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出境医 / 临床实验 / The Effects of Glycine on Atherosclerosis and Metabolic Syndrome-related Parameters.

The Effects of Glycine on Atherosclerosis and Metabolic Syndrome-related Parameters.

Study Description
Brief Summary:
The current study will test the central hypothesis that Glycine supplementation in humans improves Lipid profile and therefore reduces the risk of Atherosclerosis. Secondary outcomes including Insulin sensitivity and parameters related to Metabolic Syndrome (MetS) will also be measured. Furthermore, a mechanistic study in an ex-vivo model will test the hypothesis that Glycine via its key biosynthetic pathway involving Serine Hydroxymethyltransferase 2 (SHMT2), is athero-protective by inhibiting Sterol regulatory element-binding protein 2 (SREBP2)-mediated cholesterol biosynthesis in murine macrophage-like cell line.

Condition or disease Intervention/treatment Phase
Metabolic Syndrome Dyslipidemias Diabetes Mellitus Obesity Atherosclerosis Dietary Supplement: Glycine Phase 2 Phase 3

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: The Effects of Glycine on Atherosclerosis and Metabolic Syndrome-related Parameters: A Clinical and Ex-vivo Study.
Estimated Study Start Date : March 2019
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : June 2020
Arms and Interventions
Arm Intervention/treatment
Experimental: Glycine
Glycine total daily dose of 150mg/kg divided three times daily with meals (powder dissolved in 1 cup of water) for 12 weeks.
 Dietary Supplement: Glycine
Glycine powder to be dissolved in water.
Outcome Measures
Primary Outcome Measures :
  1. LDL Cholesterol levels [ Time Frame: 12 weeks ]
    Change in LDL Cholesterol levels


Secondary Outcome Measures :
  1. Triglyceride levels [ Time Frame: 12 weeks ]
    Change in Triglyceride levels

  2. HDL Cholesterol levels [ Time Frame: 12 weeks ]
    Change in HDL Cholesterol levels

  3. HbA1C levels [ Time Frame: 12 weeks ]
    Change in Glycated hemoglobin (HbA1C) levels


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male between the ages of 40-65 years old.
  • Fulfill at least three of the five diagnostic criteria for the Metabolic Syndrome.
  • To be able to give their written consent to participate in this study.

Exclusion Criteria:

  • Abnormal Liver function tests ≥ 3 times upper limit of normal (ULN).
  • Chronic liver disease other than NAFLD.
  • Previous gastric or small bowel surgery.
  • Abnormal Thyroid-stimulating hormone (TSH) level.
  • Known Tobacco Smoking more than 10 cigarettes per day.
  • Known alcohol consumption more than 2 drink per day.
  • Use of medications that include: Insulin or Insulin secretagogues, Thiazolidinediones, Glucocorticosteroids, Hormone replacement therapy.
  • Fever > 38.2 °C in the past 2 weeks.
  • Autoimmune or Auto-inflammatory disease.
  • Chronic kidney disease ≥ stage III.
  • Nephrotic syndrome.
  • Hemoglobin <12 g/dL.
  • Metal clips or implants that preclude magnetic resonance imaging.
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Tony Hayek, MD +972523782009 t_hayek@rmc.gov.il

Sponsors and Collaborators
Prof. Tony hayek MD
Investigators
Layout table for investigator information
Principal Investigator: Tony Hayek, MD Rambam Health Care Campus
Tracking Information
First Submitted Date  ICMJE February 19, 2019
First Posted Date  ICMJE February 21, 2019
Last Update Posted Date February 21, 2019
Estimated Study Start Date  ICMJE March 2019
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 20, 2019) 		LDL Cholesterol levels [ Time Frame: 12 weeks ]
Change in LDL Cholesterol levels
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: February 20, 2019)
  • Triglyceride levels [ Time Frame: 12 weeks ]
    Change in Triglyceride levels
  • HDL Cholesterol levels [ Time Frame: 12 weeks ]
    Change in HDL Cholesterol levels
  • HbA1C levels [ Time Frame: 12 weeks ]
    Change in Glycated hemoglobin (HbA1C) levels
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effects of Glycine on Atherosclerosis and Metabolic Syndrome-related Parameters.
Official Title  ICMJE The Effects of Glycine on Atherosclerosis and Metabolic Syndrome-related Parameters: A Clinical and Ex-vivo Study.
Brief Summary The current study will test the central hypothesis that Glycine supplementation in humans improves Lipid profile and therefore reduces the risk of Atherosclerosis. Secondary outcomes including Insulin sensitivity and parameters related to Metabolic Syndrome (MetS) will also be measured. Furthermore, a mechanistic study in an ex-vivo model will test the hypothesis that Glycine via its key biosynthetic pathway involving Serine Hydroxymethyltransferase 2 (SHMT2), is athero-protective by inhibiting Sterol regulatory element-binding protein 2 (SREBP2)-mediated cholesterol biosynthesis in murine macrophage-like cell line.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Metabolic Syndrome
  • Dyslipidemias
  • Diabetes Mellitus
  • Obesity
  • Atherosclerosis
Intervention  ICMJE Dietary Supplement: Glycine
Glycine powder to be dissolved in water.
Study Arms  ICMJE Experimental: Glycine
Glycine total daily dose of 150mg/kg divided three times daily with meals (powder dissolved in 1 cup of water) for 12 weeks.
Intervention: Dietary Supplement: Glycine
Publications *
  • Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013 Oct;13(10):709-21. doi: 10.1038/nri3520. Epub 2013 Sep 2. Review.
  • Weber C, Noels H. Atherosclerosis: current pathogenesis and therapeutic options. Nat Med. 2011 Nov 7;17(11):1410-22. doi: 10.1038/nm.2538. Review.
  • Michas G, Micha R, Zampelas A. Dietary fats and cardiovascular disease: putting together the pieces of a complicated puzzle. Atherosclerosis. 2014 Jun;234(2):320-8. doi: 10.1016/j.atherosclerosis.2014.03.013. Epub 2014 Mar 27. Review.
  • Sacks FM, Lichtenstein AH, Wu JHY, Appel LJ, Creager MA, Kris-Etherton PM, Miller M, Rimm EB, Rudel LL, Robinson JG, Stone NJ, Van Horn LV; American Heart Association. Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association. Circulation. 2017 Jul 18;136(3):e1-e23. doi: 10.1161/CIR.0000000000000510. Epub 2017 Jun 15. Review. Erratum in: Circulation. 2017 Sep 5;136(10 ):e195.
  • Rom O, Aviram M. It is not just lipids: proatherogenic vs. antiatherogenic roles for amino acids in macrophage foam cell formation. Curr Opin Lipidol. 2017 Feb;28(1):85-87. doi: 10.1097/MOL.0000000000000377.
  • Shah SH, Bain JR, Muehlbauer MJ, Stevens RD, Crosslin DR, Haynes C, Dungan J, Newby LK, Hauser ER, Ginsburg GS, Newgard CB, Kraus WE. Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events. Circ Cardiovasc Genet. 2010 Apr;3(2):207-14. doi: 10.1161/CIRCGENETICS.109.852814. Epub 2010 Feb 19.
  • Würtz P, Raiko JR, Magnussen CG, Soininen P, Kangas AJ, Tynkkynen T, Thomson R, Laatikainen R, Savolainen MJ, Laurikka J, Kuukasjärvi P, Tarkka M, Karhunen PJ, Jula A, Viikari JS, Kähönen M, Lehtimäki T, Juonala M, Ala-Korpela M, Raitakari OT. High-throughput quantification of circulating metabolites improves prediction of subclinical atherosclerosis. Eur Heart J. 2012 Sep;33(18):2307-16. doi: 10.1093/eurheartj/ehs020. Epub 2012 Mar 26.
  • Bhattacharya S, Granger CB, Craig D, Haynes C, Bain J, Stevens RD, Hauser ER, Newgard CB, Kraus WE, Newby LK, Shah SH. Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization. Atherosclerosis. 2014 Jan;232(1):191-6. doi: 10.1016/j.atherosclerosis.2013.10.036. Epub 2013 Nov 12.
  • Yang R, Dong J, Zhao H, Li H, Guo H, Wang S, Zhang C, Wang S, Wang M, Yu S, Chen W. Association of branched-chain amino acids with carotid intima-media thickness and coronary artery disease risk factors. PLoS One. 2014 Jun 9;9(6):e99598. doi: 10.1371/journal.pone.0099598. eCollection 2014.
  • Yang RY, Wang SM, Sun L, Liu JM, Li HX, Sui XF, Wang M, Xiu HL, Wang S, He Q, Dong J, Chen WX. Association of branched-chain amino acids with coronary artery disease: A matched-pair case-control study. Nutr Metab Cardiovasc Dis. 2015 Oct;25(10):937-42. doi: 10.1016/j.numecd.2015.06.003. Epub 2015 Jun 14.
  • Grajeda-Iglesias C, Aviram M. Specific Amino Acids Affect Cardiovascular Diseases and Atherogenesis via Protection against Macrophage Foam Cell Formation: Review Article. Rambam Maimonides Med J. 2018 Jul 30;9(3). doi: 10.5041/RMMJ.10337. Review.
  • Ding Y, Svingen GF, Pedersen ER, Gregory JF, Ueland PM, Tell GS, Nygård OK. Plasma Glycine and Risk of Acute Myocardial Infarction in Patients With Suspected Stable Angina Pectoris. J Am Heart Assoc. 2015 Dec 31;5(1). pii: e002621. doi: 10.1161/JAHA.115.002621.
  • Rom O, Aviram M. Endogenous or exogenous antioxidants vs. pro-oxidants in macrophage atherogenicity. Curr Opin Lipidol. 2016 Apr;27(2):204-6. doi: 10.1097/MOL.0000000000000287.
  • Rom O, Grajeda-Iglesias C, Najjar M, Abu-Saleh N, Volkova N, Dar DE, Hayek T, Aviram M. Atherogenicity of amino acids in the lipid-laden macrophage model system in vitro and in atherosclerotic mice: a key role for triglyceride metabolism. J Nutr Biochem. 2017 Jul;45:24-38. doi: 10.1016/j.jnutbio.2017.02.023. Epub 2017 Apr 6.
  • Yan-Do R, MacDonald PE. Impaired "Glycine"-mia in Type 2 Diabetes and Potential Mechanisms Contributing to Glucose Homeostasis. Endocrinology. 2017 May 1;158(5):1064-1073. doi: 10.1210/en.2017-00148. Review.
  • Yamakado M, Tanaka T, Nagao K, Ishizaka Y, Mitushima T, Tani M, Toda A, Toda E, Okada M, Miyano H, Yamamoto H. Plasma amino acid profile is associated with visceral fat accumulation in obese Japanese subjects. Clin Obes. 2012 Feb;2(1-2):29-40. doi: 10.1111/j.1758-8111.2012.00039.x. Epub 2012 May 22.
  • Gaggini M, Carli F, Rosso C, Buzzigoli E, Marietti M, Della Latta V, Ciociaro D, Abate ML, Gambino R, Cassader M, Bugianesi E, Gastaldelli A. Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance. Hepatology. 2018 Jan;67(1):145-158. doi: 10.1002/hep.29465. Epub 2017 Nov 17.
  • Mirmiran P, Bahadoran Z, Ghasemi A, Azizi F. Contribution of dietary amino acids composition to incidence of cardiovascular outcomes: A prospective population-based study. Nutr Metab Cardiovasc Dis. 2017 Jul;27(7):633-641. doi: 10.1016/j.numecd.2017.05.003. Epub 2017 May 15.
  • Petrat F, Boengler K, Schulz R, de Groot H. Glycine, a simple physiological compound protecting by yet puzzling mechanism(s) against ischaemia-reperfusion injury: current knowledge. Br J Pharmacol. 2012 Apr;165(7):2059-72. doi: 10.1111/j.1476-5381.2011.01711.x. Review.
  • Razak MA, Begum PS, Viswanath B, Rajagopal S. Multifarious Beneficial Effect of Nonessential Amino Acid, Glycine: A Review. Oxid Med Cell Longev. 2017;2017:1716701. doi: 10.1155/2017/1716701. Epub 2017 Mar 1. Review.
  • McCarty MF, Barroso-Aranda J, Contreras F. The hyperpolarizing impact of glycine on endothelial cells may be anti-atherogenic. Med Hypotheses. 2009 Aug;73(2):263-4. doi: 10.1016/j.mehy.2008.12.021. Epub 2009 Feb 18.
  • McCarty MF, DiNicolantonio JJ. The cardiometabolic benefits of glycine: Is glycine an 'antidote' to dietary fructose? Open Heart. 2014 May 28;1(1):e000103. doi: 10.1136/openhrt-2014-000103. eCollection 2014.
  • Wang W, Wu Z, Dai Z, Yang Y, Wang J, Wu G. Glycine metabolism in animals and humans: implications for nutrition and health. Amino Acids. 2013 Sep;45(3):463-77. doi: 10.1007/s00726-013-1493-1. Epub 2013 Apr 25. Review.
  • Morscher RJ, Ducker GS, Li SH, Mayer JA, Gitai Z, Sperl W, Rabinowitz JD. Mitochondrial translation requires folate-dependent tRNA methylation. Nature. 2018 Feb 1;554(7690):128-132. doi: 10.1038/nature25460. Epub 2018 Jan 24.
  • Mardinoglu A, Agren R, Kampf C, Asplund A, Uhlen M, Nielsen J. Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease. Nat Commun. 2014;5:3083. doi: 10.1038/ncomms4083.
  • Kruth HS. Macrophage foam cells and atherosclerosis. Front Biosci. 2001 Mar 1;6:D429-55. Review.
  • Díaz-Flores M, Cruz M, Duran-Reyes G, Munguia-Miranda C, Loza-Rodríguez H, Pulido-Casas E, Torres-Ramírez N, Gaja-Rodriguez O, Kumate J, Baiza-Gutman LA, Hernández-Saavedra D. Oral supplementation with glycine reduces oxidative stress in patients with metabolic syndrome, improving their systolic blood pressure. Can J Physiol Pharmacol. 2013 Oct;91(10):855-60. doi: 10.1139/cjpp-2012-0341. Epub 2013 Jun 17.
  • Heresco-Levy U, Javitt DC, Ermilov M, Mordel C, Silipo G, Lichtenstein M. Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Arch Gen Psychiatry. 1999 Jan;56(1):29-36.
  • Evins AE, Fitzgerald SM, Wine L, Rosselli R, Goff DC. Placebo-controlled trial of glycine added to clozapine in schizophrenia. Am J Psychiatry. 2000 May;157(5):826-8.
  • Mardinoglu A, Bjornson E, Zhang C, Klevstig M, Söderlund S, Ståhlman M, Adiels M, Hakkarainen A, Lundbom N, Kilicarslan M, Hallström BM, Lundbom J, Vergès B, Barrett PH, Watts GF, Serlie MJ, Nielsen J, Uhlén M, Smith U, Marschall HU, Taskinen MR, Boren J. Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD. Mol Syst Biol. 2017 Mar 2;13(3):916. doi: 10.15252/msb.20167422.
  • National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002 Dec 17;106(25):3143-421.
  • Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004 Jun;27(6):1487-95. Review.
  • Dulai PS, Sirlin CB, Loomba R. MRI and MRE for non-invasive quantitative assessment of hepatic steatosis and fibrosis in NAFLD and NASH: Clinical trials to clinical practice. J Hepatol. 2016 Nov;65(5):1006-1016. doi: 10.1016/j.jhep.2016.06.005. Epub 2016 Jun 14. Review.
  • Permutt Z, Le TA, Peterson MR, Seki E, Brenner DA, Sirlin C, Loomba R. Correlation between liver histology and novel magnetic resonance imaging in adult patients with non-alcoholic fatty liver disease - MRI accurately quantifies hepatic steatosis in NAFLD. Aliment Pharmacol Ther. 2012 Jul;36(1):22-9. doi: 10.1111/j.1365-2036.2012.05121.x. Epub 2012 May 3.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: February 20, 2019) 		50
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2020
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male between the ages of 40-65 years old.
  • Fulfill at least three of the five diagnostic criteria for the Metabolic Syndrome.
  • To be able to give their written consent to participate in this study.

Exclusion Criteria:

  • Abnormal Liver function tests ≥ 3 times upper limit of normal (ULN).
  • Chronic liver disease other than NAFLD.
  • Previous gastric or small bowel surgery.
  • Abnormal Thyroid-stimulating hormone (TSH) level.
  • Known Tobacco Smoking more than 10 cigarettes per day.
  • Known alcohol consumption more than 2 drink per day.
  • Use of medications that include: Insulin or Insulin secretagogues, Thiazolidinediones, Glucocorticosteroids, Hormone replacement therapy.
  • Fever > 38.2 °C in the past 2 weeks.
  • Autoimmune or Auto-inflammatory disease.
  • Chronic kidney disease ≥ stage III.
  • Nephrotic syndrome.
  • Hemoglobin <12 g/dL.
  • Metal clips or implants that preclude magnetic resonance imaging.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 40 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03850314
Other Study ID Numbers  ICMJE RMB-18-0621
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Prof. Tony hayek MD, Rambam Health Care Campus
Study Sponsor  ICMJE Prof. Tony hayek MD
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Tony Hayek, MD Rambam Health Care Campus
PRS Account Rambam Health Care Campus
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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