Obesity, Dysglycemia
Conditions
Keywords
Obesity, Glucose Intolerance
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.
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.
Interventions
DRUGBetaine
Betaine or placebo administered orally in divided doses over 12 weeks
DRUGPlacebo
Placebo administered orally in divided doses over 3 months
Sponsors
American Diabetes Association
Joslin Diabetes Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* 1\) Men and women aged 21-65 years old; * 2\) 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%); * 3\) overweight to grade 3 obesity (BMI 25 to 45 kg/m2).
Exclusion criteria
* 1\) cystathionine beta-synthase (CBS deficiency); * 2\) Presence of liver disease other than NAFLD; * 3\) Use of medications causing steatosis; * 4\) Known alcohol consumption ≥ 2 drink per day; * 5\) Use of medications known to cause insulin resistance; * 6\) Use of weight loss drugs (or program) within 3 months of screening; * 7\) Treatment with any experimental drug within the past 6 months; * 8\) Subjects must be willing to abstain from use of phosphodiesterase type 5 (PDE-5) inhibitors; * 9\) Pregnancy or lactation, and women of child bearing potential must use adequate contraception; * 10\) Surgery within 30 days of screening; * 11\) 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; * 12\) Uncontrolled hypertension; * 13\) eGFR \<60; 14) History of acquired immune deficiency syndrome; * 15\) History of malignancy within 5 years; * 16\) Hemoglobin \<12 g/dL (males), \<10 g/dL (females); * 17\) Triglycerides (TG) \>500 mg/dL; * 18\) Poor mental function or any other reason to expect patient difficulty in complying with study requirements; * 19\) Metal clips or implants that preclude magnetic resonance imaging.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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). |
| Endothelial Function | baseline and 12 weeks | Brachial artery reactivity to flow and nitroglycerin stimuli, assessed as percent change from baseline |
| Insulin Sensitivity | Baseline and 12 weeks | Euglycemic hyperinsulinemic clamp at baseline and at end of study (12 weeks) for assessment of: 1. glucose disposal (M) at low (25 mU/m2/min) and high (180 mU/m2/min) insulin infusion rates, reported as raw data 2. 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 |
Countries
United States
Participant flow
Recruitment details
Study subjects with overweight and T2D risk factors were screened for dysglycemia and enrolled at 1 site in the US.
Participants by arm
| Arm | Count |
|---|---|
| Betaine 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. | 14 |
| Placebo Placebo: Participants were instructed to take identical amounts and appearance of placebo through 12 weeks. | 13 |
| Total | 27 |
Baseline characteristics
| Characteristic | Placebo | Total | Betaine |
|---|---|---|---|
| Age, Continuous | 57 years STANDARD_DEVIATION 8 | 59 years STANDARD_DEVIATION 8 | 61 years STANDARD_DEVIATION 7 |
| Race/Ethnicity, Customized Race and Ethnicity Asian | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race and Ethnicity Black or African American | 2 Participants | 5 Participants | 3 Participants |
| Race/Ethnicity, Customized Race and Ethnicity Hispanic | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Race and Ethnicity White | 11 Participants | 18 Participants | 7 Participants |
| Region of Enrollment United States | 13 participants | 27 participants | 14 participants |
| Sex: Female, Male Female | 4 Participants | 8 Participants | 4 Participants |
| Sex: Female, Male Male | 9 Participants | 19 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 13 |
| other Total, other adverse events | 4 / 14 | 6 / 13 |
| serious Total, serious adverse events | 0 / 14 | 0 / 13 |
Outcome results
Primary
Change in Glucose AUC at 12 Weeks From Baseline (Glucose Tolerance)
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
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Betaine | Change in Glucose AUC at 12 Weeks From Baseline (Glucose Tolerance) | 340 mg*min/dL |
| Placebo | Change in Glucose AUC at 12 Weeks From Baseline (Glucose Tolerance) | -413 mg*min/dL |
Primary
Endothelial Function
Brachial artery reactivity to flow and nitroglycerin stimuli, assessed as percent change from baseline
Time frame: baseline and 12 weeks
Population: One participant in the placebo group was not able to complete nitroglycerine-mediated dilation assessment.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Betaine | Endothelial Function | Percent change in flow-mediated dilation | -0.5 percent change from baseline |
| Betaine | Endothelial Function | Percent change in nitroglycerine-mediated dilation | -0.9 percent change from baseline |
| Placebo | Endothelial Function | Percent change in flow-mediated dilation | -1.9 percent change from baseline |
| Placebo | Endothelial Function | Percent change in nitroglycerine-mediated dilation | -0.9 percent change from baseline |
Primary
Fasting and 2 Hour Glucose Levels, Comparing Baseline and 12 Weeks.
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
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Betaine | Fasting and 2 Hour Glucose Levels, Comparing Baseline and 12 Weeks. | fasting glucose | -5 mg/dl |
| Betaine | Fasting and 2 Hour Glucose Levels, Comparing Baseline and 12 Weeks. | 2-hour glucose | 7 mg/dl |
| Placebo | Fasting and 2 Hour Glucose Levels, Comparing Baseline and 12 Weeks. | fasting glucose | 3 mg/dl |
| Placebo | Fasting and 2 Hour Glucose Levels, Comparing Baseline and 12 Weeks. | 2-hour glucose | -4 mg/dl |
Primary
Hepatic Fat, Change From Baseline
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Betaine | Hepatic Fat, Change From Baseline | -0.01 percent change in hepatic triglyceride | Standard Error 0.02 |
| Placebo | Hepatic Fat, Change From Baseline | -0.03 percent change in hepatic triglyceride | Standard Error 0.02 |
Primary
Insulin Sensitivity
Euglycemic hyperinsulinemic clamp at baseline and at end of study (12 weeks) for assessment of: 1. glucose disposal (M) at low (25 mU/m2/min) and high (180 mU/m2/min) insulin infusion rates, reported as raw data 2. 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
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Betaine | Insulin Sensitivity | Glucose Utilization (M), 25 mU/m2/min, baseline | 90.4 umol/kg/min | Standard Error 16.5 |
| Betaine | Insulin Sensitivity | Glucose Utilization (M), 25 mU/m2/min, 12 weeks | 110.9 umol/kg/min | Standard Error 16.9 |
| Betaine | Insulin Sensitivity | Glucose Utilization (M), 180 mU/m2/min, baseline | 406.8 umol/kg/min | Standard Error 30.4 |
| Betaine | Insulin Sensitivity | Glucose Utilization (M), 180 mU/m2/min, 12 weeks | 458.1 umol/kg/min | Standard Error 38.7 |
| Betaine | Insulin Sensitivity | Endogenous Glucose Production, basal insulin | .03 umol/kg/min | Standard Error 0.09 |
| Betaine | Insulin Sensitivity | Endogenous Glucose Production, 25 mU/m2/min | -0.01 umol/kg/min | Standard Error 0.12 |
| Placebo | Insulin Sensitivity | Endogenous Glucose Production, basal insulin | -0.01 umol/kg/min | Standard Error 0.09 |
| Placebo | Insulin Sensitivity | Glucose Utilization (M), 25 mU/m2/min, baseline | 62.8 umol/kg/min | Standard Error 13.5 |
| Placebo | Insulin Sensitivity | Glucose Utilization (M), 180 mU/m2/min, 12 weeks | 393.7 umol/kg/min | Standard Error 44.1 |
| Placebo | Insulin Sensitivity | Glucose Utilization (M), 25 mU/m2/min, 12 weeks | 73.5 umol/kg/min | Standard Error 13.8 |
| Placebo | Insulin Sensitivity | Endogenous Glucose Production, 25 mU/m2/min | -0.12 umol/kg/min | Standard Error 0.13 |
| Placebo | Insulin Sensitivity | Glucose Utilization (M), 180 mU/m2/min, baseline | 332.6 umol/kg/min | Standard Error 39.1 |