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

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.

Design and Clinical Evaluation of a Novel Low-Glucose Prediction Algorithm with Mini-Dose Stable Glucagon Delivery in Post-Bariatric Hypoglycemia.

BACKGROUND: Postbariatric hypoglycemia (PBH) is a complication of bariatric surgery with limited therapeutic options. We developed an event-based system to predict and detect hypoglycemia based on continuous glucose monitor (CGM) data and recommend delivery of minidose liquid glucagon. METHODS: We performed an iterative development clinical study employing a novel glucagon delivery system: a Dexcom CGM connected to a Windows tablet running a hypoglycemia prediction algorithm and an Omnipod pump filled with an investigational stable liquid glucagon formulation. Meal tolerance testing was performed in seven participants with PBH and history of neuroglycopenia. Glucagon was administered when hypoglycemia was predicted. Primary outcome measures included the safety and feasibility of this system to predict and prevent severe hypoglycemia. Secondary outcomes included hypoglycemia prediction by the prediction algorithm, minimization of time below hypoglycemia threshold using glucagon, and prevention of rebound hyperglycemia. RESULTS: The hypoglycemia prediction algorithm alerted for impending hypoglycemia in the postmeal state, prompting delivery of glucagon (150 µg). After observations of initial incomplete efficacy to prevent hypoglycemia in the first two participants, system modifications were implemented: addition of PBH-specific detection algorithm, increased glucagon dose (300 µg), and a second glucagon dose if needed. These modifications, together with rescue carbohydrates provided to some participants, contributed to progressive improvements in glucose time above the hypoglycemia threshold (75 mg/dL). CONCLUSIONS: Preliminary results indicate that our event-based automatic monitoring algorithm successfully predicted likely hypoglycemia. Minidose glucagon therapy was well tolerated, without prolonged or severe hypoglycemia, and without rebound hyperglycemia.