Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications
Abstract
:1. Introduction
2. BCAA Catabolism and Metabolism
2.1. Insulin Resistance and Inflammation
2.2. BCAA Metabolic Gene Expression in Diabetes
3. Diabetic Retinopathy
4. Diabetic Nephropathy
5. Therapeutic and Biomarker Potential of BCAAs
6. Discussion
7. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Source | Trial Type | Molecule | Outcomes |
---|---|---|---|
Sriboonvorakul et al. [71] | A clinical trial on a cohort of T2DM patients that was compared to healthy controls following treatment with single (metformin) or multiple drug (metformin and sulfonylurea). | Metformin and Sulfonylurea |
In both of the treated T2DM groups, BCAAs were significantly lower than the healthy controls. Isoleucine was significantly lower in the single-treated T2DM group compared with the healthy controls. Valine was significantly lower in both treated T2DM groups compared with healthy controls. Leucine was significantly lower in both treated T2DM groups compared with healthy controls (p < 0.0001) |
Gong et al. [83] | An experimental study on seven-week-old male diabetic db/db mice. | Empagliflozin | EMPA significantly inhibited oxidative stress and apoptosis and recovered tight junction in diabetic retinas. EMPA suppressed aberrant BCAA accumulation, which led to downregulation of inflammation and angiogenic factors, including TNF-α, IL-6, VCAM-1, and VEGF induced by diabetes. BCKAs were increased in diabetic retinas and decreased with EMPA application. BCKDK was enhanced and BCKDHA and BCKDHB were decreased in diabetic retinas |
S Sonnet D et al. [84] | An experimental study on the iMSUD mouse model | Metformin | Metformin reduced levels of KIC in patient-derived fibroblasts by 20–50%; in the muscle by 69%, and in serum by 56% and restored levels of mitochondrial metabolites. Metformin decreased the expression of BCAT, which produces KIC in skeletal muscle. |
Riviera et al. [85] | An experimental study on C2C12 mouse myoblasts (CRL-1772; ATCC, Manassas, VA). | Metformin | Metformin inhibited mitochondrial metabolism, promoting an activation of AMPK and subsequently PGC-1. Metformin reduced KLF15 (Kruppel-like factor 15) protein levels, leading to reduced expression/activation of BCAA catabolic enzymes. Metformin enhanced KLF15 mRNA expression, the implications of which were unknown. |
Paterson et al. [86] | A clinical trial including nine non-insulin-dependent diabetic patients. | Gliclazide | Glycaemic control was improved, but fasting amino acid levels were not altered. Postprandial levels of BCAAs were significantly reduced: total BCAA (valine, leucine, and isoleucine) after 3 months of therapy (p < 0.01). |
Iwasa M, et al. [87] | A clinical trial on 84 subjects with type 2 DM, NAFL, hypertension, and dyslipidemia. | Pioglitazone and Alogliptin | BCAA levels were negatively correlated with HDL cholesterol. BCAA levels were positively correlated with ALT, suggesting an association with fatty liver changes. There were no significant correlations with HbA1c, HOMA-IR, TG, hs-CRP, or adiponectin. Serum BCAA levels in diabetics were higher than in non-diabetics. Treatment with pioglitazone and alogliptin improved serum haemoglobin A1c and decreased BCAA levels. |
NCT Number Trial | Status | Molecule Investigated | Trial Type | Primary Outcomes |
---|---|---|---|---|
NCT02351323 | Completed | glutamine and leucine | randomized, double-blind, placebo controlled, clinical trial | test the efficacy of 6 months of glutamine supplements in reducing biomarkers for IR and weight gain among 56 obese adolescents aged 12–19 years with a BMI ≥ 95th percentile and a family history of T2DM |
NCT01211717 | Completed | isoleucine, leucine, and valine | randomized, interventional clinical trial | determine the effectiveness of three BCAAs (isoleucine, leucine, and valine) on treating delayed onset muscle soreness in T2DM |
NCT02435277 NCT02151461 | Completed | leucine and metformin combinations | phase 2 trials randomized | change in fasting plasma glucose from baseline (day 1) to week 4 (day 28); change in HbA1c Levels |
NCT01593605 | Completed | resveratrol/leucine and resveratrol/HMB | randomized controlled trial | their ability to control glucose levels in persons without diabetes but with impaired fasting glucose |
NCT04461236 | Recruiting | isoleucine | randomized controlled clinical trial | change in whole-body protein metabolism in type 2 diabetic obese subjects; 24 h glucose levels in type 2 diabetic obese subjects |
NCT04424537 | Withdrawn | MRBs made with BCAD2 powder (lacking BCAAs) | randomized controlled trial | change in weight and fasting blood glucose level change in insulin sensitivity |
NCT03785951 | Unknown | wheat protein with leucine | double-blind, randomized, controlled, three-way, cross-over study | change in fasting and day-long glucose levels, and day-long insulin levels (using ELISA) |
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Tanase, D.M.; Gosav, E.M.; Botoc, T.; Floria, M.; Tarniceriu, C.C.; Maranduca, M.A.; Haisan, A.; Cucu, A.I.; Rezus, C.; Costea, C.F. Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications. J. Clin. Med. 2023, 12, 6053. https://doi.org/10.3390/jcm12186053
Tanase DM, Gosav EM, Botoc T, Floria M, Tarniceriu CC, Maranduca MA, Haisan A, Cucu AI, Rezus C, Costea CF. Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications. Journal of Clinical Medicine. 2023; 12(18):6053. https://doi.org/10.3390/jcm12186053
Chicago/Turabian StyleTanase, Daniela Maria, Evelina Maria Gosav, Tina Botoc, Mariana Floria, Claudia Cristina Tarniceriu, Minela Aida Maranduca, Anca Haisan, Andrei Ionut Cucu, Ciprian Rezus, and Claudia Florida Costea. 2023. "Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications" Journal of Clinical Medicine 12, no. 18: 6053. https://doi.org/10.3390/jcm12186053
APA StyleTanase, D. M., Gosav, E. M., Botoc, T., Floria, M., Tarniceriu, C. C., Maranduca, M. A., Haisan, A., Cucu, A. I., Rezus, C., & Costea, C. F. (2023). Depiction of Branched-Chain Amino Acids (BCAAs) in Diabetes with a Focus on Diabetic Microvascular Complications. Journal of Clinical Medicine, 12(18), 6053. https://doi.org/10.3390/jcm12186053