Metabolic Effects of Betaine: A Randomized Clinical Trial of Betaine Supplementation in Prediabetes

Abstract

Context: Plasma betaine correlates with insulin sensitivity in humans. Betaine supplementation improves metabolic effects in mice fed a high-fat diet.

Objective: To assess metabolic effects of oral betaine in obese participants with prediabetes.

Design: A 12-week, parallel arm, randomized, double-masked, placebo-controlled trial.

Setting: University-affiliated hospital.

Participants and interventions: Persons with obesity and prediabetes (N = 27) were randomly assigned to receive betaine 3300 mg orally twice daily for 10 days, then 4950 mg twice daily for 12 weeks, or placebo.

Main outcome measures: Changes from baseline in insulin sensitivity, glycemia, hepatic fat, and endothelial function.

Results: There was a 16.5-fold increase in plasma dimethylglycine [dimethylglycine (DMG); P < 0.0001] levels, but modest 1.3- and 1.5-fold increases in downstream serine and methionine levels, respectively, in the betaine vs placebo arm. Betaine tended to reduce fasting glucose levels (P = 0.08 vs placebo) but had no other effect on glycemia. Insulin area under curve after oral glucose was reduced for betaine treatment compared with placebo (P = 0.038). Insulin sensitivity, assessed by euglycemic hyperinsulinemic clamp, was not improved. Serum total cholesterol levels increased after betaine treatment compared with placebo (P = 0.032). There were no differences in change in intrahepatic triglyceride or endothelial function between groups.

Conclusion: DMG accumulation supports DMG dehydrogenase as rate limiting for betaine metabolism in persons with prediabetes. Betaine had little metabolic effect. Additional studies may elucidate mechanisms contributing to differences between preclinical and human responses to betaine, and whether supplementation of metabolites downstream of DMG improves metabolism.

Trial registration: ClinicalTrials.gov NCT01950039.

Figures

Figure 1.

Consort diagram. Disposition of study participants is shown. A total of 85 persons were screened for eligibility. Twenty-eight eligible participants were randomly assigned to receive either betaine or placebo for 12 wk. One participant in each group did not undergo hepatic MRI and MRS, due to metal implants, but were included in analyses of other end points. One participant in each group did not undergo the euglycemic-hyperinsulinemic clamps due to intravenous difficulties, but they were included in other end point analyses. One participant from the active drug group withdrew after taking the study drug for 12 wk, reporting inconvenience of the last visit scheduled, but was included in analyses through the duration of participation. One participant in the placebo group was included in the FMD analyses but could not be administered nitroglycerin and so was not included in NMD analyses. The study was completed by 13 participants in the betaine group and 13 in the placebo group. CBS, cystathionine β synthase; FMD, flow-mediated dilation, MRS, magnetic resonance spectroscopy; NMD, nitroglycerine-mediated dilation.

Figure 2.

Betaine metabolism. (A) Plasma betaine concentration assessed by liquid chromatography–mass spectrometry (LC/MS) is shown. Concentrations are shown for baseline (○) and posttreatment (●). (B) Key aspects of the betaine metabolic pathway. (C) Betaine metabolic pathway intermediates by LC/MS: placebo baseline (white column), placebo posttreatment (gray column), betaine baseline (light gray column), betaine posttreatment (black column). BADH, betaine-aldehyde dehydrogenase; BET, betaine; CHDH, choline dehydrogenase; GNMT, glycine-N-methyltransferase; PBO, placebo; post, after; pre, before; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; SARDH, sarcosine dehydrogenase; SHMT, serine hydroxymethyltransferase. *P < 0.05, **P < 0.01, ***P < 0.001.

Figure 3.

OGTT-derived measures before and after 12 wk of treatment with betaine or placebo. (A) Fasting glucose. (B) AUC for insulin during the OGTT. (C) Fasting insulin. (D) The Matsuda Composite Insulin Sensitivity Index calculated as 10,000 divided by the square root of [(glucose × insulin) (glucosemean × insulinmean)]. Baseline pretreatment (white column); posttreatment (black column). *P < 0.05, **P < 0.01. AUC, area under the curve; post, after; pre, before.

Figure 4.

Key metabolic end points at baseline and after 12 wk of treatment with betaine or placebo. (A) Insulin sensitivity is shown as M-values of glucose utilization during euglycemic-hyperinsulinemic clamp averaged over 90 to 120 mins and 210 to 240 mins, respectively, for each of two doses of insulin. (B) Endogenous glucose production: basal and clamp at low-dose insulin (25 mIU/m2/min). Placebo baseline (white column); placebo posttreatment (gray column); betaine baseline (light gray column); betaine posttreatment (black column). (B) Intrahepatic triglyceride measured by MRI and magnetic resonance spectroscopy is shown. (C) FGF21 concentrations are shown at baseline (○) and posttreatment (●). (D) Brachial artery flow-meditated dilation. (E) Brachial artery nitroglycerine-mediated dilation at baseline, pretreatment (white column), and posttreatment (black column). Post, after; pre, before.