Effects of Dietary Interventions on Serum and Macrophage Atherogenicity

Effects of Dietary Interventions (Sugars, Amino Acids and Artificial Sweeteners) on Serum and Macrophage Atherogenicity

While previous atherosclerosis-related studies have focused mainly on the atherogenicity of lipids, the proposed study aims to investigate the effects of other dietary factors, i.e. monosaccharides, disaccharides, amino acids, or artificial sweeteners, on the atherogenicity of serum or macrophages. Findings from the current proposed study may shed light on yet unknown mechanisms by which the above dietary factors could affect atherosclerosis development and CVD risk and hence could possibly assist in the future development of anti-atherogenic strategies.

Study Overview

• Status: Unknown
• Conditions: Atherosclerosis; Dietary Habits; Serum; Disease; Macrophage Atherogenicity
• Intervention / Treatment: Other: Control- water; Dietary supplement: monosaccharides; Dietary supplement: Disaccharides; Dietary supplement: Artificial Sweeteners; Dietary supplement: Amino acids

Detailed Description

Atherosclerosis is the underlying cause of cardiovascular diseases (CVD), the major cause of death worldwide. Atherosclerosis is an inflammatory disease of the arteries in which activated macrophages are abundant in the atherosclerotic lesions.

Macrophages play key roles during early atherogenesis. After differentiating from peripheral blood monocytes, the formed intimal macrophages take up oxidized/modified lipoproteins and are transformed into lipid-rich foam cells, the hallmark feature of early atherogenesis. In addition to lipoprotein uptake, lipid accumulation in macrophages can also result from alterations in cellular lipid metabolism, e.g. attenuated reverse lipid transport or enhanced rates of lipid biosynthesis. CVD and atherosclerosis development are significantly affected by nutritional factors. Although much progress has been made in understanding the role of different lipids (fatty acids, cholesterol, phospholipids or triglycerides) in atherosclerosis development and macrophage foam-cell formation, little is known about the potential impact of other nutrients, i.e. sugars or amino acids. For instance, hyperglycemia is known to enhance atherosclerosis development, and high glucose levels increases macrophage atherogenicity via pro-inflammatory and oxidative stress-related mechanisms. However, the role of monosaccharides other than glucose (fructose, galactose or mannose) and that of various disaccharides (maltose, sucrose or lactose) in macrophage foam-cell formation, the key event during early atherogenesis, is currently unknown. As for amino acids, a specific subgroup - the branched-chain amino acids (BCAAs), has recently been associated with increased CVD risk. The BCAA subgroup, composed of leucine, isoleucine, and valine, is characterized by an aliphatic structure of their side chains and by a common catabolic pathway. Recent reports have demonstrated an association between BCAAs, CVD and coronary artery disease (CAD). Serum BCAA levels have been positively associated with various CAD risk factors and with the development as well as the severity of CAD, even after controlling for other risk factors. Nevertheless, the role of BCAAs in atherosclerosis development and macrophage foam-cell formation is currently unclear. In recent decades, the availability and the consumption of various artificial sweeteners have increased considerably. In the USA for instance, approximately 30% of adults and 15% of children, report consumption of artificial sweeteners. Although the consumption of artificial sweeteners was previously associated with elevated risk for coronary heart disease (CHD), the effects of different artificial sweeteners, e.g. saccharin, aspartame, sucralose, steviol, cyclamate, and mannitol, on atherosclerosis development and their possible impact on macrophage foam-cell formation have not been investigated yet..

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Israel
  • Haifa, Israel, 320000
    • Recruiting
    • Rambam Health Care Center
    • Contact: Niroz Abu-Saleh, PhD; Phone Number: 972504278858; Email: asniroz@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Inclusion criteria will include healthy adult males between the ages of 18-50 after signing informed consent.

Exclusion Criteria:

• Exclusion criteria will include cardiovascular or pulmonary diseases, diabetes, cancer, morbid obesity (body mass index > 40 kg/m2), heavy smoking (> 20 cigarettes/day), or consumption of more than two alcoholic drinks per day.

Study Plan

How is the study designed?

Design Details

• Allocation: Non-Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

15

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Sham Comparator: Control; Dietary Interventions: Control- water, Flavered Chilled water, will be administered once after O.N fasting.	Other: Control- water; Chilled water flavored with lemon juice as control
Active Comparator: Glucose; Dietary Interventions: Glucose, Monosaccharides, at the dose of 50 g, based on oral loading tests, once.	Dietary supplement: monosaccharides; The monosaccharides; Glucose, Fructose, Galactose and mannose, will be administrated after O.N fasting, 50gr, once.
Experimental: Fructose; Dietary Interventions: Fructose, Monosaccharides, at the dose of 50 g, once.	Dietary supplement: monosaccharides; The monosaccharides; Glucose, Fructose, Galactose and mannose, will be administrated after O.N fasting, 50gr, once.
Experimental: Galactose; Dietary Interventions: Monosaccharides, at the dose of 50 g, once.	Dietary supplement: monosaccharides; The monosaccharides; Glucose, Fructose, Galactose and mannose, will be administrated after O.N fasting, 50gr, once.
Experimental: Mannose; Dietary Interventions: Monosaccharides, at the dose of 50 g, once.	Dietary supplement: monosaccharides; The monosaccharides; Glucose, Fructose, Galactose and mannose, will be administrated after O.N fasting, 50gr, once.
Experimental: Maltose; Dietary Interventions: The dose of the disaccharides - 50 g, once.	Dietary supplement: Disaccharides; The Disaccharides; Lactose, Maltose and sucrose, will be administrated after O.N fasting, 50gr, once.
Experimental: Sucrose; Dietary Interventions: The dose of the disaccharides - 50 g, once.	Dietary supplement: Disaccharides; The Disaccharides; Lactose, Maltose and sucrose, will be administrated after O.N fasting, 50gr, once.
Experimental: Lactose; Dietary Interventions: The dose of the disaccharides - 50 g, once.	Dietary supplement: Disaccharides; The Disaccharides; Lactose, Maltose and sucrose, will be administrated after O.N fasting, 50gr, once.
Experimental: Saccharin; Dietary Interventions: The dose of the different artificial sweeteners - 300 mg, is based on an average adult male body weight of 75 kg and is set not to exceed the acceptable daily intakes of saccharin, aspartame, sucralose and steviol that were reported at 15, 50, 5, and 4 mg/kg body weight/day by the USA Food and Drug Administration, once.	Dietary supplement: Artificial Sweeteners; The Artificial sweeteners: Saccharin, Aspartame, Sucralose and Steviol, will be administrated after O.N fasting, 300 mg, once.
Experimental: Aspartame; Dietary Interventions: The dose of the different artificial sweeteners - 300 mg, is based on an average adult male body weight of 75 kg and is set not to exceed the acceptable daily intakes of saccharin, aspartame, sucralose and steviol that were reported at 15, 50, 5, and 4 mg/kg body weight/day by the USA Food and Drug Administration, once.	Dietary supplement: Artificial Sweeteners; The Artificial sweeteners: Saccharin, Aspartame, Sucralose and Steviol, will be administrated after O.N fasting, 300 mg, once.
Experimental: Sucralose; Dietary Interventions: The dose of the different artificial sweeteners - 300 mg, is based on an average adult male body weight of 75 kg and is set not to exceed the acceptable daily intakes of saccharin, aspartame, sucralose and steviol that were reported at 15, 50, 5, and 4 mg/kg body weight/day by the USA Food and Drug Administration, once.	Dietary supplement: Artificial Sweeteners; The Artificial sweeteners: Saccharin, Aspartame, Sucralose and Steviol, will be administrated after O.N fasting, 300 mg, once.
Experimental: Steviol; Dietary Interventions: The dose of the different artificial sweeteners - 300 mg, is based on an average adult male body weight of 75 kg and is set not to exceed the acceptable daily intakes of saccharin, aspartame, sucralose and steviol that were reported at 15, 50, 5, and 4 mg/kg body weight/day by the USA Food and Drug Administration, once.	Dietary supplement: Artificial Sweeteners; The Artificial sweeteners: Saccharin, Aspartame, Sucralose and Steviol, will be administrated after O.N fasting, 300 mg, once.
Experimental: Leucine; Dietary Interventions: The dose of the different BCAAs Amino acids- 5 g, is set not to exceed the mean daily intakes of leucine, isoleucine and valine for adult males that were reported at 8.64, 5.01 and 5.63 g/day, respectively, once.	Dietary supplement: Amino acids; The Amino acids; Leucine, Isoleucine, and Valine, will be administrated after O.N fasting, 5g, once.
Experimental: Isoleucine; Dietary Interventions: The dose of the different BCAAs Amino acids - 5 g, is set not to exceed the mean daily intakes of leucine, isoleucine and valine for adult males that were reported at 8.64, 5.01 and 5.63 g/day, respectively, once.	Dietary supplement: Amino acids; The Amino acids; Leucine, Isoleucine, and Valine, will be administrated after O.N fasting, 5g, once.
Experimental: Valine; Dietary Interventions: The dose of the different BCAAs Amino acids- 5 g, is set not to exceed the mean daily intakes of leucine, isoleucine and valine for adult males that were reported at 8.64, 5.01 and 5.63 g/day, respectively, once.	Dietary supplement: Amino acids; The Amino acids; Leucine, Isoleucine, and Valine, will be administrated after O.N fasting, 5g, once.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
serum Oxidation dietary factors, i.e. monosaccharides, disaccharides, amino acids, or artificial atherogenicity of serum	serum oxidation level; TBARS (nmol MDA /ml)	2 years
macrophages cellular Oxidation.	oxidation level; TBARS (nmol MDA /mg protein)	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum lipids- Cholesterol	Cholesterol concentration (mg/dl)	2 years
Serum lipids- Triglycerides	Triglyceride concentration (mg/dl)	2 years
macrophages cellular lipids- Cholesterol	macrophage Cholesterol mass (mg/mg protein)	2 years
macrophages cellular lipids -Triglycerides	macrophage Triglyceride mass (mg/mg protein)	2 years

Collaborators and Investigators

• Sponsor: Rambam Health Care Campus
• Investigators: Principal Investigator: Tony Hayek, Prof., Rambam Health Care Center

Publications and helpful links

General Publications

• Swithers SE. Artificial sweeteners produce the counterintuitive effect of inducing metabolic derangements. Trends Endocrinol Metab. 2013 Sep;24(9):431-41. doi: 10.1016/j.tem.2013.05.005. Epub 2013 Jul 10.
• Dickhout JG, Basseri S, Austin RC. Macrophage function and its impact on atherosclerotic lesion composition, progression, and stability: the good, the bad, and the ugly. Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1413-5. doi: 10.1161/ATVBAHA.108.169144. No abstract available.
• 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.
• 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.
• 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.
• Huang Y, Zhou M, Sun H, Wang Y. Branched-chain amino acid metabolism in heart disease: an epiphenomenon or a real culprit? Cardiovasc Res. 2011 May 1;90(2):220-3. doi: 10.1093/cvr/cvr070.
• Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. Sweetened beverage consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009 Apr;89(4):1037-42. doi: 10.3945/ajcn.2008.27140. Epub 2009 Feb 11.
• Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab. 2011 Nov 2;14(5):575-85. doi: 10.1016/j.cmet.2011.07.015.
• 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. No abstract available.

Study record dates

Study Major Dates

• Study Start: September 1, 2016
• Primary Completion (Anticipated): May 1, 2018
• Study Completion (Anticipated): August 1, 2018

Study Registration Dates

• First Submitted: August 22, 2016
• First Submitted That Met QC Criteria: September 8, 2016
• First Posted (Estimate): September 9, 2016

Study Record Updates

• Last Update Posted (Estimate): September 27, 2016
• Last Update Submitted That Met QC Criteria: September 26, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: atherosclerosis; amino acids; sugars; artificial sweeteners; dietary interventions; macrophage atherogenicity
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis
• Other Study ID Numbers: 0285-16-RMB CTIL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED