Glycine

1.1. Sources

Glycine is a dietary amino acid that serves as both a constitutional amino acid (used to create protein structures such as enzymes) and as a neurotransmitter/neuromodulator. It is the major inhibitory neurotransmitter in the spinal cord and most glycine in neurons is synthesized de novo from serine in a process requiring folic acid.^[1] Some evidence suggests that glycine may be a conditionally essential amino acid for humans.^[2][3]

1.2. Structure

Glycine is known to be the smallest amino acid with a molar mass of 75.07g,^[4] beating out alanine (89.09g). Its low molar mass is a result of its simplistic structure:

1.3. Comparisons to other Glycinergics

D-Serine is an amino acid that is mechanistically similar to glycine in the sense that it can act on the glycine binding sites of NMDA receptors with similar potency^[5][6][7] but differs as it cannot be transported by glycine transporters due to differences in size.^[8] Possibly due to differences in transportation, D-serine is more effective at enhancing glutaminergic signalling through NMDA receptors as 1μM causes a 52+/-16% increase (further increases at 10-30μM) while 100μM of glycine is required for approximately 40% (further increases at 300-1,000μM).^[9]

D-Serine is another molecule that acts on the same receptor classes that glycine can, but appears to be practically more potent since it is cleared from the receptors at a lower rate

2.1. Kinetics

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^[10][11] as its inhibition can potentiate NDMA signalling (by increasing synaptic levels of glycine)^[12] and may also be taken up by a second transporter known as GlyT2.^[11] 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.^[13][14]

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

2.2. Glycinergic Neurotransmission

Glycine itself is a neurotransmitter with its own signalling system (similar to GABA or Agmatine).^[15] This system is inhibitory and works alongside the GABAergic system, although in the auditory brainstem^[16][17] and hypoglossal nucleus^[18] there appears to be a developmental shift towards favoring glycinergic inhibition, and glycinergic neurotransmission has been shown to have relevance in the thalamus,^[19] cerebellum,^[20] and hippocampus.^[21][22] This system and its receptors are blocked by the research drug Strychnine^[23] and when glycine activates its receptors the resulting influx of chloride (Cl^-) ions causes an inhibitory effect secondary to making actions potentials more difficult.^[24][11]

2.3. Glutaminergic Neurotransmission

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)^{[25][26][27][28]} with the GluN1 subunit having eight splice variants.^[29] 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'.^[30][31]

100μM or higher (30μM ineffective) appears to potentiate NDMA signalling and appears to be concentration-dependently increased up until 1,000μM,^[9] which is thought to be due to how glycine binding sites are unsaturated^[32] due to efficient buffering systems.^[33]

2.4. Memory and Learning

The hippocampus appears to express functional glycine receptors (glycinergic system) with inhibitory effects on neuronal excitation^[34][35] and are mostly located extrasynaptically^[36] yet colocalized with synapsin.^[37] Hippocampal cells can also release glycine upon neuronal activation^[38][39][22] and glycine appears to be stored in the presynapse of these neurons alongside glutamate,^[21] 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.^[21]

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

2.5. Bioenergetics

Intracerebroventricular injections of glycine to rats are able to induce bioenergetic dysfunction^[40][41] secondary to acting through the NDMA receptors and causing oxidative changes^[40] 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.^[40][41] Similar observations have been found with injections if D-serine^[42] and isovaleric acid^[43] which are protected against by glutamine receptor antagonists,^[40] antioxidants,^[40] or creatine.^[43]

2.6. Schizophrenia

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.^[44]

2.7. Obsession

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^[45] 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.^[45]

2.8. Sleep and Sedation

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.^[46] 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).^[47] This latter study also confirmed improved cognitive day-time performance associated with better self-reported sleep^[47] 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.^[48]

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

3.1. Cardiac Function

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.^[49]

3.2. Hemodynamics

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.^[50]

3.3. Cardiovascular Disease Risk

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.^[51] 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,^[52] but also present in aortic edothelial cells.^[53] 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.^[53]

4.1. Blood Glucose and Insulin

In a randomized crossover design, nine healthy men and women consumed water 75mg/kg bodyweight of glycine (3.6-5.4 grams) alone, 25g glucose alone, or glycine and glucose combined after a 12-hour overnight fast.^[54] Glycine alone had no effect on blood glucose compared to water, but significantly, albeit modestly, increased insulin concentrations. Compared to glucose alone, the combination of glycine plus glucose significantly lowered the peak glucose response by about 15% and the total glucose response by about 50%. However, the insulin response was similar between the glucose and glucose plus glycine conditions.

Glycine has a potent hypoglycemic effect in healthy adults that appears to be independent of insulin.

4.2. Type II Diabetes

Supplementation with 15 g/d of glycine for three months was reported to significantly reduce HbA1c compared to placebo in patients with type II diabetes who had a baseline HbA1c of 8.2% (absolute reductions of 1.4% vs 0.4%).^[55] This was associated with nearly significantly greater reductions in HOMA-IR (-10% vs -2%) and fasting blood glucose (-30% vs -12%).

5.1. Growth Hormones

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.^[56] 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.

6.1. Pancreas

Glycine has its glycinergic receptors expressed on pancreatic α-cells (those that mediate some endocrine responses such as glucagon regulation^[57]), 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.^[58]

Glycine does not interact with insulin secretion in vitro.^[58]

7.1. Minerals

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^[59][60] which tends to lead to enhanced absorption relative to the free form of the mineral in the upper intestine.^[61] Although absorption via peptide transporters can extend to most amino acids, diglycine tends to be absorbed rather than hydrolyzed^[62] which makes it an efficient carrier. Triglycine works as well, although four glycine molecules gets hydrolyzed into two diglycine molecules.^[63]

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.^[4]

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