Metabolic Effects of Betaine Supplementation

• Sponsor: Joslin Diabetes Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01950039
• Collaborator: American Diabetes Association (Other)
• Enrollment: 28
• Location: 1
• Arms: 2
• Duration (Months): 55
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Betaine is important in cellular metabolic pathways. Few epidemiologic studies link betaine levels to diabetes and cardiovascular disease. Small human studies suggest benefit for non-alcoholic liver disease. In this study we will determine if administration of betaine improves metabolic measures, liver fat and/or endothelial function in humans with glucose intolerance who are overweight.

Condition or Disease	Intervention/Treatment	Phase
Obesity; Dysglycemia	Drug: Betaine; Drug: Placebo	Phase 2

Detailed Description

This study is a single site, prospective, randomized (1:1), double masked, placebo controlled trial to assess metabolic effects of betaine compared to placebo on glycemia and insulin sensitivity, liver fat and endothelial function.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Other
• Official Title: Bedside to Bench and Back: Cardiometabolic Effects of Betaine Supplementation
• Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Dec 1, 2017
• Actual Study Completion Date: Aug 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Betaine	Drug: Betaine; Betaine or placebo administered orally in divided doses over 12 weeks; Other Names: trimethyl glycine
Placebo Comparator: Placebo	Drug: Placebo; Placebo administered orally in divided doses over 3 months

Outcome Measures

Primary Outcome Measures

1. Fasting and 2 Hour Glucose Levels, Comparing Baseline and 12 Weeks. [baseline and 12 weeks]

   Glucose levels were analyzed in the fasting state and two hours after glucose load, comparing baseline to 12 weeks.

2. Change in Glucose AUC at 12 Weeks From Baseline (Glucose Tolerance) [baseline and 12 weeks]

   Glucose tolerance was assessed by oral glucose tolerance, assessed using the change from baseline for fasting and 2 hour glucose, and change in Glucose AUC at 12 weeks from baseline was measured.

3. Hepatic Fat, Change From Baseline [baseline and 12 weeks]

   Intrahepatic triglyceride levels were assessed by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (Siemens 3T TIM Skyra, software version VD13; Siemens, Erlangen, Germany).

4. Endothelial Function [baseline and 12 weeks]

   Brachial artery reactivity to flow and nitroglycerin stimuli, assessed as percent change from baseline

5. Insulin Sensitivity [Baseline and 12 weeks]

   Euglycemic hyperinsulinemic clamp at baseline and at end of study (12 weeks) for assessment of: glucose disposal (M) at low (25 mU/m2/min) and high (180 mU/m2/min) insulin infusion rates, reported as raw data measurement of endogenous glucose production at basal and low insulin infusion (25 mU/m2/min), reported as change from measures at baseline of individual study days

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 1. Men and women aged 21-65 years old;
• 1. Dysglycemia/prediabetes is defined as impaired fasting glucose (≥100 mg/dl), impaired glucose tolerance (2 hour post 75 g oral glucose load 140-200 mg/dl) or HbA1c 5.7-6.5%);
• 1. overweight to grade 3 obesity (BMI 25 to 45 kg/m2).

Exclusion Criteria:

• 1. cystathionine beta-synthase (CBS deficiency);
• 1. Presence of liver disease other than NAFLD;
• 1. Use of medications causing steatosis;
• 1. Known alcohol consumption ≥ 2 drink per day;
• 1. Use of medications known to cause insulin resistance;
• 1. Use of weight loss drugs (or program) within 3 months of screening;
• 1. Treatment with any experimental drug within the past 6 months;
• 1. Subjects must be willing to abstain from use of phosphodiesterase type 5 (PDE-5) inhibitors;
• 1. Pregnancy or lactation, and women of child bearing potential must use adequate contraception;
• 1. Surgery within 30 days of screening;
• 1. Heart disease defined as New York Heart Association Class III or IV cardiac status or hospitalization for congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident, transient ischemic attack or any revascularization within 6 months;
• 1. Uncontrolled hypertension;
• 1. eGFR <60; 14) History of acquired immune deficiency syndrome;
• 1. History of malignancy within 5 years;
• 1. Hemoglobin <12 g/dL (males), <10 g/dL (females);
• 1. Triglycerides (TG) >500 mg/dL;
• 1. Poor mental function or any other reason to expect patient difficulty in complying with study requirements;
• 1. Metal clips or implants that preclude magnetic resonance imaging.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Joslin Diabetes Center and Brigham and Womens Hospital	Boston	Massachusetts	United States	02215

Sponsors and Collaborators

• Joslin Diabetes Center
• American Diabetes Association

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Sep 19, 2016
• Statistical Analysis Plan - Jan 9, 2014

More Information

Publications

None provided.

• Responsible Party: Joslin Diabetes Center
• ClinicalTrials.gov Identifier: NCT01950039
• Other Study ID Numbers: 2013P001265; 7-13-CE-17
• First Posted: Sep 25, 2013
• Last Update Posted: Apr 20, 2021
• Last Verified: Mar 1, 2021

• Keywords provided by Joslin Diabetes Center: Obesity; Glucose Intolerance
• Additional relevant MeSH terms: Obesity; Betaine; Glycine

Study Results

Participant Flow

Recruitment Details	Study subjects with overweight and T2D risk factors were screened for dysglycemia and enrolled at 1 site in the US.

Arm/Group Title	Betaine	Placebo
Arm/Group Description	Betaine: Participants were instructed to take betaine 3300 mg (10 ml) orally twice daily for 10 days, then 4950 mg (15 ml) orally twice daily through 12 weeks.	Placebo: Participants were instructed to take identical amounts and appearance of placebo through 12 weeks.
Period Title: Overall Study
STARTED	15	13
Study Drug Initiated	14	13
Completed Clamp	13	12
Completed MRI	13	12
Completed Endothelial Evaluation	14	12
COMPLETED	14	13
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Betaine	Placebo	Total
Arm/Group Description	Betaine: Participants were instructed to take betaine 3300 mg (10 ml) orally twice daily for 10 days, then 4950 mg (15 ml) orally twice daily through 12 weeks.	Placebo: Participants were instructed to take identical amounts and appearance of placebo through 12 weeks.	Total of all reporting groups
Overall Participants	14	13	27
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (7)	57 (8)	59 (8)
Sex: Female, Male (Count of Participants)
Female	4 28.6%	4 30.8%	8 29.6%
Male	10 71.4%	9 69.2%	19 70.4%
Race/Ethnicity, Customized (Count of Participants)
Asian	2 14.3%	0 0%	2 7.4%
Black or African American	3 21.4%	2 15.4%	5 18.5%
White	7 50%	11 84.6%	18 66.7%
Hispanic	2 14.3%	0 0%	2 7.4%
Region of Enrollment (participants) [Number]
United States	14 100%	13 100%	27 100%

Outcome Measures

1. Primary Outcome

Title	Fasting and 2 Hour Glucose Levels, Comparing Baseline and 12 Weeks.
Description	Glucose levels were analyzed in the fasting state and two hours after glucose load, comparing baseline to 12 weeks.
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betaine	Placebo
Arm/Group Description	Betaine: Participants were instructed to take betaine 3300 mg (10 ml) orally twice daily for 10 days, then 4950 mg (15 ml) orally twice daily through 12 weeks.	Placebo: Participants were instructed to take identical amounts and appearance of placebo through 12 weeks.
Measure Participants	14	13
fasting glucose	-5	3
2-hour glucose	7	-4

2. Primary Outcome

Title	Change in Glucose AUC at 12 Weeks From Baseline (Glucose Tolerance)
Description	Glucose tolerance was assessed by oral glucose tolerance, assessed using the change from baseline for fasting and 2 hour glucose, and change in Glucose AUC at 12 weeks from baseline was measured.
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betaine	Placebo
Arm/Group Description	Betaine: Participants were instructed to take betaine 3300 mg (10 ml) orally twice daily for 10 days, then 4950 mg (15 ml) orally twice daily through 12 weeks.	Placebo: Participants were instructed to take identical amounts and appearance of placebo through 12 weeks.
Measure Participants	14	13
Mean (95% Confidence Interval) [mg*min/dL]	340	-413

3. Primary Outcome

Title	Hepatic Fat, Change From Baseline
Description	Intrahepatic triglyceride levels were assessed by magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (Siemens 3T TIM Skyra, software version VD13; Siemens, Erlangen, Germany).
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betaine	Placebo
Arm/Group Description	Betaine: Participants were instructed to take betaine 3300 mg (10 ml) orally twice daily for 10 days, then 4950 mg (15 ml) orally twice daily through 12 weeks.	Placebo: Participants were instructed to take identical amounts and appearance of placebo through 12 weeks.
Measure Participants	13	12
Mean (Standard Error) [percent change in hepatic triglyceride]	-0.01 (0.02)	-0.03 (0.02)

4. Primary Outcome

Title	Endothelial Function
Description	Brachial artery reactivity to flow and nitroglycerin stimuli, assessed as percent change from baseline
Time Frame	baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

One participant in the placebo group was not able to complete nitroglycerine-mediated dilation assessment.

Arm/Group Title	Betaine	Placebo
Arm/Group Description	Betaine: Participants were instructed to take betaine 3300 mg (10 ml) orally twice daily for 10 days, then 4950 mg (15 ml) orally twice daily through 12 weeks.	Placebo: Participants were instructed to take identical amounts and appearance of placebo through 12 weeks.
Measure Participants	14	13
Percent change in flow-mediated dilation	-0.5	-1.9
Percent change in nitroglycerine-mediated dilation	-0.9	-0.9

5. Primary Outcome

Title	Insulin Sensitivity
Description	Euglycemic hyperinsulinemic clamp at baseline and at end of study (12 weeks) for assessment of: glucose disposal (M) at low (25 mU/m2/min) and high (180 mU/m2/min) insulin infusion rates, reported as raw data measurement of endogenous glucose production at basal and low insulin infusion (25 mU/m2/min), reported as change from measures at baseline of individual study days
Time Frame	Baseline and 12 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Betaine	Placebo
Arm/Group Description	Betaine: Participants were instructed to take betaine 3300 mg (10 ml) orally twice daily for 10 days, then 4950 mg (15 ml) orally twice daily through 12 weeks.	Placebo: Participants were instructed to take identical amounts and appearance of placebo through 12 weeks.
Measure Participants	13	12
Glucose Utilization (M), 25 mU/m2/min, baseline	90.4 (16.5)	62.8 (13.5)
Glucose Utilization (M), 25 mU/m2/min, 12 weeks	110.9 (16.9)	73.5 (13.8)
Glucose Utilization (M), 180 mU/m2/min, baseline	406.8 (30.4)	332.6 (39.1)
Glucose Utilization (M), 180 mU/m2/min, 12 weeks	458.1 (38.7)	393.7 (44.1)
Endogenous Glucose Production, basal insulin	.03 (.09)	-0.01 (0.09)
Endogenous Glucose Production, 25 mU/m2/min	-0.01 (0.12)	-0.12 (0.13)

Adverse Events

Time Frame	Adverse event data were collected for 14 weeks (during study drug administration and for 2 weeks after last study drug).
Arm/Group Title	Betaine		Placebo
Arm/Group Description	Betaine: Participants were instructed to take betaine 3300 mg (10 ml) orally twice daily for 10 days, then 4950 mg (15 ml) orally twice daily through 12 weeks.		Placebo: Participants were instructed to take identical amounts and appearance of placebo through 12 weeks.
All Cause Mortality
	Betaine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Serious Adverse Events
	Betaine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	Betaine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/14 (28.6%)		6/13 (46.2%)
Eye disorders
Irritation	0/14 (0%)	0	1/13 (7.7%)	1
Gastrointestinal disorders
GI infection	0/14 (0%)	0	1/13 (7.7%)	1
GI motility and defecation conditions	1/14 (7.1%)	1	0/13 (0%)	0
Hepatobiliary disorders
Hepatic and hepatobiliary disorders	1/14 (7.1%)	1	0/13 (0%)	0
Immune system disorders
Immune disorders	0/14 (0%)	0	1/13 (7.7%)	1
Metabolism and nutrition disorders
Metabolism and nutrition	1/14 (7.1%)	1	0/13 (0%)	0
Renal and urinary disorders
Renal impairment	0/14 (0%)	0	1/13 (7.7%)	1
Urinary tract signs and symptoms	0/14 (0%)	0	1/13 (7.7%)	2
Respiratory, thoracic and mediastinal disorders
Respiratory disorders NEC	0/14 (0%)	0	1/13 (7.7%)	1
Respiratory tract infections	1/14 (7.1%)	1	0/13 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.