, 2.5, and 4.1x vs. placebo across the 62.5, 125, and 250 mg doses. Glycemic reductions and the reduction of FPI levels were similar in subjects with or without T2D. The treatment-induced decrease in HbA1c was proportional to the baseline HBA1c and was more than 1% in subjects with a baseline above 7%, including those not well-controlled on GLP-1 agonists. In patients with or without diabetes, baseline mean FPI levels exceeded 20 μU/ml (139 pmol/L), levels in the upper quartile of historical T2D studies, and continued to increase in placebo-treated subjects but decreased on treatment with MSDC-0602K. Treatment with MSDC-0602K decreased FPI more than C-peptide. The ratio of C-peptide/FPI increased vs. placebo at end of study (8.54 ± 0.49, 9.69 ± 0.44, 10.45 ± 0.43, and 10.9 ± 0.53 for placebo and the three dose groups, respectively) suggesting both decreased need for secreted insulin and increased clearance of insulin. These data suggest that the new generation insulin sensitizer MSDC-0602K, focused toward MPC and away from PPAR, may be useful to treat patients suffering from combined fatty liver disease and T2D and highlight the importance of FPI. Disclosure J.R. Colca: Stock/Shareholder; Self; Cirius Therapeutics, Metabolic Solutions Development Company. B. Lee: Employee; Self; Cirius Therapeutics. J.S. Iwashita: Employee; Self; Cirius Therapeutics. H.C. Dittrich: Employee; Self; Cirius Therapeutics. S.A. Harrison: Consultant; Self; Akero, Altimmune, Axcella, Cirius, Cirius Therapeutics, Genentech, Inc., Hightide Bio, HistoIndex, Intercept Pharmaceuticals, Inc., Madrigal.
Endocrinology, Feb 1, 1994
Analogs of thiazolidinedione improve the responsiveness of insulin-resistant animals to insulin. ... more Analogs of thiazolidinedione improve the responsiveness of insulin-resistant animals to insulin. One such analog, pioglitazone (5-(4-[2-(5-ethyl-2-pyridinyl)ethoxy]benzyl)thiazolidine-2,4-dione hydrochloride), when fed to insulin-resistant animals such as the obese (ob/ob) mouse, reduces blood glucose and lipids and also lowers the plasma insulin level. Because GH can produce insulin resistance in humans and animals such as the ob/ob mouse, the present study was conducted to determine whether feeding pioglitazone can 1) inhibit the ability of GH to induce enhanced insulin resistance in obese mice, 2) ameliorate or reverse GH-induced insulin resistance once it has been induced in ob/ob mice, and 3) alter the ability of GH to promote growth in hypophysectomized rats. Female ob/ob mice were fed a control diet or a diet containing pioglitazone (20 mg/kg animal.day) for 4 days. During the last 3 days of the feeding period, the mice also received a daily sc injection of either saline or 200 micrograms S-carboxymethylated human GH (RCM-hGH), which is a GH derivative having mainly diabetogenic activity. In control-fed mice, RCM-hGH increased blood glucose and plasma insulin levels, which is an expected response to GH-induced insulin resistance. By contrast, the ability of RCM-hGH to increase blood glucose and plasma insulin levels was totally blocked in pioglitazone-fed mice. To determine whether pioglitazone can ameliorate GH-induced insulin resistance once it has been established, ob/ob mice were treated sc with either saline or 200 micrograms RCM-hGH for 3 days. Half of the saline-treated and half of the hormone-treated mice were then fed pioglitazone, whereas the remaining animals were continued on the control diet. After 48 h on the diets, the blood glucose and plasma insulin levels of the RCM-hGH treated mice fed the control diet remained elevated with respect to those in the saline-treated controls. On the other hand, the blood glucose and plasma insulin levels of the RCM-hGH treated mice fed pioglitazone were markedly reduced compared to those of the RCM-hGH-treated control-fed animals. Thus, these results suggest that pioglitazone can ameliorate GH-induced insulin resistance.(ABSTRACT TRUNCATED AT 400 WORDS)
Canadian Journal of Diabetes, 2009
... of the West Indies, Pathology, Kingston 7, Jamaica 3 University of the West Indies, Basic Med... more ... of the West Indies, Pathology, Kingston 7, Jamaica 3 University of the West Indies, Basic Medical Sciences, Kingston 7, Jamaica 4 University of the West Indies, Medicine, Kingston 7, Jamaica Objective: This study investigated the impact of Hatha yoga and conventional physical ...
Molecular metabolism, Apr 1, 2023
Objective: The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treat... more Objective: The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH. Methods: Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n ¼ 94) or 250 mg MSDC-0602K (n ¼ 101). Human hepatoma cell lines and mouse primary hepatocytes were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA metabolism in the liver of obese mice and MSDC-0602K treatment of Zucker diabetic fatty (ZDF) rats. Results: In patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, had decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades in vitro. BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2À/À) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo. Finally, while MSDC-0602K treatment improved glucose homeostasis and increased the concentrations of some BCAA metabolites in ZDF rats, it did not lower plasma BCAA concentrations. Conclusions: These data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation by activating the mTOR axis. However, the effects of MPCi on glucose homeostasis may be separable from its effects on BCAA concentrations.
Science immunology, Apr 14, 2023
The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes... more The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, SARS-CoV-2 infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyper-inflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease following influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602 K (MSDC), dampened pulmonary inflammation and promoted lung recovery, while concurrently reducing blood glucose levels and hyperlipidemia following viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized HIF-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development following SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.
bioRxiv (Cold Spring Harbor Laboratory), Jan 20, 2022
Background: A growing body of evidence supports the idea that mitochondrial dysfunction might rep... more Background: A growing body of evidence supports the idea that mitochondrial dysfunction might represent a key feature of Parkinson's disease (PD). Central regulators of energy production, mitochondria are also involved in several other essential functions such as cell death pathways and neuroinflammation which make them a potential therapeutic target for PD management. Interestingly, recent studies related to PD have reported a neuroprotective effect of targeting mitochondrial pyruvate carrier (MPC) by the insulin sensitizer MSDC-0160. As the sole point of entry of pyruvate into the mitochondrial matrix, MPC plays a crucial role in energetic metabolism which is impacted in PD. This study therefore aimed at providing insights into the mechanisms underlying the neuroprotective effect of MSDC-0160. Methods: We investigated behavioral, cellular and metabolic impact of chronic MSDC-0160 treatment in unilateral 6-OHDA PD rats. We evaluated mitochondrial related processes through. CC-BY-NC-ND 4.
Expert Opinion on Investigational Drugs, 1995
Expert Opinion on Investigational Drugs, Jun 17, 2015
Introduction: This manuscript describes 21 drug targets in the area of diabetes and related condi... more Introduction: This manuscript describes 21 drug targets in the area of diabetes and related conditions that were discontinued in 2015. Areas covered: The material for this paper was obtained by contacting biopharmaceutical companies, reviewing their pipelines, press releases and annual reports. Additionally, the authors searched clinicaltrials.gov, PubMed and general Internet search engines. Majority of the compounds were in early stages of the development. Expert opinion: Business reasons for termination of the drug projects emerge more and more frequently over the years. Safety signals usually appear early in the development and are often associated with novel drugs. 2015 medicines with inadequate efficacy were unable to compete with existing approved members of the class they represented. List of Abbreviations 11β-HSD1-11β-hydroxysteroid dehydrogenase type ACC-acetyl-CoA carboxylase BIP-basal insulin peglispro CCR-CC Chemokine Receptor DPP-4-dipeptidyl peptidase-4 EMA-European medicines agency FDA-food and drug administration GR-glucagon receptor GLP-1-glucagon-like peptide-1 HbA1c-hemoglobin A1c Article Highlights • Due to national differences in the regulatory requirements for drug approval, it is challenging to develop a drug that can be concurrently approved in multiple countries. • The key reasons for the termination of drug projects are: lack of safety and/or efficacy, business decisions and/or strategic reevaluation. • Basal insulin peglispro was, perhaps, the largest anti-diabetes drug project terminated in 2015. • The risk for termination is very low for new members of existing classes. This has resulted in five glucagon-like peptide-1receptor agonists, four dipeptidyl peptidase-4 inhibitors, three sodium/glucose cotransporter 2 inhibitors and four different types of insulin glargine currently on the market. • For capital efficiency it is critical to identify a dug project that carries a high risk of imminent failure as early in the development as possible. • Opportunities for anti-diabetes drug development include an easy to take regimen that could reduce HbA1c without compromising safety, preserve/improve β cell function, and produce clinically significant cardiovascular risk reduction and weight loss. • Development of an oral glucagon-like peptide-1 receptor agonist would further advance therapeutic and commercial success of the class.