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.

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.

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.

Baseline clinical characteristics were similar between groups.

Adverse event data were collected for 14 weeks (during study drug administration and for 2 weeks after last study drug).