Table 2.

Summary of preclinical and clinical studies that have evaluated the health impact of glycine or betaine dietary supplementation.

Population	Health Status	Dose and Duration	Health Impacts of Glycine Supplementation	Reference
Glycine dietary supplementation
Clinical studies
Adult humans:	Healthy patients	Single oral morning dose of 5 g glycine +/− 25 g glucose vs. water +/− 25 g glucose	Improves insulin response and glucose tolerance in response to glucose ingestion	[122]
4 Women
5 Men
Age: 21 to 52 y
Adult humans:	Healthy lean patients with first degree relatives of T2DM	Single oral morning dose of 5 g glycine vs. magnesium oxide (placebo)	Improves insulin response, measured during an euglycemic-hyperinsulinemic clamp; No significant alteration in insulin action	[123]
8 Women
4 Men
Age: 23.7 ± 4.1 y
Adult humans:	Patients with MetS (NCEP/ATP III criteria)	15 g glycine/day (3 times 5 g/d) dissolved in water vs. starch (placebo) for 3 months	Improves systolic blood pressure in men; Protects against oxidative damages determined from antioxidant enzymes activity in erythrocytes and leukocytes, and thiobarbituric acid reactive substances (TBARS) in plasma	[125]
29 Women
23 Men
Age: 35 to 65 y
Elderly patients:	Patients with HIV	1.33 mmol glycine/kg/day with 0.81 mmol/kg/day N-acetylcysteine for 14 days	Improves insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp before and after supplementation	[124]
9 Men
Age: 56.1 ± 1.0 y
Preclinical studies
Male Sprague Dawley rats: n = 48	High fat/high sucrose feeding vs. standard chow for 24 weeks	3.5 g glycine/kg/day in water vs. water (placebo) for 24 weeks	Improves hepatic steatosis assessed histologically	[128]
Age: NA
Male KK-Ay mice: n = 5/group	Animal model of obesity and T2DM	Semisynthetic diet containing 5% glycine vs. casein (placebo) for 4 weeks	Improves hepatic steatosis assessed histologically Improves glucose tolerance measured during a glucose tolerance test	[129]
Age: 7 weeks
Betaine dietary supplementation
Clinical studies
Adult humans:	patients with obesity and pre-diabetes	3.30 g betaine, twice daily for 10 days, followed by 4.95 g twice daily for 12 weeks vs. microcrystalline cellulose (placebo)	No major effects on glucose homeostasis (euglycemic hyperinsulinemic clamp) and liver fat deposition	[127]
8 Women
20 Men
Age: 21 to 70 y
Preclinical studies
Female	High-fat feeding for 13 weeks	1% weight/volume betaine, in water vs. water for 1 week	Improves insulin resistance and glucose homeostasis measured using glucose/insulin tolerance tests	[126]
Kunming
Mice: n = 40
Age: 6 weeks
Male C57Bl6 mice: n = 24	High-fat feeding for 16 weeks	1% weight/volume betaine, in water vs. water for 1 week	Improves insulin resistance and glucose homeostasis measured using glucose/insulin tolerance test and euglycemic hyperinsulinemic clamp; Reduces liver fat deposition quantified on chloroform-methanol extracts	[87]
Age: NA
Male C57BL6/N mice: n = 46	High-fat feeding for 12 weeks, methyl-donor supplementation was given during the last 4 weeks	15 g/kg betaine, 15 g/kg choline chloride, 7.5 g/kg methionine, 15 mg/kg folic acid, 1.5 mg/kg vitamin B12, 150 mg/kg ZnSO4	Prevented the progression of hepatic steatosis Increases phosphorylation of AMPK-α together with enhanced β-HAD activity, suggesting increased fatty acid oxidation	[34]
Age: 8 weeks

Note: MetS = Metabolic syndrome; T2DM = type 2 diabetes; NA = not available.