Re: Cancer risk associated with chronic diseases and disease markers: prospective cohort study
This study by Tu et al.(1) adds materially to the quest for a common denominator in the etiology of the major chronic diseases of the modern industrialized world. I believe their “overlooked link” between chronic disease and markers and risk of cancer” as well as “a substantial reduction in lifespan” may be extended further in the context of other recent research on multiple fronts. Specifically, inflammation has emerged in recent years as a common factor in cancer, cardiovascular disease and diabetes, as well as arthritis and other frank inflammatory diseases. While many investigators have been searching for particular dietary and environmental triggers of inflammation, and pharmaceutical investigative efforts have focused on targeting specific populations of myeloid effector cells (macrophages), a single molecular entity may be emerging as an “overlooked link”in this regard: The simplest amino acid, glycine.
By the end of the last century, the Thurman group at UNC Chapel Hill(2) had established the presence of the glycine receptor on several populations of macrophages, which receptor is the same glycine-gated chloride channel that is known to function as an inhibitory neurotransmitter receptor in CNS neurons. Importantly, in the presence of high glycine levels, the activation of macrophages was substantially inhibited, but they were still capable of responding to the presence of bacterial lipopolysaccharide(2). The increased chloride ion influx serves to hyperpolarize the cell membrane, inhibiting depolarization and downstream cellular activation events. More recently, the advent of metabolomics has enabled a plethora of studies establishing an inverse association of plasma glycine levels among patients with insulin resistance and diabetes(3), cardiovascular disease(4) and cancer(5). This suggests that low blood glycine levels may engender a hyper-inflammatory state, predisposing the body to the spectrum of chronic diseases rooted in chronic inflammation, including cancer.
Glycine is still widely considered a nonessential amino acid because the human body can make it from simpler components. Hence, some may dismiss the concept of “glycine deficiency” among those with normal physiology. However, this conclusion is not logically tenable in the context of certain other nutrients such as Vitamin D, another “nonessential” nutrient for which deficiency disease has long been recognized. Moreover, normal plasma levels of glycine in human populations (about 100-400 micromolar), while generally adequate for glycine’s biochemical functions (including protein synthesis and intermediary metabolism), may not be adequate for glycine’s cellular physiological function in stabilizing membrane voltage and therefore tempering cellular activation in macrophages and other cells. This function seems to require plasma levels in the range of 0.5 – 1 mM(2).
Since glycine comprises one third mole fraction of collagen (gelatin), we may postulate that such chronic diseases have been on the rise because consumption of glycine-rich bones and connective tissues has been on the decline in recent decades. An obvious objection to this hypothesis may be based on the fact that the modern diet in the industrialized world is historically very high in protein content. Thus, the high consumption of meat, fish and poultry means that the intake of all the protein amino acids—including glycine—is historically high.
However, the particulars of amino acid metabolism suggest a more complex relationship between glycine and methionine, the latter of which is abundant in muscle meats. Specifically, glycine is the only substrate for glycine-N-methyltransferase (GNMT), which comprises the only major clearance pathway for methionine. Activated by the absorption of a methionine-rich meal, the clearance of excess of methionine requires two to three mole equivalents of glycine per mole of methionine(6). Hence, the high consumption of methionine-rich, glycine-poor muscle meats as dietary staples, might be hypothesized to cause a net reduction in plasma glycine levels.
In fact this hypothesis was recently proved to be true by Schmidt et al. at Oxford, in their large and meticulous analysis of dietary consumption and plasma amino acid levels among EPIC study participants in the UK(7). In their comparison of meat-eaters, fish-eaters, vegetarians and vegans, Schmidt et al. reported that although the meat-eaters consumed more glycine than those eating all the other diets (3.12 v. 2.61 g/day among vegans), the meat-eaters had the lowest plasma levels of glycine 390 v 452 μM in vegans). No other amino acids evidenced such an inverse relationship. Moreover, the well known lower prevalence of cancer and other chronic diseases among vegans v. meat-eaters might now be explained by differences in glycine levels.
Finally, in addition to observational studies, a clinical trial in Mexico City a decade ago(8) actually reported the reversal of type 2 diabetes with the consumption of 15g/day of supplemental glycine for 90 days, as evidenced by the reduction of hemoglobin A1c levels from 8.3% to 6.9%. Observationally, the inverse association of type 2 diabetes and prediabetes with plasma glycine has been abundantly documented, as shown by the recent SRMA of 46 studies(3)3, all since 2011.
Assuming Tu et al. have blood samples remaining from their study(1), the analysis of amino acids—especially glycine—might help to reveal an “overlooked link” with greater specificity and practical import.
1. Tu H, Wen CP, Tsai SP, et al. Cancer risk associated with chronic diseases and disease markers: prospective cohort study. BMJ 2018;360:k134.
2. Wheeler MD, Ikejema K, Enomoto N, et al. Glycine: a new anti-inflammatory immunonutrient (Review). Cell Mol Life Sci 1999;56:843–856
3. Guasch-Ferré M, Hruby A,Toledo E, et al. Metabolomics in Prediabetes and Diabetes: A Systematic Review
and Meta-analysis. Diabetes Care 2016;39:833–846 | DOI: 10.2337/dc15-2251
4. Ding Y, Svingen GFT, Pedersen ER, et al. Plasma Glycine and Risk of Acute Myocardial Infarction in Patients
With Suspected Stable Angina Pectoris. J Am Heart Assoc. 2016;5:
e002621 doi: 10.1161/JAHA.115.002621
5. Osman D,, Ali O, Obada M., et al. Chromatographic determination of some biomarkers of liver cirrhosis and hepatocellular carcinoma in Egyptian patients Biomed Chromatogr.2017;31. doi: 10.1002/bmc.3893. Epub 2016 Dec 28.
6. Luka Z, Mudd SH, Wagner C. Glycine N-methyltransferase and regulation of S-adenosylmethionine levels (Minireview). J Biol Chem 2009; 284:22,507-11
7. Schmidt JA, Rinaldi S, Scalbert A, et al. Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: a cross-sectional analysis in the EPIC-Oxford cohort. Eur J Clin Nutrition 2016;70:306–12. doi:10.1038/ejcn.2015.144
8. Cruz M, Maldonado-Bernal C, R. Mondragón-Gonzalez R, et al. Glycine treatment decreases proinflammatory cytokines andincreases interferon- in patients with Type 2 diabetes. J Endocrinol Invest 2008;31:694-99
Competing interests:
No competing interests
07 February 2018
Joel Brind
Professor
Baruch College, City University of New York
Department of Natural Sciences, Box A0506, Baruch College, CUNY, 1 Bernard Baruch Way, New York, NY 10010 USA
Rapid Response:
Re: Cancer risk associated with chronic diseases and disease markers: prospective cohort study
This study by Tu et al.(1) adds materially to the quest for a common denominator in the etiology of the major chronic diseases of the modern industrialized world. I believe their “overlooked link” between chronic disease and markers and risk of cancer” as well as “a substantial reduction in lifespan” may be extended further in the context of other recent research on multiple fronts. Specifically, inflammation has emerged in recent years as a common factor in cancer, cardiovascular disease and diabetes, as well as arthritis and other frank inflammatory diseases. While many investigators have been searching for particular dietary and environmental triggers of inflammation, and pharmaceutical investigative efforts have focused on targeting specific populations of myeloid effector cells (macrophages), a single molecular entity may be emerging as an “overlooked link”in this regard: The simplest amino acid, glycine.
By the end of the last century, the Thurman group at UNC Chapel Hill(2) had established the presence of the glycine receptor on several populations of macrophages, which receptor is the same glycine-gated chloride channel that is known to function as an inhibitory neurotransmitter receptor in CNS neurons. Importantly, in the presence of high glycine levels, the activation of macrophages was substantially inhibited, but they were still capable of responding to the presence of bacterial lipopolysaccharide(2). The increased chloride ion influx serves to hyperpolarize the cell membrane, inhibiting depolarization and downstream cellular activation events. More recently, the advent of metabolomics has enabled a plethora of studies establishing an inverse association of plasma glycine levels among patients with insulin resistance and diabetes(3), cardiovascular disease(4) and cancer(5). This suggests that low blood glycine levels may engender a hyper-inflammatory state, predisposing the body to the spectrum of chronic diseases rooted in chronic inflammation, including cancer.
Glycine is still widely considered a nonessential amino acid because the human body can make it from simpler components. Hence, some may dismiss the concept of “glycine deficiency” among those with normal physiology. However, this conclusion is not logically tenable in the context of certain other nutrients such as Vitamin D, another “nonessential” nutrient for which deficiency disease has long been recognized. Moreover, normal plasma levels of glycine in human populations (about 100-400 micromolar), while generally adequate for glycine’s biochemical functions (including protein synthesis and intermediary metabolism), may not be adequate for glycine’s cellular physiological function in stabilizing membrane voltage and therefore tempering cellular activation in macrophages and other cells. This function seems to require plasma levels in the range of 0.5 – 1 mM(2).
Since glycine comprises one third mole fraction of collagen (gelatin), we may postulate that such chronic diseases have been on the rise because consumption of glycine-rich bones and connective tissues has been on the decline in recent decades. An obvious objection to this hypothesis may be based on the fact that the modern diet in the industrialized world is historically very high in protein content. Thus, the high consumption of meat, fish and poultry means that the intake of all the protein amino acids—including glycine—is historically high.
However, the particulars of amino acid metabolism suggest a more complex relationship between glycine and methionine, the latter of which is abundant in muscle meats. Specifically, glycine is the only substrate for glycine-N-methyltransferase (GNMT), which comprises the only major clearance pathway for methionine. Activated by the absorption of a methionine-rich meal, the clearance of excess of methionine requires two to three mole equivalents of glycine per mole of methionine(6). Hence, the high consumption of methionine-rich, glycine-poor muscle meats as dietary staples, might be hypothesized to cause a net reduction in plasma glycine levels.
In fact this hypothesis was recently proved to be true by Schmidt et al. at Oxford, in their large and meticulous analysis of dietary consumption and plasma amino acid levels among EPIC study participants in the UK(7). In their comparison of meat-eaters, fish-eaters, vegetarians and vegans, Schmidt et al. reported that although the meat-eaters consumed more glycine than those eating all the other diets (3.12 v. 2.61 g/day among vegans), the meat-eaters had the lowest plasma levels of glycine 390 v 452 μM in vegans). No other amino acids evidenced such an inverse relationship. Moreover, the well known lower prevalence of cancer and other chronic diseases among vegans v. meat-eaters might now be explained by differences in glycine levels.
Finally, in addition to observational studies, a clinical trial in Mexico City a decade ago(8) actually reported the reversal of type 2 diabetes with the consumption of 15g/day of supplemental glycine for 90 days, as evidenced by the reduction of hemoglobin A1c levels from 8.3% to 6.9%. Observationally, the inverse association of type 2 diabetes and prediabetes with plasma glycine has been abundantly documented, as shown by the recent SRMA of 46 studies(3)3, all since 2011.
Assuming Tu et al. have blood samples remaining from their study(1), the analysis of amino acids—especially glycine—might help to reveal an “overlooked link” with greater specificity and practical import.
Correspondence to: joelbrind@yahoo.com
References cited
1. Tu H, Wen CP, Tsai SP, et al. Cancer risk associated with chronic diseases and disease markers: prospective cohort study. BMJ 2018;360:k134.
2. Wheeler MD, Ikejema K, Enomoto N, et al. Glycine: a new anti-inflammatory immunonutrient (Review). Cell Mol Life Sci 1999;56:843–856
3. Guasch-Ferré M, Hruby A,Toledo E, et al. Metabolomics in Prediabetes and Diabetes: A Systematic Review
and Meta-analysis. Diabetes Care 2016;39:833–846 | DOI: 10.2337/dc15-2251
4. Ding Y, Svingen GFT, Pedersen ER, et al. Plasma Glycine and Risk of Acute Myocardial Infarction in Patients
With Suspected Stable Angina Pectoris. J Am Heart Assoc. 2016;5:
e002621 doi: 10.1161/JAHA.115.002621
5. Osman D,, Ali O, Obada M., et al. Chromatographic determination of some biomarkers of liver cirrhosis and hepatocellular carcinoma in Egyptian patients Biomed Chromatogr.2017;31. doi: 10.1002/bmc.3893. Epub 2016 Dec 28.
6. Luka Z, Mudd SH, Wagner C. Glycine N-methyltransferase and regulation of S-adenosylmethionine levels (Minireview). J Biol Chem 2009; 284:22,507-11
7. Schmidt JA, Rinaldi S, Scalbert A, et al. Plasma concentrations and intakes of amino acids in male meat-eaters, fish-eaters, vegetarians and vegans: a cross-sectional analysis in the EPIC-Oxford cohort. Eur J Clin Nutrition 2016;70:306–12. doi:10.1038/ejcn.2015.144
8. Cruz M, Maldonado-Bernal C, R. Mondragón-Gonzalez R, et al. Glycine treatment decreases proinflammatory cytokines andincreases interferon- in patients with Type 2 diabetes. J Endocrinol Invest 2008;31:694-99
Competing interests: No competing interests