Dimethylglycine accumulates in uremia and predicts elevated plasma homocysteine concentrations.

BACKGROUND: Hyperhomocysteinemia is a risk factor for atherosclerosis that is common in chronic renal failure (CRF), but its cause is unknown. Homocysteine metabolism is linked to betaine-homocysteine methyl transferase (BHMT), a zinc metalloenzyme that converts glycine betaine (GB) to N,N dimethylglycine (DMG). DMG is a known feedback inhibitor of BHMT. We postulated that DMG might accumulate in CRF and contribute to hyperhomocysteinemia by inhibiting BHMT activity. METHODS: Plasma and urine concentrations of GB and DMG were measured in 33 dialysis patients (15 continuous ambulatory peritoneal dialysis and 18 hemodialysis), 33 patients with CRF, and 33 age-matched controls. Concentrations of fasting plasma total homocysteine (tHcy), red cell and serum folate, vitamins B(6) and B(12), serum zinc, and routine biochemistry were also measured. Groups were compared, and determinants of plasma tHcy were identified by correlations and stepwise linear regression. RESULTS: Plasma DMG increased as renal function declined and was twofold to threefold elevated in dialysis patients. Plasma GB did not differ between groups. The fractional excretion of GB (FE(GB)) was increased tenfold, and FED(MG) was doubled in CRF patients compared with controls. Plasma tHcy correlated positively with plasma DMG, the plasma DMG:GB ratio, plasma creatinine, and FE(GB) and negatively with serum folate, zinc, and plasma GB. In the multiple regression model, only plasma creatinine, plasma DMG, or the DMG:GB ratio was independent predictors of tHcy. CONCLUSIONS: DMG accumulates in CRF and independently predicts plasma tHcy concentrations. These findings suggest that reduced BHMT activity is important in the pathogenesis of hyperhomocysteinemia in CRF.

Glycine betaine excretion is not directly linked to plasma glucose concentrations in hyperglycaemia.

Diabetes mellitus subjects, type 1 and type 2, have increased glycine betaine excretion compared to normal subjects that correlated with plasma glucose and HbA(1C) concentrations. The current study was undertaken to determine whether elevated glucose concentration directly increases glycine betaine excretion in an animal model. Non-pregnant female Coopworth sheep received an intravenous glucose load (12.5,25 and 50% w/v; rate 200 ml/h) for 6 h followed by a 12 h physiological saline washout (0.9% w/v). Plasma and urine samples were analyzed for glycine betaine and glucose. Urine volumes and osmolality were also measured. Using the non-parametric Kruskal Wallis analysis of variance test we found no difference in glycine betaine excretion between glucose loaded and saline infused control animals (P=0.861). However, a significant negative correlation (r=-0.28, P<0.001) was observed between urine osmolality and glycine betaine excretion independent of treatment. We conclude that acute elevations of plasma glucose concentrations did not result in increased glycine betaine excretion and is therefore unlikely to be directly responsible for elevated glycine betaine excretion observed in diabetes mellitus subjects.

Elevated glycine betaine excretion in diabetes mellitus patients is associated with proximal tubular dysfunction and hyperglycemia.

In an ambulatory population of diabetic subjects (Type 1 and Type 2), the urine excretion of the renal osmolyte, glycine betaine, was compared to known markers of glycemic control, renal dysfunction and to the excretion of related betaines, including trigonelline, proline betaine, carnitine and acetyl-carnitine. Of the 85 subjects, 20 patients had urine glycine betaine concentrations above the reference range for normal subjects. Plasma glycine betaine concentrations were within reference ranges for normal subjects. Patients with elevated glycine betaine excretion tended to have lower plasma glycine betaine concentrations, but this did not reach statistical significance. One way analysis of variance found excretion is independent of treatment, duration of diagnosed diabetes, blood pressure and body mass index (BMI). An association between glycine betaine excretion and glycemic control was observed with statistically significant correlations occurring with both plasma glucose (r = 0.43, P < 0.001) and glycated haemoglobin (HbA1c) (r = 0.35, P < 0.005). The excretion of carnitine, acetyl-carnitine and proline betaine were related to glycine betaine excretion (r = 0.49, P < 0.001; r = 0.40, P < 0.001; r = 0.27, P < 0.05, respectively). Urine carnitine and acetyl-carnitine concentrations were also related to plasma glucose concentrations (r = 0.30, P < 0.01). Increased urine retinol binding protein concentrations (RBP), a marker of proximal tubular dysfunction, correlated with elevated urine glycine betaine excretion and plasma HbA1c (r = 0.28, P < 0.01). These results suggest poor glycemic control is associated with the increase in urine glycine betaine, carnitine, acetyl-carnitine and RBP excretion in diabetic patients. However, < 50% of the observed increase in glycine betaine excretion has been accounted for by the variables measured, suggesting other unidentified processes may also be involved.