Developmental Effects of (Pre-)Gestational Diabetes on Offspring: Systematic Screening Using Omics Approaches.
Shashikadze Bachuki,Flenkenthaler Florian,Stöckl Jan B,Valla Libera,Renner Simone,Kemter Elisabeth,Wolf Eckhard,Fröhlich Thomas
Worldwide, gestational diabetes affects 2-25% of pregnancies. Due to related disturbances of the maternal metabolism during the periconceptional period and pregnancy, children bear an increased risk for future diseases. It is well known that an aberrant intrauterine environment caused by elevated maternal glucose levels is related to elevated risks for increased birth weights and metabolic disorders in later life, such as obesity or type 2 diabetes. The complexity of disturbances induced by maternal diabetes, with multiple underlying mechanisms, makes early diagnosis or prevention a challenging task. Omics technologies allowing holistic quantification of several classes of molecules from biological fluids, cells, or tissues are powerful tools to systematically investigate the effects of maternal diabetes on the offspring in an unbiased manner. Differentially abundant molecules or distinct molecular profiles may serve as diagnostic biomarkers, which may also support the development of preventive and therapeutic strategies. In this review, we summarize key findings from state-of-the-art Omics studies addressing the impact of maternal diabetes on offspring health.
Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance.
Petersen Max C,Madiraju Anila K,Gassaway Brandon M,Marcel Michael,Nasiri Ali R,Butrico Gina,Marcucci Melissa J,Zhang Dongyan,Abulizi Abudukadier,Zhang Xian-Man,Philbrick William,Hubbard Stevan R,Jurczak Michael J,Samuel Varman T,Rinehart Jesse,Shulman Gerald I
The Journal of clinical investigation
Nonalcoholic fatty liver disease (NAFLD) is a risk factor for type 2 diabetes (T2D), but whether NAFLD plays a causal role in the pathogenesis of T2D is uncertain. One proposed mechanism linking NAFLD to hepatic insulin resistance involves diacylglycerol-mediated (DAG-mediated) activation of protein kinase C-ε (PKCε) and the consequent inhibition of insulin receptor (INSR) kinase activity. However, the molecular mechanism underlying PKCε inhibition of INSR kinase activity is unknown. Here, we used mass spectrometry to identify the phosphorylation site Thr1160 as a PKCε substrate in the functionally critical INSR kinase activation loop. We hypothesized that Thr1160 phosphorylation impairs INSR kinase activity by destabilizing the active configuration of the INSR kinase, and our results confirmed this prediction by demonstrating severely impaired INSR kinase activity in phosphomimetic T1160E mutants. Conversely, the INSR T1160A mutant was not inhibited by PKCε in vitro. Furthermore, mice with a threonine-to-alanine mutation at the homologous residue Thr1150 (InsrT1150A mice) were protected from high fat diet-induced hepatic insulin resistance. InsrT1150A mice also displayed increased insulin signaling, suppression of hepatic glucose production, and increased hepatic glycogen synthesis compared with WT controls during hyperinsulinemic clamp studies. These data reveal a critical pathophysiological role for INSR Thr1160 phosphorylation and provide further mechanistic links between PKCε and INSR in mediating NAFLD-induced hepatic insulin resistance.
Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2.
Copps K D,White M F
The insulin receptor substrate proteins IRS1 and IRS2 are key targets of the insulin receptor tyrosine kinase and are required for hormonal control of metabolism. Tissues from insulin-resistant and diabetic humans exhibit defects in IRS-dependent signalling, implicating their dysregulation in the initiation and progression of metabolic disease. However, IRS1 and IRS2 are regulated through a complex mechanism involving phosphorylation of >50 serine/threonine residues (S/T) within their long, unstructured tail regions. In cultured cells, insulin-stimulated kinases (including atypical PKC, AKT, SIK2, mTOR, S6K1, ERK1/2 and ROCK1) mediate feedback (autologous) S/T phosphorylation of IRS, with both positive and negative effects on insulin sensitivity. Additionally, insulin-independent (heterologous) kinases can phosphorylate IRS1/2 under basal conditions (AMPK, GSK3) or in response to sympathetic activation and lipid/inflammatory mediators, which are present at elevated levels in metabolic disease (GRK2, novel and conventional PKCs, JNK, IKKβ, mPLK). An emerging view is that the positive/negative regulation of IRS by autologous pathways is subverted/co-opted in disease by increased basal and other temporally inappropriate S/T phosphorylation. Compensatory hyperinsulinaemia may contribute strongly to this dysregulation. Here, we examine the links between altered patterns of IRS S/T phosphorylation and the emergence of insulin resistance and diabetes.
Impaired Amino Acid and TCA Metabolism and Cardiovascular Autonomic Neuropathy Progression in Type 1 Diabetes.
Mathew Anna V,Jaiswal Mamta,Ang Lynn,Michailidis George,Pennathur Subramaniam,Pop-Busui Rodica
While diabetes is characterized by hyperglycemia, nutrient metabolic pathways like amino acid and tricarboxylic acid (TCA) cycle are also profoundly perturbed. As glycemic control alone does not prevent complications, we hypothesized that these metabolic disruptions are responsible for the development and progression of diabetic cardiovascular autonomic neuropathy (CAN). We performed standardized cardiovascular autonomic reflex tests and targeted fasting plasma metabolomic analysis of amino acids and TCA cycle intermediates in subjects with type 1 diabetes and healthy control subjects followed for 3 years. Forty-seven participants with type 1 diabetes (60% female and mean ± SD age 35 ± 13 years, diabetes duration 13 ± 7 years, and HbA 7.9 ± 1.2%) had lower fumarate levels and higher threonine, serine, proline, asparagine, aspartic acid, phenylalanine, tyrosine, and histidine levels compared with 10 age-matched healthy control subjects. Higher baseline fumarate levels and lower baseline amino acid levels-asparagine and glutamine-correlate with CAN (lower baseline SD of normal R-R interval [SDNN]). Baseline glutamine and ornithine levels also associated with the progression of CAN (lower SDNN at 3 years) and change in SDNN, respectively, after adjustment for baseline HbA, blood glucose, BMI, cholesterol, urine microalbumin-to- creatinine ratio, estimated glomerular filtration rate, and years of diabetes. Therefore, significant changes in the anaplerotic flux into the TCA cycle could be the critical defect underlying CAN progression.
Association of plasma free amino acids with hyperuricemia in relation to diabetes mellitus, dyslipidemia, hypertension and metabolic syndrome.
Mahbub M H,Yamaguchi Natsu,Takahashi Hidekazu,Hase Ryosuke,Ishimaru Yasutaka,Sunagawa Hiroshi,Amano Hiroki,Kobayashi-Miura Mikiko,Kanda Hideyuki,Fujita Yasuyuki,Yamamoto Hiroshi,Yamamoto Mai,Kikuchi Shinya,Ikeda Atsuko,Kageyama Naoko,Nakamura Mina,Tanabe Tsuyoshi
Previous studies demonstrated independent contributions of plasma free amino acids (PFAAs) and high uric acid (UA) concentrations to increased risks of lifestyle-related diseases (LSRDs), but the important associations between these factors and LSRDs remain unknown. We quantified PFAAs and UA amongst Japanese subjects without LSRDs (no-LSRD, n = 2805), and with diabetes mellitus (DM, n = 415), dyslipidemia (n = 3207), hypertension (n = 2736) and metabolic syndrome (MetS, n = 717). The concentrations of most amino acids differed significantly between the subjects with and without hyperuricemia (HU) and also between the no-LSRD and LSRD groups (p < 0.05 to 0.001). After adjustment, the logistic regression analyses revealed that lysine in DM, alanine, proline and tyrosine in dyslipidemia, histidine, lysine and ornithine in hypertension, and lysine and tyrosine in MetS demonstrated significant positive associations with HU among the patients with LSRDs only (p < 0.05 to 0.005). By contrast, arginine, asparagine and threonine showed significant inverse associations with HU in the no-LSRD group only (p < 0.05 to 0.01). For the first time, we provide evidence for distinct patterns of association between PFAAs and HU in LSRDs, and postulate the possibility of interplay between PFAAs and UA in their pathophysiology.
Human umbilical vein endothelium-derived exosomes play a role in foetoplacental endothelial dysfunction in gestational diabetes mellitus.
Sáez Tamara,Salsoso Rocío,Leiva Andrea,Toledo Fernando,de Vos Paul,Faas Marijke,Sobrevia Luis
Biochimica et biophysica acta. Molecular basis of disease
Gestational diabetes mellitus (GDM) characterizes by foetoplacental endothelial dysfunction. Human umbilical vein endothelial cells (HUVECs) from women with GDM show increased L-arginine transport via the human cationic amino acid transporter 1 (hCAT-1). Moreover, expression of endothelial nitric oxide synthase (eNOS) and nitric oxide synthesis are increased. Exosomes are increased in maternal plasma from GDM. We evaluated the role of foetoplacental endothelial exosomes on endothelial dysfunction in GDM. Exosomes were isolated from HUVECs from normal (Ex) and GDM (Ex) pregnancies. HUVECs were exposed (8h) to Ex or Ex and used for wound recovery assay (up to 8h), L-arginine transport, hCAT-1 and eNOS expression and activity, reactive oxygen species (ROS) generation, and 44 and 42kDa mitogen activated protein kinases (p44/42) and protein kinase B/Akt (Akt) activation. Wound recovery was slower in GDM compared with normal pregnancies and was recovered by Ex. However, Ex delayed wound recovery in cells from normal pregnancies. GDM-increased L-arginine transport, hCAT-1 and eNOS expression and activity, and p44/42 activation were blocked by Ex, but Ex increased these parameters and ROS generation, and reduced eNOS phosphorylation at threonine in cells from normal pregnancies. Inhibition of p44/42, but not Akt reversed GDM-increased L-arginine uptake. In conclusion foetoplacental endothelial-released exosomes play a role in the maintenance of a GDM phenotype in HUVECs. It is suggested that Ex and Ex cargo are different with differential effects in cells from normal or GDM pregnancies. This phenomenon could contribute to the understanding of mechanisms behind foetoplacental endothelial dysfunction in GDM pregnancies.
First trimester metabolomics 1H-NMR study of the urinary profile predicts gestational diabetes mellitus development in obese women.
The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians
OBJECTIVE:Obesity is one of the main risk factors for the development gestational diabetes mellitus (GDM). Thus, we aim to identify changes in the urinary metabolomics profile of obese women at first trimester of pregnancy in order to predict later GDM diagnosis. RESEARCH DESIGN AND METHODS:In this nested case-control study, urine samples collected in the first trimester of pregnancy obtained from obese women who developed GDM ( = 29) and obese women who did not develop diabetes ( = 25 NO GDM) were analyzed with Nuclear Magnetic Resonance spectroscopy combined with Multivariate Statistical Analysis. GDM diagnosis was obtained with one-step oral glucose load. RESULTS:OPLS-DA significantly separated the GDM women from NO GDM women. Specifically, GDM women were characterized by a higher level of tryptophan, trigonelline, hippurate, and threonine, and lower levels of 1-methylnicotinamide, 3-hydroxykynurenine, glycocholate, isoleucine, kynurenine, and valine compared to NO GDM women. CONCLUSION:In a prevalently Caucasian population, the changes of some metabolites such as tryptophan, trigonelline, and branch-chained amino acids in the urinary profile of obese women in the first trimester are able to make unequivocal prediction of those which later test positive for GDM. This approach could be useful to diagnose much earlier obese women with GDM allowing lifestyle counselling and other interventions.
Global metabolomic profiling reveals hepatic biosignatures that reflect the unique metabolic needs of late-term mother and fetus.
Saini Nipun,Virdee Manjot,Helfrich Kaylee K,Kwan Sze Ting Cecilia,Smith Susan M
Metabolomics : Official journal of the Metabolomic Society
OBJECTIVE:Gestational disorders including preeclampsia, growth restriction and diabetes are characterized, in part, by altered metabolic interactions between mother and fetus. Understanding their functional relevance requires metabolic characterization under normotypic conditions. METHODS:We performed untargeted metabolomics on livers of pregnant, late-term C57Bl/6J mice (N = 9 dams) and their fetuses (pooling 4 fetuses/litter), using UPLC-MS/MS. RESULTS:Multivariate analysis of 730 hepatic metabolites revealed that maternal and fetal metabolite profiles were highly compartmentalized, and were significantly more similar within fetuses (ρ = 0.81), or within dams (ρ = 0.79), than within each maternal-fetal dyad (ρ = - 0.76), suggesting that fetal hepatic metabolism is under distinct and equally tight metabolic control compared with its respective dam. The metabolite profiles were consistent with known differences in maternal-fetal metabolism. The reduced fetal glucose reflected its limited capacity for gluconeogenesis and dependence upon maternal plasma glucose pools. The fetal decreases in essential amino acids and elevations in their alpha-keto acid carnitine conjugates reflects their importance as secondary fuel sources to meet fetal energy demands. Whereas, contrasting elevations in fetal serine, glycine, aspartate, and glutamate reflects their contributions to endogenous nucleotide synthesis and fetal growth. Finally, the elevated maternal hepatic lipids and glycerol were consistent with a catabolic state that spares glucose to meet competing maternal-fetal energy demands. CONCLUSIONS:The metabolite profile of the late-term mouse dam and fetus is consistent with prior, non-rodent analyses utilizing plasma and urine. These data position mouse as a suitable model for mechanistic investigation into how maternal-fetal metabolism adapts (or not) to gestational stressors.
A serine/alanine polymorphism in the nucleotide-binding fold-2 of the sulphonylurea receptor-1 (S1369A) is associated with enhanced glucose-induced insulin secretion during pregnancy.
Krugluger W,Festa A,Shnawa N,Bucher J,Boltz-Nitulescu G,Schernthaner G,Hopmeier P
Journal of inherited metabolic disease
The sulphonylurea receptor-1 (SUR-1) regulates glucose-induced insulin secretion by controlling K+-ATP channel activity of the pancreatic beta-cell membrane. In this study, we investigated the putative role of a T/G-polymorphism (exon 33, codon 1369; S1369A) in the adenosine diphosphate-sensing nucleotide-binding fold-2 (NBF-2) of the SUR-1 on glucose-induced insulin secretion during an oral glucose tolerance test in pregnant women (PW; n=182). Compared to PW with the T/T genotype, statistically significant elevated C-peptide concentrations were found 60 min after glucose intake in PW with the T/G and G/G genotype (T/T 9.0+/-0.4 ng/ml vs T/G 10.8+/-0.4 ng/ml or G/G 10.8+/-0.7 ng/ml, p=0.01). Furthermore, compared to PW with T/T genotype the deltaC-peptide (60/0 min) was significantly enhanced in PW with T/G or G/G genotype (T/T 6.7+/-0.3 vs T/G 8.9+/-0.4 or G/G 8.9+/-0.7, p=0.0009). A significant correlation of C-peptide concentrations with blood glucose (BG) 60 min after glucose intake was only found in PW with the T/T genotype (r=0.6, p<0.0004). Similarly, a significant correlation of insulin concentrations with BG 60 min after glucose intake was observed in PW with T/T genotype (r=0.5, p<0.0001) and T/G genotype (r=0.24, p<0.03) but not in PW with G/G genotype (r=0.01, p=0.9). From our data we conclude that in PW with the alanine substitution in the NBF-2 region, the insulin response of the pancreatic beta-cell after glucose intake is enhanced and does not correlate with actual BG levels.
Physiologic and molecular alterations in carbohydrate metabolism during pregnancy and gestational diabetes mellitus.
Yamashita H,Shao J,Friedman J E
Clinical obstetrics and gynecology
Recent progress suggests that postreceptor mechanisms that contribute to insulin resistance of pregnancy appear to be multifactorial, but are exerted at the beta-subunit of the insulin receptor and at the level of IRS-1. Gestational diabetes mellitus represents the combination of acquired and intrinsic abnormalities of insulin action. The resistance to insulin-mediated glucose transport appears to be greater in skeletal muscle from GDM subjects than from pregnancy alone. There is also a modest but significant decrease in maximal insulin receptor tyrosine phosphorylation in muscle from obese GDM subjects. Results also suggest that increased insulin receptor serine/threonine phosphorylation and PC-1 could underlie the insulin resistance of pregnancy and pathogenesis of GDM. Whether additional defects are exerted further downstream from IRS-1 remains to be investigated.
Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM.
Shao J,Catalano P M,Yamashita H,Ruyter I,Smith S,Youngren J,Friedman J E
The cellular mechanisms for the insulin resistance of pregnancy and gestational diabetes mellitus (GDM) are unknown. The membrane protein plasma cell membrane glycoprotein-1 (PC-1) has been identified as an inhibitor of insulin receptor tyrosine kinase (IRTK) activity. We investigated insulin receptor function and PC-1 levels in muscle from three groups of obese subjects: women with GDM, pregnant women with normal glucose tolerance, and nonpregnant control subjects. Subjects (n = 6 for each group) were similar in age and degree of obesity (body fat >30%). IRTK activity, insulin receptor tyrosine phosphorylation, and protein levels of membrane glycoprotein PC-1 were determined in rectus abdominus muscle biopsies obtained at the time of either elective cesarean section or gynecological surgery. No significant differences were evident in basal insulin receptor tyrosine phosphorylation or IRTK activity in the three groups. After maximal insulin (10(-7) mol/l) stimulation, IRTK activity measured with the artificial substrate poly(Glu,Tyr) increased in all subjects but was lower in women with GDM by 25% (P < 0.05) and 39% (P < 0.001) compared with pregnant and nonpregnant control subjects, respectively. Similarly, insulin receptor tyrosine phosphorylation was significantly decreased in subjects with GDM (P < 0.05) compared with pregnant and nonpregnant control subjects. Treatment of the insulin receptors with alkaline phosphatase to dephosphorylate serine/threonine residues increased insulin-stimulated IRTK activity significantly in pregnant control and GDM subjects (P < 0.05), but these rates were still lower compared with nonpregnant control subjects (P < 0.05). PC-1 content in muscle from GDM subjects was increased by 63% compared with pregnant control subjects (P < 0.05) and by 206% compared with nonpregnant control subjects (P < 0.001). PC-1 content was negatively correlated with insulin receptor phosphorylation (r = -0.55, P < 0.05) and IRTK activity (r = -0.66, P < 0.05). These results indicate that pregnant control and GDM subjects had increased PC-1 content and suggest excessive phosphorylation of serine/threonine residues in muscle insulin receptors and that both may contribute to decreased IRTK activity. These changes worsen in women with GDM when controlling for obesity. These postreceptor defects in insulin signaling may contribute to the pathogenesis of GDM and the increased risk for type 2 diabetes later in life.
Metabolic dysfunction in pregnancy: Fingerprinting the maternal metabolome using proton nuclear magnetic resonance spectroscopy.
Scott Hannah D,Buchan Marrissa,Chadwick Caylin,Field Catherine J,Letourneau Nicole,Montina Tony,Leung Brenda M Y,Metz Gerlinde A S
Endocrinology, diabetes & metabolism
Aims:Maternal metabolic disorders place the mother at risk for negative pregnancy outcomes with potentially long-term health impacts for the child. Metabolic syndrome, a cluster of features associated with increased risk of metabolic disorders, such as cardiovascular disease, diabetes and stroke, affects roughly one in five Canadians. Metabolomics is a relatively new technique that may be a useful tool to identify women at risk of metabolic disorders. This study set out to characterize urinary metabolic biomarkers of pregnant women with obesity and of pregnant women who later developed gestational diabetes mellitus (pre-GDM), compared to controls. Methods and Materials:Second trimester urine samples were collected through the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort and examined with H nuclear magnetic resonance (NMR) spectroscopy. Multivariate analysis was used to examine group differences, and machine learning feature selection tools identified the metabolites contributing to separation. Results:Obesity and pre-GDM metabolomes were distinct from controls and from each other. In each comparison, the glycine, serine and threonine pathways were the most impacted. Pantothenate, formic acid and glycine were downregulated by obesity, while formic acid, dimethylamine and galactose were downregulated in pre-GDM. The three most impacted metabolites for the comparison of obesity versus pre-GDM groups were upregulated creatine/caffeine, downregulated sarcosine/dimethylamine and upregulated maltose/sucrose in individuals who later developed GDM. Conclusion:These findings suggest a role for urinary metabolomics in the prediction of GDM and metabolic marker identification for potential diagnostics and prognostics in women at risk.
Maternal Early Pregnancy Serum Metabolites and Risk of Gestational Diabetes Mellitus.
Enquobahrie Daniel A,Denis Marie,Tadesse Mahlet G,Gelaye Bizu,Ressom Habtom W,Williams Michelle A
The Journal of clinical endocrinology and metabolism
CONTEXT:Significant gaps remain in the understanding of genetic and environmental risk factors, as well as related mechanisms that contribute to gestational diabetes mellitus (GDM). OBJECTIVES:This study aimed to investigate early pregnancy maternal serum metabolites and subsequent risk of GDM. DESIGN:Information on participant characteristics and GDM diagnosis was collected using in-person interviews and medical record abstraction, respectively. Early pregnancy serum samples were used for nontargeted metabolite profiling using a gas chromatography-mass spectrometry platform. Lasso regression was used to select a set of metabolites that are jointly associated with GDM case-control status. We evaluated the predictive performance of the set of selected metabolites using a receiver operating characteristics curve and area under the curve. PARTICIPANTS:A total of 178 GDM cases and 180 controls participated in a pregnancy cohort study. RESULTS:A set of 17 metabolites (linoleic acid, oleic acid, myristic acid, d-galactose, d-sorbitol, o-phosphocolamine, l-alanine, l-valine, 5-hydroxy-l-tryptophan, l-serine, sarcosine, l-pyroglutamic acid, l-mimosine, l-lactic acid, glycolic acid, fumaric acid, and urea) differentiated GDM cases from controls. Fold changes of relative abundance of these metabolites among GDM cases compared with controls ranged from 1.47 (linoleic acid) to 0.78 (5-hydroxy-l-tryptophan). Addition of these selected metabolites to a set of well-known GDM risk factors improved the area under the curve significantly from 0.71 to 0.87 (P = 3.97E-07). CONCLUSIONS:We identified combinations of metabolites in early pregnancy that are associated with subsequent risk of GDM. Replication of findings may improve understanding of GDM pathogenesis and may have implications for the design of GDM prevention and early diagnosis protocols.
Metabolomic profiling in the prediction of gestational diabetes mellitus.
Bentley-Lewis Rhonda,Huynh Jennifer,Xiong Grace,Lee Hang,Wenger Julia,Clish Clary,Nathan David,Thadhani Ravi,Gerszten Robert
AIMS/HYPOTHESIS:Metabolomic profiling in populations with impaired glucose tolerance has revealed that branched chain and aromatic amino acids (BCAAs) are predictive of type 2 diabetes. Because gestational diabetes mellitus (GDM) shares pathophysiological similarities with type 2 diabetes, the metabolite profile predictive of type 2 diabetes could potentially identify women who will develop GDM. METHODS:We conducted a nested case-control study of 18- to 40-year-old women who participated in the Massachusetts General Hospital Obstetrical Maternal Study between 1998 and 2007. Participants were enrolled during their first trimester of a singleton pregnancy and fasting serum samples were collected. The women were followed throughout pregnancy and identified as having GDM or normal glucose tolerance (NGT) in the third trimester. Women with GDM (n = 96) were matched to women with NGT (n = 96) by age, BMI, gravidity and parity. Liquid chromatography-mass spectrometry was used to measure the levels of 91 metabolites. RESULTS:Data analyses revealed the following characteristics (mean ± SD): age 32.8 ± 4.4 years, BMI 28.3 ± 5.6 kg/m(2), gravidity 2 ± 1 and parity 1 ± 1. Six metabolites (anthranilic acid, alanine, glutamate, creatinine, allantoin and serine) were identified as having significantly different levels between the two groups in conditional logistic regression analyses (p < 0.05). The levels of the BCAAs did not differ significantly between GDM and NGT. CONCLUSIONS/INTERPRETATION:Metabolic markers identified as being predictive of type 2 diabetes may not have the same predictive power for GDM. However, further study in a racially/ethnically diverse population-based cohort is necessary.
Large-Scale Longitudinal Metabolomics Study Reveals Different Trimester-Specific Alterations of Metabolites in Relation to Gestational Diabetes Mellitus.
Zhao Hongzhi,Li Han,Chung Arthur Chi Kong,Xiang Li,Li Xiaona,Zheng Yuanyuan,Luan Hemi,Zhu Lin,Liu Wenyu,Peng Yang,Zhao Yaxing,Xu Shunqing,Li Yuanyuan,Cai Zongwei
Journal of proteome research
Despite the increasing research attention paid to gestational diabetes mellitus (GDM) due to its high prevalence, limited knowledge is available about its pathogenesis. In this study, 428 serum samples were collected from 107 pregnant women suffering from GDM and 107 matched healthy controls. The nontargeted metabolomics data of maternal serum samples from the first (T1, n = 214) and second trimesters (T2, n = 214) were acquired by using ultrahigh performance liquid chromatography coupled with Orbitrap mass spectrometry (MS). A total of 93 differential metabolites were identified on the basis of the accurate mass and MS/MS fragmentation. After false discovery rate correction, the levels of 31 metabolites in GDM group were significantly altered in the first trimester. The differential metabolites were mainly attributed to purine metabolism, fatty acid β-oxidation, urea cycle, and tricarboxylic acid cycle pathways. The fold changes across pregnancy (T2/T1) of six amino acids (serine, proline, leucine/isoleucine, glutamic acid, tyrosine, and ornithine), a lysophosphatidylcholine (LysoPC(20:4)), and uric acid in GDM group were significantly different from those in the control groups, suggesting that these 8 metabolites might have contributed to the occurrence and progression of GDM. The findings revealed that the amino acid metabolism, lipid metabolism, and other pathways might be disturbed prior to GDM onset and during the period from the first to the second trimester of pregnancy.
Altered plasma serine and 1-deoxydihydroceramide profiles are associated with diabetic neuropathy in type 2 diabetes and obesity.
Fridman V,Zarini S,Sillau S,Harrison K,Bergman B C,Feldman E L,Reusch J E B,Callaghan B C
Journal of diabetes and its complications
Recent studies suggest that the accumulation of atypical, 1-deoxysphingolipids that lack the C1 hydroxyl group may be associated with diabetic neuropathy (DN). We hypothesized that specific plasma 1-deoxysphingolipids associate with DN severity, and that alterations in plasma serine and alanine associate with 1-deoxysphingolipid elevation in patients with type 2 diabetes (T2D). We examined individual 1-deoxysphingolipid species using LC/MS/MS in plasma samples from 75 individuals including lean controls (LC, n = 19), those with obesity (n = 19), obesity with T2D without DN (ob/T2D, n = 18), and obesity with T2D with DN (Ob/T2D/DN, n = 19). We observed a step wise increase in 1-deoxydihydroceramides across these four groups (spearman correlation coefficient r = 0.41, p = 0.0002). Mean total concentrations of 1-deoxydihydroceramides, and most individual 1-deoxydihydroceramide species, were higher in ob/T2D/DN versus LC group (8.939 vs. 5.195 pmol/100 μL for total 1-deoxydihydroceramides p = 0.005). No significant differences in 1-deoxydihydroceramides were observed between the ob/T2D and ob/T2D/DN groups. l-alanine was higher and l-serine lower in ob/T2D/DN versus LC groups (326.2 vs. 248.0 μM, p = 0.0086 and 70.2 vs. 89.8 μM, p = 0.0110), consistent with a potential contribution of these changes to the observed 1-deoxysphingolipids profiles. 1-deoxydihydroceramides correlated inversely with leg intraepidermal nerve fiber density (CC -0.40, p = 0.003). These findings indicate that 1-deoxydihydroceramides may be important biomarkers and/or mediators of DN.
Type 1 diabetes mellitus in mice increases hippocampal D-serine in the acute phase after streptozotocin injection.
Suzuki Masataka,Sasabe Jumpei,Furuya Shigeki,Mita Masashi,Hamase Kenji,Aiso Sadakazu
Diabetes mellitus (DM) is known to be a risk factor in the development of deficits in cognition, learning, and memory. In DM animal models, including the streptozotocin (STZ)-induced diabetic rodent model, abnormalities in the regulation of several neurotransmitters have been reported. However, the role in DM of d-serine, an endogenous co-agonist of glutamatergic N-methyl-d-aspartate receptors, remains unknown. Here, we measured the amounts of d-/l-serine and l-glutamate in the hippocampi of STZ-treated mice using a 2D-HPLC system from acute to chronic phases after the induction of DM. STZ treatment significantly increased the d-serine level by 23.7% in the hippocampus compared with vehicle treatment at 1 week after the injection, whereas it did not affect the levels of l-serine. In contrast, l-glutamate levels in the hippocampus were elevated at 3 days after STZ injection and rather decreased at 1 week after that. Such alterations in the amino acids were not evident in the chronic phases. We further tested whether the STZ-induced d-serine increase was caused by DM pathophysiology. In vivo, subcutaneous insulin implants into STZ-treated mice restored the elevated d-serine levels in the hippocampus. An in vitro study using primary cultured hippocampal neurons revealed that treatments of STZ did not directly affect the level of d-serine secreted in the cultured media. These results indicate that DM pathology caused by insulin deficiency triggers transient d-serine increase and l-glutamate alteration in the hippocampus. Such aberrant regulations of excitatory neurotransmitters may be relevant to the formation of DM-related dysfunction of the central nervous system (CNS).
L-serine supplementation lowers diabetes incidence and improves blood glucose homeostasis in NOD mice.
Holm Laurits J,Haupt-Jorgensen Martin,Larsen Jesper,Giacobini Jano D,Bilgin Mesut,Buschard Karsten
Sphingolipids are a diverse group of lipids with important roles in beta-cell biology regulating insulin folding and controlling apoptosis. Sphingolipid biosynthesis begins with the condensation of L-serine and palmitoyl-CoA. Here we tested the effect of L-serine supplementation on autoimmune diabetes development and blood glucose homeostasis in female NOD mice. We found that continuous supplementation of L-serine reduces diabetes incidence and insulitis score. In addition, L-serine treated mice had an improved glucose tolerance test, reduced HOMA-IR, and reduced blood glucose levels. L-serine led to a small reduction in body weight accompanied by reduced food and water intake. L-serine had no effect on pancreatic sphingolipids as measured by mass spectrometry. The data thus suggests that L-serine could be used as a therapeutic supplement in the treatment of Type 1 Diabetes and to improve blood glucose homeostasis.
Metabolomic Biomarkers in Gestational Diabetes Mellitus: A Review of the Evidence.
Alesi Simon,Ghelani Drishti,Rassie Kate,Mousa Aya
International journal of molecular sciences
Gestational diabetes mellitus (GDM) is the fastest growing type of diabetes, affecting between 2 to 38% of pregnancies worldwide, varying considerably depending on diagnostic criteria used and sample population studied. Adverse obstetric outcomes include an increased risk of macrosomia, and higher rates of stillbirth, instrumental delivery, and birth trauma. Metabolomics, which is a platform used to analyse and characterise a large number of metabolites, is increasingly used to explore the pathophysiology of cardiometabolic conditions such as GDM. This review aims to summarise metabolomics studies in GDM (from inception to January 2021) in order to highlight prospective biomarkers for diagnosis, and to better understand the dysfunctional metabolic pathways underlying the condition. We found that the most commonly deranged pathways in GDM include amino acids (glutathione, alanine, valine, and serine), carbohydrates (2-hydroxybutyrate and 1,5-anhydroglucitol), and lipids (phosphatidylcholines and lysophosphatidylcholines). We also highlight the possibility of using certain metabolites as predictive markers for developing GDM, with the use of highly stratified modelling techniques. Limitations for metabolomic research are evaluated, and future directions for the field are suggested to aid in the integration of these findings into clinical practice.
L-serine: a neglected amino acid with a potential therapeutic role in diabetes.
Holm Laurits J,Buschard Karsten
APMIS : acta pathologica, microbiologica, et immunologica Scandinavica
L-serine is classified as a non-essential amino acid; however, L-serine is indispensable having a central role in a broad range of cellular processes. Growing evidence suggests a role for L-serine in the development of diabetes mellitus and its related complications, with L-serine being positively correlated to insulin secretion and sensitivity. L-serine metabolism is altered in type 1, type 2, and gestational diabetes, and L-serine supplementations improve glucose homeostasis and mitochondrial function, and reduce neuronal death. Additionally, L-serine lowers the incidence of autoimmune diabetes in NOD mice. Dietary supplementations of L-serine are generally regarded as safe (GRAS) by the FDA. Therefore, we believe that L-serine should be considered as an emerging therapeutic option in diabetes, although work remains in order to fully understand the role of L-serine in diabetes.
Associations of TMPRSS6 Polymorphisms with Gestational Diabetes Mellitus in Chinese Han Pregnant Women: a Preliminary Cohort Study.
Biological trace element research
Body iron status is likely to be associated with type 2 diabetes (T2DM) and gestational diabetes mellitus (GDM); transmembrane protease serine 6 (TMPRSS6) polymorphisms may be associated with T2DM risk through their effects on body iron status. However, it remains unknown whether the TMPRSS6 single nucleotide polymorphisms (SNPs) affect the risk of GDM development. We aimed to determine whether the TMPRSS6 SNPs rs855791 (V736A) and rs4820268 (D521D) are associated with the risk of GDM in pregnant women. The two SNPs in TMPRSS6 gene were genotyped and examined for their associations with body iron status and GDM risk in 398 unrelated Chinese Han pregnant women. The 2 TMPRSS6 SNPs rs855791 and rs4820268 were both significantly associated with serum iron and transferrin saturation (P < 0.01 for all) rather than ferritin. After adjustment for covariates, the C allele of rs4820268 was nominally and significantly associated with an increased risk of GDM (OR = 2.531; 95%CI = 1.044-6.136, P = 0.040); when concentrations of ferritin were further adjusted, the association was still significant (OR = 2.528; 95%CI = 1.043-6.126, P = 0.040). There was a significant trend (P = 0.065) in the association between the T allele of rs855791 and an increased GDM risk in this study population. The 2 TMPRSS6 SNPs rs855791 and rs4820268 were both significantly associated with serum iron and transferrin saturation, and TMPRSS6 variants might be associated with the risk of GDM. Furthermore, the effects of TMPRSS6 SNPs on the risk of GDM may not be completely explained by the mediation of body iron status. Further studies are warranted.
Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance.
Gaggini Melania,Carli Fabrizia,Rosso Chiara,Buzzigoli Emma,Marietti Milena,Della Latta Veronica,Ciociaro Demetrio,Abate Maria Lorena,Gambino Roberto,Cassader Maurizio,Bugianesi Elisabetta,Gastaldelli Amalia
Hepatology (Baltimore, Md.)
Plasma concentrations of amino acids (AAs), in particular, branched chain AAs (BCAAs), are often found increased in nonalcoholic fatty liver disease (NAFLD); however, if this is due to increased muscular protein catabolism, obesity, and/or increased insulin resistance (IR) or impaired tissue metabolism is unknown. Thus, we evaluated a) if subjects with NAFLD without obesity (NAFLD-NO) compared to those with obesity (NAFLD-Ob) display altered plasma AAs compared to controls (CTs); and b) if AA concentrations are associated with IR and liver histology. Glutamic acid, serine, and glycine concentrations are known to be altered in NAFLD. Because these AAs are involved in glutathione synthesis, we hypothesized they might be related to the severity of NAFLD. We therefore measured the AA profile of 44 subjects with NAFLD without diabetes and who had a liver biopsy (29 NAFLD-NO and 15 NAFLD-Ob) and 20 CTs without obesity, by gas chromatography-mass spectrometry, homeostasis model assessment of insulin resistance, hepatic IR (Hep-IR; Hep-IR = endogenous glucose production × insulin), and the new glutamate-serine-glycine (GSG) index (glutamate/[serine + glycine]) and tested for an association with liver histology. Most AAs were increased only in NAFLD-Ob subjects. Only alanine, glutamate, isoleucine, and valine, but not leucine, were increased in NAFLD-NO subjects compared to CTs. Glutamate, tyrosine, and the GSG-index were correlated with Hep-IR. The GSG-index correlated with liver enzymes, in particular, gamma-glutamyltransferase (R = 0.70), independent of body mass index. Ballooning and/or inflammation at liver biopsy were associated with increased plasma BCAAs and aromatic AAs and were mildly associated with the GSG-index, while only the new GSG-index was able to discriminate fibrosis F3-4 from F0-2 in this cohort. CONCLUSION:Increased plasma AA concentrations were observed mainly in subjects with obesity and NAFLD, likely as a consequence of increased IR and protein catabolism. The GSG-index is a possible marker of severity of liver disease independent of body mass index. (Hepatology 2018;67:145-158).
Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBalpha.
Tuttle R L,Gill N S,Pugh W,Lee J P,Koeberlein B,Furth E E,Polonsky K S,Naji A,Birnbaum M J
The physiological performance of an organ depends on an interplay between changes in cellular function and organ size, determined by cell growth, proliferation and death. Nowhere is this more evident than in the endocrine pancreas, where disturbances in function or mass result in severe disease. Recently, the insulin signal-transduction pathway has been implicated in both the regulation of hormone secretion from beta cells in mammals as well as the determination of cell and organ size in Drosophila melanogaster. A prominent mediator of the actions of insulin and insulin-like growth factor 1 (IGF-1) is the 3'-phosphoinositide-dependent protein kinase Akt, also known as protein kinase B (PKB). Here we report that overexpression of active Akt1 in the mouse beta cell substantially affects compartment size and function. There was a significant increase in both beta-cell size and total islet mass, accompanied by improved glucose tolerance and complete resistance to experimental diabetes.
Maternal BMI and Glycemia Impact the Fetal Metabolome.
Lowe William L,Bain James R,Nodzenski Michael,Reisetter Anna C,Muehlbauer Michael J,Stevens Robert D,Ilkayeva Olga R,Lowe Lynn P,Metzger Boyd E,Newgard Christopher B,Scholtens Denise M,
OBJECTIVE:We used targeted metabolomics to determine associations of maternal BMI and glucose levels with cord blood metabolites and associations of cord blood metabolites with newborn birth weight and adiposity in mother-offspring dyads. RESEARCH DESIGN AND METHODS:Targeted metabolomic assays were performed on cord blood serum samples from European ancestry, Afro-Caribbean, Thai, and Mexican American newborns (400 from each ancestry group) whose mothers participated in the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and who had anthropometric measurements at birth. RESULTS:Meta-analysis across the four cohorts demonstrated significant correlation of all cord blood metabolites analyzed with maternal fasting levels of the same metabolites at ∼28 weeks' gestation except for triglycerides, asparagine/aspartate, arginine, and the acylcarnitine C14-OH/C12-DC. Meta-analyses also demonstrated that maternal BMI with or without adjustment for maternal glucose was associated with cord blood metabolites including the branched-chain amino acids and their metabolites as well as phenylalanine. One-hour but not fasting glucose was associated with cord blood 3-hydroxybutyrate and its carnitine ester, a medium-chain acylcarnitine, and glycerol. A number of cord blood metabolites were associated with newborn birth weight and sum of skinfolds, including a negative association of triglycerides and positive association of 3-hydroxybutyrate, its carnitine ester, and serine with both newborn outcomes. CONCLUSIONS:Maternal BMI and glycemia are associated with different components of the newborn metabolome, consistent with their independent effects on newborn size at birth. Maternal BMI is associated with a newborn metabolic signature characteristic of insulin resistance and risk of type 2 diabetes in adults.
Mechanism of insulin receptor kinase inhibition in non-insulin-dependent diabetes mellitus patients. Phosphorylation of serine 1327 or threonine 1348 is unaltered.
Kellerer M,Coghlan M,Capp E,Mühlhöfer A,Kroder G,Mosthaf L,Galante P,Siddle K,Häring H U
The Journal of clinical investigation
The tyrosine kinase activity of insulin receptor isolated from the skeletal muscle of NIDDM patients has previously been found to be decreased compared with the activity of receptor from nondiabetic subjects but the mechanism underlying this defect is unknown. Phosphorylation of receptor serine/threonine residues has been proposed to exert an inhibitory influence on receptor tyrosine kinase activity and Ser 1327 and Thr 1348 have been identified as specific sites of phosphorylation in the insulin receptor COOH terminal domain. To address the potential negative regulatory role of phosphorylation of these residues in vivo, we assessed the extent of phosphorylation of each site in insulin receptor isolated from the skeletal muscle of 12 NIDDM patients and 13 nondiabetic, control subjects. Phosphorylation of Ser 1327 and Thr 1348 was determined using antibodies that specifically recognize insulin receptor phosphorylated at these sites. In addition, a phosphotyrosine-specific antibody was used to monitor receptor tyrosine phosphorylation. The extent of insulin-induced tyrosine autophosphorylation was decreased in receptor isolated from diabetic versus nondiabetic muscle, thus confirming earlier reports. In contrast, there was no significant difference in the extent of phosphorylation of either Ser 1327 or Thr 1348 in receptor isolated from diabetic or nondiabetic muscle as assessed by immunoprecipitation (Ser 1327: 5.6 +/- 1.6% diabetics vs. 4.7 +/- 2.0% control; Thr 1348: 3.8 +/- 1.0% diabetics vs. 3.2 +/- 1.2% control). Moreover, within each group there was no correlation between the level of tyrosine kinase activity and the extent of serine/threonine phosphorylation. It is concluded that the stoichiometry of serine/threonine phosphorylation of insulin receptor in vivo is low, and that increased phosphorylation of Ser 1327 or Thr 1348 is not responsible for the decreased insulin receptor tyrosine kinase activity observed in the skeletal muscle of NIDDM patients.
Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta).
Cho H,Mu J,Kim J K,Thorvaldsen J L,Chu Q,Crenshaw E B,Kaestner K H,Bartolomei M S,Shulman G I,Birnbaum M J
Science (New York, N.Y.)
Glucose homeostasis depends on insulin responsiveness in target tissues, most importantly, muscle and liver. The critical initial steps in insulin action include phosphorylation of scaffolding proteins and activation of phosphatidylinositol 3-kinase. These early events lead to activation of the serine-threonine protein kinase Akt, also known as protein kinase B. We show that mice deficient in Akt2 are impaired in the ability of insulin to lower blood glucose because of defects in the action of the hormone on liver and skeletal muscle. These data establish Akt2 as an essential gene in the maintenance of normal glucose homeostasis.
Defective insulin secretion and increased susceptibility to experimental diabetes are induced by reduced Akt activity in pancreatic islet beta cells.
Bernal-Mizrachi Ernesto,Fatrai Szabolcs,Johnson James D,Ohsugi Mitsuru,Otani Kenichi,Han Zhiqiang,Polonsky Kenneth S,Permutt M Alan
The Journal of clinical investigation
The insulin and IGF signaling pathways are critical for development and maintenance of pancreatic beta cell mass and function. The serine-threonine kinase Akt is one of several mediators regulated by these pathways. We have studied the role of Akt in pancreatic beta cell physiology by generating transgenic mice expressing a kinase-dead mutant of this enzyme in beta cells. Reduction of Akt activity in transgenic animals resulted in impaired glucose tolerance due to defective insulin secretion. The mechanisms involved in dysregulation of secretion in these mice lie at the level of insulin exocytosis and are not the result of abnormalities in glucose signaling or function of voltage-gated Ca2+ channels. Therefore, transgenic mice showed increased susceptibility to developing glucose intolerance and diabetes following fat feeding. These observations suggest that Akt plays a novel and important role in the regulation of distal components of the secretory pathway and that this enzyme represents a therapeutic target for improvement of beta cell function in diabetes.
Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents.
Morino Katsutaro,Petersen Kitt Falk,Dufour Sylvie,Befroy Douglas,Frattini Jared,Shatzkes Nadine,Neschen Susanne,White Morris F,Bilz Stefan,Sono Saki,Pypaert Marc,Shulman Gerald I
The Journal of clinical investigation
To further explore the nature of the mitochondrial dysfunction and insulin resistance that occur in the muscle of young, lean, normoglycemic, insulin-resistant offspring of parents with type 2 diabetes (IR offspring), we measured mitochondrial content by electron microscopy and insulin signaling in muscle biopsy samples obtained from these individuals before and during a hyperinsulinemic-euglycemic clamp. The rate of insulin-stimulated muscle glucose uptake was approximately 60% lower in the IR offspring than the control subjects and was associated with an approximately 60% increase in the intramyocellular lipid content as assessed by H magnetic resonance spectroscopy. Muscle mitochondrial density was 38% lower in the IR offspring. These changes were associated with a 50% increase in IRS-1 Ser312 and IRS-1 Ser636 phosphorylation and an approximately 60% reduction in insulin-stimulated Akt activation in the IR offspring. These data provide new insights into the earliest defects that may be responsible for the development of type 2 diabetes and support the hypothesis that reductions in mitochondrial content result in decreased mitochondrial function, which predisposes IR offspring to intramyocellular lipid accumulation, which in turn activates a serine kinase cascade that leads to defects in insulin signaling and action in muscle.
Gene loci associated with insulin secretion in islets from non-diabetic mice.
Keller Mark P,Rabaglia Mary E,Schueler Kathryn L,Stapleton Donnie S,Gatti Daniel M,Vincent Matthew,Mitok Kelly A,Wang Ziyue,Ishimura Takanao,Simonett Shane P,Emfinger Christopher H,Das Rahul,Beck Tim,Kendziorski Christina,Broman Karl W,Yandell Brian S,Churchill Gary A,Attie Alan D
The Journal of clinical investigation
Genetic susceptibility to type 2 diabetes is primarily due to β-cell dysfunction. However, a genetic study to directly interrogate β-cell function ex vivo has never been previously performed. We isolated 233,447 islets from 483 Diversity Outbred (DO) mice maintained on a Western-style diet, and measured insulin secretion in response to a variety of secretagogues. Insulin secretion from DO islets ranged >1,000-fold even though none of the mice were diabetic. The insulin secretory response to each secretagogue had a unique genetic architecture; some of the loci were specific for one condition, whereas others overlapped. Human loci that are syntenic to many of the insulin secretion QTL from mouse are associated with diabetes-related SNPs in human genome-wide association studies. We report on three genes, Ptpn18, Hunk and Zfp148, where the phenotype predictions from the genetic screen were fulfilled in our studies of transgenic mouse models. These three genes encode a non-receptor type protein tyrosine phosphatase, a serine/threonine protein kinase, and a Krϋppel-type zinc-finger transcription factor, respectively. Our results demonstrate that genetic variation in insulin secretion that can lead to type 2 diabetes is discoverable in non-diabetic individuals.
The serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling.
Uchimura Kohei,Hayata Manabu,Mizumoto Teruhiko,Miyasato Yoshikazu,Kakizoe Yutaka,Morinaga Jun,Onoue Tomoaki,Yamazoe Rika,Ueda Miki,Adachi Masataka,Miyoshi Taku,Shiraishi Naoki,Ogawa Wataru,Fukuda Kazuki,Kondo Tatsuya,Matsumura Takeshi,Araki Eiichi,Tomita Kimio,Kitamura Kenichiro
The effects of high-fat diet (HFD) and postprandial endotoxemia on the development of type 2 diabetes are not fully understood. Here we show that the serine protease prostasin (PRSS8) regulates hepatic insulin sensitivity by modulating Toll-like receptor 4 (TLR4)-mediated signalling. HFD triggers the suppression of PRSS8 expression by inducing endoplasmic reticulum (ER) stress and increases the TLR4 level in the liver. PRSS8 releases the ectodomain of TLR4 by cleaving it, which results in a reduction in the full-length form and reduces the activation of TLR4. Liver-specific PRSS8 knockout (LKO) mice develop insulin resistance associated with the increase in hepatic TLR4. Restoration of PRSS8 expression in livers of HFD, LKO and db/db mice decreases the TLR4 level and ameliorates insulin resistance. These results identify a novel physiological role for PRSS8 in the liver and provide new insight into the development of diabetes resulting from HFD or metabolic endotoxemia.
Serine Catabolism Feeds NADH when Respiration Is Impaired.
Yang Lifeng,Garcia Canaveras Juan Carlos,Chen Zihong,Wang Lin,Liang Lingfan,Jang Cholsoon,Mayr Johannes A,Zhang Zhaoyue,Ghergurovich Jonathan M,Zhan Le,Joshi Shilpy,Hu Zhixian,McReynolds Melanie R,Su Xiaoyang,White Eileen,Morscher Raphael J,Rabinowitz Joshua D
NADH provides electrons for aerobic ATP production. In cells deprived of oxygen or with impaired electron transport chain activity, NADH accumulation can be toxic. To minimize such toxicity, elevated NADH inhibits the classical NADH-producing pathways: glucose, glutamine, and fat oxidation. Here, through deuterium-tracing studies in cultured cells and mice, we show that folate-dependent serine catabolism also produces substantial NADH. Strikingly, when respiration is impaired, serine catabolism through methylene tetrahydrofolate dehydrogenase (MTHFD2) becomes a major NADH source. In cells whose respiration is slowed by hypoxia, metformin, or genetic lesions, mitochondrial serine catabolism inhibition partially normalizes NADH levels and facilitates cell growth. In mice with engineered mitochondrial complex I deficiency (NDUSF4-/-), serine's contribution to NADH is elevated, and progression of spasticity is modestly slowed by pharmacological blockade of serine degradation. Thus, when respiration is impaired, serine catabolism contributes to toxic NADH accumulation.
Thymus-specific serine protease controls autoreactive CD4 T cell development and autoimmune diabetes in mice.
Viret Christophe,Leung-Theung-Long Stéphane,Serre Laurent,Lamare Camille,Vignali Dario A A,Malissen Bernard,Carrier Alice,Guerder Sylvie
The Journal of clinical investigation
Type 1 diabetes is a chronic autoimmune disease in which genetic predispositions affect the immune system, leading to a loss of T cell tolerance to β cells and consequent T cell-mediated destruction of insulin-producing islet cells. Genetic studies have suggested that PRSS16 is linked to a diabetes susceptibility locus of the extended HLA class I region in humans. PRSS16 encodes what we believe to be a novel protease, thymus-specific serine protease (TSSP), which shows predominant expression in thymic epithelial cells and is suspected to have a restricted role in the class II presentation pathway. Consistently, Tssp is necessary for the intrathymic selection of few class II-restricted T cell receptor specificities in B6 mice. To directly assess the role of Tssp in autoimmune diabetes, we generated Tssp-deficient (Tssp°) NOD mice. While remaining immunocompetent, Tssp° NOD mice were protected from diabetes and severe insulitis. Diabetes resistance of Tssp° NOD mice was a property of the CD4 T cell compartment that is acquired during thymic selection and correlated with an impaired selection of CD4 T cells specific for islet antigens. Hence, in the NOD mouse, Tssp is a critical regulator of diabetes development through the selection of the autoreactive CD4 T cell repertoire.
Associations among the plasma amino acid profile, obesity, and glucose metabolism in Japanese adults with normal glucose tolerance.
Takashina Chisa,Tsujino Ichizo,Watanabe Taku,Sakaue Shinji,Ikeda Daisuke,Yamada Asuka,Sato Takahiro,Ohira Hiroshi,Otsuka Yoshinori,Oyama-Manabe Noriko,Ito Yoichi M,Nishimura Masaharu
Nutrition & metabolism
BACKGROUND:Amino acids (AAs) are emerging as a new class of effective molecules in the etiology of obesity and diabetes mellitus. However, most investigations have focused on subjects with obesity and/or impaired glucose regulation; the possible involvement of AAs in the initial phase of glucose dysregulation remains poorly understood. Furthermore, little attention has been given to possible associations between the pattern/degree of fat deposition and the plasma AA profile. Our objective was therefore to determine the relationships between plasma AA concentrations and the type/degree of obesity and glucose regulation in Japanese adults with normal glucose tolerance. METHODS:Eighty-three subjects with normal glucose tolerance were classified as obese or nonobese and as visceral obesity or nonvisceral obesity. Correlations between the plasma levels of 23 AAs and somatometric measurements, visceral fat area (VFA), subcutaneous fat area (SFA), and 75-g oral glucose tolerance test results were analyzed. RESULTS:Obesity or visceral obesity was associated with higher levels of branched-chain AAs (isoleucine, leucine, and valine), lysine, tryptophan, cystine, and glutamate but lower levels of asparagine, citrulline, glutamine, glycine, and serine (p < 0.04). Age- and gender-adjusted analyses indicated that VFA was positively correlated with tryptophan and glutamate levels, whereas VFA and SFA were negatively correlated with citrulline, glutamine, and glycine levels (p < 0.05). The fasting and 2-h plasma glucose levels or the homeostasis model assessment of insulin resistance were positively correlated with valine, glutamate, and tyrosine levels but negatively correlated with citrulline, glutamine, and glycine levels. The homeostasis model assessment for the β-cell function index was positively correlated with leucine, tryptophan, valine, and glutamate levels but negatively correlated with citrulline, glutamine, glycine, and serine levels (p < 0.05). CONCLUSIONS:The present study identified specific associations between 10 AAs and the type/degree of obesity, and indices of glucose/insulin regulation, in Japanese adults with preserved glucose metabolism. With the growing concern about the increasing prevalence of obesity and diabetes, the possible roles of these AAs as early markers and/or precursors warrant further investigation.
Abnormal circulating amino acid profiles in multiple metabolic disorders.
Okekunle Akinkunmi Paul,Li Ying,Liu Liyan,Du Shanshan,Wu Xiaoyan,Chen Yang,Li Yanchuan,Qi Jiayue,Sun Changhao,Feng Rennan
Diabetes research and clinical practice
AIM:To evaluate circulating amino acids (AA) profiles in obesity, type 2 diabetes (T2D) and metabolic syndrome (MetS). METHODS:Serum AA were profiled among 200; healthy, obese, T2D and MetS subjects matched by sex, age and BMI using ultra-high performance liquid chromatography tandem quadruple mass spectrometry (UPLC-TQ-MS). A meta-analysis, including 47 case-control studies (including the current study) on serum AA in obesity, T2D and MetS searched through October 2016 was conducted to explore the AA differences in obesity, T2D and MetS. RESULTS:In comparison with healthy controls, 14 AA (10 increased and 4 decreased) were significantly altered (P<0.05) in all non-healthy subjects. Also, mean differences of valine (obese: 34.13 [27.70, 40.56]µmol/L, P<0.001, T2D: 19.49 [3.31, 35.68]µmol/L, P<0.05, MetS: 29.18 [16.04, 42.33]µmol/L, P<0.001), glutamic acid (obese: 18.62 [11.64, 25.61]µmol/L, P<0.001, T2D: 19.94 [0.28, 39.61]µmol/L, P<0.05, MetS: 12.45 [3.98, 20.91]µmol/L, P<0.001), proline (obese: 16.72 [6.20, 27.24]µmol/L, P<0.001, T2D: 20.72 [15.82, 25.61]µmol/L, P<0.001, MetS: 29.95 [25.18, 34.71]µmol/L, P<0.001) and isoleucine (obese: 11.39 [8.54, 14.24]µmol/L, P<0.001, T2D: 7.37 [1.52, 13.22]µmol/L, P<0.05, MetS: 10.40 [4.90, 15.89]µmol/L, P<0.001) were significantly higher compared to healthy controls. Similarly, mean differences of glycine (obese: -30.99 [-39.69, -22.29]µmol/L, P<0.001, T2D: -30.37 [-41.80, -18.94]µmol/L, P<0.001 and MetS: -35.24 [-39.28, -31.21]µmol/L, P<0.001) were significantly lower compared to healthy controls. CONCLUSION:In both the case-control study and meta-analysis, obesity was related to the most circulating AA changes, followed by MetS and T2D. Valine, isoleucine, glutamic acid and proline increased, while Glycine decreased in all metabolic disorders.
Metabolomics and Type 2 Diabetes: Translating Basic Research into Clinical Application.
Klein Matthias S,Shearer Jane
Journal of diabetes research
Type 2 diabetes (T2D) and its comorbidities have reached epidemic proportions, with more than half a billion cases expected by 2030. Metabolomics is a fairly new approach for studying metabolic changes connected to disease development and progression and for finding predictive biomarkers to enable early interventions, which are most effective against T2D and its comorbidities. In metabolomics, the abundance of a comprehensive set of small biomolecules (metabolites) is measured, thus giving insight into disease-related metabolic alterations. This review shall give an overview of basic metabolomics methods and will highlight current metabolomics research successes in the prediction and diagnosis of T2D. We summarized key metabolites changing in response to T2D. Despite large variations in predictive biomarkers, many studies have replicated elevated plasma levels of branched-chain amino acids and their derivatives, aromatic amino acids and α-hydroxybutyrate ahead of T2D manifestation. In contrast, glycine levels and lysophosphatidylcholine C18:2 are depressed in both predictive studies and with overt disease. The use of metabolomics for predicting T2D comorbidities is gaining momentum, as are our approaches for translating basic metabolomics research into clinical applications. As a result, metabolomics has the potential to enable informed decision-making in the realm of personalized medicine.
Glutathione metabolism in type 2 diabetes and its relationship with microvascular complications and glycemia.
Lutchmansingh Fallon K,Hsu Jean W,Bennett Franklyn I,Badaloo Asha V,McFarlane-Anderson Norma,Gordon-Strachan Georgiana M,Wright-Pascoe Rosemarie A,Jahoor Farook,Boyne Michael S
AIMS/HYPOTHESES:We hypothesized that there is decreased synthesis of glutathione (GSH) in type 2 diabetes (T2DM) especially in the presence of microvascular complications, and this is dependent on the degree of hyperglycemia. METHODS:In this case-control study, we recruited 16 patients with T2DM (7 without and 9 with microvascular complications), and 8 age- and sex-matched non-diabetic controls. We measured GSH synthesis rate using an infusion of [2H2]-glycine as isotopic tracer and collection of blood samples for liquid chromatography mass spectrometric analysis. RESULTS:Compared to the controls, T2DM patients had lower erythrocyte GSH concentrations (0.90 ± 0.42 vs. 0.35 ± 0.30 mmol/L; P = 0.001) and absolute synthesis rates (1.03 ± 0.55 vs. 0.50 ± 0.69 mmol/L/day; P = 0.01), but not fractional synthesis rates (114 ± 45 vs. 143 ± 82%/day; P = 0.07). The magnitudes of changes in patients with complications were greater for both GSH concentrations and absolute synthesis rates (P-values ≤ 0.01) compared to controls. There were no differences in GSH concentrations and synthesis rates between T2DM patients with and without complications (P-values > 0.1). Fasting glucose and HbA1c did not correlate with GSH concentration or synthesis rates (P-values > 0.17). CONCLUSIONS:Compared to non-diabetic controls, patients with T2DM have glutathione deficiency, especially if they have microvascular complications. This is probably due to reduced synthesis and increased irreversible utilization by non-glycemic mechanisms.
Serum and plasma amino acids as markers of prediabetes, insulin resistance, and incident diabetes.
Gar C,Rottenkolber M,Prehn C,Adamski J,Seissler J,Lechner A
Critical reviews in clinical laboratory sciences
Presently, routine screening misses many cases of prediabetes and early type 2 diabetes (T2D). Therefore, better biomarkers are needed for a simple and early detection of abnormalities of glucose metabolism and prediction of future T2D. Possible candidates for this include plasma or serum amino acids because glucose and amino acid metabolism are closely connected. This review presents the available evidence of this connectivity and discusses its clinical implications. First, we examine the underlying physiological, pre-analytical, and analytical issues. Then, we summarize results of human studies that evaluate amino acid levels as markers for insulin resistance, prediabetes, and future incident T2D. Finally, we illustrate the interconnection of amino acid levels and metabolic syndrome with our own data from a deeply phenotyped human cohort. We also discuss how amino acids may contribute to the pathophysiology of T2D. We conclude that elevated branched-chain amino acids and reduced glycine are currently the most robust and consistent amino acid markers for prediabetes, insulin resistance, and future T2D. Yet, we are cautious regarding the clinical potential even of these parameters because their discriminatory power is insufficient and their levels depend not only on glycemia, but also on other components of the metabolic syndrome. The identification of more precise intermediates of amino acid metabolism or combinations with other biomarkers will, therefore, be necessary to obtain in order to develop laboratory tests that can improve T2D screening.
Metabolite Profiles of Diabetes Incidence and Intervention Response in the Diabetes Prevention Program.
Walford Geoffrey A,Ma Yong,Clish Clary,Florez Jose C,Wang Thomas J,Gerszten Robert E,
Identifying novel biomarkers of type 2 diabetes risk may improve prediction and prevention among individuals at high risk of the disease and elucidate new biological pathways relevant to diabetes development. We performed plasma metabolite profiling in the Diabetes Prevention Program (DPP), a completed trial that randomized high-risk individuals to lifestyle, metformin, or placebo interventions. Previously reported markers, branched-chain and aromatic amino acids and glutamine/glutamate, were associated with incident diabetes (P < 0.05 for all), but these associations were attenuated upon adjustment for clinical and biochemical measures. By contrast, baseline levels of betaine, also known as glycine betaine (hazard ratio 0.84 per SD log metabolite level, P = 0.02), and three other metabolites were associated with incident diabetes even after adjustment. Moreover, betaine was increased by the lifestyle intervention, which was the most effective approach to preventing diabetes, and increases in betaine at 2 years were also associated with lower diabetes incidence (P = 0.01). Our findings indicate betaine is a marker of diabetes risk among high-risk individuals both at baseline and during preventive interventions and they complement animal models demonstrating a direct role for betaine in modulating metabolic health.
Diabetes and branched-chain amino acids: What is the link?
Journal of diabetes
Branched-chain amino acids (BCAA) have increasingly been studied as playing a role in diabetes, with the PubMed search string "diabetes" AND "branched chain amino acids" showing particular growth in studies of the topic over the past decade (Fig. ). In the Young Finn's Study, BCAA and, to a lesser extent, the aromatic amino acids phenylalanine and tyrosine were associated with insulin resistance (IR) in men but not in women, whereas the gluconeogenic amino acids alanine, glutamine, or glycine, and several other amino acids (i.e. histidine, arginine, and tryptophan) did not show an association with IR. Obesity may track more strongly than metabolic syndrome and diabetes with elevated BCAA. In a study of 1302 people aged 40-79; higher levels of BCAA tracked with older age, male sex, and metabolic syndrome, as well as with obesity, cardiovascular risk, dyslipidemia, hypertension, and uric acid. Medium- and long-chain acylcarnitines, by-products of mitochondrial catabolism of BCAAs, as well as branched-chain keto acids and the BCAA themselves distinguished obese people having versus not having features of IR, and in a study of 898 patients with essential hypertension, the BCAA and tyrosine and phenylalanine were associated with metabolic syndrome and impaired fasting glucose. In a meta-analysis of three genome-wide association studies, elevations in BCAA and, to a lesser extent, in alanine tracked with IR, whereas higher levels of glutamine and glycine were associated with lesser likelihood of IR. Given these associations with IR, it is not surprising that a number of studies have shown higher BCAA levels in people with and prior to development of type 2 diabetes (T2D), although this has particularly been shown in Caucasian and Asian ethnic groups while not appearing to occur in African Americans. Similarly, higher BCAA levels track with cardiovascular disease. [Figure: see text] The metabolism of BCAA involves two processes: (i) a reversible process catalysed by a branched-chain aminotransferase (BCAT), either cytosolic or mitochondrial, requiring pyridoxal to function as an amino group carrier, by which the BCAA with 2-ketoglutarate produce a branched-chain keto acid plus glutamate; and (ii) the irreversible mitochondrial process catalysed by branched-chain keto acid dehydrogenase (BCKDH) leading to formation of acetyl-coenzyme A (CoA), propionyl-CoA, and 2-methylbutyryl-CoA from leucine, valine, and isoleucine, respectively, which enter the tricarboxylic acid (Krebs) cycle as acetyl-CoA, propionyl-CoA, and 2-methylbutyryl-CoA, respectively, leading to ATP formation. The BCAA stimulate secretion of both insulin and glucagon and, when given orally, of both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), with oral administration leading to greater and more prolonged insulin and glucagon secretion. Insulin may particularly reduce BCAA turnover to a greater extent than that of other amino acids, and decreases the appearance and increases the uptake of amino acids. However, older studies of the effect of glucose or insulin on BCAA concentrations and rates of leucine appearance and oxidation showed no reduction in T2D, although the higher baseline levels of BCAA in obesity have long been recognized. Impaired function of BCAT and BCKDH has been posited, either as a primary genetic abnormality or due to effects of elevated fatty acids, proinflammatory cytokines, or insulin levels with consequent accumulation of branched-chain keto acids and metabolites such as diacylglycerol and ceramide, potentially contributing to the development of further insulin resistance, and decreased skeletal muscle BCAT and BCKDH expression has been shown in people with diabetes, supporting this concept. A Mendelian randomization study used measured variation in genes involved in BCAA metabolism to test the hypothesis of a causal effect of modifiable exposure on IR, showing that variants in protein phosphatase, Mg /Mn dependent 1K (PPM1K), a gene encoding the mitochondrial phosphatase activating the BCKDH complex, are associated with T2D, but another such study suggested that genetic variations associated with IR are causally related to higher BCAA levels. Another hypothesis involves the mammalian target of rapamycin complex 1 (mTORC1), which is activated by BCAA, as well as by insulin and glucose via cellular ATP availability. If this is the relevant pathway, BCAA overload may cause insulin resistance by activation of mammalian target of rapamycin (mTOR), as well as by leading to increases in acylcarnitines, with mTOR seen in this scenario as a central signal of cross-talk between the BCAA and insulin. At this point, whether whole-body or tissue-specific BCAA metabolism is increased or decreased in states of insulin-resistant obesity and T2D is uncertain. Insulin action in the hypothalamus induces but overfeeding decreases hepatic BCKDH, leading to the concept that hypothalamic insulin resistance impairs BCAA metabolism in obesity and diabetes, so that plasma BCAAs may be markers of hypothalamic insulin action rather than direct mediators of changes in IR. A way to address this may be to understand the effects of changes in diet and other interventions on BCAA, as well as on IR and T2D. In an animal model, lowering dietary BCAA increased energy expenditure and improved insulin sensitivity. Two large human population studies showed an association of estimated dietary BCAA intake with T2D risk, although another population study showed higher dietary BCAA to be associated with lower T2D risk. Ethnic differences, reflecting underlying differences in genetic variants, may be responsible for such differences. In the study of Asghari et al. in the current issue of the Journal of Diabetes, BCAA intake was associated with the development of subsequent IR. Studies of bariatric surgery suggest lower basal and post-insulin infusion BCAA levels are associated with greater insulin sensitivity, with reductions in BCAA not seen with weight loss per se with gastric band procedures, but occurring after Roux-en-Y gastric bypass, an intervention that may have metabolic benefits over and above those from reduction in body weight. The gut microbiota may be important for the supply of the BCAA to mammalian hosts, either by de novo biosynthesis or by modifying nutrient absorption. A final fascinating preliminary set of observations is that of the effects of empagliflozin on metabolomics; evidence of increased Krebs cycle activation and of higher levels of BCAA metabolites, such as acylcarnitines, suggests that sodium-glucose cotransporter 2 (SGLT2) inhibition may, to some extent, involve BCAA metabolism. Certainly, we do not yet have a full understanding of these complex associations. However, the suggestion of multiple roles of BCAA in the development of IR promises to be important and to lead to the development of novel effective T2D therapies.
Extent reflecting overall dietary amino acids composition adherence to the human requirement amino acids pattern is associated with the development of type 2 diabetes.
Duan Wei,Zi Tianqi,Zhao Yanhe,Shan Ruiqi,Wu Huanyu,Sun Hu,Tian Zhen,Wang Jiemei,Liu Liyan,Zhang Yuntao,Li Ying,Sun Changhao
This study aimed to elucidate whether dietary amino acids (AAs) composition is associated with type 2 diabetes mellitus (T2DM) and to investigate how serum AAs profiles mediated this association. Two prospective cohorts of 1750 and 4024 adults were enrolled. Dietary AAs compositions index (AACI) was developed to reflect the overall quality of dietary AAs composition. Multivariate linear regression and logistic regression models were used to examine associations of AACI and T2DM. The AACI was associated with the incidence of T2DM with the relative risk and 95%CI from the bottom to the top tertiles being 1.00, 1.49 (0.88-2.51) and 2.27 (1.20-4.28), and 1.00, 1.58 (1.13-2.19) and 2.33 (1.56-3.47) in the two cohorts, respectively. The AACI was positively associated with serum valine, isoleucine, glutamic acid and phenylalanine, and it was negatively associated with serum glycine and histidine in both cohorts (<0.01). Valine, glutamic acid and histidine consistently and partially mediated the association between the AACI and T2DM in the two cohorts, with total mediation effects of 33.4% and 54.6%, respectively. Dietary AAs composition was associated with the incidence of T2DM, meanwhile, the relationship was mediated by some degree of serum AAs. Future dietary strategies should focus on the improvement of the overall quality of dietary AAs compositions.
[The association between plasma levels of 20 amino acids and risk of diabetes].
Wang F H,Liu J,Deng Q J,Qi Y,Wang M,Wang Y,Sun J Y,Liu J,Li Y,Zhao D
Zhonghua nei ke za zhi
To investigate the association between the plasma levels of 20 amino acids and the risk of diabetes in middle-aged and elderly population. This study was a part of the Chinese multi-provincial cohort study conducted in communities of Shougang. In 2007 and 2012, the population was investigated for diabetes and other risk factors. Blood samples collected from 475 people were tested for various amino acid levels by liquid chromatography-tandem mass spectrometry. A multivariate logistic regression analysis was used to analyze the association between plasma amino acid levels and diabetes risk. The age of the selected population at baseline was (58.7±6.3) years, and the blood glucose level at baseline was (5.68±1.34) mmol/L. Among them, 56 (11.79%) subjects were diabetes. Multivariate logistic regression analyses showed that after adjusting for age, gender, body mass index, systolic blood pressure and dyslipidemia, individuals with plasma branched-chain amino acid (valine, leucine and isoleucine) and cysteine in the highest tertile levels were at high risk of diabetes with the of 3.61 (95% 1.48-8.80), 3.27 (95% 1.34-7.99), 2.46 (95% 1.04-5.84) and 2.09 (95% 1.02-4.27), respectively. After 5 years' followed up, 5.73% (24/419) subjects developed diabetes. Compared with those in the lowest tertile, individuals with plasma branched-chain amino acid (total concentration), phenylalanine, and tyrosine levels at baseline in the highest tertile had 3.69 times, 3.61 times and 4.14 times higher risk to develop new diabetes, respectively. In contrast, individuals with plasma glycine level in the highest tertile had only 76% ( 0.24, 95% 0.06-0.91) risk for the development of diabetes compared with those with plasma glycine level in the lowest tertile. The increase in plasma branched-chain amino acid and cysteine levels is significantly associated with an increase in incident diabetes. Subjects with higher levels of branched-chain amino acids and aromatic amino acids (phenylalanine, tyrosine) had a significantly higher risk of developing new-onset diabetes, while those with higher glycine levels had a significantly lower risk of developing diabetes in 5 years.
First-Trimester Maternal Serum Amino Acids and Acylcarnitines Are Significant Predictors of Gestational Diabetes.
Nevalainen Jaana,Sairanen Mikko,Appelblom Heidi,Gissler Mika,Timonen Susanna,Ryynänen Markku
The review of diabetic studies : RDS
BACKGROUND:Current screening methods for gestational diabetes mellitus (GDM) are insufficient in detecting the risk of GDM in the first trimester of the pregnancy. Recent metabolomic studies have detected altered amino acid and acylcarnitine concentrations in type 2 diabetes (T2D). Because of the similarities between T2D and GDM, the determination of these metabolites may be useful in early screening for GDM. AIM:To evaluate the association between GDM and first-trimester maternal serum concentrations of ten amino acids and 31 acylcarnitines. METHODS:This retrospective case-control study included data from pregnant women screened at Oulu University Hospital between 1.1.2008 and 31.12.2011. A total of 31,146 women participated voluntarily in a first-trimester combined screening (for chromosomal abnormalities). The study population included 69 women who developed GDM during pregnancy and 295 women without diabetes before or after pregnancy. The serum concentrations of ten amino acids and 31 acylcarnitines were analyzed from frozen serum samples taken in the first-trimester screening. Multiple of median (MoM) values were compared between the two groups. RESULTS:In the GDM group, serum levels of arginine were significantly higher (1.13 MoM vs. 0.97 MoM), and those of glycine (0.93 MoM vs. 1.03 MoM) and 3-hydroxy-isovalerylcarnitine (0.86 MoM vs. 1.03 MoM) significantly lower compared to the control group (all p < 0.01). In each case, arginine, glycine, and 3-hydroxy-isovaleryl-carnitine would have detected 46%, 32%, and 39% of GDM cases, with a false-positive rate of 20%. Combining these three metabolites with the first-trimester serum marker pregnancy-associated plasma protein A (PAPP-A) and prior risk (age, BMI, and smoking) achieved a detection rate of 72%. CONCLUSION:There are significant differences in the serum levels of arginine, glycine, and 3-hydroxy-isovalerylcarnitine between controls and women who subsequently develop GDM. These differences were already existent in the first trimester of the pregnancy. The use of metabolites in combination with prior risk and first-trimester PAPP-A represents a reliable method to identify women at risk of GDM.
Glycine normalizes hepatic triglyceride-rich VLDL secretion by triggering the CNS in high-fat fed rats.
Yue Jessica T Y,Mighiu Patricia I,Naples Mark,Adeli Khosrow,Lam Tony K T
RATIONALE:Dysregulation of hepatic triglyceride (TG)-rich very low-density lipoproteins (VLDL-TG) in obesity and type 2 diabetes contributes to the dyslipidemia that leads to cardiovascular morbidity. The central nervous system (CNS), particularly the hypothalamus, regulates hepatic lipid metabolism. Although the underlying neurocircuitry remains elusive, glycine has been documented to enhance CNS N-methyl-d-aspartate (NMDA) receptor-mediated transmission. OBJECTIVE:We tested the hypothesis that glycine regulates hepatic VLDL-TG secretion by potentiating NMDA receptor-mediated transmission in the CNS. METHODS AND RESULTS:Using 10-hour fasted male Sprague-Dawley rats implanted with stereotaxic cannulae into an extrahypothalamic region termed the dorsal vagal complex (DVC) and vascular catheters to enable direct DVC infusion and blood sampling, respectively, the rate of hepatic VLDL-TG secretion was measured following tyloxapol (an inhibitor of lipoprotein lipase) injection. Direct DVC infusion of glycine lowered VLDL-TG secretion, whereas NMDA receptor blocker MK-801 fully negated glycine's effect. NR1 subunit of NMDA receptor antagonist 7-chlorokynurenic acid, adenoviral injection of NR1 short hairpin RNA (shRNA), and hepatic vagotomy also nullified glycine's effect. Finally, DVC glycine normalized the hypersecretion of VLDL-TG induced by high-fat feeding. CONCLUSIONS:Molecular and pharmacological inhibition of the NR1-containing NMDA receptors in the DVC negated the ability of glycine to inhibit hepatic secretion of VLDL-TG in vivo. Importantly, the hypersecretion of VLDL-TG from the liver induced by a model of high-fat feeding was restored by the hepatic lipid control of CNS glycine sensing. These findings collectively suggest that glycine or glycine analogues may have therapeutic benefits in lowering plasma lipid levels in diabetes and obesity by triggering the CNS.
Inhibition of glycine transporter-1 in the dorsal vagal complex improves metabolic homeostasis in diabetes and obesity.
Yue Jessica T Y,Abraham Mona A,Bauer Paige V,LaPierre Mary P,Wang Peili,Duca Frank A,Filippi Beatrice M,Chan Owen,Lam Tony K T
Impaired glucose homeostasis and energy balance are integral to the pathophysiology of diabetes and obesity. Here we show that administration of a glycine transporter 1 (GlyT1) inhibitor, or molecular GlyT1 knockdown, in the dorsal vagal complex (DVC) suppresses glucose production, increases glucose tolerance and reduces food intake and body weight gain in healthy, obese and diabetic rats. These findings provide proof of concept that GlyT1 inhibition in the brain improves glucose and energy homeostasis. Considering the clinical safety and efficacy of GlyT1 inhibitors in raising glycine levels in clinical trials for schizophrenia, we propose that GlyT1 inhibitors have the potential to be repurposed as a treatment of both obesity and diabetes.
Association of Gly972Arg polymorphism of IRS1 gene with type 2 diabetes mellitus in lean participants of a national health survey in Mexico: a candidate gene study.
Burguete-Garcia Ana I,Cruz-Lopez Miguel,Madrid-Marina Vicente,Lopez-Ridaura Ruy,Hernández-Avila Mauricio,Cortina Bernardo,Gómez Rosa E,Velasco-Mondragón Eduardo
Metabolism: clinical and experimental
Type 2 diabetes mellitus (T2D) is a main public health problem in the Mexican population. It is characterized by insulin resistance in peripheral tissues and a relative deficiency in the pancreatic beta-cell functions. Diverse single nucleotide polymorphisms (SNPs) of the IRS1 gene have been associated with insulin resistance and T2D risk. The aim of this study was to identify the association between known IRS1 polymorphisms (Pro512Ala, Asn1137Asp, Gly972Arg, and Arg158Pro) in a sample of diabetic patients compared with healthy controls selected from Mexico's 2000 National Health Survey, both with normal body mass index (BMI). We identified 444 diabetes cases that were age matched with the same number of controls. Genotypic and allelic frequencies were evaluated, and conditional logistic regression was used to evaluate the association between the SNPs and diabetes risk. Of the 4 SNPs studied, only Gly972Arg showed significant differences between cases and controls, with allele frequency of 2.6% in controls as compared with 7.9% in cases. Subjects with at least 1 copy of the Gly972Arg polymorphism of the IRS1 gene showed a greater risk for diabetes, with a crude odds ratio of 3.26 (95% confidence interval, 2.00-5.33); after adjusting for BMI, age, family history of T2D, and sex, the odds ratio was 2.91 (95% confidence interval, 1.73-4.90). Our results suggest the participation of Gly972Arg polymorphism of IRS1 in the genetic susceptibility to TD2 in Mexican population. The restriction of including only participants with normal BMI might increase the power to detect genetic determinants of T2D.
Glycine treatment decreases proinflammatory cytokines and increases interferon-gamma in patients with type 2 diabetes.
Cruz M,Maldonado-Bernal C,Mondragón-Gonzalez R,Sanchez-Barrera R,Wacher N H,Carvajal-Sandoval G,Kumate J
Journal of endocrinological investigation
BACKGROUND:Amino acids have been shown to stimulate insulin secretion and decrease glycated hemoglobin (A1C) in patients with Type 2 diabetes. In vitro, glycine reduces tumor necrosis factor (TNF)-alpha secretion and increases interleukin-10 secretion in human monocytes stimulated with lipopolysaccharide. The aim of this study was to determine whether glycine modifies the proinflammatory profiles of patients with Type 2 diabetes. MATERIALS/SUBJECTS AND METHODS:Seventy-four patients, with Type 2 diabetes were enrolled in the study. The mean age was 58.5 yr, average age of diagnosis was 5 yr, the mean body mass index was 28.5 kg/m2, the mean fasting glucose level was 175.5 mg/dl and the mean A1C level was 8%. They were allocated to one of two treatments, 5 g/d glycine or 5 g/d placebo, po tid, for 3 months. RESULTS:A1C levels of patients given glycine were significantly lower after 3 months of treatment than those of the placebo group. A significant reduction in TNF-receptor I levels was observed in patients given glycine compared with placebo. There was a decrease of 38% in the interferon (IFN)-gamma level of the group treated with placebo, whereas that of the group treated with glycine increased up to 43%. These data showed that patients treated with glycine had a significant decrease in A1C and in proinflammatory cytokines and also an important increase of IFN-gamma. CONCLUSION:Treatment with glycine is likely to have a beneficial effect on innate and adaptive immune responses and may help prevent tissue damage caused by chronic inflammation in patients with Type 2 diabetes.
Variability of plasma and urine betaine in diabetes mellitus and its relationship to methionine load test responses: an observational study.
Lever Michael,Slow Sandy,McGregor David O,Dellow Warwick J,George Peter M,Chambers Stephen T
BACKGROUND:Since betaine is an osmolyte and methyl donor, and abnormal betaine loss is common in diabetes mellitus (>20% patients), we investigated the relationship between betaine and the post-methionine load rise in homocysteine, in diabetes and control subjects. The post-methionine load test is reported to be both an independent vascular risk factor and a measure of betaine sufficiency. METHODS:Patients with type 2 diabetes (n = 34) and control subjects (n = 17) were recruited. We measured baseline fasting plasma and 4-hour post-methionine load (L-methionine, 0.1 mg/kg body weight) concentrations of homocysteine, betaine, and the betaine metabolite N,N-dimethylglycine. Baseline urine excretions of betaine, dimethylglycine and glucose were measured on morning urine samples as the ratio to urine creatinine. Statistical determinants of the post-methionine load increase in homocysteine were identified in multiple linear regression models. RESULTS:Plasma betaine concentrations and urinary betaine excretions were significantly (p < 0.001) more variable in the subjects with diabetes compared with the controls. Dimethylglycine excretion (p = 0.00014) and plasma dimethylglycine concentrations (p = 0.039) were also more variable. In diabetes, plasma betaine was a significant negative determinant (p < 0.001) of the post-methionine load increase in homocysteine. However, it was not conclusive that this was different from the relationship in the controls. In the patients with diabetes, a strong relationship was found between urinary betaine excretion and urinary glucose excretion (but not with plasma glucose). CONCLUSIONS:Both high and low plasma betaine concentrations, and high and low urinary betaine excretions, are more prevalent in diabetes. The availability of betaine affects the response in the methionine load test. The benefits of increasing betaine intake should be investigated.
Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine.
Sekhar Rajagopal V,McKay Siripoom V,Patel Sanjeet G,Guthikonda Anuradha P,Reddy Vasumathi T,Balasubramanyam Ashok,Jahoor Farook
OBJECTIVE:Sustained hyperglycemia is associated with low cellular levels of the antioxidant glutathione (GSH), which leads to tissue damage attributed to oxidative stress. We tested the hypothesis that diminished GSH in adult patients with uncontrolled type 2 diabetes is attributed to decreased synthesis and measured the effect of dietary supplementation with its precursors cysteine and glycine on GSH synthesis rate and oxidative stress. RESEARCH DESIGN AND METHODS:We infused 12 diabetic patients and 12 nondiabetic control subjects with [²H₂]-glycine to measure GSH synthesis. We also measured intracellular GSH concentrations, reactive oxygen metabolites, and lipid peroxides. Diabetic patients were restudied after 2 weeks of dietary supplementation with the GSH precursors cysteine and glycine. RESULTS:Compared with control subjects, diabetic subjects had significantly higher fasting glucose (5.0 ± 0.1 vs. 10.7 ± 0.5 mmol/l; P < 0.001), lower erythrocyte concentrations of glycine (514.7 ± 33.1 vs. 403.2 ± 18.2 μmol/l; P < 0.01), and cysteine (25.2 ± 1.5 vs. 17.8 ± 1.5 μmol/l; P < 0.01); lower concentrations of GSH (6.75 ± 0.47 vs. 1.65 ± 0.16 μmol/g Hb; P < 0.001); diminished fractional (79.21 ± 5.75 vs. 44.86 ± 2.87%/day; P < 0.001) and absolute (5.26 ± 0.61 vs. 0.74 ± 0.10 μmol/g Hb/day; P < 0.001) GSH synthesis rates; and higher reactive oxygen metabolites (286 ± 10 vs. 403 ± 11 Carratelli units [UCarr]; P < 0.001) and lipid peroxides (2.6 ± 0.4 vs. 10.8 ± 1.2 pg/ml; P < 0.001). Following dietary supplementation in diabetic subjects, GSH synthesis and concentrations increased significantly and plasma oxidative stress and lipid peroxides decreased significantly. CONCLUSIONS:Patients with uncontrolled type 2 diabetes have severely deficient synthesis of glutathione attributed to limited precursor availability. Dietary supplementation with GSH precursor amino acids can restore GSH synthesis and lower oxidative stress and oxidant damage in the face of persistent hyperglycemia.
Metabolomics profiles associated with HbA1c levels in patients with type 2 diabetes.
Yun Jun Ho,Lee Heun-Sik,Yu Ho-Yeong,Kim Yeon-Jung,Jeon Hyun Jeong,Oh Taekeun,Kim Bong-Jo,Choi Hyung Jin,Kim Jeong-Min
Glycated hemoglobin (HbA1c) is an indicator of the average blood glucose concentration. Failing to control HbA1c levels can accelerate the development of complications in patients with diabetes. Although metabolite profiles associated with HbA1c level in diabetes patients have been characterized using different platforms, more studies using high-throughput technology will be helpful to identify additional metabolites related to diabetes. Type 2 diabetes (T2D) patients were divided into two groups based on the HbA1c level: normal (HbA1c ≤6%) and high (HbA1c ≥9%) in both discovery and replication sets. A targeted metabolomics approach was used to quantify serum metabolites and multivariate logistic regression was used to identify significant differences between groups. The concentrations of 22 metabolites differed significantly between the two groups in the discovery set. In the replication set, the levels of 21 metabolites, including 16 metabolites identified in the discovery set, differed between groups. Among these, concentrations of eleven amino acids and one phosphatidylcholine (PC), lysoPC a C16:1, were higher and four metabolites, including three PCs (PC ae C36:1, PC aa C26:0, PC aa C34:2) and hexose, were lower in the group with normal HbA1c group than in the group with high HbA1c. Metabolites with high concentrations in the normal HbA1c group, such as glycine, valine, and PCs, may contribute to reducing HbA1c levels in patients with T2D. The metabolite signatures identified in this study provide insight into the mechanisms underlying changes in HbA1c levels in T2D.
Plasma Glycine and Risk of Acute Myocardial Infarction in Patients With Suspected Stable Angina Pectoris.
Ding Yunpeng,Svingen Gard F T,Pedersen Eva R,Gregory Jesse F,Ueland Per M,Tell Grethe S,Nygård Ottar K
Journal of the American Heart Association
BACKGROUND:Glycine is an amino acid involved in antioxidative reactions, purine synthesis, and collagen formation. Several studies demonstrate inverse associations of glycine with obesity, hypertension, and diabetes mellitus. Recently, glycine-dependent reactions have also been linked to lipid metabolism and cholesterol transport. However, little evidence is available on the association between glycine and coronary heart disease. Therefore, we assessed the association between plasma glycine and acute myocardial infarction (AMI). METHODS AND RESULTS:A total of 4109 participants undergoing coronary angiography for suspected stable angina pectoris were studied. Cox regression was used to estimate the association between plasma glycine and AMI, obtained via linkage to the CVDNOR project. During a median follow-up of 7.4 years, 616 patients (15.0%) experienced an AMI. Plasma glycine was higher in women than in men and was associated with a more favorable baseline lipid profile and lower prevalence of obesity, hypertension, and diabetes mellitus (all P<0.001). After multivariate adjustment for traditional coronary heart disease risk factors, plasma glycine was inversely associated with risk of AMI (hazard ratio per SD: 0.89; 95% CI, 0.82-0.98; P=0.017). The inverse association was generally stronger in those with apolipoprotein B, low-density lipoprotein cholesterol, or apolipoprotein A-1 above the median (all Pinteraction≤0.037). CONCLUSIONS:Plasma glycine was inversely associated with risk of AMI in patients with suspected stable angina pectoris. The associations were stronger in patients with apolipoprotein B, low-density lipoprotein cholesterol, or apolipoprotein A-1 levels above the median. These results motivate further studies to elucidate the relationship between glycine and lipid metabolism, in particular in relation to cholesterol transport and atherosclerosis. CLINICAL TRIAL REGISTRATION:URL: https://www.clinicaltrials.gov. Unique identifier: NCT00354081.
Metabolomics insights into early type 2 diabetes pathogenesis and detection in individuals with normal fasting glucose.
Merino Jordi,Leong Aaron,Liu Ching-Ti,Porneala Bianca,Walford Geoffrey A,von Grotthuss Marcin,Wang Thomas J,Flannick Jason,Dupuis Josée,Levy Daniel,Gerszten Robert E,Florez Jose C,Meigs James B
AIMS/HYPOTHESIS:Identifying the metabolite profile of individuals with normal fasting glucose (NFG [<5.55 mmol/l]) who progressed to type 2 diabetes may give novel insights into early type 2 diabetes disease interception and detection. METHODS:We conducted a population-based prospective study among 1150 Framingham Heart Study Offspring cohort participants, age 40-65 years, with NFG. Plasma metabolites were profiled by LC-MS/MS. Penalised regression models were used to select measured metabolites for type 2 diabetes incidence classification (training dataset) and to internally validate the discriminatory capability of selected metabolites beyond conventional type 2 diabetes risk factors (testing dataset). RESULTS:Over a follow-up period of 20 years, 95 individuals with NFG developed type 2 diabetes. Nineteen metabolites were selected repeatedly in the training dataset for type 2 diabetes incidence classification and were found to improve type 2 diabetes risk prediction beyond conventional type 2 diabetes risk factors (AUC was 0.81 for risk factors vs 0.90 for risk factors + metabolites, p = 1.1 × 10). Using pathway enrichment analysis, the nitrogen metabolism pathway, which includes three prioritised metabolites (glycine, taurine and phenylalanine), was significantly enriched for association with type 2 diabetes risk at the false discovery rate of 5% (p = 0.047). In adjusted Cox proportional hazard models, the type 2 diabetes risk per 1 SD increase in glycine, taurine and phenylalanine was 0.65 (95% CI 0.54, 0.78), 0.73 (95% CI 0.59, 0.9) and 1.35 (95% CI 1.11, 1.65), respectively. Mendelian randomisation demonstrated a similar relationship for type 2 diabetes risk per 1 SD genetically increased glycine (OR 0.89 [95% CI 0.8, 0.99]) and phenylalanine (OR 1.6 [95% CI 1.08, 2.4]). CONCLUSIONS/INTERPRETATION:In individuals with NFG, information from a discrete set of 19 metabolites improved prediction of type 2 diabetes beyond conventional risk factors. In addition, the nitrogen metabolism pathway and its components emerged as a potential effector of earliest stages of type 2 diabetes pathophysiology.
An Assay of Selected Serum Amino Acids in Patients with Type 2 Diabetes Mellitus.
Drábková Petra,Šanderová Jana,Kovařík Jakub,kanďár Roman
Advances in clinical and experimental medicine : official organ Wroclaw Medical University
BACKGROUND:Amino acids are the building blocks of proteins. In case of insulin resistance, which is typical for type 2 diabetes mellitus (T2DM), proteolysis is increased and protein synthesis is decreased; therefore, we can observe changes in the levels of amino acids in diabetics vs. non-diabetics. OBJECTIVES:The aim of this study was to find differences in the levels of selected amino acids between patients with diabetes (type 2) and a control group. MATERIAL AND METHODS:Amino acids were derivatized with naphthalene-2,3-dicarboxaldehyde in the presence of potassium cyanide to form fluorescent 1-cyanobenz(f)isoindole product. Amino acids derivatives were measured using a high-performance liquid chromatography with fluorescence detection. The serum levels of glucose were determined using an automatic biochemistry analyzer, glycated hemoglobin HbA1c was measured by cation exchange chromatography. RESULTS:A total of 19 serum amino acids in T2DM patients and non-diabetics were measured. There were 9 amino acids, which were significantly different in these groups (p<0.05). Significantly decreased levels of arginine, asparagine, glycine, serine, threonine and significantly increased levels of alanine, isoleucine, leucine, valine in diabetics were found. CONCLUSIONS:Significant difference in metabolism of amino acids between diabetics and non-diabetics were observed. The altered levels of amino acids in diabetic patients could be a suitable predictor of diabetes.
Metabolomics of Type 1 and Type 2 Diabetes.
Arneth Borros,Arneth Rebekka,Shams Mohamed
International journal of molecular sciences
Type 1 and type 2 diabetes mellitus (DM) are chronic diseases that affect nearly 425 million people worldwide, leading to poor health outcomes and high health care costs. High-throughput metabolomics screening can provide vital insight into the pathophysiological pathways of DM and help in managing its effects. The primary aim of this study was to contribute to the understanding and management of DM by providing reliable evidence of the relationships between metabolites and type 1 diabetes (T1D) and metabolites and type 2 diabetes (T2D). Information for the study was obtained from the PubMed, MEDLINE, and EMBASE databases, and leads to additional articles that were obtained from the reference lists of the studies examined. The results from the selected studies were used to assess the relationships between diabetes (T1D and/or T2D) and metabolite markers-such as glutamine, glycine, and aromatic amino acids-in patients. Seventy studies were selected from the three databases and from the reference lists in the records retrieved. All studies explored associations between various metabolites and T1D or T2D. This review identified several plasma metabolites associated with T2D prediabetes and/or T1D and/or T2D in humans. The evidence shows that metabolites such as glucose, fructose, amino acids, and lipids are typically altered in individuals with T1D and T2D. These metabolites exhibit significant predictive associations with T2D prediabetes, T1D, and/or T2D. The current review suggests that changes in plasma metabolites can be identified by metabolomic techniques and used to identify and analyze T1D and T2D biomarkers. The results of the metabolomic studies can be used to help create effective interventions for managing these diseases.
Leucine-glycine and carnosine dipeptides prevent diabetes induced by multiple low-doses of streptozotocin in an experimental model of adult mice.
Journal of diabetes investigation
AIMS/INTRODUCTION:Peptides are considered to be quasi-hormones and effective molecules for regulation of the cells function and prevention of metabolic disorders. Di- and tripeptides gastrointestinal absorption ability have been proposed to prevent diabetes progression. MATERIALS AND METHODS:Small peptides with different sequences of specific amino acids were synthesized based on a solid phase peptide synthesis protocol, and carnosine (A) and glutathione were examined for the prevention of diabetes induced by multiple low-doses of streptozotocin in mice. RESULTS:The peptides A, Leu-Gly (D) and Pro-Pro showed preventive effects on blood glucose elevation and impairment of the signaling and performance of β-cells. The β-cell function assessed by immunofluorescence and blood glucose level in mice exposed to diabetes treated by the peptides A and D was similar to the normal mice. The peptide D prevented bodyweight loss caused by diabetes induction. The use of D and A peptides dramatically prevented the incidence of disruption in β-cells signaling by maintaining the natural balance of intracellular Akt-2 and cyclic adenosine monophosphate. CONCLUSIONS:The results proved that peptide D (Leu-Gly), named Hannaneh, inhibits the bodyweight loss caused by diabetes induction. The Hannaneh and carnosine dipeptides, with preservation of normal β-cell signaling and anti dipeptidyl peptidase-4 activity, prevented blood glucose increases in mice at risk of diabetes. These dipeptides might be regarded as the pharmaceutical agents for the prevention of diabetes.
Comprehensive analysis of serum metabolites in gestational diabetes mellitus by UPLC/Q-TOF-MS.
Liu Tianhu,Li Jiaxun,Xu Fengcheng,Wang Mengni,Ding Shijia,Xu Hongbing,Dong Fang
Analytical and bioanalytical chemistry
Gestational diabetes mellitus (GDM) refers to the first sign or onset of diabetes mellitus during pregnancy rather than progestation. In recent decades, more and more research has focused on the etiology and pathogenesis of GDM in order to further understand GDM progress and recovery. Using an advanced metabolomics platform based on ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS), we explored the changes in serum metabolites between women with GDM and healthy controls during and after pregnancy. Some significant differences were discovered using multivariate analysis including partial least-squares discriminant analysis (PLS-DA) and orthogonal PLS-DA (OPLS-DA). The dysregulated metabolites were further compared and verified in several databases to understand how these compounds might function as potential biomarkers. Analyses of the metabolic pathways associated with these potential biomarkers were subsequently explored. A total of 35 metabolites were identified, contributing to GDM progress to some extent. The identified biomarkers were involved in some important metabolic pathways including glycine, serine, and threonine metabolism; steroid hormone biosynthesis; tyrosine metabolism; glycerophospholipid metabolism; and fatty acid metabolism. The above mentioned metabolic pathways mainly participate in three major metabolic cycles in humans, including lipid metabolism, carbohydrate metabolism, and amino acid metabolism. In this pilot study, the valuable comprehensive analysis gave us further insight into the etiology and pathophysiology of GDM, which might benefit the feasibility of a rapid, accurate diagnosis and reasonable treatment as soon as possible but also prevent GDM and its related short- and long-term complications.
Amino acid profiling in the gestational diabetes mellitus.
Rahimi Najmeh,Razi Farideh,Nasli-Esfahani Ensieh,Qorbani Mostafa,Shirzad Nooshin,Larijani Bagher
Journal of diabetes and metabolic disorders
BACKGROUND:The prevalence of gestational diabetes mellitus (GDM) is increasing globally which is associated with various side effects for mothers and fetus. It seems that metabolomic profiling of the amino acids may be useful in early diagnosis of metabolic diseases. This study aimed to explore the association of the amino acids profiles with GDM. METHODS:Eighty three pregnant women with gestational age ≥25 weeks were randomly selected among pregnant women referred to prenatal care clinic in Arash hospital of Tehran, Iran. Women divided into three groups including 1) 25 pregnant women with normal glucose tolerance test, 2) 27 pregnant women with diabetes type 2 (T2D) (n: 27) and 3) 31 women with GDM (n: 31). Plasma levels of amino acids were measured by high performance liquid chromatography and were compared in three groups. Statistical analysis was performed using SPSS 16. RESULTS:Compared with normal mothers, GDM mothers showed higher plasma concentrations of Arginine ( = 0.01), Glycine ( = 0.01) and Methionine ( = 0.04), whereas the pregnant women with T2D had higher plasma levels of Asparagine ( = 0.01), Tyrosine ( < 0.01), Valine ( < 0.01), Phenylalanine ( < 0.01), Glutamine ( < 0.01) and Isolucine ( < 0.01). The results of regression analyses confirmed the significantly elevated in plasma concentration of Asparagine (OR:3.64, CI 1.22-10.47), Threonine (OR:3.38, CI 1.39-8.25), Aspartic acid (OR:3.92, CI 1.19-12.91), Phenylalanine (OR:2.66, CI 1.01-6.94), Glutamine (OR:2.53, CI 1.02-6.26) and Arginine (OR:1.96, CI 1.02-3.76) after adjustment for gestational age and BMI in GDM mothers compared to normal ones. CONCLUSIONS:Amino acids levels are associated with risk of GDM and diabetes mellitus. However further prospective studies are needed to clarify the role of different metabolites involved in mechanism of GDM.
Amino acid profile in women with gestational diabetes mellitus treated with metformin or insulin.
Huhtala Mikael S,Tertti Kristiina,Pellonperä Outi,Rönnemaa Tapani
Diabetes research and clinical practice
AIMS:We compared the effects of metformin and insulin treatments of gestational diabetes mellitus (GDM) on amino acid metabolism. METHODS:217 pregnant women diagnosed with GDM were randomized to receive either metformin or insulin. H nuclear magnetic spectroscopy was used to determine serum concentrations of alanine, glutamine, glycine, isoleucine, leucine, valine, histidine, phenylalanine, tyrosine, glucose and lactate at the time of diagnosis and at 36 gestational weeks (gw). RESULTS:Majority of the amino acid concentrations increased from 30 to 36 gw. The rise in alanine (16% vs. 8%, p < 0.0001), isoleucine (11% vs. 5%, p = 0.035) and lactate (29% vs. 14% p = 0.015) was larger in the metformin group compared to insulin group. Baseline alanine, glycine, isoleucine, leucine, valine and tyrosine were positively related to slightly earlier delivery. Alanine at 36 gw was positively associated with birth weight and glutamine with gestational hypertension or preeclampsia. Lactate at 36 gw was not associated with any adverse outcome. CONCLUSIONS:Compared to insulin metformin caused a greater increase in serum alanine, isoleucine and lactate concentrations. Although the observed differences in the metabolic variables were relatively small and not outright concerning, additional studies and follow-up data are required to ensure the safety of metformin use in pregnancy. The trial was registered in Clinicaltrials.gov, NCT01240785; http://clinicaltrials.gov/ct2/show/NCT01240785.
Glycine Metabolism and Its Alterations in Obesity and Metabolic Diseases.
Alves Anaïs,Bassot Arthur,Bulteau Anne-Laure,Pirola Luciano,Morio Béatrice
Glycine is the proteinogenic amino-acid of lowest molecular weight, harboring a hydrogen atom as a side-chain. In addition to being a building-block for proteins, glycine is also required for multiple metabolic pathways, such as glutathione synthesis and regulation of one-carbon metabolism. Although generally viewed as a non-essential amino-acid, because it can be endogenously synthesized to a certain extent, glycine has also been suggested as a conditionally essential amino acid. In metabolic disorders associated with obesity, type 2 diabetes (T2DM), and non-alcoholic fatty liver disease (NAFLDs), lower circulating glycine levels have been consistently observed, and clinical studies suggest the existence of beneficial effects induced by glycine supplementation. The present review aims at synthesizing the recent advances in glycine metabolism, pinpointing its main metabolic pathways, identifying the causes leading to glycine deficiency-especially in obesity and associated metabolic disorders-and evaluating the potential benefits of increasing glycine availability to curb the progression of obesity and obesity-related metabolic disturbances. This study focuses on the importance of diet, gut microbiota, and liver metabolism in determining glycine availability in obesity and associated metabolic disorders.
Glycine Transporter-1 and glycine receptor mediate the antioxidant effect of glycine in diabetic rat islets and INS-1 cells.
Chen Lei,Zhang Junqing,Li Changhong,Wang Ziwei,Li Jingjing,Zhao Dan,Wang Suxia,Zhang Hong,Huang Youyuan,Guo Xiaohui
Free radical biology & medicine
Oxidative stress is the main inducer of β-cell damage, which underlies the pathogenesis of diabetes. Evidence suggests that glycine, a recognized antioxidant, may improve β-cell function; however, its mechanism in protecting diabetic β-cells against oxidative stress has not been directly investigated. Using a streptozotocin-induced diabetic rat model and INS-1 pancreatic β-cells, we evaluated whether glycine can attenuate diabetic β-cell damage induced by oxidative stress. In diabetic rats, glycine stimulated insulin secretion; enhanced plasma glutathione (GSH), catalase and superoxide dismutase levels; reduced plasma 8-hydroxy-2 deoxyguanosine and islet p22 levels; and improved islet β-cell mitochondrial degeneration and insulin granule degranulation. In INS-1 cells, glycine reduced the intracellular reactive oxygen species (ROS) concentration and inhibited apoptosis induced by high glucose or HO. Glycine transporter-1 inhibitor blocked the antioxidative effect of glycine by reducing the intracellular GSH content, and glycine receptor inhibitor reversed the glycine antioxidative effect by blocking p22. Collectively, our findings reveal a mechanism by which glycine protects diabetic β-cells against damage caused by oxidative stress by increasing glycine transporter-1-mediated synthesis of GSH and by reducing glycine receptor-mediated ROS production.
Assessing the causal association of glycine with risk of cardio-metabolic diseases.
Wittemans Laura B L,Lotta Luca A,Oliver-Williams Clare,Stewart Isobel D,Surendran Praveen,Karthikeyan Savita,Day Felix R,Koulman Albert,Imamura Fumiaki,Zeng Lingyao,Erdmann Jeanette,Schunkert Heribert,Khaw Kay-Tee,Griffin Julian L,Forouhi Nita G,Scott Robert A,Wood Angela M,Burgess Stephen,Howson Joanna M M,Danesh John,Wareham Nicholas J,Butterworth Adam S,Langenberg Claudia
Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.
Glycine increases glyoxalase-1 function by promoting nuclear factor erythroid 2-related factor 2 translocation into the nucleus of kidney cells of streptozotocin-induced diabetic rats.
Journal of diabetes investigation
AIMS/INTRODUCTION:We have previously reported that glycine suppresses the advanced glycation end-products signaling pathway and mitigates subsequent oxidative stress in the kidneys of diabetic rats. In the present study, we investigated whether this beneficial effect was associated with upregulation of glyoxalase-1 (Glo1) and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2). MATERIALS AND METHODS:Both healthy rats and streptozotocin-induced diabetic rats were administrated with glycine (1% added to the drinking water) for 12 weeks. The function of Glo1, messenger ribonucleic acid (mRNA) and protein expressions of Nrf2, and markers of oxidative status were measured in the kidneys. The mRNA expressions of other downstream signaling molecules of the Nrf2 pathway were also determined. RESULTS:The mRNA and protein expressions, as well as the activity of Glo1, were decreased in the kidneys of diabetic rats, accompanied by diminished glutathione levels. After glycine treatment, these parameters of Glo1 function were markedly increased. Compared with the control group, the levels of Nrf2 mRNA and protein in the total kidney lysis were both markedly elevated in the diabetic group and glycine-treated group. However, the nuclear translocation of Nrf2 was significantly increased in the glycine-treated group than in the diabetic group. In addition, the anti-oxidant capacity and the expressions of other downstream molecules of the Nrf2 signaling pathway were significantly increased after glycine treatment. CONCLUSIONS:The present study shows that glycine might enhance the function of Glo1 and restore anti-oxidant defense by promoting the nuclear translocation of Nrf2, thus inhibiting advanced glycation end-products formation and protecting against renal oxidative stress.
The Profile of Plasma Free Amino Acids in Type 2 Diabetes Mellitus with Insulin Resistance: Association with Microalbuminuria and Macroalbuminuria.
Saleem Tahia,Dahpy Marwa,Ezzat Ghada,Abdelrahman Ghada,Abdel-Aziz Essam,Farghaly Rania
Applied biochemistry and biotechnology
Altered plasma levels of branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) may predict the development of insulin resistance and other type 2 diabetes mellitus (T2DM) associated comorbidities. To elucidate the role of plasma free amino acids (PFAAs) profile as a biomarker for early detection of diabetic kidney disease, quantitative measurement of PFAAs profile was determined for 90 T2DM subjects, 30 were free of nephropathy, 30 with microalbuminuria, 30 with macroalbuminuria, and in addition to 30 healthy controls. The plasma levels of valine, leucine, isoleucine, phenylalanine, citrulline, and total BCAAs were significantly increased in diabetic normoalbuminuria group when compared to controls. However, the total BCAAs level was significantly decreased in diabetic patients with micro and macroalbuminuria. Other amino acid plasma levels as tyrosine, arginine, ornithine, glycine, and the total AAAs level were significantly decreased in all diabetic subgroups compared to controls. Significant positive correlations between total BCAAs, valine, leucine, isoleucine, serum insulin, glucose, and HOMA-IR values in the diabetic normoalbuminuria group were found. The use of altered PFAAs profile as a prognostic factor in T2DM patients at risk for microalbuminuria or macroalbuminuria might reduce or prevent the incidence of end-stage diabetic renal disease.
Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.
Xie Weijia,Wood Andrew R,Lyssenko Valeriya,Weedon Michael N,Knowles Joshua W,Alkayyali Sami,Assimes Themistocles L,Quertermous Thomas,Abbasi Fahim,Paananen Jussi,Häring Hans,Hansen Torben,Pedersen Oluf,Smith Ulf,Laakso Markku, , , , ,Dekker Jacqueline M,Nolan John J,Groop Leif,Ferrannini Ele,Adam Klaus-Peter,Gall Walter E,Frayling Timothy M,Walker Mark
Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.
Genetic association of insulin receptor substrate-1 (IRS-1, rs1801278) gene with insulin resistant of type 2 diabetes mellitus in a Pakistani population.
Molecular biology reports
Insulin resistance (IR), a pathological condition of type 2 diabetes mellitus (T2DM) is characterized by an inability of body's tissue to respond the secreted or administered insulin, a necessary step for cellular glucose transportation. The prevalence of insulin resistance progresses with age, especially in overweight people with central obesity. Insulin receptor substrates (IRS) are important molecular proteins in the insulin signalling pathway, where IRS-1 plays a key function in cells insulin sensitivity. The common mutation (rs1801278; r.2963G > A: Gly972Arg) of the IRS-1 gene occurs when residue glycine changes to arginine at codon 972. The objective of this study was to detect the genetic association of rs1801278 polymorphism of the IRS-1 gene with insulin resistance in type 2 diabetes from the Lahore region of Pakistan. A total of 322 subjects (161 cases and 161 healthy individuals) were included. DNA was isolated for detection of the genotype distribution and allele frequencies by PCR-RFLP. The results showed a significant difference in the genotype distribution and allele frequency between the T2DM cases and controls for single nucleotide polymorphism (SNP) rs1801278 (OR 17.61, 95% CI 8.06-38.4, p < 0.001). In conclusion, association between rs1801278 polymorphism of the IRS-1 gene and insulin resistance in T2DM has been established in a Pakistani population.
Insulin resistance and glycine metabolism in humans.
Adeva-Andany M,Souto-Adeva G,Ameneiros-Rodríguez E,Fernández-Fernández C,Donapetry-García C,Domínguez-Montero A
Plasma glycine level is low in patients with obesity or diabetes and the improvement of insulin resistance increases plasma glycine concentration. In prospective studies, hypoglycinemia at baseline predicts the risk of developing type 2 diabetes and higher serum glycine level is associated with decreased risk of incident type 2 diabetes. Consistently, plasma glycine concentration is lower in the lean offspring of parents with type 2 diabetes compared to healthy subjects. Among patients with type 2 diabetes, hypoglycinemia occurs before clinical manifestations of the disease, but the pathophysiological mechanisms underlying glycine deficit and its potential clinical repercussions are unclear. Glycine participates in several metabolic pathways, being required for relevant human physiological processes. Humans synthesize glycine from glyoxylate, glucose (via serine), betaine and likely from threonine and during the endogenous synthesis of L-carnitine. Glycine conjugates bile acids and other acyl moieties producing acyl-glycine derivatives. The glycine cleavage system catalyzes glycine degradation to carbon dioxide and ammonium while tetrahydrofolate is converted into 5,10-methylene-tetrahydrofolate. Glycine is utilized to synthesize serine, sarcosine, purines, creatine, heme group, glutathione, and collagen. Glycine is a major quantitative component of collagen. In addition, the role of glycine maintaining collagen structure is critical, as glycine residues are required to stabilize the triple helix of the collagen molecule. This quality of glycine likely contributes to explain the occurrence of medial arterial calcification and the elevated cardiovascular risk associated with diabetes and chronic kidney disease, as emerging evidence links normal collagen content with the initiation and progression of vascular calcification in humans.
Glycine mitigates renal oxidative stress by suppressing Nox4 expression in rats with streptozotocin-induced diabetes.
Wang Ziwei,Zhang Junqing,Wang Limei,Li Wei,Chen Lei,Li Jingjing,Zhao Dan,Zhang Hong,Guo Xiaohui
Journal of pharmacological sciences
Glycine exerts renoprotective effects, but the mechanism remains unclear. Glycine is increasingly recognized as a factor that attenuates oxidative stress, a key mechanism underlying diabetic nephropathy. In this study, we investigated the effects of glycine on diabetic renal injury and oxidative stress by adding 1% glycine in the drinking water of rats with streptozotocin-induced diabetes for 20 weeks. Glycine levels decreased in the plasma and kidney homogenates of diabetic rats but were restored by oral glycine administration. In these diabetic rats, glycine attenuated renal damage, as evidenced by the decreased mesangial expansion, tubular interstitial fibrosis, and neutrophil gelatinase-associated lipocalin (NGAL) expression. Glycine also ameliorated the raise in urinary malondialdehyde (MDA) levels and partially restored renal glutathione levels in diabetic rats. Renal levels of the Nox4 mRNA and protein, a major source of renal oxidative stress, were suppressed by the treatment with glycine. Immunohistological analysis revealed that glycine had protective effects on the tubular area rather than the glomerular area. Our results strongly suggest that the protective effect of glycine on renal oxidative stress and structural damage may be linked to enhancement of GSH synthesis and suppression of renal Nox4 expression in diabetic rats.
Metabolomics-Based Prospective Studies and Prediction of Type 2 Diabetes Mellitus Risks.
Satheesh Gopika,Ramachandran Surya,Jaleel Abdul
Metabolic syndrome and related disorders
The preceding decade has witnessed an intense upsurge in the diabetic population across the world making type 2 diabetes mellitus (T2DM) more of an epidemic than a lifestyle disease. Metabolic disorders are often latent for a while before becoming clinically evident, thus reinforcing the pursuit of early biomarkers of metabolic alterations. A prospective study along with metabolic profiling is the most appropriate way to detect the early pathophysiological changes in metabolic diseases such as T2DM. The aim of this review was to summarize the different potential biomarkers of T2DM identified in prospective studies, which used tools of metabolomics. The review also demonstrates on how metabolomic profiling-based prospective studies can be used to address a concern like population-specific disease mechanism. We performed a literature search on metabolomics-based prospective studies on T2DM using the key words "metabolomics," "Type 2 diabetes," "diabetes mellitus", "metabolite profiling," "prospective study," "metabolism," and "biomarker." Additional articles that were obtained from the reference lists of the articles obtained using the above key words were also examined. Articles on dietary intake, type 1 diabetes mellitus, and gestational diabetes were excluded. The review revealed that many studies showed a direct association of branched-chain amino acids and an inverse association of glycine with T2DM. Majority of the prospective studies conducted were targeted metabolomics-based, with Caucasians as their study cohort. The whole disease risk in populations, including Asians, could therefore not be identified. This review proposes the utility of prospective studies in conjunction with metabolomics platform to unravel the altered metabolic pathways that contribute to the risk of T2DM.
Protective effect of glycine in streptozotocin-induced diabetic cataract through aldose reductase inhibitory activity.
Li Wei,Zhang Yujie,Shao Na
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
Glycine is a proteinogenic amino acid that serves as a precursor for several proteins. The anti-cataract effects of lysine and other amino acid mixtures in animal models have been reported. Normal rats were administered saline and formed the normal control group (group I). Diabetic rats were administered streptozotocin and were the diabetic control group (group II). Rats were administered glycine (250 mg and 500 mg/kg of body weight) formed groups III and IV, respectively. Diabetic rats were administered sorbinil and were served as positive control (group V). The body weight changes, serum glucose, plasma insulin, total protein, glutathione (GSH) content, and mRNA and protein levels of aldose reductase were determined. Glycine treatment increased body weight gain, reduced blood glucose, and increased plasma insulin levels compared to diabetic control rats, and also increased GSH content and decreased mRNA and protein levels of aldose reductase compared to their respective controls. In summary, glycine supplementation effectively inhibited aldose reductase enzyme activity in experimental diabetic rats.
Metabolite biomarkers of type 2 diabetes mellitus and pre-diabetes: a systematic review and meta-analysis.
Long Jianglan,Yang Zhirui,Wang Long,Han Yumei,Peng Cheng,Yan Can,Yan Dan
BMC endocrine disorders
BACKGROUND:We aimed to explore metabolite biomarkers that could be used to identify pre-diabetes and type 2 diabetes mellitus (T2DM) using systematic review and meta-analysis. METHODS:Four databases, the Cochrane Library, EMBASE, PubMed and Scopus were selected. A random effect model and a fixed effect model were applied to the results of forest plot analyses to determine the standardized mean difference (SMD) and 95% confidence interval (95% CI) for each metabolite. The SMD for every metabolite was then converted into an odds ratio to create an metabolite biomarker profile. RESULTS:Twenty-four independent studies reported data from 14,131 healthy individuals and 3499 patients with T2DM, and 14 included studies reported 4844 healthy controls and a total of 2139 pre-diabetes patients. In the serum and plasma of patients with T2DM, compared with the healthy participants, the concentrations of valine, leucine, isoleucine, proline, tyrosine, lysine and glutamate were higher and that of glycine was lower. The concentrations of isoleucine, alanine, proline, glutamate, palmitic acid, 2-aminoadipic acid and lysine were higher and those of glycine, serine, and citrulline were lower in prediabetic patients. Metabolite biomarkers of T2DM and pre-diabetes revealed that the levels of alanine, glutamate and palmitic acid (C16:0) were significantly different in T2DM and pre-diabetes. CONCLUSIONS:Quantified multiple metabolite biomarkers may reflect the different status of pre-diabetes and T2DM, and could provide an important reference for clinical diagnosis and treatment of pre-diabetes and T2DM.
A Glycine-Insulin Autocrine Feedback Loop Enhances Insulin Secretion From Human β-Cells and Is Impaired in Type 2 Diabetes.
Yan-Do Richard,Duong Eric,Manning Fox Jocelyn E,Dai Xiaoqing,Suzuki Kunimasa,Khan Shara,Bautista Austin,Ferdaoussi Mourad,Lyon James,Wu Xichen,Cheley Stephen,MacDonald Patrick E,Braun Matthias
The secretion of insulin from pancreatic islet β-cells is critical for glucose homeostasis. Disrupted insulin secretion underlies almost all forms of diabetes, including the most common form, type 2 diabetes (T2D). The control of insulin secretion is complex and affected by circulating nutrients, neuronal inputs, and local signaling. In the current study, we examined the contribution of glycine, an amino acid and neurotransmitter that activates ligand-gated Cl(-) currents, to insulin secretion from islets of human donors with and without T2D. We find that human islet β-cells express glycine receptors (GlyR), notably the GlyRα1 subunit, and the glycine transporter (GlyT) isoforms GlyT1 and GlyT2. β-Cells exhibit significant glycine-induced Cl(-) currents that promote membrane depolarization, Ca(2+) entry, and insulin secretion from β-cells from donors without T2D. However, GlyRα1 expression and glycine-induced currents are reduced in β-cells from donors with T2D. Glycine is actively cleared by the GlyT expressed within β-cells, which store and release glycine that acts in an autocrine manner. Finally, a significant positive relationship exists between insulin and GlyR, because insulin enhances the glycine-activated current in a phosphoinositide 3-kinase-dependent manner, a positive feedback loop that we find is completely lost in β-cells from donors with T2D.
An association between glycine and insulin levels is observed in patients with pulmonary tuberculosis and type 2 diabetes.
Zenil-Vega Mariela,Cerón Eduarda,López-Bello Guadalupe,Moreno Julia,Juárez-Cruz Eliuth,Castillejos-López Manuel,Bernal-Alcántara Demetrio,Sommer Bettina,Alvarado-Vasquez Noé
Clinical nutrition (Edinburgh, Scotland)
BACKGROUND & AIMS:Adequate nutrition from which amino acids are part gives us protection against infectious or metabolic diseases. In particular, glycine has immunomodulatory properties and is a secretagogue of insulin. However, its absorption rate or plasma levels are impaired in bacterial infection or high glucose levels. The aim of this study was to evaluate the association between glycine and insulin plasma levels in patients with pulmonary tuberculosis (PTB) and type 2 diabetes mellitus (DM2). METHODS:Plasma levels of insulin and glycine were determined in four groups: 1) patients with PTB; 2) patients with PTB-DM2; 3) household contacts with DM2 (C-DM2), and 4) healthy household contacts (H-C). Likewise, we analyzed the plasma levels of glucose, serine, arginine, lysine, taurine, and glutamic acid. RESULTS:We observed significant differences in the glycine levels between PTB and PTB-DM2 vs C-DM2 and H-C groups (P < 0.05). We observed also important differences in insulin and glucose levels after comparisons between PTB, PTB-DM2, and C-DM2 vs. H-C groups (P < 0.05). A correlation between glycine and insulin levels in the PTB (r = 0.326) and PTB-DM2 (r = 0.318) groups was found. CONCLUSION:Our results showed a significant association between glycine and insulin plasma levels in patients with PTB and PTB-DM2, which suggests that the determination of glycine levels could be used as a reference test to evaluate both pathologic conditions. An additional support to the above is that significant changes in the glucose levels in these groups were observed, too.
Impaired "Glycine"-mia in Type 2 Diabetes and Potential Mechanisms Contributing to Glucose Homeostasis.
Yan-Do Richard,MacDonald Patrick E
The onset and/or progression of type 2 diabetes (T2D) can be prevented if intervention is early enough. As such, much effort has been placed on the search for indicators predictive of prediabetes and disease onset or progression. An increasing body of evidence suggests that changes in plasma glycine may be one such biomarker. Circulating glycine levels are consistently low in patients with T2D. Levels of this nonessential amino acid correlate negatively with obesity and insulin resistance. Plasma glycine correlates positively with glucose disposal, and rises with interventions such as exercise and bariatric surgery that improve glucose homeostasis. A role for glycine in the regulation of glucose, beyond being a potential biomarker, is less clear, however. Dietary glycine supplementation increases insulin, reduces systemic inflammation, and improves glucose tolerance. Emerging evidence suggests that glycine, a neurotransmitter, also acts directly on target tissues that include the endocrine pancreas and the brain via glycine receptors and as a coligand for N-methyl-d-aspartate glutamate receptors to control insulin secretion and liver glucose output, respectively. Here, we review the current evidence supporting a role for glycine in glucose homeostasis via its central and peripheral actions and changes that occur in T2D.