Monounsaturated Fatty Acid Supplementation for Overweight and Obese Individuals With Prediabetes

NCT05560971 | Active Not Recruiting DMC

• 1 other identifier: 2022P001764
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to understand and determine whether Palmitoleic acid (POA), monounsaturated omega-7 fatty acid (exists in regular diet), improves insulin sensitivity and decreases liver fat accumulation in humans. Unlike others, the study will use POA as a dietary supplement, rather than complex oils, which contain a significant amount of saturated fat palmitic acid. Palmitic acid has known harmful effects on the body. Hence, eliminating palmitic acid from supplementation of POA might increase its benefits. This trial stems from the preclinical discoveries that POA acting as a fat hormone, has beneficial effects on the liver, muscle, vessels, and fat tissue. Supporting this, higher POA levels in humans have been shown to be correlated with a reduced risk of developing type-2 diabetes and cardiovascular diseases such as heart attacks. In animals, it has been observed that POA improves sugar metabolism in a number of mechanisms related to the liver and muscle. Based on these findings, the design of this study is a double-blind placebo-controlled trial that tests the effects of POA on insulin sensitivity of overweight and obese adult individuals with pre-diabetes.

Conditions

PreDiabetes; Insulin Resistance; Overweight; Obesity

Keywords

Palmitoleic acid; Obesity; Insulin resistance; Dietary supplement; Prediabetes

Outcome Measures

Primary Outcomes (1)

• Insulin sensitivity M value change before and 8 weeks after POA vs placebo intake

  Insulin sensitivity (M values) will be evaluated by hyperinsulinemic euglycemic clamp (gold standard) from the same individuals before and after taking POA vs. placebo. The investigators will compare M values before and after taking POA vs placebo intake. Hence the investigators are looking for delta changes and expect 20% statistically significant improvement with POA and no significant change with placebo. The investigators calculated sample size and powered the study for only this primary endpoint to see at least 20% difference.

  8 weeks

Secondary Outcomes (4)

• Modified mixed meal tolerance test

  8 weeks

• Liver fat quantification

  8 weeks

• Total body fat mass and body composition

  8 weeks

• Serum; fasting glucose, insulin, LDL cholesterol, hsCRP, circulating inflammatory cytokines (TNF-a, IL-6), FABP4, glucagon

  8 weeks

Study Arms (2)

Palmitoleic acid

ACTIVE COMPARATOR

The treatment arm will receive Palmitoleic acid (POA) supplement as Provinal® 420 mg capsules with at least 90% pure POA Ethyl Ester (less than 1% palmitic acid). Participants will be asked to consume 2 Provinal® 420 mg capsules twice a day for 8 weeks.

Dietary Supplement: Palmitoleic acid

Placebo

PLACEBO COMPARATOR

The placebo is a medium chain fatty acid in triglyceride form. The placebo has no shown health effects, neither beneficial or detrimental. Participants will be asked to consume 2 placebo capsules daily twice a day for 8 weeks.

Other: Placebo

Interventions

Palmitoleic acid DIETARY_SUPPLEMENT

Participants will be randomized to either POA or placebo and will be asked to take 2 capsules of the POA or placebo twice a day for 8 weeks.

Also known as: Provinal®

Palmitoleic acid

Placebo OTHER

Medium chain fatty acids in triglyceride form in capsules with the same shape, color, size and odor of POA capsules

Placebo

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Overweight and obese individuals with prediabetes and/or impaired glucose tolerance
• Age 18 to 70 years
• BMI 25-40 kg/m2
• HbA1c between 5.6 - 6.5, Impaired fasting plasma glucose levels (\>99, ≤126 mg/dL) or OGTT blood glucose at 2 hours between 140-200 mg/dL or HOMA-IR \>2.5
• BP \<150/90 with or without medication
• GFR\>60
• ALT, AST \<300
• Normal thyroid function is defined as screening TSH within normal ranges, with or without medication

You may not qualify if:

• Use of any medications (except thyroid hormone with normal TSH, anti-hypertensives with blood pressure \<150/90 and non-steroidal rescue inhalers for asthma)
• Pregnancy or breastfeeding
• Use of over-the-counter (OTC) supplements (except vitamin D). The investigators will ensure that study participants are not using supplements containing fish oil or other lipid supplements (e.g., macadamia oil, krill oil, flaxseed, primrose oil, sea buckthorn oil) within 3 months of study participation
• Greater than 3 servings/day combined of cheese, whole-fat milk, kefir, or whole-fat yogurt for the last 3 months before the study.
• Diagnosed with any type of diabetes mellitus and/or taking glucose-lowering medications
• Recent weight loss (more than 7% of total body weight loss in last 3 months)
• Established major chronic diseases such as major cardiovascular disease (history of myocardial infarction, stroke, symptomatic heart failure, coronary artery bypass graft, Atrial fibrillation, symptomatic peripheral arterial disease), bleeding disorder or anticoagulation use, active cancer, end-stage renal disease, proteinuria (\>3g/day), dementia, severe chronic obstructive pulmonary disease (needs systemic steroid therapy), significant liver disease (ALT or AST\>300)
• History of ongoing smoking cigarettes \>1 pack/day, alcohol abuse, or illicit drug abuse
• Treatment with any investigational drug in the one month preceding the study

Sponsors & Collaborators

• Brigham and Women's Hospital: lead
• Tersus Life Sciences LLC: collaborator

Study Sites (1)

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Related Publications (36)

• Burak MF, Inouye KE, White A, Lee A, Tuncman G, Calay ES, Sekiya M, Tirosh A, Eguchi K, Birrane G, Lightwood D, Howells L, Odede G, Hailu H, West S, Garlish R, Neale H, Doyle C, Moore A, Hotamisligil GS. Development of a therapeutic monoclonal antibody that targets secreted fatty acid-binding protein aP2 to treat type 2 diabetes. Sci Transl Med. 2015 Dec 23;7(319):319ra205. doi: 10.1126/scitranslmed.aac6336. Epub 2015 Dec 23.

  PMID: 26702093 BACKGROUND

• Cao H, Sekiya M, Ertunc ME, Burak MF, Mayers JR, White A, Inouye K, Rickey LM, Ercal BC, Furuhashi M, Tuncman G, Hotamisligil GS. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab. 2013 May 7;17(5):768-78. doi: 10.1016/j.cmet.2013.04.012.

  PMID: 23663740 BACKGROUND

• Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell. 2008 Sep 19;134(6):933-44. doi: 10.1016/j.cell.2008.07.048.

  PMID: 18805087 BACKGROUND

• Olefsky JM. Fat talks, liver and muscle listen. Cell. 2008 Sep 19;134(6):914-6. doi: 10.1016/j.cell.2008.09.001.

  PMID: 18805083 BACKGROUND

• Dimopoulos N, Watson M, Sakamoto K, Hundal HS. Differential effects of palmitate and palmitoleate on insulin action and glucose utilization in rat L6 skeletal muscle cells. Biochem J. 2006 Nov 1;399(3):473-81. doi: 10.1042/BJ20060244.

  PMID: 16822230 BACKGROUND

• Maedler K, Spinas GA, Dyntar D, Moritz W, Kaiser N, Donath MY. Distinct effects of saturated and monounsaturated fatty acids on beta-cell turnover and function. Diabetes. 2001 Jan;50(1):69-76. doi: 10.2337/diabetes.50.1.69.

  PMID: 11147797 BACKGROUND

• Maedler K, Oberholzer J, Bucher P, Spinas GA, Donath MY. Monounsaturated fatty acids prevent the deleterious effects of palmitate and high glucose on human pancreatic beta-cell turnover and function. Diabetes. 2003 Mar;52(3):726-33. doi: 10.2337/diabetes.52.3.726.

  PMID: 12606514 BACKGROUND

• Gravena C, Mathias PC, Ashcroft SJ. Acute effects of fatty acids on insulin secretion from rat and human islets of Langerhans. J Endocrinol. 2002 Apr;173(1):73-80. doi: 10.1677/joe.0.1730073.

  PMID: 11927386 BACKGROUND

• Cimen I, Kocaturk B, Koyuncu S, Tufanli O, Onat UI, Yildirim AD, Apaydin O, Demirsoy S, Aykut ZG, Nguyen UT, Watkins SM, Hotamisligil GS, Erbay E. Prevention of atherosclerosis by bioactive palmitoleate through suppression of organelle stress and inflammasome activation. Sci Transl Med. 2016 Sep 28;8(358):358ra126. doi: 10.1126/scitranslmed.aaf9087.

  PMID: 27683551 BACKGROUND

• Duckett SK, Volpi-Lagreca G, Alende M, Long NM. Palmitoleic acid reduces intramuscular lipid and restores insulin sensitivity in obese sheep. Diabetes Metab Syndr Obes. 2014 Nov 20;7:553-63. doi: 10.2147/DMSO.S72695. eCollection 2014.

  PMID: 25429233 BACKGROUND

• Yang ZH, Miyahara H, Hatanaka A. Chronic administration of palmitoleic acid reduces insulin resistance and hepatic lipid accumulation in KK-Ay Mice with genetic type 2 diabetes. Lipids Health Dis. 2011 Jul 21;10:120. doi: 10.1186/1476-511X-10-120.

  PMID: 21774832 BACKGROUND

• Lima EA, Silveira LS, Masi LN, Crisma AR, Davanso MR, Souza GI, Santamarina AB, Moreira RG, Martins AR, de Sousa LG, Hirabara SM, Rosa Neto JC. Macadamia oil supplementation attenuates inflammation and adipocyte hypertrophy in obese mice. Mediators Inflamm. 2014;2014:870634. doi: 10.1155/2014/870634. Epub 2014 Sep 22.

  PMID: 25332517 BACKGROUND

• Riserus U, Willett WC, Hu FB. Dietary fats and prevention of type 2 diabetes. Prog Lipid Res. 2009 Jan;48(1):44-51. doi: 10.1016/j.plipres.2008.10.002. Epub 2008 Nov 7.

  PMID: 19032965 BACKGROUND

• Guo X, Jiang X, Chen K, Liang Q, Zhang S, Zheng J, Ma X, Jiang H, Wu H, Tong Q. The Role of Palmitoleic Acid in Regulating Hepatic Gluconeogenesis through SIRT3 in Obese Mice. Nutrients. 2022 Apr 1;14(7):1482. doi: 10.3390/nu14071482.

  PMID: 35406095 BACKGROUND

• Bolsoni-Lopes A, Festuccia WT, Chimin P, Farias TS, Torres-Leal FL, Cruz MM, Andrade PB, Hirabara SM, Lima FB, Alonso-Vale MI. Palmitoleic acid (n-7) increases white adipocytes GLUT4 content and glucose uptake in association with AMPK activation. Lipids Health Dis. 2014 Dec 20;13:199. doi: 10.1186/1476-511X-13-199.

  PMID: 25528561 BACKGROUND

• de Souza CO, Teixeira AAS, Biondo LA, Lima Junior EA, Batatinha HAP, Rosa Neto JC. Palmitoleic Acid Improves Metabolic Functions in Fatty Liver by PPARalpha-Dependent AMPK Activation. J Cell Physiol. 2017 Aug;232(8):2168-2177. doi: 10.1002/jcp.25715. Epub 2017 Mar 24.

  PMID: 27925195 BACKGROUND

• Yang ZH, Takeo J, Katayama M. Oral administration of omega-7 palmitoleic acid induces satiety and the release of appetite-related hormones in male rats. Appetite. 2013 Jun;65:1-7. doi: 10.1016/j.appet.2013.01.009. Epub 2013 Jan 30.

  PMID: 23376733 BACKGROUND

• Tovar R, Gavito AL, Vargas A, Soverchia L, Hernandez-Folgado L, Jagerovic N, Baixeras E, Ciccocioppo R, Rodriguez de Fonseca F, Decara J. Palmitoleoylethanolamide Is an Efficient Anti-Obesity Endogenous Compound: Comparison with Oleylethanolamide in Diet-Induced Obesity. Nutrients. 2021 Jul 28;13(8):2589. doi: 10.3390/nu13082589.

  PMID: 34444748 BACKGROUND

• Chan KL, Pillon NJ, Sivaloganathan DM, Costford SR, Liu Z, Theret M, Chazaud B, Klip A. Palmitoleate Reverses High Fat-induced Proinflammatory Macrophage Polarization via AMP-activated Protein Kinase (AMPK). J Biol Chem. 2015 Jul 3;290(27):16979-88. doi: 10.1074/jbc.M115.646992. Epub 2015 May 18.

  PMID: 25987561 BACKGROUND

• de Souza CO, Valenzuela CA, Baker EJ, Miles EA, Rosa Neto JC, Calder PC. Palmitoleic Acid has Stronger Anti-Inflammatory Potential in Human Endothelial Cells Compared to Oleic and Palmitic Acids. Mol Nutr Food Res. 2018 Oct;62(20):e1800322. doi: 10.1002/mnfr.201800322. Epub 2018 Aug 28.

  PMID: 30102465 BACKGROUND

• Weimann E, Silva MBB, Murata GM, Bortolon JR, Dermargos A, Curi R, Hatanaka E. Topical anti-inflammatory activity of palmitoleic acid improves wound healing. PLoS One. 2018 Oct 11;13(10):e0205338. doi: 10.1371/journal.pone.0205338. eCollection 2018.

  PMID: 30307983 BACKGROUND

• Tang J, Yang B, Yan Y, Tong W, Zhou R, Zhang J, Mi J, Li D. Palmitoleic Acid Protects against Hypertension by Inhibiting NF-kappaB-Mediated Inflammation. Mol Nutr Food Res. 2021 Jun;65(12):e2001025. doi: 10.1002/mnfr.202001025. Epub 2021 May 10.

  PMID: 33865240 BACKGROUND

• Trico D, Mengozzi A, Nesti L, Hatunic M, Gabriel Sanchez R, Konrad T, Lalic K, Lalic NM, Mari A, Natali A; EGIR-RISC Study Group. Circulating palmitoleic acid is an independent determinant of insulin sensitivity, beta cell function and glucose tolerance in non-diabetic individuals: a longitudinal analysis. Diabetologia. 2020 Jan;63(1):206-218. doi: 10.1007/s00125-019-05013-6. Epub 2019 Nov 1.

  PMID: 31676981 BACKGROUND

• Mozaffarian D, Cao H, King IB, Lemaitre RN, Song X, Siscovick DS, Hotamisligil GS. Circulating palmitoleic acid and risk of metabolic abnormalities and new-onset diabetes. Am J Clin Nutr. 2010 Dec;92(6):1350-8. doi: 10.3945/ajcn.110.003970. Epub 2010 Oct 13.

  PMID: 20943795 BACKGROUND

• Stefan N, Kantartzis K, Celebi N, Staiger H, Machann J, Schick F, Cegan A, Elcnerova M, Schleicher E, Fritsche A, Haring HU. Circulating palmitoleate strongly and independently predicts insulin sensitivity in humans. Diabetes Care. 2010 Feb;33(2):405-7. doi: 10.2337/dc09-0544. Epub 2009 Nov 4.

  PMID: 19889804 BACKGROUND

• Hiraoka-Yamamoto J, Ikeda K, Negishi H, Mori M, Hirose A, Sawada S, Onobayashi Y, Kitamori K, Kitano S, Tashiro M, Miki T, Yamori Y. Serum lipid effects of a monounsaturated (palmitoleic) fatty acid-rich diet based on macadamia nuts in healthy, young Japanese women. Clin Exp Pharmacol Physiol. 2004 Dec;31 Suppl 2:S37-8. doi: 10.1111/j.1440-1681.2004.04121.x.

  PMID: 15649284 BACKGROUND

• Garg ML, Blake RJ, Wills RB. Macadamia nut consumption lowers plasma total and LDL cholesterol levels in hypercholesterolemic men. J Nutr. 2003 Apr;133(4):1060-3. doi: 10.1093/jn/133.4.1060.

  PMID: 12672919 BACKGROUND

• Curb JD, Wergowske G, Dobbs JC, Abbott RD, Huang B. Serum lipid effects of a high-monounsaturated fat diet based on macadamia nuts. Arch Intern Med. 2000 Apr 24;160(8):1154-8. doi: 10.1001/archinte.160.8.1154.

  PMID: 10789609 BACKGROUND

• Griel AE, Cao Y, Bagshaw DD, Cifelli AM, Holub B, Kris-Etherton PM. A macadamia nut-rich diet reduces total and LDL-cholesterol in mildly hypercholesterolemic men and women. J Nutr. 2008 Apr;138(4):761-7. doi: 10.1093/jn/138.4.761.

  PMID: 18356332 BACKGROUND

• Pinnick KE, Neville MJ, Fielding BA, Frayn KN, Karpe F, Hodson L. Gluteofemoral adipose tissue plays a major role in production of the lipokine palmitoleate in humans. Diabetes. 2012 Jun;61(6):1399-403. doi: 10.2337/db11-1810. Epub 2012 Apr 9.

  PMID: 22492525 BACKGROUND

• Imamura F, Fretts A, Marklund M, Ardisson Korat AV, Yang WS, Lankinen M, Qureshi W, Helmer C, Chen TA, Wong K, Bassett JK, Murphy R, Tintle N, Yu CI, Brouwer IA, Chien KL, Frazier-Wood AC, Del Gobbo LC, Djousse L, Geleijnse JM, Giles GG, de Goede J, Gudnason V, Harris WS, Hodge A, Hu F; InterAct Consortium; Koulman A, Laakso M, Lind L, Lin HJ, McKnight B, Rajaobelina K, Riserus U, Robinson JG, Samieri C, Siscovick DS, Soedamah-Muthu SS, Sotoodehnia N, Sun Q, Tsai MY, Uusitupa M, Wagenknecht LE, Wareham NJ, Wu JH, Micha R, Forouhi NG, Lemaitre RN, Mozaffarian D; Fatty Acids and Outcomes Research Consortium (FORCE). Fatty acid biomarkers of dairy fat consumption and incidence of type 2 diabetes: A pooled analysis of prospective cohort studies. PLoS Med. 2018 Oct 10;15(10):e1002670. doi: 10.1371/journal.pmed.1002670. eCollection 2018 Oct.

  PMID: 30303968 BACKGROUND

• Dyerberg J, Bang HO, Hjorne N. Fatty acid composition of the plasma lipids in Greenland Eskimos. Am J Clin Nutr. 1975 Sep;28(9):958-66. doi: 10.1093/ajcn/28.9.958.

  PMID: 1163480 BACKGROUND

• Bang HO, Dyerberg J, Hjoorne N. The composition of food consumed by Greenland Eskimos. Acta Med Scand. 1976;200(1-2):69-73. doi: 10.1111/j.0954-6820.1976.tb08198.x.

  PMID: 961471 BACKGROUND

• Adler GK, Hornik ES, Murray G, Bhandari S, Yadav Y, Heydarpour M, Basu R, Garg R, Tirosh A. Acute effects of the food preservative propionic acid on glucose metabolism in humans. BMJ Open Diabetes Res Care. 2021 Jul;9(1):e002336. doi: 10.1136/bmjdrc-2021-002336.

  PMID: 34312159 BACKGROUND

• Kampmann U, Mosekilde L, Juhl C, Moller N, Christensen B, Rejnmark L, Wamberg L, Orskov L. Effects of 12 weeks high dose vitamin D3 treatment on insulin sensitivity, beta cell function, and metabolic markers in patients with type 2 diabetes and vitamin D insufficiency - a double-blind, randomized, placebo-controlled trial. Metabolism. 2014 Sep;63(9):1115-24. doi: 10.1016/j.metabol.2014.06.008. Epub 2014 Jun 19.

  PMID: 25044176 BACKGROUND

• Tripathy D, Wessman Y, Gullstrom M, Tuomi T, Groop L. Importance of obtaining independent measures of insulin secretion and insulin sensitivity during the same test: results with the Botnia clamp. Diabetes Care. 2003 May;26(5):1395-401. doi: 10.2337/diacare.26.5.1395.

  PMID: 12716795 BACKGROUND

MeSH Terms

Conditions

Prediabetic State; Insulin Resistance; Overweight; Obesity

Interventions

palmitoleic acid

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Overnutrition; Nutrition Disorders; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Mehmet Furkan Burak, MD

  Brigham and Women's Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Participants and study staff both blinded.
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Physician

Model Details: Interventional double-blinded study with participants randomized to either POA or placebo

Study Record Dates

• First Submitted: September 27, 2022
• First Posted: September 30, 2022
• Study Start: November 1, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: February 5, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)