Vascular protective properties of supplemental glycine
Supplemental glycine, via activation of glycine-gated chloride channels that are expressed on a number of types of cells, including Kupffer cells, macrophages, lymphocytes, platelets, cardiomyocytes and endothelial cells, has been found to exert anti-inflammatory, immunomodulatory, cytoprotective, platelet-stabilising and antiangiogenic effects in rodent studies that may be of clinical relevance.1–17 The plasma concentration of glycine in normally nourished individuals—around 200 µM—is near the Km for activation of these channels, implying that the severalfold increases in plasma glycine achievable with practical supplementation can be expected to further activate these channels in vivo.18 ,19 The impact on membrane polarisation of such activation will hinge on the intracellular chloride content; cells which actively concentrate chloride against a gradient will be depolarised by channel activation, whereas other cells will experience hyperpolarisation. In cells that fail to concentrate chloride and that express voltage-activated calcium channels, glycine tends to suppress calcium influx; this effect is thought to mediate much of the protection afforded by glycine.1 The role of chloride channel activation in the mediation of glycine's physiological effects is commonly assessed by the concurrent application of the chloride channel inhibitor strychnine; if this abolishes glycine's effect, this effect is most likely mediated by chloride channels.
From the standpoint of vascular health, a recent report that glycine can stabilise platelets is of evident interest.7 When rats were fed diets containing 2.5–5% glycine, bleeding time approximately doubled, and the amplitude of platelet aggregation in whole blood triggered by ADP or collagen was halved. This effect was blocked by strychnine, and the investigators were able to confirm that platelets express glycine-gated chloride channels. They also demonstrated that human platelets likewise were glycine responsive and expressed such channels. Studies evaluating the interaction of glycine with aspirin or other pharmaceutical platelet-stabilising agents would clearly be appropriate, as would a clinical study examining the impact of supplemental glycine on platelet function.
Another recent study has established that cardiomyocytes express chloride channels.17 This may rationalise evidence that preadministration of glycine (500 mg/kg intraperitoneal) reduces the infarct size by 21% when rats are subsequently subjected to cardiac ischaemia-reperfusion injury; this effect was associated with increases in ventricular ejection fraction and fractional shortening in the glycine pretreated animals as compared with the controls.17 This protection was associated with a reduction in cardiomyocyte apoptosis, blunted activation of p38 MAP kinase and JNK and decreased Fas ligand expression. A previous study had reported that 3 mM glycine promoted increased survival of cardiomyocytes in vitro subjected to 1 h of ischaemia and then reoxygenated, and was also protective in an ex vivo model of cardiac ischaemia reperfusion.20
Vascular endothelial cells express glycine-gated chloride channels, and it has been suggested that glycine might exert an antiatherosclerotic effect by hyperpolarising the vascular endothelium.19 Since such cells do not express voltage-gated calcium channels, the impact of endothelial hyperpolarisation is to increase calcium influx, as calcium follows the charge gradient.21 This in turn would be expected to promote the calcium-mediated activation of endothelial nitric oxide synthase. Moreover, endothelial polarisation influences nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity; this is boosted by depolarisation and conversely inhibited by hyperpolarisation.22–24 The vascular-protective impact of potassium-rich diets is suspected to be mediated in part by the endothelial hyperpolarisation that results from modest physiological increases in the plasma potassium level (reflecting increased activity of the electrogenic sodium pump).25 ,26 Other factors being equal, an increase in endothelial nitric oxide generation coupled with a decrease in superoxide production could be expected to have an antiatherogenic and antihypertensive effect. Also speaking in favour of the antiatherosclerotic potential for glycine is a study demonstrating that glycine exerts an anti-inflammatory effect on human coronary arterial cells exposed to tumour necrosis factor (TNF) α in vitro; activation of NF-κB was suppressed, as was the expression of E-selectin and interleukin-6.27 So far, there are no published studies evaluating the impact of dietary glycine on atherogenesis in rodent models. Evidence that glycine has an antihypertensive effect in sucrose-fed rats is discussed below.
Glycine is a biosynthetic precursor for creatine, haeme, nucleic acids and the key intracellular antioxidant glutathione. Measures which raise or conserve intracellular glutathione levels may be of benefit from the standpoint of oxidant-mediated mechanisms that impair vascular health. A recent clinical study reports that concurrent supplementation of elderly participants with glycine and cysteine (100 mg/kg/day of each, cysteine administered as its N-acetyl derivative) reverses the marked age-related reduction in erythrocyte glutathione levels while lowering the serum markers of oxidative stress28; the authors, however, did not prove that the supplemental glycine was crucial for this effect.
With respect to diabetes, it is of interest that high intakes of glycine have the potential to oppose the formation of Amadori products, precursors to the advanced glycation endproducts (AGEs) that mediate diabetic complications.29 ,30 Indeed, supplementation of human diabetics with glycine—5 g, 3-4 times daily—is reported to decrease haemoglobin glycation.31 ,32 A similar effect has been reported in streptozotocin-treated diabetic rats.33 These studies did not measure AGEs per se, so their findings should be interpreted cautiously. Nonetheless, glycine supplementation has delayed the progression of cataract, inhibited microaneurysm formation, normalised the proliferative response of blood mononuclear cells and aided the humoral immune response in diabetic rats, effects which suggest that glycine may have potential for prevention of some diabetic complications.34–36 In a recent controlled but unblinded study, patients with diabetes experiencing auditory neuropathy achieved improvements in hearing acuity and auditory nerve conduction while ingesting 20 g glycine daily for 6 months.37