Oxidative stress and the JNK pathway as a potential therapeutic target for diabetes. Kaneto Hideaki,Kawamori Dan,Nakatani Yoshihisa,Gorogawa Shin-ichi,Matsuoka Taka-aki Drug news & perspectives Oxidative stress is produced under diabetic conditions and is likely involved in progression of pancreatic beta-cell dysfunction found in diabetes. Possibly due to low levels of antioxidant enzyme expressions, beta-cells are vulnerable to oxidative stress. When beta-cell-derived cell lines or isolated rat islets were exposed to oxidative stress, insulin gene expression was markedly decreased. Furthermore, when diabetic C57BL/ KsJ-db/db mice were treated with antioxidants, glucose tolerance was ameliorated. Histological analyses of the pancreata revealed that the beta-cell mass is significantly larger in the mice treated with the antioxidants. The antioxidant treatment also preserved the amounts of insulin content and insulin mRNA. As a possible mechanism underlying the phenomena, expression of pancreatic and duodenal homeobox factor-1 (PDX-1), an important transcription factor for the insulin gene, was more clearly visible in the nuclei of islet cells after the antioxidant treatment. Furthermore, oxidative stress induces nucleocytoplasmic translocation of PDX-1 through activation of the c-Jun N-terminal kinase (JNK) pathway, which leads to suppression of insulin gene expression. Taken together, oxidative stress and consequent activation of the JNK pathway are involved in progression of beta-cell dysfunction found in diabetes, and thus are a therapeutic target for diabetes. 10.1358/dnp.2004.17.7.863704
    Branched-chain amino acids supplementation protects streptozotocin-induced insulin secretion and the correlated mechanism. Lu Ming,Zhang Xiujuan,Zheng Dongmei,Jiang Xiuyun,Chen Qing BioFactors (Oxford, England) Significant evidence demonstrates that oxidative stress can impair insulin secretion and contribute to the development of type 2 diabetes. Branched-chain amino acids (BCAAs) are reported to be positively related to insulin secretion. This study aimed to determine how oxidative stress affects the function of islets and whether BCAAs can ameliorate the oxidative stress, and accompanying c-jun N-terminal kinase (JNK), protein kinase D1 (PKD1), and pancreatic/duodenal homeobox-1 (PDX-1) changes induced by streptozotocin (STZ). Plasma glucose, plasma insulin, and JNK, PKD1 and PDX-1 mRNA and protein expression were measured in rats treated with STZ and BCAAs. The glucose level in STZ-induced diabetic rats was much higher than that in control animals, and the elevated plasma glucose level in diabetic rats could be significantly inhibited by BCAAs treatment. Consistent with the change in glucose levels, the levels of insulin were also affected by BCAAs treatment. The mRNA and protein expression of JNK, PDX-1, and PKD1 were significantly altered in diabetic rats compared with the control group (P<0.01) and treatment with a low dose of BCAA reversed these changes in those above markers significantly (P<0.01). The present study demonstrated that STZ-induced oxidative stress could reduce serum insulin levels and alter the JNK, PDX-1, and PKD1 expression. BCAAs restored the levels of serum insulin reversed changes in JNK, PDX-1, and PKD1 expression. 10.1002/biof.1188
    Branched-chain amino acids attenuate early kidney injury in diabetic rats. Mi Na,Zhang Xiu Juan,Ding Yan,Li Guo Hua,Wang Wei Dong,Xian Hui Xia,Xu Jin Biochemical and biophysical research communications Diabetic nephropathy (DN) is the most severe diabetic microvascular complication. The pathogenesis of diabetic nephropathy is complex, and oxidative stress plays an important role in the development of diabetic nephropathy. Elevated reactive oxygen species (ROS) levels activate various signaling pathways and influence the activities of transforming growth factor-β (TGF-β) and matrix metalloproteinase-9 (MMP-9), which contributes to glomerular hypertrophy. Branched-chain amino acids (BCAAs) are widely used in clinical treatment, and BCAAs can reduce the oxidative stress associated with the diabetic pancreas and some liver diseases. Thus, the aim of the present study was to determine whether BCAAs could attenuate oxidative stress in the kidneys of streptozotocin (STZ)-induced diabetic rats to prevent early diabetic kidney injury. Male Wistar rats were fed for two weeks with a normal chow diet or a high-fat diet in which 40% of calories were derived from fat. After this two-week period, the mice fed normal chow were injected with vehicle, while the high-fat diet group was injected intraperitoneally (i.p.) with 40 mg/kg STZ. The STZ-treated group was randomly divided into four subgroups that were treated with different doses of BCAAs or vehicle for two months by oral gavage. Plasma glucose, plasma creatinine, urinary protein and JNK, TGF-β, and MMP-9 mRNA and protein expression levels were measured in the rats. The ROS levels and proteinuria in the STZ-induced diabetic rats were significantly higher than those in the control groups. Moreover, early kidney injury occurred in the STZ-induced diabetic rats. However, BCAAs treatment decreased ROS levels, proteinuria and kidney injury. Moreover, JNK, TGF-β and MMP-9 mRNA and protein levels were significantly increased in the diabetic rats when compared with the control rats, and BCAAs treatment reversed these changes. Our results suggest that BCAAs counter oxidative stress in the kidneys of diabetic rats and alleviate diabetic kidney injury via the JNK/TGF-β/MMP-9 pathway. 10.1016/j.bbrc.2015.09.017
    Branched-chain amino acids in metabolic signalling and insulin resistance. Lynch Christopher J,Adams Sean H Nature reviews. Endocrinology Branched-chain amino acids (BCAAs) are important nutrient signals that have direct and indirect effects. Frequently, BCAAs have been reported to mediate antiobesity effects, especially in rodent models. However, circulating levels of BCAAs tend to be increased in individuals with obesity and are associated with worse metabolic health and future insulin resistance or type 2 diabetes mellitus (T2DM). A hypothesized mechanism linking increased levels of BCAAs and T2DM involves leucine-mediated activation of the mammalian target of rapamycin complex 1 (mTORC1), which results in uncoupling of insulin signalling at an early stage. A BCAA dysmetabolism model proposes that the accumulation of mitotoxic metabolites (and not BCAAs per se) promotes β-cell mitochondrial dysfunction, stress signalling and apoptosis associated with T2DM. Alternatively, insulin resistance might promote aminoacidaemia by increasing the protein degradation that insulin normally suppresses, and/or by eliciting an impairment of efficient BCAA oxidative metabolism in some tissues. Whether and how impaired BCAA metabolism might occur in obesity is discussed in this Review. Research on the role of individual and model-dependent differences in BCAA metabolism is needed, as several genes (BCKDHA, PPM1K, IVD and KLF15) have been designated as candidate genes for obesity and/or T2DM in humans, and distinct phenotypes of tissue-specific branched chain ketoacid dehydrogenase complex activity have been detected in animal models of obesity and T2DM. 10.1038/nrendo.2014.171
    Branched-chain amino acid supplementation reduces oxidative stress and prolongs survival in rats with advanced liver cirrhosis. Iwasa Motoh,Kobayashi Yoshinao,Mifuji-Moroka Rumi,Hara Nagisa,Miyachi Hirohide,Sugimoto Ryosuke,Tanaka Hideaki,Fujita Naoki,Gabazza Esteban C,Takei Yoshiyuki PloS one Long-term supplementation with branched-chain amino acids (BCAA) is associated with prolonged survival and decreased frequency of development of hepatocellular carcinoma (HCC) in patients with liver cirrhosis. However, the pharmaceutical mechanism underlying this association is still unclear. We investigated whether continuous BCAA supplementation increases survival rate of rats exposed to a fibrogenic agent and influences the iron accumulation, oxidative stress, fibrosis, and gluconeogenesis in the liver. Further, the effects of BCAA on gluconeogenesis in cultured cells were also investigated. A significant improvement in cumulative survival was observed in BCAA-supplemented rats with advanced cirrhosis compared to untreated rats with cirrhosis (P<0.05). The prolonged survival due to BCAA supplementation was associated with reduction of iron contents, reactive oxygen species production and attenuated fibrosis in the liver. In addition, BCAA ameliorated glucose metabolism by forkhead box protein O1 pathway in the liver. BCAA prolongs survival in cirrhotic rats and this was likely the consequences of reduced iron accumulation, oxidative stress and fibrosis and improved glucose metabolism in the liver. 10.1371/journal.pone.0070309
    Branched-chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation. Zhenyukh Olha,González-Amor Maria,Rodrigues-Diez Raul R,Esteban Vanesa,Ruiz-Ortega Marta,Salaices Mercedes,Mas Sebastian,Briones Ana M,Egido Jesus Journal of cellular and molecular medicine Branched-chain amino acids (BCAA: leucine, isoleucine and valine) are essential amino acids implicated in glucose metabolism and maintenance of correct brain function. Elevated BCAA levels can promote an inflammatory response in peripheral blood mononuclear cells. However, there are no studies analysing the direct effects of BCAA on endothelial cells (ECs) and its possible modulation of vascular function. In vitro and ex vivo studies were performed in human ECs and aorta from male C57BL/6J mice, respectively. In ECs, BCAA (6 mmol/L) increased eNOS expression, reactive oxygen species production by mitochondria and NADPH oxidases, peroxynitrite formation and nitrotyrosine expression. Moreover, BCAA induced pro-inflammatory responses through the transcription factor NF-κB that resulted in the release of intracellular adhesion molecule-1 and E-selectin conferring endothelial activation and adhesion capacity to inflammatory cells. Pharmacological inhibition of mTORC1 intracellular signalling pathway decreased BCAA-induced pro-oxidant and pro-inflammatory effects in ECs. In isolated murine aorta, BCAA elicited vasoconstrictor responses, particularly in pre-contracted vessels and after NO synthase blockade, and triggered endothelial dysfunction, effects that were inhibited by different antioxidants, further demonstrating the potential of BCAA to induce oxidative stress with functional impact. In summary, we demonstrate that elevated BCAA levels generate inflammation and oxidative stress in ECs, thereby facilitating inflammatory cells adhesion and endothelial dysfunction. This might contribute to the increased cardiovascular risk observed in patients with elevated BCAA blood levels. 10.1111/jcmm.13759
    Effect of valine on myotube insulin sensitivity and metabolism with and without insulin resistance. Rivera Madison E,Lyon Emily S,Johnson Michele A,Sunderland Kyle L,Vaughan Roger A Molecular and cellular biochemistry Population data have consistently demonstrated a correlation between circulating branched-chain amino acids (BCAA) and insulin resistance. Most recently valine catabolite, 3-hydroxyisobutyrate, has emerged as a potential cause of BCAA-mediated insulin resistance; however, it is unclear if valine independently promotes insulin resistance. It is also unclear if excess valine influences the ability of cells to degrade BCAA. Therefore, this study investigated the effect of valine on muscle insulin signaling and related metabolism in vitro. C2C12 myotubes were treated with varying concentrations (0.5 mM-2 mM) of valine for up to 48 h. qRT-PCR and western blot were used to measure metabolic gene and protein expression, respectively. Insulin sensitivity (indicated by pAkt:Akt), metabolic gene and protein expression, and cell metabolism were also measured following valine treatment both with and without varying levels of insulin resistance. Mitochondrial and glycolytic metabolism were measured via oxygen consumption and extracellular acidification rate, respectively. Valine did not alter regulators of mitochondrial biogenesis or glycolysis; however, valine reduced branched-chain alpha-keto acid dehydrogenase a (Bckdha) mRNA (but not protein) expression which was exacerbated by insulin resistance. Valine treatment had no effect on pAkt:Akt following either acute or 48-h treatment, regardless of insulin stimulation or varying levels of insulin resistance. In conclusion, despite consistent population data demonstrating a relationship between circulating BCAA (and related metabolites) and insulin resistance, valine does not appear to independently alter insulin sensitivity or worsen insulin resistance in the myotube model of skeletal muscle. 10.1007/s11010-020-03720-y
    Isolated high home systolic blood pressure in patients with type 2 diabetes is a prognostic factor for the development of diabetic nephropathy: KAMOGAWA-HBP study. Kitagawa Nobuko,Ushigome Emi,Tanaka Toru,Hasegawa Goji,Nakamura Naoto,Ohnishi Masayoshi,Tsunoda Sei,Ushigome Hidetaka,Yokota Isao,Kitagawa Noriyuki,Hamaguchi Masahide,Asano Mai,Yamazaki Masahiro,Fukui Michiaki Diabetes research and clinical practice BACKGROUND:Isolated high home systolic blood pressure (IH-HSBP) has been revealed to be correlated with cardiovascular disease and diabetic nephropathy, however, the prognostic significance of IH-HSBP with the development of diabetic nephropathy is unclear. METHODS:In this prospective 2-year cohort study of 477 patients with normoalbuminuria, we investigated the effect of IH-HSBP on the development of diabetic nephropathy defined by diabetic nephropathy advanced from normoalbuminuira to micro or macroalbuminuria. RESULTS:Among 477 patients, 67 patients showed the development of diabetic nephropathy. In the multivariate logistic regression analyses, IH-HSBP was prognostic factor for the development of nephropathy after adjusting for sex, age, duration of diabetes mellitus, body mass index, total cholesterol, hemoglobin A1c, creatinine, smoking habits and use of renin-angiotensin-aldosterone system inhibitors (odds ratio: 2.53, 95% confidence interval: 1.16-5.56, p = 0.020). CONCLUSION:IH-HSBP in patients with type 2 diabetes with normoalbuminuria was prognostic factor for the development of diabetic nephropathy. We should pay more attention to IH-HSBP to prevent the development of diabetic nephropathy. 10.1016/j.diabres.2019.107920
    Serum levels of CTRP3 in diabetic nephropathy and its relationship with insulin resistance and kidney function. Moradi Nariman,Fadaei Reza,Khamseh Mohammad Ebrahim,Nobakht Ali,Rezaei Mohammad Jafar,Aliakbary Fereshteh,Vatannejad Akram,Hosseini Jalil PloS one BACKGROUND:C1q TNF related protein 3 (CTRP3) is an adipokine secreted from adipose tissue. Previous studies have suggested that CTRP3 improves insulin sensitivity and reduces inflammation. Human studies have evaluated circulating levels of this adipokine in patients with diabetes mellitus (DM), diabetic retinopathy, metabolic syndrome, and coronary artery diseases. However, circulating levels of this adipokine in patients with diabetic nephropathy have not been evaluated. The present study aimed to assess serum levels of CTRP3 in patients with type 2 diabetes mellitus (T2DM) and diabetic nephropathy (T2DM-NP) and its relationship with metabolic and inflammatory markers. METHODS:This cross-sectional study was performed on 55 controls, 54 patients with T2DM, and 55 patients with T2DM-NP. Serum levels of CTRP3, adiponectin, TNF-α, and IL-6 were measured by ELISA technique. RESULTS:Serum levels of CTRP3 were significantly lower in patients with T2DM (257.61 ± 69.79 ng/mL, p < 0.001) and T2DM-NP (222.03 ± 51.99 ng/mL, p < 0.001) compared to controls (328.17 ± 80.73 ng/mL), and those with T2DM-NP compared to T2DM group. CTRP3 was independently associated with HOMA-IR (r = -0.327, p < 0.05) and adiponectin (r = 0.436, p < 0.01) in T2DM group. In T2DM-NP patients, CTRP3 independently was associated with eGFR (r = 0.428, p < 0.01) and HOMA-IR (r = -0.436, p < 0.01). Furthermore, CTRP3 revealed a ability to differentiate T2DM-NP patients from controls (area under curve (95% confidence interval): 0.881 (0.820-0.943) and p < 0.001). CONCLUSION:Decreased serum levels of CTRP3 in patients with T2DM and diabetic nephropathy and its association with pathologic mechanism in these patients suggested a possible role for CTRP3 in pathogenesis of diabetic nephropathy; nevertheless, further studies are required in this regard. 10.1371/journal.pone.0215617
    Proinsulin/insulin ratio as a predictor of insulin resistance in patients with diabetic nephropathy. El-Messallamy Fawzy A F,El-Ashmawy Hazem M,El Shabrawy Arafa M,Radwan Samia E Diabetes & metabolic syndrome Patients with Diabetic nephropathy (DN) have an increase in cardiovascular mortality, and since IR may be a contributing factor. Therefore, the aim of this study was to assess the role of pro insulin/insulin ratio as a predictor of insulin resistance in patients with diabetic nephropathy PATIENTS AND METHODS: A Case-control study was conducted in a total of 50 patients who diagnosed with type 2 diabetes mellitus from July 2017 to March 2018. The patients were divided into 2 groups according to presence of diabetic nephropathy. Demographic and clinical data were collected. RESULTS: There is a significant increase in serum pro insulin/insulin ratio in patients with diabetic nephropathy patients compared to patients without diabetic nephropathy An association was found between increase serum pro insulin/insulin ratio and increase predicting of insulin resistance. Cut-off value of serum pro insulin/insulin ratio ≥0.1145 with sensitivity and specificity of 92.3 and 60.3 respectively as a predictor for insulin resistance CONCLUSION: This study demonstrate a strong relationship between insulin resistance and CKD and this relationship was stronger in the presence of obesity. Pro insulin/insulin ratio was found to be a significant predictor for insulin resistance. 10.1016/j.dsx.2019.04.036
    Diabetes and branched-chain amino acids: What is the link? Bloomgarden Zachary 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. 10.1111/1753-0407.12645
    Metabolomic determination of pathogenesis of late-onset preeclampsia. Bahado-Singh Ray O,Syngelaki Argyro,Mandal Rupsari,Graham Stewart F,Akolekar Ranjit,Han Beomsoo,Bjondahl Trent C,Dong Edison,Bauer Samuel,Alpay-Savasan Zeynep,Turkoglu Onur,Ogunyemi Dotun,Poon Liona C,Wishart David S,Nicolaides Kypros H 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:Our primary objective was to apply metabolomic pathway analysis of first trimester maternal serum to provide an insight into the pathogenesis of late-onset preeclampsia (late-PE) and thereby identify plausible therapeutic targets for PE. METHODS:NMR-based metabolomics analysis was performed on 29 cases of late-PE and 55 unaffected controls. In order to achieve sufficient statistical power to perform the pathway analysis, these cases were combined with a group of previously analyzed specimens, 30 late-PE cases and 60 unaffected controls. Specimens from both groups of cases and controls were collected in the same clinical centers during the same time period. In addition, NMR analyses were performed in the same lab and using the same techniques. RESULTS:We identified abnormalities in branch chain amino acids (valine, leucine and isoleucine) and propanoate, glycolysis, gluconeogenesis and ketone body metabolic pathways. The results suggest insulin resistance and metabolic syndrome, mitochondrial dysfunction and disturbance of energy metabolism, oxidative stress and lipid dysfunction in the pathogenesis of late PE and suggest a potential role for agents that reduce insulin resistance in PE. CONCLUSIONS:Branched chain amino acids are known markers of insulin resistance and strongly predict future diabetes development. The analysis provides independent evidence linking insulin resistance and late-PE and suggests a potentially important therapeutic role for pharmacologic agents that reduce insulin resistance for late-PE. 10.1080/14767058.2016.1185411
    Effect of metformin on plasma metabolite profile in the Copenhagen Insulin and Metformin Therapy (CIMT) trial. Safai N,Suvitaival T,Ali A,Spégel P,Al-Majdoub M,Carstensen B,Vestergaard H,Ridderstråle M, Diabetic medicine : a journal of the British Diabetic Association AIM:Metformin is the first-line treatment for Type 2 diabetes. However, not all people benefit from this drug. Our aim was to investigate the effects of metformin on the plasma metabolome and whether the pretreatment metabolite profile can predict HbA outcome. METHODS:Post hoc analysis of the Copenhagen Insulin and Metformin Therapy (CIMT) trial, a multicentre study from May 2008 to December 2012, was carried out. We used a non-target method to analyse 87 plasma metabolites in participants with Type 2 diabetes (n = 370) who were randomized in a 1 : 1 ratio to 18 months of metformin or placebo treatment. Metabolites were measured by liquid chromatography-mass spectrometry at baseline and at 18-month follow-up and the data were analysed using a linear mixed-effect model. RESULTS:At baseline, participants who were on metformin before the trial (n = 312) had higher levels of leucine/isoleucine and five lysophosphatidylethanolamines (LPEs), and lower levels of carnitine and valine compared with metformin-naïve participants (n = 58). At follow-up, participants randomized to metformin (n = 188) had elevated levels of leucine/isoleucine and reduced carnitine, tyrosine and valine compared with placebo (n = 182). At baseline, participants on metformin treatment with the highest levels of carnitine C10:1 and leucine/isoleucine had the lowest HbA (P-interaction = 0.02 and 0.03, respectively). This association was not significant with HbA at follow-up. CONCLUSIONS:Metformin treatment is associated with decreased levels of valine, tyrosine and carnitine, and increased levels of leucine/isoleucine. None of the identified metabolites can predict the HbA -lowering effect of metformin. Further studies of the association between metformin, carnitine and leucine/isoleucine are warranted. 10.1111/dme.13636
    Effects of individual branched-chain amino acids deprivation on insulin sensitivity and glucose metabolism in mice. Xiao Fei,Yu Junjie,Guo Yajie,Deng Jiali,Li Kai,Du Ying,Chen Shanghai,Zhu Jianmin,Sheng Hongguang,Guo Feifan Metabolism: clinical and experimental OBJECTIVE:We recently discovered that leucine deprivation increases hepatic insulin sensitivity via general control nondepressible (GCN) 2/mammalian target of rapamycin (mTOR) and AMP-activated protein kinase (AMPK) pathways. The goal of the present study was to investigate whether the above effects were leucine specific or were also induced by deficiency of other branched chain amino acids including valine and isoleucine. METHODS:Following depletion of BCAAs, changes in metabolic parameters and the expression of genes and proteins involved in regulation of insulin sensitivity and glucose metabolism were analyzed in mice and cell lines including human HepG2 cells, primary mouse hepatocytes and a mouse myoblast cell line C2C12. RESULTS:Valine or isoleucine deprivation for 7 days has similar effect on improving insulin sensitivity as leucine, in wild type and insulin-resistant mice models. These effects are possibly mediated by decreased mTOR/S6K1 and increased AMPK signaling pathways, in a GCN2-dependent manner. Similar observations were obtained in in vitro studies. In contrast to leucine withdrawal, valine or isoleucine deprivation for 7 days significantly decreased fed blood glucose levels, possibly due to reduced expression of a key gluconeogenesis gene, glucose-6-phosphatase. Finally, insulin sensitivity was rapidly improved in mice 1 day following maintenance on a diet deficient for any individual BCAAs. CONCLUSIONS:Our results show that while improvement on insulin sensitivity is a general feature of BCAAs depletion, individual BCAAs have specific effects on metabolic pathways, including those that regulate glucose level. These observations provide a conceptual framework for delineating the molecular mechanisms that underlie amino acid regulation of insulin sensitivity. 10.1016/j.metabol.2014.03.006
    Nine Amino Acids Are Associated With Decreased Insulin Secretion and Elevated Glucose Levels in a 7.4-Year Follow-up Study of 5,181 Finnish Men. Vangipurapu Jagadish,Stancáková Alena,Smith Ulf,Kuusisto Johanna,Laakso Markku Diabetes Several amino acids (AAs) have been shown to be associated with insulin resistance and increased risk of type 2 diabetes, but no previous studies have investigated the association of AAs with insulin secretion in a longitudinal setting. Our study included 5,181 participants of the cross-sectional METabolic Syndrome In Men (METSIM) study having metabolomics data on 20 AAs. A total of 4,851 had a 7.4-year follow-up visit. Nine AAs (phenylalanine, tryptophan, tyrosine, alanine, isoleucine, leucine, valine, aspartate, and glutamate) were significantly ( < 5.8 × 10) associated with decreases in insulin secretion (disposition index) and the elevation of fasting or 2-h glucose levels. Five of these AAs (tyrosine, alanine, isoleucine, aspartate, and glutamate) were also found to be significantly associated with an increased risk of incident type 2 diabetes after adjustment for confounding factors. Our study is the first population-based large cohort to report that AAs are associated not only with insulin resistance but also with decreased insulin secretion. 10.2337/db18-1076
    The Relationship between Branched-Chain Amino Acid Related Metabolomic Signature and Insulin Resistance: A Systematic Review. Zhao Xue,Han Qing,Liu Yujia,Sun Chenglin,Gang Xiaokun,Wang Guixia Journal of diabetes research Recent studies have shown the positive association between increased circulating BCAAs (valine, leucine, and isoleucine) and insulin resistance (IR) in obese or diabetic patients. However, results seem to be controversial in different races, diets, and distinct tissues. Our aims were to evaluate the relationship between BCAA and IR as well as later diabetes risk and explore the phenotypic and genetic factors influencing BCAA level based on available studies. We performed systematic review, searching MEDLINE, EMASE, ClinicalTrials.gov, the Cochrane Library, and Web of Science from inception to March 2016. After selection, 23 studies including 20,091 participants were included. Based on current evidence, we found that BCAA is a useful biomarker for early detection of IR and later diabetic risk. Factors influencing BCAA level can be divided into four parts: race, gender, dietary patterns, and gene variants. These factors might not only contribute to the elevated BCAA level but also show obvious associations with insulin resistance. Genes related to BCAA catabolism might serve as potential targets for the treatment of IR associated metabolic disorders. Moreover, these factors should be controlled properly during study design and data analysis. In the future, more large-scale studies with elaborate design addressing BCAA and IR are required. 10.1155/2016/2794591
    Suppression of Endogenous Glucose Production by Isoleucine and Valine and Impact of Diet Composition. Arrieta-Cruz Isabel,Su Ya,Gutiérrez-Juárez Roger Nutrients Leucine has been shown to acutely inhibit hepatic glucose production in rodents by a mechanism requiring its metabolism to acetyl-CoA in the mediobasal hypothalamus (MBH). In the early stages, all branched-chain amino acids (BCAA) are metabolized by a shared set of enzymes to produce a ketoacid, which is later metabolized to acetyl-CoA. Consequently, isoleucine and valine may also modulate glucose metabolism. To examine this possibility we performed intrahypothalamic infusions of isoleucine or valine in rats and assessed whole body glucose kinetics under basal conditions and during euglycemic pancreatic clamps. Furthermore, because high fat diet (HFD) consumption is known to interfere with central glucoregulation, we also asked whether the action of BCAAs was affected by HFD. We fed rats a lard-rich diet for a short interval and examined their response to central leucine. The results showed that both isoleucine and valine individually lowered blood glucose by decreasing liver glucose production. Furthermore, the action of the BCAA leucine was markedly attenuated by HFD feeding. We conclude that all three BCAAs centrally modulate glucose metabolism in the liver and that their action is disrupted by HFD-induced insulin resistance. 10.3390/nu8020079
    Association between insulin resistance and plasma amino acid profile in non-diabetic Japanese subjects. Yamada Chizumi,Kondo Masumi,Kishimoto Noriaki,Shibata Takeo,Nagai Yoko,Imanishi Tadashi,Oroguchi Takashige,Ishii Naoaki,Nishizaki Yasuhiro Journal of diabetes investigation AIMS/INTRODUCTION:Elevation of the branched-chain amino acids (BCAAs), valine, leucine and isoleucine; and the aromatic amino acids, tyrosine and phenylalanine, has been observed in obesity-related insulin resistance. However, there have been few studies on Asians, who are generally less obese and less insulin-resistant than Caucasian or African-Americans. In the present study, we investigated the relationship between homeostasis model assessment of insulin resistance (HOMA-IR) and plasma amino acid concentration in non-diabetic Japanese participants. MATERIALS AND METHODS:A total of 94 healthy men and women were enrolled, and plasma amino acid concentration was measured by liquid chromatography/mass spectrometry after overnight fasting. The associations between HOMA-IR and 20 amino acid concentrations, and anthropometric and clinical parameters of lifestyle-related diseases were evaluated. RESULTS:The mean age and body mass index were 40.1 ± 9.6 years and 22.7 ± 3.9, respectively. Significantly positive correlations were observed between HOMA-IR and valine, isoleucine, leucine, tyrosine, phenylalanine and total BCAA concentration. Compared with the HOMA-IR ≤ 1.6 group, the HOMA-IR > 1.6 group showed significantly exacerbated anthropometric and clinical parameters, and significantly elevated levels of valine, isoleucine, leucine, tyrosine, phenylalanine and BCAA. CONCLUSIONS:The present study shows that the insulin resistance-related change in amino acid profile is also observed in non-diabetic Japanese subjects. These amino acids include BCAAs (valine, isoleucine and leucine) and aromatic amino acids (tyrosine and phenylalanine), in agreement with previous studies carried out using different ethnic groups with different degrees of obesity and insulin resistance. 10.1111/jdi.12323
    A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Jang Cholsoon,Oh Sungwhan F,Wada Shogo,Rowe Glenn C,Liu Laura,Chan Mun Chun,Rhee James,Hoshino Atsushi,Kim Boa,Ibrahim Ayon,Baca Luisa G,Kim Esl,Ghosh Chandra C,Parikh Samir M,Jiang Aihua,Chu Qingwei,Forman Daniel E,Lecker Stewart H,Krishnaiah Saikumari,Rabinowitz Joshua D,Weljie Aalim M,Baur Joseph A,Kasper Dennis L,Arany Zoltan Nature medicine Epidemiological and experimental data implicate branched-chain amino acids (BCAAs) in the development of insulin resistance, but the mechanisms that underlie this link remain unclear. Insulin resistance in skeletal muscle stems from the excess accumulation of lipid species, a process that requires blood-borne lipids to initially traverse the blood vessel wall. How this trans-endothelial transport occurs and how it is regulated are not well understood. Here we leveraged PPARGC1a (also known as PGC-1α; encoded by Ppargc1a), a transcriptional coactivator that regulates broad programs of fatty acid consumption, to identify 3-hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, as a new paracrine regulator of trans-endothelial fatty acid transport. We found that 3-HIB is secreted from muscle cells, activates endothelial fatty acid transport, stimulates muscle fatty acid uptake in vivo and promotes lipid accumulation in muscle, leading to insulin resistance in mice. Conversely, inhibiting the synthesis of 3-HIB in muscle cells blocks the ability of PGC-1α to promote endothelial fatty acid uptake. 3-HIB levels are elevated in muscle from db/db mice with diabetes and from human subjects with diabetes, as compared to those without diabetes. These data unveil a mechanism in which the metabolite 3-HIB, by regulating the trans-endothelial flux of fatty acids, links the regulation of fatty acid flux to BCAA catabolism, providing a mechanistic explanation for how increased BCAA catabolic flux can cause diabetes. 10.1038/nm.4057
    Genetic Support for a Causal Role of Insulin Resistance on Circulating Branched-Chain Amino Acids and Inflammation. Wang Qin,Holmes Michael V,Davey Smith George,Ala-Korpela Mika Diabetes care OBJECTIVE:Insulin resistance has deleterious effects on cardiometabolic disease. We used Mendelian randomization analyses to clarify the causal relationships of insulin resistance (IR) on circulating blood-based metabolites to shed light on potential mediators of the IR to cardiometabolic disease relationship. RESEARCH DESIGN AND METHODS:We used 53 single nucleotide polymorphisms associated with IR from a recent genome-wide association study (GWAS) to explore their effects on circulating lipids and metabolites. We used published summary-level data from two GWASs of European individuals; data on the exposure (IR) were obtained from meta-GWASs of 188,577 individuals, and data on the outcomes (58 metabolic measures assessed by nuclear magnetic resonance) were taken from a GWAS of 24,925 individuals. RESULTS:One-SD genetically elevated IR (equivalent to 55% higher geometric mean of fasting insulin, 0.89 mmol/L higher triglycerides, and 0.46 mmol/L lower HDL cholesterol) was associated with higher concentrations of all branched-chain amino acids (BCAAs)-isoleucine (0.56 SD; 95% CI 0.43, 0.70), leucine (0.42 SD; 95% CI 0.28, 0.55), and valine (0.26 SD; 95% CI 0.12, 0.39)-as well as with higher glycoprotein acetyls (an inflammation marker) (0.47 SD; 95% CI 0.32, 0.62) ( < 0.0003 for each). Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy. CONCLUSIONS:We provide robust evidence that IR causally affects each individual BCAA and inflammation. Taken together with existing studies, this implies that BCAA metabolism lies on a causal pathway from adiposity and IR to type 2 diabetes. 10.2337/dc17-1642
    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. 10.1007/s12010-019-02956-9
    Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels. Mahendran Yuvaraj,Jonsson Anna,Have Christian T,Allin Kristine H,Witte Daniel R,Jørgensen Marit E,Grarup Niels,Pedersen Oluf,Kilpeläinen Tuomas O,Hansen Torben Diabetologia AIMS/HYPOTHESIS:Fasting plasma levels of branched-chain amino acids (BCAAs) are associated with insulin resistance, but it remains unclear whether there is a causal relation between the two. We aimed to disentangle the causal relations by performing a Mendelian randomisation study using genetic variants associated with circulating BCAA levels and insulin resistance as instrumental variables. METHODS:We measured circulating BCAA levels in blood plasma by NMR spectroscopy in 1,321 individuals from the ADDITION-PRO cohort. We complemented our analyses by using previously published genome-wide association study (GWAS) results from the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) (n = 46,186) and from a GWAS of serum BCAA levels (n = 24,925). We used a genetic risk score (GRS), calculated using ten established fasting serum insulin associated variants, as an instrumental variable for insulin resistance. A GRS of three variants increasing circulating BCAA levels was used as an instrumental variable for circulating BCAA levels. RESULTS:Fasting plasma BCAA levels were associated with higher HOMA-IR in ADDITION-PRO (β 0.137 [95% CI 0.08, 0.19] p = 6 × 10). However, the GRS for circulating BCAA levels was not associated with fasting insulin levels or HOMA-IR in ADDITION-PRO (β -0.011 [95% CI -0.053, 0.032] p = 0.6 and β -0.011 [95% CI -0.054, 0.031] p = 0.6, respectively) or in GWAS results for HOMA-IR from MAGIC (β for valine-increasing GRS -0.012 [95% CI -0.069, 0.045] p = 0.7). By contrast, the insulin-resistance-increasing GRS was significantly associated with increased BCAA levels in ADDITION-PRO (β 0.027 [95% CI 0.005, 0.048] p = 0.01) and in GWAS results for serum BCAA levels (β 1.22 [95% CI 0.71, 1.73] p = 4 × 10, β 0.96 [95% CI 0.45, 1.47] p = 3 × 10, and β 0.67 [95% CI 0.16, 1.18] p = 0.01 for isoleucine, leucine and valine levels, respectively) and instrumental variable analyses in ADDITION-PRO indicated that HOMA-IR is causally related to higher circulating fasting BCAA levels (β 0.73 [95% CI 0.26, 1.19] p = 0.002). CONCLUSIONS/INTERPRETATION:Our results suggest that higher BCAA levels do not have a causal effect on insulin resistance while increased insulin resistance drives higher circulating fasting BCAA levels. 10.1007/s00125-017-4222-6
    Identification of Urinary Metabolite Biomarkers of Type 2 Diabetes Nephropathy Using an Untargeted Metabolomic Approach. Chen Chao-Jung,Liao Wen-Ling,Chang Chiz-Tzung,Lin Yu-Ning,Tsai Fuu-Jen Journal of proteome research Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM). To discover early stage biomarkers of DN, untargeted liquid chromatography-mass spectrometry-based metabolomic analysis was performed in urine samples from healthy subjects and patients with micro- or macroalbuminuria due to nondiabetic disease (macro), type 2 DM without microalbuminuria (T2DM), and type 2 DM with microalbuminuria (T2DM+micro). Levels of four metabolites were significantly different among groups, and they were quantified in a larger group of 267 urine samples. Two metabolites were also discovered and validated in targeted metabolic study of amino acids. For diagnosis of nephropathy, N1-methylguanosine had the highest area-under-the-curve (AUC) value of 0.75 when compared to those of valine (0.68), xanthosine (0.67), and 7-methyluric acid (0.69). After combining fasting blood glucose and diastolic blood pressure (DBP) with N1-methylguanosine, the AUC increased to 0.987. To distinguish between T2DM and T2DM+micro conditions, xanthosine and N1-methylguanosine have AUC value of 0.612 and 0.624, respectively. After adjustment of HbA1c and DBP, AUC values of xanthosine and N1-methylguanosine increased to 0.716 and 0.723, respectively, and could be used to predict the development of nephropathy in T2DM patients. 10.1021/acs.jproteome.8b00644
    BCAA Metabolism and Insulin Sensitivity - Dysregulated by Metabolic Status? Gannon Nicholas P,Schnuck Jamie K,Vaughan Roger A Molecular nutrition & food research Branched-chain amino acids (BCAAs) appear to influence several synthetic and catabolic cellular signaling cascades leading to altered phenotypes in mammals. BCAAs are most notably known to increase protein synthesis through modulating protein translation, explaining their appeal to resistance and endurance athletes for muscle hypertrophy, expedited recovery, and preservation of lean body mass. In addition to anabolic effects, BCAAs may increase mitochondrial content in skeletal muscle and adipocytes, possibly enhancing oxidative capacity. However, elevated circulating BCAA levels have been correlated with severity of insulin resistance. It is hypothesized that elevated circulating BCAAs observed in insulin resistance may result from dysregulated BCAA degradation. This review summarizes original reports that investigated the ability of BCAAs to alter glucose uptake in consequential cell types and experimental models. The review also discusses the interplay of BCAAs with other metabolic factors, and the role of excess lipid (and possibly energy excess) in the dysregulation of BCAA catabolism. Lastly, this article provides a working hypothesis of the mechanism(s) by which lipids may contribute to altered BCAA catabolism, which often accompanies metabolic disease. 10.1002/mnfr.201700756
    OLIVe: A Genetically Encoded Fluorescent Biosensor for Quantitative Imaging of Branched-Chain Amino Acid Levels inside Single Living Cells. Yoshida Tomoki,Nakajima Hitomi,Takahashi Sena,Kakizuka Akira,Imamura Hiromi ACS sensors Branched-chain amino acids (BCAAs) are essential amino acids, controlling cellular metabolic processes as signaling molecules; therefore, utilization of intracellular BCAAs may be regulated by the availability of nutrients in the environment. However, spatial and temporal regulation of intracellular BCAA concentration in response to environmental conditions has been unclear due to the lack of suitable methods for measuring BCAA concentrations inside single living cells. Here, we developed a Förster resonance energy transfer (FRET)-based genetically encoded biosensor for BCAAs, termed optical biosensor for leucine-isoleucine-valine (OLIVe). The biosensor showed approximately 2-fold changes in FRET values corresponding to BCAA concentrations. Importantly, FRET signals from HeLa cells expressing OLIVe in the cytoplasm and nucleus correlated with bulk intracellular BCAA concentrations determined from populations of cells by a biochemical method, and were decreased by knockdown of L-type amino acid transporter 1 (LAT1), a transporter for BCAAs, indicating that OLIVe can reliably report intracellular BCAA concentrations inside single living cells. We also succeeded in imaging BCAA concentrations in the mitochondria using mitochondria-targeted OLIVe. Using the BCAA imaging technique, we found apparently correlated concentrations between the cytoplasm and the mitochondria. We also found that extracellular non-BCAA amino acids affected intracellular BCAA concentrations. Of these amino acids, extracellular glutamine markedly increased intracellular BCAA concentrations in a LAT1-dependent manner. Unexpectedly, extracellular pyruvate was also found to have significant positive effects on maintaining intracellular BCAA concentrations, suggesting that the cells have pyruvate-dependent systems to import BCAAs and/or to regulate BCAA metabolism. 10.1021/acssensors.9b02067
    Metabolomic profile associated with insulin resistance and conversion to diabetes in the Insulin Resistance Atherosclerosis Study. Palmer Nicholette D,Stevens Robert D,Antinozzi Peter A,Anderson Andrea,Bergman Richard N,Wagenknecht Lynne E,Newgard Christopher B,Bowden Donald W The Journal of clinical endocrinology and metabolism CONTEXT:Metabolomic profiling of amino acids and acylcarnitines has revealed consistent patterns associated with metabolic disease. OBJECTIVE:This study used metabolomic profiling to identify analytes associated with insulin sensitivity (SI) and conversion to type 2 diabetes (T2D). DESIGN:A multiethnic cohort from the Insulin Resistance Atherosclerosis Study. SETTING:Community-based. PATIENTS:A total of 196 subjects (European American, Hispanic, and African American) were selected to represent extremes of the SI distribution and conversion to T2D between baseline and followup exams. MAIN OUTCOME:Mass spectrometry-based profiling of 69 metabolites. Subjects participated in a frequently sampled i.v. glucose tolerance test to measure SI and acute insulin response. T2D status was determined by a 2-hour oral glucose tolerance test. RESULTS:Logistic regression analysis from 72 high and 75 low SI subjects revealed significantly decreased glycine and increased valine, leucine, phenylalanine, and combined glutamine and glutamate (P = .0079-7.7 × 10(-6)) in insulin-resistant subjects. Ethnic-stratified results were strongest in European Americans. Comparing amino acid profiles between subjects that converted to T2D (76 converters; 70 nonconverters) yielded a similar pattern of associations: decreased glycine and increased valine, leucine, and combined glutamine and glutamate (P = .016-.00010). Importantly, β-cell function as a covariate revealed a similar pattern of association. CONCLUSIONS:A distinct pattern of differences in amino acids were observed when comparing subjects with high and low levels of SI. This pattern was associated with conversion to T2D, remaining significant when accounting for β-cell function, emphasizing a link between this metabolic profile and insulin resistance. These results demonstrate a consistent metabolic signature associated with insulin resistance and conversion to T2D, providing potential insight into underlying mechanisms of disease pathogenesis. 10.1210/jc.2014-2357
    Branched-chain amino acid catabolism rather than amino acids plasma concentrations is associated with diet-induced changes in insulin resistance in overweight to obese individuals. Haufe S,Engeli S,Kaminski J,Witt H,Rein D,Kamlage B,Utz W,Fuhrmann J C,Haas V,Mähler A,Schulz-Menger J,Luft F C,Boschmann M,Jordan J Nutrition, metabolism, and cardiovascular diseases : NMCD BACKGROUND & AIMS:3-Hydroxyisobutyrate (3-HIB), a catabolic intermediate of the BCAA valine, which stimulates muscle fatty acid uptake, has been implicated in the pathogenesis of insulin resistance. We tested the hypothesis that circulating 3-HIB herald insulin resistance and that metabolic improvement with weight loss are related to changes in BCAAs and 3-HIB. METHODS AND RESULTS:We analyzed plasma and urine in 109 overweight to obese individuals before and after six months on hypocaloric diets reduced in either carbohydrates or fat. We calculated the homeostasis model assessment index (HOMA-IR) and whole body insulin sensitivity from oral glucose tolerance tests and measured intramyocellular fat by magnetic resonance spectroscopy. BCAAs and 3-HIB plasma concentrations were inversely related to insulin sensitivity but not to intramyocellular fat content at baseline. With 7.4 ± 4.5% weight loss mean BCAA and 3-HIB plasma concentrations did not change, irrespective of dietary macronutrient content. Individual changes in 3-HIB with 6-month diet but not BCAAs were correlated to the change in whole body insulin sensitivity and HOMA-IR independently of BMI changes. CONCLUSIONS:3-HIB relates to insulin sensitivity but is not associated with intramyocellular fat content in overweight to obese individuals. Moreover, changes in 3-HIB rather than changes in BCAAs are associated with metabolic improvements with weight loss. Registration number for clinical trials: ClinicalTrials.gov Identifier: NCT00956566. 10.1016/j.numecd.2017.07.001
    High dietary intake of branched-chain amino acids is associated with an increased risk of insulin resistance in adults. Asghari Golaleh,Farhadnejad Hossein,Teymoori Farshad,Mirmiran Parvin,Tohidi Maryam,Azizi Fereidoun Journal of diabetes BACKGROUND:The aim of this study was to investigate the association between branched-chain amino acid (BCAA) intake and markers of insulin metabolism in adults. METHODS:This cohort study was conducted within the framework of the Tehran Lipid and Glucose Study on 1205 subjects, aged ≥20 years, who were followed-up for a mean of 2.3 years. Dietary intake of BCAAs, including valine, leucine, and isoleucine, was determined using a valid and reliable food frequency questionnaire. Hyperinsulinemia, β-cell dysfunction, insulin resistance (IR), and insulin insensitivity were determined according to optimal cut-off values. Logistic regression was to estimate the occurrence of IR across tertiles of BCAA intake. RESULTS:The mean (± SD) age and BCAA intake of participants (43% male) at baseline were 42.7 ± 13.1 years and 13.8 ± 5.1 g/day, respectively. The incidence of hyperinsulinemia, β-cell dysfunction, insulin insensitivity, and IR was 19.5%, 24.0%, 28.0%, and 12.5%, respectively. After adjustment for confounding variables, subjects in the highest tertile for total BCAAs (odds ratio [OR] 1.67; 95% confidence interval [CI] 1.03-2.71), leucine (OR 1.75; 95% CI 1.09-2.82), and valine (OR 1.61; 95% CI 1.01-2.60) intake had a greater risk of incident IR than subjects in the lowest tertile. A higher intake of isoleucine was not associated with risk of incident IR. There was no association of total BCAAs, leucine, isoleucine, and valine intake with the risk of hyperinsulinemia, insulin insensitivity, or β-cell dysfunction. CONCLUSION:The findings of this study support the hypothesis that higher intakes of BCAAs may have adverse effects on the development of IR. 10.1111/1753-0407.12639
    The Effects of BCAAs on Insulin Resistance in Athletes. Shou Jian,Chen Pei-Jie,Xiao Wei-Hua Journal of nutritional science and vitaminology The toxic catabolic intermediates of branched chain amino acids can cause insulin resistance, and are involved in different mechanisms in different metabolic tissues. In skeletal muscle, 3-hydroxy-isobutyrate produced by valine promotes skeletal muscle fatty acid uptake, resulting in the accumulation of incompletely oxidized lipids in skeletal muscle, causing skeletal muscle insulin resistance. In the liver, branched-chain α-keto acids decompose in large amounts, promote hepatic gluconeogenesis, and lead to the accumulation of multiple acylcarnitines, which damages the mitochondrial tricarboxylic acid cycle, resulting in the accumulation of incomplete oxidation products, oxidative stress in mitochondria, and hepatic insulin resistance. In adipose tissue, the expression of branched-chain amino acid catabolic enzymes (branched-chain amino acid transaminase, branched-chain α-keto acid dehydrogenase) is reduced, resulting in an increased level of plasma branched-chain amino acids, thereby causing massive decomposition of branched-chain amino acids in tissues such as skeletal muscle and liver, and inducing insulin resistance. However, branched-chain amino acids, as a common nutritional supplement for athletes, do not induce insulin resistance. A possible explanation for this phenomenon is that exercise can enhance the mitochondrial oxidative potential of branched-chain amino acids, alleviate or even eliminate the accumulation of branched-chain amino acid catabolic intermediates, and promotes branched-chain amino acids catabolism into beta-aminoisobutyric acid, increasing plasma beta-aminoisobutyric acid concentration, improving insulin resistance. This article reveals the mechanism of BCAA-induced insulin resistance and the relationship between exercise and BCAAs metabolism, adds a guarantee for the use of BCAAs, and provides a new explanation for the occurrence of diabetes and how exercise improves diabetes. 10.3177/jnsv.65.383
    Branched-chain and aromatic amino acids are predictors of insulin resistance in young adults. Würtz Peter,Soininen Pasi,Kangas Antti J,Rönnemaa Tapani,Lehtimäki Terho,Kähönen Mika,Viikari Jorma S,Raitakari Olli T,Ala-Korpela Mika Diabetes care OBJECTIVE:Branched-chain and aromatic amino acids are associated with the risk for future type 2 diabetes; however, the underlying mechanisms remain elusive. We tested whether amino acids predict insulin resistance index in healthy young adults. RESEARCH DESIGN AND METHODS:Circulating isoleucine, leucine, valine, phenylalanine, tyrosine, and six additional amino acids were quantified in 1,680 individuals from the population-based Cardiovascular Risk in Young Finns Study (baseline age 32 ± 5 years; 54% women). Insulin resistance was estimated by homeostasis model assessment (HOMA) at baseline and 6-year follow-up. Amino acid associations with HOMA of insulin resistance (HOMA-IR) and glucose were assessed using regression models adjusted for established risk factors. We further examined whether amino acid profiling could augment risk assessment of insulin resistance (defined as 6-year HOMA-IR >90th percentile) in early adulthood. RESULTS:Isoleucine, leucine, valine, phenylalanine, and tyrosine were associated with HOMA-IR at baseline and for men at 6-year follow-up, while for women only leucine, valine, and phenylalanine predicted 6-year HOMA-IR (P < 0.05). None of the other amino acids were prospectively associated with HOMA-IR. The sum of branched-chain and aromatic amino acid concentrations was associated with 6-year insulin resistance for men (odds ratio 2.09 [95% CI 1.38-3.17]; P = 0.0005); however, including the amino acid score in prediction models did not improve risk discrimination. CONCLUSIONS:Branched-chain and aromatic amino acids are markers of the development of insulin resistance in young, normoglycemic adults, with most pronounced associations for men. These findings suggest that the association of branched-chain and aromatic amino acids with the risk for future diabetes is at least partly mediated through insulin resistance. 10.2337/dc12-0895
    Plasma levels of lysine, tyrosine, and valine during pregnancy are independent risk factors of insulin resistance and gestational diabetes. Park Sunmin,Park Jin Young,Lee Ju Hong,Kim Sung-Hoon Metabolic syndrome and related disorders BACKGROUND:This study compared plasma concentrations of amino acids in pregnant women with and without gestational diabetes mellitus (GDM) and identified the association between plasma amino acid levels and GDM, insulin resistance, and insulin secretion at 24-28 weeks of pregnancy. METHODS:Circulating amino acid levels were evaluated using high-performance liquid chromatography at 24-28 weeks of pregnancy in 25 non-GDM and 64 GDM women after adjusting for covariates such as maternal age, body mass index (BMI) before pregnancy, BMI and gestational age at screening GDM, and daily caloric intake. Backward stepwise logistic regression analysis was used to identify the predictors of developing GDM, and homeostatic model assessments for insulin resistance (HOMA-IR) and β-cell function (HOMA-B). RESULTS:Circulating levels of amino acids except threonine and tyrosine were significantly higher in GDM women than non-GDM women. Along with the intakes of energy, protein, and fat from animal sources, the intakes of each amino acid were significantly higher in the GDM group without a direct correlation to plasma amino acid levels. The variation in GDM development was explained by maternal age, diastolic blood pressure, and plasma lysine levels (R(2)=0.691). Height, BMI before pregnancy, systolic blood pressure, and plasma tyrosine and valine levels accounted for the variation in HOMA-IR (R(2)=0.589). The 53.3% variation of HOMA-B was explained by maternal age, BMI at GDM screening, plasma insulin level at 1 h during the oral glucose tolerance test (OGTT), and plasma valine level. CONCLUSIONS:Circulating concentrations of lysine, tyrosine, and valine were independently and positively associated with GDM through modifying insulin resistance and secretion. 10.1089/met.2014.0113
    Metabolomic study of the protective effect of Gandi capsule for diabetic nephropathy. Liu Yue,Chen Xiaofei,Liu Yan,Chen Ting,Zhang Qijiang,Zhang Hai,Zhu Zhenyu,Chai Yifeng,Zhang Jian Chemico-biological interactions Diabetic nephropathy (DN) is the one of the leading causes of end-stage renal disease (ESRD) in clinical. However, it is still lack of accurate biomarkers and effective methods for diagnosing and curing DN. Therefore, there is an urgent need to develop a definite strategy for the identification of reliable and versatile biomarkers for risk assessment of DN and search for therapeutic approaches that can effectively attenuate DN progression. Treatment with Gandi capsule (GDC) not only decreased the levels of urinary albumin excretion, but also increased the levels of estimated glomerular filtration rate (eGFR), indicating that it produces a renal protective effect on diabetic nephropathy. Based on metabolomics investigation including UHPLC-MS analysis and multivariate statistical analysis, sixteen disordered metabolites were screened out and considered as potential biomarkers corresponding to DN, which were mostly improved and partially returned to normalcy in GDC treatment group. Therefore, it was suggested that GDC was a promising therapeutic agent against DN. The underlying mechanisms of GDC attenuating the development of DN may be improving abnormal metabolic disorders by retrieving the imbalance of glycine metabolism, tryptophan metabolism, valine, leucine and isoleucine degradation, purine metabolism, nitrotoluene degradation, phenylalanine metabolism, fatty acid metabolism, tyrosine metabolism and bile acid metabolism pathways. The data obtained in this study may provide key clues to enhance our understanding of the metabolic mechanism of DN and shed new insights into the therapeutic mechanism of GDC. 10.1016/j.cbi.2019.108815