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

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Abstract

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.

Introduction

Glycine betaine (N,N,N-trimethylglycine) is a small zwitterionic compound, known to play an important role in the normal physiology of the kidney and liver. In the kidney, glycine betaine is one of five organic osmolytes actively accumulated intracellularly in the renal medulla, to balance high external solute concentrations and minimize the osmotic gradient across the cell membrane [1], [2]. Other osmolytes found in the kidney include sorbitol, inositol [3], glycerophosphorylcholine (GPC) [1] and taurine [4]. Each osmolyte exhibits a specific distribution pattern in the kidney along the corticopapillary axes [2], [5]. Methylamines, such as glycine betaine and GPC, unlike sorbitol and inositol, are also counteracting solutes that offset the protein destabilizing effects of urea without disturbing normal cell function [6].

In the liver, glycine betaine functions as an osmolyte [7] and is also involved in the biosynthesis of methionine, in that it donates a methyl group to homocysteine producing dimethylglycine and methionine. This reaction is catalysed by betaine homocysteine methyltransferase (BHMT) [8]. Recently, attention has been directed towards a possible therapeutic role for glycine betaine in lowering plasma homocysteine concentrations, which is a risk factor for vascular disease [9], [10].

Glycine betaine is mainly derived from the diet, as it is a normal constituent of plants [11]. It is absorbed in the ileum via ‘imino’ porters along with other dietary betaines such as proline betaine (legumes) and trigonelline (coffee). Glycine betaine can also be synthesised by oxidation of choline in the liver and kidney. These sources are thought to contribute modestly to the glycine betaine pool if a normal diet is consumed.

In a healthy non-diabetic population, plasma concentrations are stable over prolonged periods suggesting homeostatic control [12], [13]. Glycine betaine is freely filtered in the kidney, with most being resorbed from the glomerular filtrate via active Na+ dependent transporters within the proximal tubule (fractional clearance <5% of creatinine). These transporters have high specificity for glycine betaine and can distinguish between proline betaine and trigonelline, unlike the imino porters in the intestinal brush border. However glycine betaine excretion is increased in the presence of proline betaine [12]. A likely mechanism is that proline betaine acts as a competitive inhibiter of the glycine betaine Na+ dependent transporters in the proximal tubule. It is possible that dietary betaines and structurally related compounds, such as carnitine and acyl-carnitine derivatives, also inhibit resorption of glycine betaine.

We have previously observed up to 5-fold increase in glycine betaine excretion in diabetic patients compared with normal controls while plasma concentrations remain stable [14]. To identify factors for the increase in glycine betaine excretion, we have studied a cohort of patients with diabetes mellitus and compared glycine betaine excretion with glomerular and tubular dysfunction, excretion of dietary betaines and structurally related compounds, as well as markers of glycemic control.

Our findings indicate poor glycemic control and tubular dysfunction is responsible for the increased excretion of low molecular weight (LMW) compounds such as glycine betaine, carnitine, acetyl-carnitine and retinol binding protein (RBP).

Section snippets

Study design

Ambulatory diabetic subjects >20 years of age were recruited through the specialist diabetes clinic at Christchurch Hospital, Christchurch, New Zealand. Diagnosis of diabetes mellitus was in accordance with the WHO study group report classification [15]. Type 1 patients were classified as patients that required insulin therapy for survival and were diagnosed before 30 years of age. All other patients, meeting the glycemic criteria for diabetes mellitus, were classified as Type 2. Laboratory

Results

Eighty-five patients were recruited into the study. Patient characteristics are shown in Table 1. The reference ranges, medians, means, S.D. and ranges for glycine betaine, proline betaine, trigonelline, carnitine, acetyl-carnitine in plasma and urine are presented in Table 2, Table 3, respectively. Markers of glycemic control, plasma glucose and HbA1c are reported in Table 2. Markers of renal function, RBP and albumin, are reported in Table 3. As previously described [14], urine glycine

Discussion

In this study of ambulatory diabetic subjects we found excretion of glycine betaine was elevated in 30% of the population, compared with the reference range established previously for normals [14]. In contrast, plasma glycine betaine was within the normal range. There was no association between glycine betaine excretion and patient characteristics including age, duration of known diabetes, type of diabetes and treatment regimens, but more detailed prospective clinical studies are needed to

Acknowledgments

Assistance from the Canterbury Medical Research Foundation, the NZ Kidney Foundation and the NZ Lotteries Board are acknowledged. Helpful comments from Dr Peter Elder, Dr John Lewis and Associate Professor John Leader are also acknowledged.

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