scholarly journals Branched-chain amino acid metabolism is regulated by ERRα in primary human myotubes and is further impaired by glucose loading in type 2 diabetes

Diabetologia ◽  
2021 ◽  
Author(s):  
Rasmus J. O. Sjögren ◽  
David Rizo-Roca ◽  
Alexander V. Chibalin ◽  
Elin Chorell ◽  
Regula Furrer ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Amino Acid ◽  
Glucose Homeostasis ◽  
Gene Set ◽  
Branched Chain Amino Acid ◽  
Human Myotubes ◽  
Branched Chain ◽  
The Impact

Abstract Aims/hypothesis Increased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolism is partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified. Methods Plasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadriceps muscles were harvested from skeletal muscle-specific Ppargc1a knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and quantitative RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PPARGC1A and ESRRA in the expression of the BCAA gene set. Radiolabelled leucine was used to analyse the impact of oestrogen-related receptor α (ERRα) knockdown on leucine oxidation. Results Impairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37–56% after an OGTT in the NGT group, whereas no changes were detected in individuals with type 2 diabetes. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of branched-chain amino acid transaminase 2, branched-chain keto acid dehydrogenase complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, encoded by PPARGC1A), 61% of the analysed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletal muscle-specific Ppargc1a knockout mice. ESRRA (encoding ERRα) silencing completely abrogated the PGC-1α-induced upregulation of BCAA-related genes in primary human myotubes. Conclusions/interpretation Metabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease in circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via PGC-1α is ERRα-dependent. Graphical abstract

scholarly journals Effects of Ingestion Routes on Hormonal and Metabolic Profiles in Gastric-Bypassed Humans

2013 ◽  
Vol 98 (5) ◽  
pp. E856-E861 ◽  
Author(s):  
Andreas Lindqvist ◽  
Peter Spégel ◽  
Mikael Ekelund ◽  
Hindrik Mulder ◽  
Leif Groop ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Weight Loss ◽  
Amino Acid ◽  
Nutrient Intake ◽  
Gastrostomy Tube ◽  
Simultaneous Increase ◽  
Branched Chain Amino Acid ◽  
Branched Chain ◽  
The Impact

Context: Gastric bypass surgery (GBP) results in the rapid resolution of type 2 diabetes. Most studies aiming to explain the underlying mechanisms are limited to data obtained after a postsurgical recovery period, making assessment of confounding influences from, for example, weight loss and altered nutrient intake difficult. Objective: To examine the impact of GBP on hormonal and metabolite profiles under conditions of identical nutrient intake independent of weight loss, we studied GBP patients fitted with a gastrostomy tube to enable the administration of nutrients to bypassed segments of the gut. Thus, this model allowed us to simulate partially the preoperative condition and compare this with the postoperative situation in the same patient. Design: Patients (n = 4) were first given a mixed meal test (MMT) orally and then via the gastrostomy tube, preceded by overnight and 2-hour fasting, respectively. Blood samples were assessed for hormones and metabolites. Results: The oral MMT yielded 4.6-fold increase in plasma insulin (P < .05), 2-fold in glucagon-like peptide-1 (P < .05), and 2.5-fold in glucose-dependent insulinotropic peptide (P < .05) plasma levels, compared with the gastrostomy MMT. The changes in hormone levels were accompanied by elevated branched-chain amino acid levels (1.4–2-fold, P < .05) and suppressed fatty acid levels (∼50%, P < .05). Conclusions: These data, comparing identical nutrient delivery, demonstrate markedly higher incretin and insulin responses after oral MMT than after gastric MMT, thereby providing a potential explanation for the rapid remission of type 2 diabetes observed after GBP. The simultaneous increase in branched-chain amino acid questions its role as a marker for insulin resistance.

Isoleucine supplementation for ten days does not modify protein and branched-chain amino acid turnover in type 2 diabetes

2020 ◽  
Vol 40 ◽  
pp. 451
Author(s):  
R.A. Wierzchowska-Mcnew ◽  
M.P. Engelen ◽  
G.A. ten Have ◽  
J.J. Thaden ◽  
N.E. Deutz
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acid ◽  
Branched Chain Amino Acid ◽  
Amino Acid Turnover ◽  
Branched Chain ◽  
Modify Protein

scholarly journals Early metabolic features of genetic liability to type 2 diabetes: cohort study with repeated metabolomics across early life

2019 ◽  
Author(s):  
Joshua A. Bell ◽  
Caroline J. Bull ◽  
Marc J. Gunter ◽  
David Carslake ◽  
George Davey Smith ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acid ◽  
Genetic Risk ◽  
Early Life ◽  
List Type ◽  
Adult Type ◽  
Genetic Liability ◽  
Branched Chain Amino Acid ◽  
Branched Chain

AbstractBackgroundType 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterising liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to detailed metabolic traits across early life.Methods and FindingsData were from up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children cohort. Linear models were used to examine effects of a genetic risk score (GRS, including 162 variants) for adult type 2 diabetes on 4 repeated measures of 229 traits from targeted nuclear magnetic resonance (NMR) metabolomics. These traits included lipoprotein subclass-specific cholesterol and triglyceride content, amino and fatty acids, inflammatory glycoprotein acetyls, and others, and were measured in childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y). For replication, two-sample Mendelian randomization (MR) was conducted using summary data from genome-wide association studies of metabolic traits from NMR in an independent sample of adults (N range 13,476 to 24,925; mean (SD) age range 23.9y (2.1y) to 61.3y (2.9y)). Among ALSPAC participants (49.7% male), the prevalence of type 2 diabetes was very low across time points (< 5 cases when first assessed at age 16y; 7 cases (0.4%) when assessed at age 25y). At age 8y, type 2 diabetes liability (per SD-higher GRS) was associated with lower lipids in high-density lipoprotein (HDL) particle subtypes – e.g. −0.03 SD (95% CI = −0.06, −0.003; P = 0.03) for total lipids in very-large HDL. At age 16y, associations remained strongest with lower lipids in HDL and became stronger with pre-glycemic traits including citrate (−0.06 SD, 95% CI = −0.09, −0.02; P = 1.41×10−03) and with glycoprotein acetyls (0.05 SD, 95% CI = 0.01, 0.08; P = 0.01). At age 18y, associations were stronger with branched chain amino acids including valine (0.06 SD; 95% CI = 0.02, 0.09; P = 1.24×10−03), while at age 25y, associations had strengthened with VLDL lipids and remained consistent with previously altered traits including HDL lipids. Results of two-sample MR in an independent sample of adults indicated persistent patterns of effect of type 2 diabetes liability, with higher type 2 diabetes liability positively associated with VLDL lipids and branched chain amino acid levels, and inversely associated with HDL lipids – again for large and very large HDL particularly (−0.004 SD (95% CI = −0.007, −0.002; P = 8.45×10−04) per 1 log odds of type 2 diabetes for total lipids in large HDL). Study limitations include modest sample sizes for ALSPAC analyses and limited coverage of protein and hormonal traits; insulin was absent as it is not quantified by NMR and not consistently available at each time point. Analyses were restricted to white-Europeans which reduced confounding by population structure but limited inference to other ethnic groups.ConclusionsOur results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability which precedes higher branched chain amino acid and inflammatory glycoprotein acetyl levels. This feature is apparent in childhood as early as age 8y, decades before the clinical onset of disease.Author summaryWhy was this study done?Type 2 diabetes develops for many years before diagnosis. Clinical disease is characterised by numerous metabolic perturbations that are detectable in circulation, but which of these reflect the developmental stages of type 2 diabetes – as opposed to independent causes of type 2 diabetes or markers of other disease processes – is unknown. Revealing traits specific to type 2 diabetes development could inform the targeting of key pathways to prevent the clinical onset of disease and its complications.Genetic liability to type 2 diabetes is less prone to confounding than measured type 2 diabetes or blood glucose and may help reveal early perturbations in the blood that arise in response to type 2 diabetes liability itself.What did the researchers do and find?We examined effects of genetic liability to adult type 2 diabetes, based on a genetic risk score including 162 variants, on detailed metabolic traits measured on the same individuals across four stages of early life – childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y).We found that higher type 2 diabetes liability was associated most consistently across ages with lower lipid content in certain subtypes of HDL particles. Effects were more gradual on higher lipid content in VLDL particles and on higher branched chain amino acid and inflammatory glycoprotein acetyl levels.What do these findings mean?Signs of type 2 diabetes liability are detectable in the blood in childhood, decades before the disease becomes noticeable. These signs, taken to reflect the early features of, or coincident with, disease, likely involve lower lipid content in HDL particles, followed by higher levels of branched chain amino acids and inflammation.Genetic risk scores for adult diseases can be integrated with metabolic measurements taken earlier in life to help to reveal the timing at which signs of disease liability become visible and the traits most central to its development.

scholarly journals Branched-chain amino acid, meat intake and risk of type 2 diabetes in the Women’s Health Initiative

2017 ◽  
Vol 117 (11) ◽  
pp. 1523-1530 ◽  
Author(s):  
Masoud Isanejad ◽  
Andrea Z. LaCroix ◽  
Cynthia A. Thomson ◽  
Lesley Tinker ◽  
Joseph C. Larson ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Amino Acid ◽  
Women's Health ◽  
Meat Intake ◽  
Health Initiative ◽  
Branched Chain Amino Acid ◽  
Total Meat ◽  
Branched Chain ◽  
The Women’S Health Initiative

AbstractKnowledge regarding association of dietary branched-chain amino acid (BCAA) and type 2 diabetes (T2D), and the contribution of BCAA from meat to the risk of T2D are scarce. We evaluated associations between dietary BCAA intake, meat intake, interaction between BCAA and meat intake and risk of T2D. Data analyses were performed for 74 155 participants aged 50−79 years at baseline from the Women’s Health Initiative for up to 15 years of follow-up. We excluded from analysis participants with treated T2D, and factors potentially associated with T2D or missing covariate data. The BCAA and total meat intake was estimated from FFQ. Using Cox proportional hazards models, we assessed the relationship between BCAA intake, meat intake, and T2D, adjusting for confounders. A 20 % increment in total BCAA intake (g/d and %energy) was associated with a 7 % higher risk for T2D (hazard ratio (HR) 1·07; 95 % CI 1·05, 1·09). For total meat intake, a 20 % increment was associated with a 4 % higher risk of T2D (HR 1·04; 95 % CI 1·03, 1·05). The associations between BCAA intake and T2D were attenuated but remained significant after adjustment for total meat intake. These relations did not materially differ with or without adjustment for BMI. Our results suggest that dietary BCAA and meat intake are positively associated with T2D among postmenopausal women. The association of BCAA and diabetes risk was attenuated but remained positive after adjustment for meat intake suggesting that BCAA intake in part but not in full is contributing to the association of meat with T2D risk.

scholarly journals Association of branched-chain amino acid intake trajectory in adulthood with the risk of type 2 diabetes and its related risk factors

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Wei-Qi Wang ◽  
Tian-Shu Han ◽  
Wan-Ying Hou ◽  
Xi-Yun Ren ◽  
Wei Duan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Type 2 Diabetes ◽  
Amino Acid ◽  
Acid Intake ◽  
Branched Chain Amino Acid ◽  
Related Risk ◽  
Amino Acid Intake ◽  
Branched Chain

Discriminative Ability of Plasma Branched-Chain Amino Acid Levels for Glucose Intolerance in Families At Risk for Type 2 Diabetes

2016 ◽  
Vol 14 (3) ◽  
pp. 175-181 ◽  
Author(s):  
Sjaam Jainandunsing ◽  
J.L. Darcos Wattimena ◽  
Adrie J.M. Verhoeven ◽  
Janneke G. Langendonk ◽  
Trinet Rietveld ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
At Risk ◽  
Amino Acid ◽  
Glucose Intolerance ◽  
Discriminative Ability ◽  
Branched Chain Amino Acid ◽  
Amino Acid Levels ◽  
Branched Chain
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