Glycine

Glycine (abbreviated as Gly) is a conditionally essential amino acid discovered in 1820 by French chemist Henri Braconnot through acid hydrolysis of gelatin.^[1] Glycine is the simplest amino acid in nature, with a single hydrogen atom as its side chain. Glycine was found to be as sweet as glucose and, hence, its name was derived from the Greek word glykys, meaning sweet.

Glycine is the primary amino acid in collagen, making up one-third of its amino acids in the repeated form of tripeptides (glycine-proline-Y and glycine-X-hydroxyproline, where X and Y can be any amino acid).^[2][3] Accordingly, collagenous proteins are the best dietary source of glycine. However, any dietary source of protein will provide varying amounts of glycine. According to the USDA Food Composition Database, the glycine content of most meats and seafoods is 1-2 grams per 100 grams of cooked food, eggs contain 0.4 grams per 100 grams of whole egg, and milk contains 0.08 grams per 100 grams of milk.

Glycine is also synthesized within the body. The main pathway is synthesis from serine via glycine hydroxymethyltransferase (GHMT), which produces roughly 2.5 grams of glycine per day.^[4] Glycine is also synthesized in lesser amounts (~0.5 grams per day) from choline (via sarcosine), threonine degradation, carnitine synthesis, and the transamination of glyoxylate.^[4]

Glycine is a colorless, odorless, sweet-tasting crystalline solid with a molecular weight of 75.067 g/mol. ^[5] Like all amino acids, glycine has a central carbon with one amino group, one carboxy acid group, and one side chain that makes each amino acid unique. For glycine, this side chain is a single hydrogen atom, which is why glycine is the simplest and smallest amino acid in nature. Glycine is a nonpolar neutral amino acid, meaning it has no net electrical charge and does not interact with water.

Glycine serves many important roles in the body through structural and regulatory actions. As an amino acid, glycine plays an essential role in protein synthesis, especially collagen synthesis. A glycine molecule must represent every third amino acid in collagen for stability, and mutations that result in substitutions of glycine results in a variety of connective tissue disorders collectively known as brittle bone disease.^[6]. Glycine also plays a special role in enzyme structure and function by providing flexibility in their active sites, therefore allowing them to change their conformation as necessary to bind with substrates.^[7][8]

Glycine is a precursor for the synthesis of several biologically important compounds, including porphyrins and heme,^[9] creatine (glycine + arginine + methionine),^[10] and glutathione (glycine + cysteine + glutamate),^[11] and purines.^[12] Additionally, glycine is conjugated with bile acids (along with taurine) before being excreted into the biliary system, thereby playing a central role in lipid digestion and absorption.^[13]

Finally, glycine is an important signaling molecule throughout the body. Glycine acts as both an inhibitory and excitatory neurotransmitter in the brain and spinal cord, where it is involved in reflex coordination, the processing of sensory signals, and the sensation of pain.^[14] Whereas the inhibitory functions are owed to a direct effect of glycine binding glycine-specific receptors,^[15] the excitatory effects are mediated by glutamate and the N-methyl-D-aspartate (NMDA) receptor.^[16][17] Outside of the nervous system, glycine plays a role in immunomodulation and inflammation through binding chloride channels in the cell membranes of leukocytes and macrophages, thereby suppressing calcium influx.^[18]

Glycine is an amino acid necessary for protein synthesis, especially collagen synthesis, and the biosynthesis of heme, creatine, glutathione, and purines. Glycine also functions as both an inhibitory and an excitatory neurotransmitter, functions as a signaling molecule in the immune system, is necessary for the proper function of some enzymes, and plays a role in lipid digestion and absorption.

Glycine is a conditionally essential amino acid in humans because humans are unable to synthesize enough glycine to satisfy metabolic requirements.^[4] The average adult human (70 kg; 30-50 years; sedentary) requires nearly 15 grams of glycine per day to synthesize collagen (12 g/d), non-collagen proteins (1 g/d), and other important compounds such as porphyrins (240 mg/d), purines (206 mg/d), creatine (420 mg/d), glutathione (567 mg/d), and bile salts (60 mg/d).^[4] However, glycine synthesis is limited to about 2.5 grams per day, suggesting that humans require about 12 grams of dietary glycine to satisfy daily metabolic requirements.^[4]

This problem is due primarily to the stoichiometry of the reaction catalyzed by GHMT, which requires glycine and tetrahydrofolate (THF) to be produced in equimolar amounts regardless of any differences in the metabolic demand for either.^[19]

L-serine + THF ↔ 5,10 methylene-THF + glycine + H₂O

As far as 5,10 methylene-THF is concerned, synthesis is not constrained because glycine can be diverted to its production via the glycine cleavage system (CVS).^[20] However, this reaction is thermodynamically irreversible, and 5,10 methylene-THF cannot, therefore, produce glycine. Rather, 5,10 methylene-THF must first be converted to 5-methyl THF, which must then donate its methyl group to regenerate THF to produce glycine via GHMT. Accordingly, the production of glycine via GHMT relies on the rate of methylation reactions within the body.^[19]

Further evidence of glycine’s essentiality comes from nitrogen balance studies. A controlled feeding study in healthy young men reported that reducing total protein intake from 1.5 g/kg (3.8 g glycine) to 0.6 g/kg (1.5 g glycine) did not affect rates of de novo glycine synthesis, but that providing these amounts of protein exclusively from essential amino acids resulted in significant reductions in de novo glycine synthesis (37% for 1.5 g/kg and 66% for 0.6 g/kg).^[21] An earlier study by the same lab reported that reducing total protein intake from 1.5 g/kg (3.8 g glycine) to 0.4 g/kg (1.0 g glycine) led to a significant reduction in de novo glycine synthesis of about 40% in young men and 33% in elderly men.^[22] These studies suggest that the amino acid composition of the diet influences glycine metabolism, especially at low total protein intakes. If glycine were truly nonessential, then its synthesis in the body should not depend on dietary intake.

The imbalance between glycine synthesis and requirements in humans has been explained from an evolutionary perspective.^[23] Collagen is the most abundant protein in the animal kingdom and first appeared in small animals that required low amounts relative to their size. Glycine synthesis was therefore satisfactory for life. However, larger animals show little evidence for evolving new metabolic pathways and therefore inherited a regulatory system poorly suited to their greatly enhanced collagen needs.

This evolutionary explanation requires that the glycine biosynthesis constraint applies to any large animal. Notably, osteoarthritis has been documented in in a variety of present-day mammals, both in the wild and in captivity.^[24] Skeletal and joint diseases have been found in elephants^[25] and rhinoceroses,^[26] great apes such as chimpanzees, gorillas, and bonobos,^[27] and Neanderthals.^[28] Moreover, glycine is supplemented in the diets of livestock to maximize growth, collagen production, skeletal muscle development, nitrogen retention, mucin production, immune function, antioxidant capacity.^[29]

Considering glycine’s essential role in collagen production, the appearance of skeletal and joint diseases in animals and humans with aging is a possible example of Bruce Ames Triage Theory, which posits that short-term survival is prioritized over long-term health when nutrient availability is limited.^[30] From an evolutionary standpoint, the selective pressure to eliminate the glycine constraint is probably low because it does not affect survival or reproduction. However, a chronic glycine deficit may affect quality of life due to a down-regulation of collagen turnover and nonessential metabolic processes.

Consuming 10 grams per day of dietary glycine could increase the serum concentrations to levels associated with a 200% increase in rates of type-II collagen synthesis compared to current glycine concentrations.^[31]

Evidence in humans suggests that a glycine shortage also affects glutathione status. Glutathione is created from the amino acids: glutamate, cysteine, and glycine. Glutamate and cysteine combine to form gamma-glutamylcysteine, which then combines with glycine to form glutathione. People with genetic defects in this latter step show increased levels of urinary 5-oxoproline (pyroglutamic acid).^[32] Increased urinary 5-oxoproline concentrations have also been found after depleting the body’s glycine pool with benzoic acid^[33] and after feeding healthy adults a glycine-free diet.^[34] On the other hand, glycine supplementation has been shown to reduce urinary 5-oxoproline concentrations and increase glutathione status.^[35] These studies collectively demonstrate that the production and availability of glutathione is sensitive to glycine status and may be less than optimal under circumstances of limited glycine availability. A chronic glycine shortage could, therefore, have long-term implications for the body’s exposure to oxidative stress.^[36]

Importantly, it remains unknown which metabolic processes involving glycine are prioritized in the presence of glycine insufficiency. Therefore, the absence of 5-oxoproline in the urine is not of itself an indication of a satisfactory glycine status, but rather an indication that glycine status is not sufficient to support glutathione production. It is possible that 5-oxoproline levels could be considered normal when a glycine insufficiency is still present, affecting other metabolic pathways such as collagen synthesis.

Nonetheless, urinary 5-oxoproline levels serve as a way to identify populations that do not obtain enough glycine to support glutathione synthesis.^[37] For example, vegetarians have significantly higher levels of 5-oxoproline than omnivores, and higher 5-oxoproline levels significantly correlated with lower dietary protein intake.^[38] Preterm infants have higher urinary levels of 5-oxoproline than full-term infants,^[39] and nitrogen balance studies have suggested that glycine supplementation may be necessary to assure a satisfactory rate of lean tissue growth in preterm infants.^[40]

Glycine is a conditionally essential amino acid for humans. Dietary requirements are estimated to be around 12 grams per day. Glycine insufficiency is not life-threatening, but a chronic shortage may have detrimental effects on collagen turnover and glutathione status, which in turn could increase levels of oxidative stress and the risk of suffering from skeletal and joint diseases.

In rats, daily supplementation with the human equivalent dose (HED)^[41] of 0.5 g/kg glycine for two weeks induced non-pathological changes in glial cell morphology in the hippocampus and cerebellum.^[42] Follow-up research also reported no pathological changes in brain morphology with daily supplementation of 0.8 g/kg (HED) for five months, although it did cause a reduction in the expression of class B, N-type calcium channels in the cortex and hippocampus.^[43] The authors speculate this to be a normal physiological adaptation to increased glycine availability.

Clinical trials have safely used doses of 0.5 g/kg body weight for eight weeks^[44] and 0.8 g/kg for six weeks.^[45][46][47] A case report documents the safety of supplementing with 0.8 g/kg for five years.^[48]

No toxicity with glycine supplementation has been observed with doses up to 0.8 g/kg body weight (64 grams per day for a 176 lb adult).

Glycine supplementation was well tolerated without major adverse effects in a study involving 10 obese adults supplementing with 5 grams of glycine at each of three meals (15 g/d).^[49]

In an earlier study, minor digestive symptoms, including mild abdominal pain and soft stools, were reported in 12 healthy adults who were administered 9 g per day of glycine on an empty stomach before bed. Taking 9 grams of glycine with each of three meals did not cause daytime sleepiness.^[50]

Glycine is well tolerated and does not cause daytime sleepiness when supplemented with meals, but 9 grams on an empty stomach has been noted to cause mild abdominal discomfort.

Glycine is absorbed as a free amino acid or constituent of peptides along the entire small intestine, with most absorption occurring in the duodenum and upper jejunum.^[51] As a free amino acid, glycine is absorbed via two transporter systems, one of which is used by all neutral amino acids.^[52] The other transport system involves the imino acid carrier (no, that isn’t a typo) that also transports proline, alanine, and sarcosine.^[53][54]

Glycine may also be absorbed in the form of a peptide, linked to either one other amino acid (dipeptide) or two other amino acids (tripeptide). Peptide absorption relies on different transport systems than free amino acids and are absorbed more rapidly.^[55][56][57] While some peptides make it into circulation intact, such as glycyl-L-proline,^[57] most are broken down into amino acids by enzymes within enterocytes before being released into circulation.^[51][58]

Plasma glycine concentrations peak around 45-60 minutes in healthy adults after consuming free glycine, with a return to fasting levels by 3-4 hours.^[59][60] Consuming glycine in the form of a peptide (diglycine or triglycine) results in a larger (9-12-fold vs 7-fold increase above fasting levels) and more rapid (30-45 vs 45-60 minutes) peak of serum glycine.^[59] Glycine absorption is marginally reduced in adults with type II diabetes compared to healthy adults.^[61] Glycine absorption is significantly increased in adults with systemic bacterial infections,^[62] whereas diglycine absorption is not affected.^[63]

Consuming glycine alongside glucose modestly reduces peak glycine levels and the total serum glycine concentrations over two hours.^[60] Both glucose and galactose have been shown to inhibit the absorption of glycine^[64][65] and, to a lesser extent, diglycine.^[66] This interaction is likely owed to an allosteric interaction between sugars and amino acids at the brush-border membrane.^[67] Whether this observation has a practical value in human nutrition is unknown, although it has been suggested to be of importance in populations living on high-carbohydrate diets with marginal protein intakes.^[68]

Serum glycine concentrations peak 30-60 minutes after ingestion, with a larger and more rapid peak occurring when glycine is consumed as a peptide compared to a free amino acid. Absorption is enhanced in people with systemic infections and reduced in people with type II diabetes. Glucose inhibits glycine absorption, although the practical significance seems low.

Glycine catabolism occurs through two primary pathways: decarboxylation and deamination by the mitochondrial glycine cleavage enzyme system (GCS), and conversion into serine by serine hydroxymethyltranserase (SHMT).^[1] The predominance of these pathways in glycine metabolism is evidenced by isotopic tracer studies, which report that roughly 54% of ingested glycine ends up as serine, 20% as urea, 15% as glutamine and glutamate amino-nitrogen, 7% as alanine, and 3-8% as the branch-chain amino acids (BCAAs), proline, ornithine, and methionine.^[69]

Both pathways are intricately linked to one another. The GCS uses tetrahydrofolate (THF) and glycine to produce 5,10-methylene-THF and ammonia. SHMT uses 5,10-methylene-THF and glycine to produce THF and serine.^[1]

The importance of the GCS in glycine catabolism is clearly demonstrated by its defect in humans, which results in extremely high serum glycine levels and associated neurological disorders referred to as glycine encephalopathy (also known as nonketotic hyperglycinemia).^[70][71] Glucagon^[72] and metabolic acidosis^[73] increase GCS activity and glycine degradation. The reaction catalyzed by the glycine cleavage system is reversible in vitro, but deficient activity of the human complex leads to hyperglycinemia, suggesting that the reaction in vivo proceeds predominantly in the direction of glycine breakdown.

Small amounts of glycine are also used in various other pathways for the synthesis of porphyrins, purines, creatine, glutathione, and bile salts.^[4] Glycine also plays a central role in protein synthesis, especially collagen, where it represents every third amino acid in the protein’s primary structure.^[3]

Glycine is degraded by via the glycine cleavage enzyme system, converted into serine, or used for biosynthesis of proteins, porphyrins, purines, creatine, glutathione, and bile salts.

Glycine can be taken into cells via the glycine transporter-1 (GlyT1) which appears to have a role in determinining synaptic concentrations of glycine and serine^[74][75] as its inhibition can potentiate NDMA signalling (by increasing synaptic levels of glycine)^[76] and may also be taken up by a second transporter known as GlyT2.^[75] The alanine–serine–cysteine transporter-1 (AscT1) may also play a role in regulating synaptic concentrations of glycine and serine by modifying uptake into glial cells.^[77][78]

There are a few transporters that draw glycine into cells, and they appear to have a regulatory role in controlling levels of synaptic glycine

Glycine itself is a neurotransmitter with its own signalling system (similar to GABA or Agmatine).^[79] This system is inhibitory and works alongside the GABAergic system, although in the auditory brainstem^[80][81] and hypoglossal nucleus^[82] there appears to be a developmental shift towards favoring glycinergic inhibition, and glycinergic neurotransmission has been shown to have relevance in the thalamus,^[83] cerebellum,^[84] and hippocampus.^[85][86] This system and its receptors are blocked by the research drug Strychnine^[87] and when glycine activates its receptors the resulting influx of chloride (Cl^-) ions causes an inhibitory effect secondary to making actions potentials more difficult.^[88][75]

Glycine has a role in glutaminergic neurotransmission as the NMDA receptors (a subset of glutamate receptors) tend to be tetramers composed of two glycine-binding units (the GluN1 subunits) and glutamate-binding units (GluN2)^{[89][90][91][92]} with the GluN1 subunit having eight splice variants.^[93] On the GluN1 receptors both glycine (D-serine may be used as well) and glutamate are required to induce signalling, which causes these glutamate receptors to be known as 'glycine dependent' and glycine as a 'coagonist'.^[94][95]

100μM or higher (30μM ineffective) appears to potentiate NDMA signalling and appears to be concentration-dependently increased up until 1,000μM,^[96] which is thought to be due to how glycine binding sites are unsaturated^[97] due to efficient buffering systems.^[98]

The hippocampus appears to express functional glycine receptors (glycinergic system) with inhibitory effects on neuronal excitation^[99][100] and are mostly located extrasynaptically^[101] yet colocalized with synapsin.^[102] Hippocampal cells can also release glycine upon neuronal activation^{[103][104][86]} and glycine appears to be stored in the presynapse of these neurons alongside glutamate,^[85] most glycine (according to immunohistology) appears to be stored presynaptically and most clusters of glycine observed (84.3+/-2.8%) were facing NMDA glutaminergic receptors.^[85]

Glycine is involved in signalling through the hippocampus, and it seems that both the glycinergic and the glutaminergic systems can be involved here

Intracerebroventricular injections of glycine to rats are able to induce bioenergetic dysfunction^[105][106] secondary to acting through the NDMA receptors and causing oxidative changes^[105] which then negatively influence various enzymes such as citrate synthase and Na⁺/K⁺ ATP synthase as well as impairing the electron transport chain at multiple complexes.^[105][106] Similar observations have been found with injections if D-serine^[107] and isovaleric acid^[108] which are protected against by glutamine receptor antagonists,^[105] antioxidants,^[105] or creatine.^[108]

800mg/kg of glycine daily for six weeks in persons with schizophrenia on stable antipsychotic therapy noted that supplementation was associated with a 23+/-8% reduction in negative symptoms and a lesser but also therapeutic effect on cognitive and positive symptoms.^[109]

A case study exists where an individual with both OCD and body dysmorphic disorder that, over the course of five years, had a significant reduction in symptoms when taking 800mg/kg glycine daily^[110] which is the dose used in schizophrenia trials; the authors hypothesized that his symptoms were related to insufficient NDMA receptor signalling, and benefits manifested within 34 days.^[110]

In female participants given 3g of glycine an hour prior to sleep, supplementation appears to reduce fatigue in the morning and improve self-reported sleep quality more than placebo.^[111] Later, 3g of glycine was tested in otherwise healthy persons reporting dissatisfaction with their sleep who were then subject to an EEG via polysomnography; it was reported that glycine improved subjective sleep quality associated with shortened sleep latency and time to reach slow wave sleep (REM sleep and overall sleep architecture not affected).^[112] This latter study also confirmed improved cognitive day-time performance associated with better self-reported sleep^[112] and has been replicated where 3g of glycine taken an hour before sleep (in persons with mildly impaired sleep) was able to reduce fatigue the next day but that after three days this was no longer significant, whereas performance tasks (psychomotor vigilence) were consistently improved.^[113]

Low doses of glycine supplementation appear to benefit the subjective sensation of a good night's sleep associated with reduced sleep latency (time taken to fall alseep) and improved performance the next day, and the subjective sensation lasts for only about one day whereas performance benefits persist

Cardiomyocytes express glycine-gated chloride channels and the administration of glycine (500 mg/kg intraperitoneal) was shown to significantly reduce the infarct size by 21% when rats were 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.^[114]

Glycine has been noted to blunt platelet aggregation in vitro (1-10 mM) in a dose-dependent manner and double bleeding time in rats fed a diet containing 2.5–5% glycine.^[115]

Plasma glycine concentrations have been significantly associated with an 11% reduced risk of suffering a heart attack in a cohort of 4109 adults from Norway over a 7.4-year follow-up.^[116] The inverse associations between glycine and suffering a heart attack were stronger among patients with serum apoB, LDL cholesterol, or apoA‐1 levels above the cohort average.

Glycine can be methylated into sarcosine via glycine N-methyltransferase (GNMT), which is mainly confined to the liver and kidney,^[117] but also present in aortic edothelial cells.^[118] Genetic deletion of GNMT in mice has been reported to exacerbate the development of atherosclerosic lesions, dyslipidemia, and inflammation, impair reverse cholesterol transport, and increase the accumulation of oxidized LDL particles and foam cells.^[118]

Several studies have reported significant associations between higher serum glycine concentrations and greater insulin sensitivity in primarily European and American adults without diabetes. Insulin sensitivity was assessed with the use of a hyperinsulinemic-euglycemic clamp,^[119][120] the HOMA-index,^{[121][122][123]} an oral glucose tolerance test (OGTT),^[124] and an insulin suppression test.^[125]

However, changes in serum glycine concentrations are likely a side-effect of developing insulin resistance rather than being a causative factor. Two Mendelian randomization studies of European adults reported no significant association between insulin sensitivity and genetically determined serum glycine concentrations.^[126][127] Both studies investigated SNP rs715 at the CPS1 gene in European cohorts. One study assessed insulin sensitivity with both the hyperinsulinemic-euglycemic clamp and insulin suppression test,^[126] while the other used the HOMA-index.^[127]

Additionally, three months of insulin sensitizer therapy (45 mg of pioglitazone per day plus 1 g of metformin twice per day) in obese adults with prediabetes or type II diabetes resulted in significant increases in serum glycine concentrations compared to placebo.^[128]

Finally, a master’s degree thesis project involving 10 obese adults (aged 42-58 years) with one or more criteria of metabolic syndrome reported that consuming 5 grams of glycine with each of three meals (15 g/d) for four weeks did not significantly affect HOMA-IR or the Matsuda-index.^[129]

Low serum glycine levels are associated with insulin resistance. However, Mendelian randomization studies and controlled trials suggest that low glycine levels are caused by insulin resistance rather than being causative in its development.

Serum glycine levels have been associated with a lower 2-hour postprandial glucose level following an oral glucose tolerance test in adults with normal and impaired glucose tolerance.^[130] Additionally, a clinical trial involving eight elderly adults (60-75 years) reported significant reductions in fasting glucose (12%; from 106 to 94 mg/dL) after two weeks of supplementing with 100 mg/kg glycine (8 g/d) and 100 mg/kg cysteine (as NAC).^[131]

A small study involving nine healthy adults reported that consuming 75 mg of glycine per kg fat-free mass (3.6-5.4 grams) with 25 grams of glucose significantly reduced peak glucose by 15% (105 vs 124 mg/dL) and the total glucose response over two hours by 50% compared to glucose alone.^[60] The total insulin response was not different between conditions, although the insulin peak tended to be lower and slightly delayed. Consuming glycine alone significantly, but modestly, increased insulin levels compared to water, and marginally reduced blood glucose.

Similar observations were made in a follow-up study by the same lab when glycine was combined with 130 mg of leucine per kg fat-free mass (5.3-8.7 grams).^[132] That is, glycine plus leucine consumed with 25 grams of glucose reduced peak glucose by 11% (111 vs 125 mg/dL) and the total glucose response over two hours by 66% compared to glucose alone. This time, however, the total insulin response was significantly increased by 24% with no changes to peak insulin. Consuming glycine plus leucine alone significantly, but modestly, increased insulin levels compared to water, and marginally reduced blood glucose.

The benefits of glycine for reducing postprandial glucose levels may be owed to greater insulin secretion. Glycine has been reported to increase the release of glucagon-like peptide 1 (GLP-1),^[133] which potentiates glucose-mediated insulin secretion. Glycine has also been reported to significantly increase the insulin response to hyperglycemia during a hyperglycemic clamp when 5 grams is consumed 30 minutes beforehand.^[134]

Modest doses of glycine (3-5 grams) taken with meals appears to reduce the postprandial glucose response, possibly due to a potentiation of the insulin response via GLP-1.

In a rat model of type II diabetes, glycine supplementation was shown to significantly reduce HbA1c, advanced glycation end-product (AGE) concentrations in both the serum and the lens of the eye, and cataract severity.^[135] Glycine has been reported in vitro to reduce glycation of human lens proteins.^[136][137]

Glycine reduces HbA1c and glycation of the eye lens in animal models of type II diabetes.

People with type II diabetes have significantly higher levels of urinary glycine excretion^[138] and lower levels of serum glycine concentrations^[139] than healthy controls. Higher serum glycine concentrations are associated with a reduced risk of developing type II diabetes,^[140] even after adjustment for lifestyle factors and metabolic syndrome criteria.^[124]

A study involving 12 adults with uncontrolled diabetes reported significantly lower levels of red blood cell glycine concentrations than healthy controls (-22%), which was restored with daily supplementation of 100 mg glycine per kg body weight for 14 days.^[141] However, there were no significant effects on fasting glucose or HbA1c. It may have been that two weeks was too short of a period to observe glycemic benefits.

In contrast, a double-blind, randomized controlled trial involving 74 men and women with type II diabetes reported that supplementation with 5 g glycine per meal (15 g/d) for three months resulted in significant reductions in HbA1c compared to placebo (absolute change of -1.4% vs -0.4%), as well as nearly significant reductions in fasting glucose (-23% vs -10%) and HOMA-IR (-9% vs -2%).^[142]

Supplementation with 5 grams of glycine per meal (15 g/d) for three months has been reported to benefit glycemic control in patients with type II diabetes.

A single 22.5g bolus of glycine has been reported to significantly increase growth hormone concentrations for up to 180 minutes after ingestion in healthy men and women.^[143] The maximal increase was reported to be a 3.6-fold increase above basal levels at 90 minutes, with a significant elevation of 60% still present after 180 minutes. The increase in growth hormone had a rapid onset, with a 60% increase observed within five minutes of ingesting glycine.

Glycine has its glycinergic receptors expressed on pancreatic α-cells (those that mediate some endocrine responses such as glucagon regulation^[144]), and appears to stimulate glucagon release when it acts upon these cells with a threshold of 300-400μM and maximal stimulation at 1.2mM reaching four-fold secretion.^[145]

Glycine does not interact with insulin secretion in vitro.^[145]

Glycine is sometimes bound to minerals such as zinc or magnesium as a 'diglycinate' chelation, which enables the minerals to be absorbed via peptide transporters in an intact form^[146][147] which tends to lead to enhanced absorption relative to the free form of the mineral in the upper intestine.^[148] Although absorption via peptide transporters can extend to most amino acids, diglycine tends to be absorbed rather than hydrolyzed^[149] which makes it an efficient carrier. Triglycine works as well, although four glycine molecules gets hydrolyzed into two diglycine molecules.^[150]

Additionally, due to glycine being the smallest amino acid the overall molecular weight of supplements is lower when glycine is used as a chelation relative to heavier amino acids.^[151]

Two glycine molecules in a dipeptide form (Diglycinate) are sometimes used as a way to enhance the absorption of mineral supplementation since, only when bound to a dipeptide, can be absorbed through a different set of transporters