Is Glycine an 'Antidote'

Editorial Open Heart: first published as 10.1136/openhrt-2014-000103 on 28 May 2014. Downloaded from The cardiometabolic benefits of glycine: Is glycine an ‘antidote’ to dietary fructose? Mark F McCarty,1 James J DiNicolantonio2 To cite: McCarty MF, VASCULAR PROTECTIVE PROPERTIES OF gated chloride channels. They also demon- DiNicolantonio JJ. The SUPPLEMENTAL GLYCINE strated that human platelets likewise were glycine cardiometabolic benefits of glycine: Is glycine an Supplemental glycine, via activation of responsive and expressed such channels. Studies ‘antidote’ to dietary glycine-gated chloride channels that are evaluating the interaction of glycine with aspirin fructose?. Open Heart expressed on a number of types of cells, or other pharmaceutical platelet-stabilising 2014;1:e000103. including Kupffer cells, macrophages, lym- agents would clearly be appropriate, as would a doi:10.1136/openhrt-2014- phocytes, platelets, cardiomyocytes and endo- clinical study examining the impact of supple- 000103 thelial cells, has been found to exert mental glycine on platelet function. anti-inflammatory, immunomodulatory, cyto- Another recent study has established that car- protective, platelet-stabilising and antiangio- diomyocytes express chloride channels.17 This genic effects in rodent studies that may be of may rationalise evidence that preadministration Accepted 26 April 2014 – clinical relevance.1 17 The plasma concentra- of glycine (500 mg/kg intraperitoneal) reduces tion of glycine in normally nourished indivi- the infarct size by 21% when rats are subse- — — duals around 200 µM is near the Km for quently subjected to cardiac ischaemia- activation of these channels, implying that reperfusion injury; this effect was associated the severalfold increases in plasma glycine with increases in ventricular ejection fraction achievable with practical supplementation and fractional shortening in the glycine pre- 17 can be expected to further activate these treated animals as compared with the controls. http://openheart.bmj.com/ channels in vivo.18 19 The impact on mem- This protection was associated with a reduction brane polarisation of such activation will in cardiomyocyte apoptosis, blunted activation hinge on the intracellular chloride content; of p38 MAP kinase and JNK and decreased Fas cells which actively concentrate chloride ligand expression. A previous study had against a gradient will be depolarised by reported that 3 mM glycine promoted increased channel activation, whereas other cells will survival of cardiomyocytes in vitro subjected to experience hyperpolarisation. In cells that 1 h of ischaemia and then reoxygenated, and fail to concentrate chloride and that express was also protective in an ex vivo model of voltage-activated calcium channels, glycine cardiac ischaemia reperfusion.20 on September 25, 2021 by guest. Protected copyright. tends to suppress calcium influx; this effect is Vascular endothelial cells express glycine- thought to mediate much of the protection gated chloride channels, and it has been sug- afforded by glycine.1 The role of chloride gested that glycine might exert an antiathero- channel activation in the mediation of gly- sclerotic effect by hyperpolarising the cine’s physiological effects is commonly vascular endothelium.19 Since such cells do assessed by the concurrent application of the not express voltage-gated calcium channels, chloride channel inhibitor strychnine; if this the impact of endothelial hyperpolarisation is abolishes glycine’s effect, this effect is most to increase calcium influx, as calcium follows likely mediated by chloride channels. the charge gradient.21 This in turn would be From the standpoint of vascular health, a expected to promote the calcium-mediated 1NutriGuard Research, Inc, Encinitas, California, USA recent report that glycine can stabilise platelets is activation of endothelial nitric oxide synthase. 2 7 fl Department of Preventive of evident interest. When rats were fed diets Moreover, endothelial polarisation in uences Cardiology, Saint Luke’s Mid containing 2.5–5% glycine, bleeding time nicotinamide adenine dinucleotide phos- America Heart Institute, approximately doubled, and the amplitude of phate (NADPH) oxidase activity; this is Kansas City, Missouri, USA platelet aggregation in whole blood triggered by boosted by depolarisation and conversely 22–24 Correspondence to ADP or collagen was halved. This effect was inhibited by hyperpolarisation. The Dr James J DiNicolantonio; blocked by strychnine, and the investigators were vascular-protective impact of potassium-rich [email protected] able to confirm that platelets express glycine- diets is suspected to be mediated in part by McCarty MF, DiNicolantonio JJ. Open Heart 2014;1:e000103. doi:10.1136/openhrt-2014-000103 1 Open Heart Open Heart: first published as 10.1136/openhrt-2014-000103 on 28 May 2014. Downloaded from the endothelial hyperpolarisation that results from and vascular function in rats.38 39 Glycine decreased the modest physiological increases in the plasma potassium elevated non-esterified fatty acid content of the liver of level (reflecting increased activity of the electrogenic sucrose-fed rats, increased the state IV oxidation rate of sodium pump).25 26 Other factors being equal, an hepatic mitochondria, corrected an elevation of blood increase in endothelial nitric oxide generation coupled pressure, normalised the serum triglycerides and insulin, with a decrease in superoxide production could be prevented an increase in abdominal fat mass and, in the expected to have an antiatherogenic and antihyperten- vasculature, boosted glutathione, decreased oxidative sive effect. Also speaking in favour of the antiathero- stress and normalised endothelium-dependent vasodila- sclerotic potential for glycine is a study demonstrating tion. Of likely relevance to these findings is a recent clin- that glycine exerts an anti-inflammatory effect on human ical report that supplemental glycine (15 g daily in three coronary arterial cells exposed to tumour necrosis factor divided doses) administered to patients with metabolic (TNF) α in vitro; activation of NF-κB was suppressed, as syndrome lessened indices of oxidative stress in erythro- was the expression of E-selectin and interleukin-6.27 So cytes and leucocytes, while lowering systolic blood pres- far, there are no published studies evaluating the impact sure.40 These findings are of considerable interest, of dietary glycine on atherogenesis in rodent models. particularly in the light of evidence that high dietary Evidence that glycine has an antihypertensive effect in fructose intakes can promote metabolic syndrome and sucrose-fed rats is discussed below. non-alcoholic fatty liver disease in humans and increase – Glycine is a biosynthetic precursor for creatine, LDL cholesterol.41 43 haeme, nucleic acids and the key intracellular antioxi- The protective effects of glycine in sucrose-fed rats, dant glutathione. Measures which raise or conserve and in humans with metabolic syndrome, are not intracellular glutathione levels may be of benefitfrom readily explained on the basis of the known metabolic the standpoint of oxidant-mediated mechanisms that effects of glycine. Fructose is known to exert its adverse impair vascular health. A recent clinical study reports effects primarily via its impact on liver metabolism; it is that concurrent supplementation of elderly participants catabolised almost exclusively in the liver, and its oxida- with glycine and cysteine (100 mg/kg/day of each, cyst- tion, unlike that of glucose, is not regulated by meta- eine administered as its N-acetyl derivative) reverses the bolic need.41 44 As a result, a high intake of fructose marked age-related reduction in erythrocyte glutathione floods the liver with substrate and suppresses hepatic levels while lowering the serum markers of oxidative fatty acid oxidation, while promoting de novo lipogen- stress28; the authors, however, did not prove that the sup- esis and triglyceride synthesis; increased generation of plemental glycine was crucial for this effect. malonyl-coenzyme A is responsible for the first two With respect to diabetes, it is of interest that high effects, whereas an increase in glycerol-3-phosphate http://openheart.bmj.com/ intakes of glycine have the potential to oppose the for- contributes importantly to fructose’s stimulatory impact mation of Amadori products, precursors to the advanced on triglyceride synthesis. These effects also increase glycation endproducts (AGEs) that mediate diabetic hepatic production of diacylglycerols, which impair complications.29 30 Indeed, supplementation of human hepatic insulin sensitivity via activation of protein kinase diabetics with glycine—5 g, 3-4 times daily—is reported C-ε.45 46 The increased triglyceride content of to decrease haemoglobin glycation.31 32 A similar effect fructose-exposed hepatocytes can be expected to stabil- has been reported in streptozotocin-treated diabetic ise apoB100 and accelerate secretion of very-low-density rats.33 These studies did not measure AGEs per se, so lipoprotein (VLDL) particles47 48; this phenomenon their findings should be interpreted cautiously. may explain the elevation of LDL cholesterol induced on September 25, 2021 by guest. Protected copyright. Nonetheless, glycine supplementation has delayed the by high-fructose intakes.42 The increased hepatic secre- progression of cataract, inhibited microaneurysm forma- tion of VLDL triglyceride presumably is responsible for tion, normalised the proliferative

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