Glycine betaine excretion is not directly linked to plasma glucose concentrations in hyperglycaemia
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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Cited by (9)
Identification of urine metabolites associated with 5-year changes in biomarkers of glucose homoeostasis
2018, Diabetes and MetabolismCitation Excerpt :With respect to our present findings, previous investigations had already revealed altered betaine metabolism in diabetes patients, with significantly higher urinary betaine excretion in such patients [22,23] linked to hyperglycaemia and proximal tubular dysfunction [22] as well as plasma glucose or HbA1c levels [22]. The latter authors further showed that plasma glucose infusion did not lead to increased betaine excretion in female sheep and suggested that increased betaine excretion may not be directly caused by elevated plasma glucose levels or glycosuria in diabetes [24]. A more recent study [25] based on 2400 subjects confirmed the increased betaine excretion in diabetes patients, and also found a non-linear association between betaine excretion and HbA1c with a strong positive association for HbA1c levels > 6%.
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2011, Journal of Biological ChemistryCitation Excerpt :Glycine betaine is primarily diet-derived but can be synthesized from choline in the liver and kidney as well as by gut microbiota (10, 55, 56, 67, 68). Although the precise reason for its elevation in concentration is uncertain, it might also be an indicator of the compensatory increase of organic osmolytes of the body, particularly in the proximal tubules of the kidney, in response to high blood glucose concentrations (55, 56, 69–71). Therefore, glycine betaine may serve as an early indicator of diabetic nephropathy and reduced SLC6A20 function, for which only a few, relatively poor markers currently exist (7).
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