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

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Abstract

Diabetes mellitus subjects, type 1 and type 2, have increased glycine betaine excretion compared to normal subjects that correlated with plasma glucose and HbA1C 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.

Introduction

During antidiuresis glycine betaine is accumulation in the renal cortex were it acts as an organic osmolytes to maintain cell volume and as a counteracting solute offering protection against the protein destabilising effects of urea [1]. The same mechanism has been observed in several mammalian species including rabbits, dogs, rats, and humans [2]. If diuresis occurs intracellular organic solutes are rapidly lost from inner medullary cells and pass primarily into the blood stream although some appear to be shed from the kidney into the urine [3]. Glycine betaine has been shown to be accumulated by other cell types during osmotic stress including the brain [4], rat liver macrophages [5], [6], human peripheral blood-derived monocytes and macrophages [7], and rat liver sinusoidal endothelial cells [8].

Glycine betaine is supplied from the diet either as glycine betaine or its metabolic precursor choline, and is present in the blood where the concentrations appear to be homeostatically controlled [9]. It is freely filtered by the kidney but most is reabsorbed in the proximal tubules with only small amounts reaching the urine (<4% of creatinine clearance) [9]. Elevated urinary glycine betaine (up to five fold) excretion has been found in 30% of subjects with diabetes mellitus, type 1 and type 2, whereas plasma concentrations remain within the normal reference range [10], [11]. One possible explanation has been suggested by results of a cohort study which found elevated urinary excretion of glycine betaine was strongly associated with both plasma glucose concentration (r=0.43, P<0.001) and HbA1C concentration (r=0.35, P<0.005) [11].

It seemed possible that increased plasma or urine glucose concentrations associated with diabetes is directly linked to elevations in glycine betaine excretion. To test this hypothesis we infused concentrated solutions of glucose into sheep to measure the effect of elevated blood glucose concentrations on the excretion of glycine betaine.

Section snippets

Animals

Eight 15-month-old non pregnant female Coopworth sheep with a mean live weight of 64.4±3.25 (S.D.) kg from the Lincoln University Research Farm were held in metabolism crates indoors for the study. Their feed was rye grass/white clover pasture. All procedures involving these animals were conducted with approval from Lincoln University Animal Ethics Committee.

Experimental procedure

The animals were fasted for 24 h prior to the experiment but had free access to drinking water that continued during the study. Venous

Pre-infusion period (saline only)

During the initial saline infusion both plasma and urinary glucose concentrations in the glucose treatment groups were not significantly different from those of the control group.

Six hour glucose infusion

Almost immediately after the glucose infusions began, plasma glucose concentrations in the glucose-treated animals increased (Fig. 1). The mean plasma glucose concentrations over the 6 h glucose load were; control saline, 2.62 mmol/l; 12.5% glucose, 7.5 mmol/l; 25% glucose, 15.94 mmol/l; and 50% glucose, 29.6 mmol/l.

Discussion

The sheep kidney has a similar structure to that of humans, and uses the same organic solutes in the inner medulla during antidiuresis. It could therefore be expected to respond with changes of similar magnitude and time periods as in humans. The sheep is also a convenient size making it possible to take multiple blood samples and maintain urinary catheterisation for long periods of time without anaesthetic and is therefore a suitable model species to test an hypothesis developed from human

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