L‐serine: a neglected amino acid with a potential therapeutic role in diabetes

Holm, Laurits J.; Buschard, Karsten

doi:10.1111/apm.12987

Cited by 53 publications

(46 citation statements)

References 43 publications

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“…37 Serine is synthesized by glycine activity, and it is possible that depressed levels in those with higher diabetes risk are reflective of depressed glycine levels and the consequent metabolic imbalances. 41 Enzymes involved in serine biosynthesis have been linked to insulin signaling and sensitivity in animal studies, while a lack of serine in cancer cells results in altered mitochondrial metabolism akin to metabolic disturbances resulting in insulin resistance. 41 Further research into the roles of ornithine, proline and serine in diabetes development is required to clarify these inconsistencies and whether these species contribute to or merely indicate higher diabetes risk.…”

Section: Discussionmentioning

confidence: 99%

Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population

Gunther

Khoo

Tai

et al. 2020

BMJ Open Diab Res Care

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IntroductionWe evaluated whether concentrations of serum acylcarnitines and amino acids are associated with risk of type 2 diabetes and can improve predictive diabetes models in an Asian population.Research design and methodsWe used data from 3313 male and female participants from the Singapore Prospective Study Program cohort who were diabetes-free at baseline. The average age at baseline was 48.0 years (SD: 11.9 years), and participants were of Chinese, Malay, and Indian ethnicity. Diabetes cases were identified through self-reported physician diagnosis, fasting glucose and glycated hemoglobin concentrations, and linkage to national disease registries. We measured fasting serum concentrations of 45 acylcarnitines and 14 amino acids. The association between metabolites and incident diabetes was modeled using Cox proportional hazards regression with adjustment for age, sex, ethnicity, height, and parental history of diabetes, and correction for multiple testing. Metabolites were added to the Atherosclerosis Risk in Communities (ARIC) predictive diabetes risk model to assess whether they could increase the area under the receiver operating characteristic curve (AUC).ResultsParticipants were followed up for an average of 8.4 years (SD: 2.1 years), during which time 314 developed diabetes. Branched-chain amino acids (HR: 1.477 per SD; 95% CI 1.325 to 1.647) and the alanine to glycine ratio (HR: 1.572; 95% CI 1.426 to 1.733) were most strongly associated with diabetes risk. Additionally, the acylcarnitines C4 and C16-OH, and the amino acids alanine, combined glutamate/glutamine, ornithine, phenylalanine, proline, and tyrosine were significantly associated with higher diabetes risk, and the acylcarnitine C8-DC and amino acids glycine and serine with lower risk. Adding selected metabolites to the ARIC model resulted in a significant increase in AUC from 0.836 to 0.846.ConclusionsWe identified acylcarnitines and amino acids associated with risk of type 2 diabetes in an Asian population. A subset of these modestly improved the prediction of diabetes when added to an established diabetes risk model.

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Section: Discussionmentioning

confidence: 99%

Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population

Gunther

Khoo

Tai

et al. 2020

BMJ Open Diab Res Care

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“…Contrarily, serine supplementation is being explored as a potential therapy. Exogenous supplementation has proven to be effective in many cases reducing oxidative stress and reducing cytokine levels, but endogenous synthesis (as discussed above) augments the inflammatory response [77]. Therefore, balancing the anti-oxidant effects of serine with the pro-inflammatory nature of its endogenous synthesis is something to consider when developing a serine-based therapy for retinopathies in which inflammation contributes to the pathogenesis.…”

Section: Serine Is An Anti-oxidant and Mediator Of Inflammationmentioning

confidence: 99%

“…Studies have demonstrated a correlation between serine deficiency and systemic diabetes [77]. Inflammation potentially increases the expression and activity of SRR, and consequently increases the availability of D-serine for receptor binding [40].…”

Section: Diabetic Retinopathymentioning

confidence: 99%

“…In SRR null models with streptozocin (STZ) induced DR, degeneration of RGCs appeared attenuated, there was a reduction in neovascularization and the retina appeared significantly healthier than the control [40]. Most interestingly, multiple studies have found that if diabetic patients are treated with a serine supplement, blood glucose levels were reduced [77,82]. Currently, no mechanism is known to explain how this happens.…”

Section: Diabetic Retinopathymentioning

confidence: 99%

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The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

Sinha

Ikelle

Naash

et al. 2020

Cells

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In the past, the importance of serine to pathologic or physiologic anomalies was inadequately addressed. Omics research has significantly advanced in the last two decades, and metabolomic data of various tissues has finally brought serine metabolism to the forefront of metabolic research, primarily for its varied role throughout the central nervous system. The retina is one of the most complex neuronal tissues with a multitude of functions. Although recent studies have highlighted the importance of free serine and its derivatives to retinal homeostasis, currently few reviews exist that comprehensively analyze the topic. Here, we address this gap by emphasizing how and why the de novo production and demand for serine is exceptionally elevated in the retina. Many basic physiological functions of the retina require serine. Serine-derived sphingolipids and phosphatidylserine for phagocytosis by the retinal pigment epithelium (RPE) and neuronal crosstalk of the inner retina via D-serine require proper serine metabolism. Moreover, serine is involved in sphingolipid–ceramide balance for both the outer retina and the RPE and the reductive currency generation for the RPE via serine biosynthesis. Finally and perhaps the most vital part of serine metabolism is free radical scavenging in the entire retina via serine-derived scavengers like glycine and GSH. It is hard to imagine that a single tissue could have such a broad and extensive dependency on serine homeostasis. Any dysregulation in serine mechanisms can result in a wide spectrum of retinopathies. Therefore, most critically, this review provides a strong argument for the exploration of serine-based clinical interventions for retinal pathologies.

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“…Decreased plasma serine concentrations have been reported in both T1DM [17,41] and T2DM [42]. It has been suggested that serine depletion plays a role in the development of diabetes mellitus and its related complications, and that L-serine should be considered as an emerging therapeutic option in diabetes [43].…”

Section: Decreases In Serine Concentrationmentioning

confidence: 99%

Dual Effects of Beta-Hydroxy-Beta-Methylbutyrate (HMB) on Amino Acid, Energy, and Protein Metabolism in the Liver and Muscles of Rats with Streptozotocin-Induced Type 1 Diabetes

2020

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Beta-hydroxy-beta-methyl butyrate (HMB) is a unique product of leucine catabolism with positive effects on protein balance. We have examined the effects of HMB (200 mg/kg/day via osmotic pump for 7 days) on rats with diabetes induced by streptozotocin (STZ, 100 mg/kg intraperitoneally). STZ induced severe diabetes associated with muscle wasting, decreased ATP in the liver, and increased α-ketoglutarate in muscles. In plasma, liver, and muscles increased branched-chain amino acids (BCAAs; valine, isoleucine, and leucine) and decreased serine. The decreases in mass and protein content of muscles and increases in BCAA concentration were more pronounced in extensor digitorum longus (fast-twitch muscle) than in soleus muscle (slow-twitch muscle). HMB infusion to STZ-treated animals increased glycemia and serine in the liver, decreased BCAAs in plasma and muscles, and decreased ATP in the liver and muscles. The effects of HMB on the weight and protein content of tissues were nonsignificant. We concluded that fast-twitch muscles are more sensitive to STZ than slow-twitch muscles and that HMB administration to STZ-treated rats has dual effects. Adjustments of BCAA concentrations in plasma and muscles and serine in the liver can be considered beneficial, whereas the increased glycemia and decreased ATP concentrations in the liver and muscles are detrimental.

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L‐serine: a neglected amino acid with a potential therapeutic role in diabetes

Cited by 53 publications

References 43 publications

Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population

Serum acylcarnitines and amino acids and risk of type 2 diabetes in a multiethnic Asian population

The Intersection of Serine Metabolism and Cellular Dysfunction in Retinal Degeneration

Dual Effects of Beta-Hydroxy-Beta-Methylbutyrate (HMB) on Amino Acid, Energy, and Protein Metabolism in the Liver and Muscles of Rats with Streptozotocin-Induced Type 1 Diabetes

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