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Møller PM, Kjøbsted R, Petersen MH, de Almeida ME, Pedersen AJT, Wojtaszewski JFP, Højlund K. Effect of acute exercise and exercise training on the ability of insulin to clear branched-chain amino acids from plasma in obesity and type 2 diabetes. Diabetologia 2025:10.1007/s00125-025-06454-y. [PMID: 40404819 DOI: 10.1007/s00125-025-06454-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 02/20/2025] [Indexed: 05/24/2025]
Abstract
AIMS/HYPOTHESIS Insulin resistance in obesity and type 2 diabetes is associated with elevated plasma branched-chain amino acid (BCAA) levels. Here, we examined whether the ability of insulin to clear plasma BCAAs and any influence of acute exercise or exercise training on this response are intact in obesity and type 2 diabetes. METHODS In four case-control studies of participants with type 2 diabetes matched to glucose-tolerant individuals with obesity and lean individuals, who underwent hyperinsulinaemic-euglycaemic clamps, we examined the effect of insulin on plasma BCAAs (studies I-IV), with or without prior acute exercise (60 min, 70%V ˙ O 2max ) (study II), and before and after 10 weeks of endurance exercise training (study III) or 8 weeks of high-intensity interval training (study IV). RESULTS Insulin sensitivity was reduced in individuals with type 2 diabetes compared with individuals with obesity (study I-IV) and lean individuals (studies I and IV), and in individuals with obesity vs lean individuals (study I) (all p<0.05). Exercise training (studies III and IV) increased insulin sensitivity in all groups (all p<0.01). Plasma BCAAs were elevated in individuals with type 2 diabetes compared with individuals with obesity (studies I, III and IV) and lean individuals (studies I and IV) (all p<0.05). The ability of insulin to reduce plasma BCAAs was significantly attenuated in participants with type 2 diabetes compared with both lean individuals (studies I and IV) and individuals with obesity (studies I, II and IV) (all p<0.05). Acute exercise slightly reduced plasma BCAAs in both individuals with type 2 diabetes and individuals with obesity but did not potentiate insulin's ability to reduce plasma BCAAs (study II). Exercise training had no impact on fasting BCAAs and did not affect insulin's ability to reduce plasma BCAAs in any group (studies III and IV) or rescue the attenuated insulin suppression of plasma BCAAs in participants with type 2 diabetes. CONCLUSIONS/INTERPRETATION Our results demonstrate that insulin's ability to suppress plasma BCAAs is impaired in type 2 diabetes but is intact in individuals with obesity. Although acute exercise reduces fasting BCAA levels, neither acute exercise nor exercise training affects insulin's ability to suppress plasma BCAAs in glucose-tolerant individuals with or without obesity or in individuals with type 2 diabetes.
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Affiliation(s)
- Pauline M Møller
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Rasmus Kjøbsted
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Maria H Petersen
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
| | - Martin E de Almeida
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | | | - Jørgen F P Wojtaszewski
- The August Krogh Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark
| | - Kurt Højlund
- Steno Diabetes Center Odense, Odense University Hospital, Odense, Denmark.
- Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
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Wang L, Li L, Liu J, Sheng C, Yang M, Hu Z, Yue R. Associated factors and principal pathophysiological mechanisms of type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2025; 16:1499565. [PMID: 40416523 PMCID: PMC12098035 DOI: 10.3389/fendo.2025.1499565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 04/11/2025] [Indexed: 05/27/2025] Open
Abstract
Type 2 diabetes mellitus(T2DM) as a common chronic disease with an increasing prevalence worldwide that poses a great threat to individual health, and is characterized by chronic hyperglycemia resulting from insulin resistance (IR) coupled with β-cell dysfunction. Mitochondrial dysfunction, obesity, gut microbiota, oxidative stress and inflammation have emerged as a significant contributor to the etiology of T2DM, affecting various metabolic processes critical for glucose homeostasis. This short review underscores their role in enhancing T2DM-related molecular mechanisms and explores recent advancements in diabetic management, further highlights the importance of personalized care plans to address the complexities of the T2DM and aims to improve patient quality of life and long-term health outcome.
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Affiliation(s)
| | | | | | | | | | - Zhipeng Hu
- Department of Endocrinology, Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Rensong Yue
- Department of Endocrinology, Hospital of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
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Xu Y, Huang J, Tang S, Sun Y, Li H, Li P, Li X, Hattori M, Wu X, Zhang H, Wang Z. Anti-diabetes activity of (R)-gentiandiol in KKAy type 2 mice. Sci Rep 2025; 15:15730. [PMID: 40325051 PMCID: PMC12052974 DOI: 10.1038/s41598-025-00422-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Accepted: 04/28/2025] [Indexed: 05/07/2025] Open
Abstract
Swertiamarin is a major component of many traditional Chinese Swertia herbs that show significant antidiabetic activity. (R)-Gentiandiol and (S)-gentiandiol are metabolites of swertiamarin found in vivo. The antidiabetic activity of swertiamarin and its nitrogen-containing metabolites (R)-gentiandiol and (S)-gentiandiol was evaluated in this research, and their mechanism of action was investigated after evaluating the serum metabolic profile of KK/Upj-Ay type 2 mice. The pharmaceutical effects of swertiamarin, (R)-gentiandiol, and (S)-gentiandiol were tested by biochemical indices and histopathological observations. Moreover, the mechanism underlying the action of three compounds against type 2 diabetes was elucidated using a metabolomic method. It was shown that (R)-gentiandiol significantly improved pathological changes in the kidney and pancreas. The levels of total cholesterol, triglyceride, and high-density and low-density lipoprotein cholesterol improved considerably after treatment with (R)-gentiandiol, compared to their levels in model mice. However, the levels of these compounds showed no improvement after treatment with (S)-gentiandiol. In total, 15 biomarkers were identified in KK/Upj-Ay type 2 mice, and the levels of 10 biomarkers were measured after treatment with (R)-gentiandiol. (R)-Gentiandiol reduced the abnormalities in metabolic pathways, including lipid metabolism, amino acid metabolism, carbohydrate metabolism, and nucleotide metabolism. Additionally, glycine, serine, and threonine metabolism related to the regulation of glycine was affected the most. The study indicated that the antidiabetic effects of Swertia herbs may due to (R)-gentiandiol which is a metabolite of swertiamarin in vivo. This study helps clarify the active metabolites of swertiamarin, provide greater insights into the clinical antidiabetic effects of Swertia herbs and bring novel ideas for developing new drugs from antidiabetic herbs.
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Affiliation(s)
- Yaqi Xu
- Department of Pharmaceutical Analysis, College of Pharmacy, Heilongjiang University of Chinese Medicine, Heping road 24, Harbin, 150040, China
| | - Jinyue Huang
- Department of Pharmaceutical Analysis, College of Pharmacy, Heilongjiang University of Chinese Medicine, Heping road 24, Harbin, 150040, China
| | - Shuhan Tang
- Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
- Heilongjiang Hospital, Beijing Children's Hospital, Youyi road 57, Harbin, 150000, China
| | - Yidan Sun
- Department of Pharmaceutical Analysis, College of Pharmacy, Heilongjiang University of Chinese Medicine, Heping road 24, Harbin, 150040, China
| | - Hao Li
- Department of Pharmaceutical Analysis, College of Pharmacy, Heilongjiang University of Chinese Medicine, Heping road 24, Harbin, 150040, China
| | - Pengyu Li
- Department of Pharmaceutical Analysis, College of Pharmacy, Heilongjiang University of Chinese Medicine, Heping road 24, Harbin, 150040, China
| | - Xianna Li
- Department of Pharmaceutical Analysis, College of Pharmacy, Heilongjiang University of Chinese Medicine, Heping road 24, Harbin, 150040, China
| | - Masao Hattori
- Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | - Xiuhong Wu
- Department of Pharmaceutical Analysis, College of Pharmacy, Heilongjiang University of Chinese Medicine, Heping road 24, Harbin, 150040, China
| | - Hailong Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China
| | - Zhigang Wang
- Department of Pharmaceutical Analysis, College of Pharmacy, Heilongjiang University of Chinese Medicine, Heping road 24, Harbin, 150040, China.
- Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.
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Asakura J, Nagao M, Shinohara M, Hosooka T, Kuwahara N, Nishimori M, Tanaka H, Satomi-Kobayashi S, Matsui S, Sasaki T, Kitamura T, Otake H, Ishida T, Ogawa W, Hirata KI, Toh R. Impaired cardiac branched-chain amino acid metabolism in a novel model of diabetic cardiomyopathy. Cardiovasc Diabetol 2025; 24:167. [PMID: 40240904 PMCID: PMC12004671 DOI: 10.1186/s12933-025-02725-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 04/05/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Systemic insulin resistance plays an important role in the pathogenesis of type 2 diabetes and its complications. Although impaired branched-chain amino acid (BCAA) metabolism has been reported to be involved in the development of diabetes, the relationship between cardiac BCAA metabolism and the pathogenesis of diabetic cardiomyopathy (DbCM) remains unclear. OBJECTIVES The aim of this study was to investigate BCAA metabolism in insulin-resistant hearts by using a novel mouse model of DbCM. METHODS The cardiac phenotypes of adipocyte-specific 3'-phosphoinositide-dependent kinase 1 (PDK1)-deficient (A-PDK1KO) mice were assessed by histological analysis and echocardiography. The metabolic characteristics and cardiac gene expression were determined by mass spectrometry or RNA sequencing, respectively. Cardiac protein expression was evaluated by Western blot analysis. RESULTS A-PDK1KO mouse hearts exhibited hypertrophy with prominent insulin resistance, consistent with cardiac phenotypes and metabolic disturbances previously reported as DbCM characteristics. RNA sequencing revealed the activation of BCAA uptake in diabetic hearts. In addition, the key enzymes involved in cardiac BCAA catabolism were downregulated at the protein level in A-PDK1KO mice, leading to the accumulation of BCAAs in the heart. Mechanistically, the accumulation of the BCAA leucine caused cardiac hypertrophy via the activation of mammalian target of rapamycin complex 1 (mTORC1). CONCLUSIONS A-PDK1KO mice closely mimic the cardiac phenotypes and metabolic alterations observed in human DbCM and exhibit impaired BCAA metabolism in the heart. This model may contribute to a better understanding of DbCM pathophysiology and to the development of novel therapies for this disease.
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Affiliation(s)
- Junko Asakura
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Manabu Nagao
- Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Masakazu Shinohara
- Division of Molecular Epidemiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
- The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
| | - Tetsuya Hosooka
- Laboratory of Nutritional Physiology, Graduate School of Integrated Pharmaceutical and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
| | - Naoya Kuwahara
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Makoto Nishimori
- Division of Molecular Epidemiology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
| | - Hidekazu Tanaka
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Seimi Satomi-Kobayashi
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Sho Matsui
- Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology Graduate School of Agriculture, Kyoto University, 7-10-2 Tomogaoka, Suma-ku, Kyoto, 654-0142, Japan
| | - Tsutomu Sasaki
- Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology Graduate School of Agriculture, Kyoto University, 7-10-2 Tomogaoka, Suma-ku, Kyoto, 654-0142, Japan
| | - Tadahiro Kitamura
- Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, Japan
| | - Hiromasa Otake
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tatsuro Ishida
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
- Division of Nursing Practice, Kobe University Graduate School of Health Sciences, Kobe, Japan
| | - Wataru Ogawa
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Japan
| | - Ken-Ichi Hirata
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
- Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Ryuji Toh
- Division of Evidence-Based Laboratory Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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Tang SS, Zhao XF, An XD, Sun WJ, Kang XM, Sun YT, Jiang LL, Gao Q, Li ZH, Ji HY, Lian FM. Classification and identification of risk factors for type 2 diabetes. World J Diabetes 2025; 16:100371. [PMID: 39959280 PMCID: PMC11718467 DOI: 10.4239/wjd.v16.i2.100371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 10/24/2024] [Accepted: 11/26/2024] [Indexed: 12/30/2024] Open
Abstract
The risk factors for type 2 diabetes mellitus (T2DM) have been increasingly researched, but the lack of systematic identification and categorization makes it difficult for clinicians to quickly and accurately access and understand all the risk factors, which are categorized in this paper into five categories: Social determinants, lifestyle, checkable/testable risk factors, history of illness and medication, and other factors, which are discussed in a narrative review. Meanwhile, this paper points out the problems of the current research, helps to improve the systematic categorisation and practicality of T2DM risk factors, and provides a professional research basis for clinical practice and industry decision-making.
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Affiliation(s)
- Shan-Shan Tang
- College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, Jilin Province, China
| | - Xue-Fei Zhao
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Xue-Dong An
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Wen-Jie Sun
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Xiao-Min Kang
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Yu-Ting Sun
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Lin-Lin Jiang
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Qing Gao
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Ze-Hua Li
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Hang-Yu Ji
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
| | - Feng-Mei Lian
- Department of Endocrinology, Guang’anmen Hospital, Beijing 100053, China
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Gong Q, Wang J, Luo D, Xu Y, Zhang R, Li X, Yin Z, Fang J, Wang H. Accumulation of branched-chain amino acids deteriorates the neuroinflammatory response of Müller cells in diabetic retinopathy via leucine/Sestrin2-mediated sensing of mTOR signaling. Acta Diabetol 2025; 62:227-240. [PMID: 39150511 PMCID: PMC11861416 DOI: 10.1007/s00592-024-02349-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/22/2024] [Indexed: 08/17/2024]
Abstract
AIMS This study aimed to investigate branched-chain amino acid (BCAA) catabolism in diabetic retinopathy (DR). METHODS Wild-type and db/db mice were fed BCAAs (5 or 10 mg/kg/day) for 12 weeks, and hyperglycemia-exposed Müller cells were treated with BCAAs (2 or 5 mmol/L) for 24 and 48 h. BCAA levels were measured using MS/MS. Western blotting was performed to detect proteins. Flow cytometry, oxygen consumption rate, and Cell Counting Kit-8 assays were used to evaluate Müller cell viability. Each experiment was conducted at least thrice. RESULTS BCAAs and branched-chain α-keto acids (BCKAs) were increased in the retina and systemic tissues of diabetic mice, and these changes were further enhanced to approximately 2-fold by extra BCAAs compared to wild-type group. In vitro, BCAAs and BCKAs were induced in hyperglycemic Müller cells, and augmented by BCAA supplementation. The aberrant BCAA catabolism was accompanied by mTORC1 activation and subsequently induced TNF-ɑ, VEGFA, GS, and GFAP in retinas and Müller cells under diabetic conditions. The cell apoptosis rate increased by approximately 50%, and mitochondrial respiration was inhibited by hyperglycemia and BCAA in Müller cells. Additionally, mTORC1 signaling was activated by leucine in Müller cells. Knockdown of Sestrin2 or LeuRS significantly abolished the leucine-induced mTORC1 phosphorylation and protected Müller cell viability under diabetic conditions. CONCLUSIONS We found that BCAA catabolism is hindered in DR through mTORC1 activation. Leucine plays a key role in inducing mTORC1 by sensing Sestrin2 in Müller cells. Targeting Sestrin2 may ameliorate the toxic effects of BCAA accumulation on Müller cells in DR.
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Affiliation(s)
- Qiaoyun Gong
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- National Clinical Research Center for Eye Diseases, No. 100 Haining Road, Hongkou District, Shanghai, 200080, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai, China
| | - Jingyi Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- National Clinical Research Center for Eye Diseases, No. 100 Haining Road, Hongkou District, Shanghai, 200080, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai, China
| | - Dawei Luo
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- National Clinical Research Center for Eye Diseases, No. 100 Haining Road, Hongkou District, Shanghai, 200080, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai, China
| | - Yupeng Xu
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- National Clinical Research Center for Eye Diseases, No. 100 Haining Road, Hongkou District, Shanghai, 200080, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai, China
| | - Rulin Zhang
- Department of Laboratory Medicine, Shanghai General Hospital, Shanghai, China
| | - Xin Li
- Department of Ultrasound, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China
| | - Zihan Yin
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- National Clinical Research Center for Eye Diseases, No. 100 Haining Road, Hongkou District, Shanghai, 200080, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai, China
| | - Junwei Fang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
- National Clinical Research Center for Eye Diseases, No. 100 Haining Road, Hongkou District, Shanghai, 200080, China
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai, China
| | - Haiyan Wang
- Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
- National Clinical Research Center for Eye Diseases, No. 100 Haining Road, Hongkou District, Shanghai, 200080, China.
- Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.
- Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China.
- Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Disease, Shanghai, China.
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Rodrigo‐Carbó C, Madinaveitia‐Nisarre L, Pérez‐Calahorra S, Gracia‐Rubio I, Cebollada A, Galindo‐Lalana C, Mateo‐Gallego R, Lamiquiz‐Moneo I. Low-calorie, high-protein diets, regardless of protein source, improve glucose metabolism and cardiometabolic profiles in subjects with prediabetes or type 2 diabetes and overweight or obesity. Diabetes Obes Metab 2025; 27:268-279. [PMID: 39420528 PMCID: PMC11618321 DOI: 10.1111/dom.16013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 09/23/2024] [Accepted: 10/01/2024] [Indexed: 10/19/2024]
Abstract
AIM The aim was to study the effect of two low-calorie, high-protein (HP) diets, with most of the protein coming from animal or plant sources, on glycaemic and other cardiometabolic outcomes in subjects with overweight or obesity and glucose metabolism disorders. MATERIALS AND METHODS A total of 117 participants aged >18 years with body mass index over 27.5 kg/m2 and prediabetes or type 2 diabetes mellitus (T2DM) were randomized to one of two HP low-calorie diets (35% of total calories from protein), in which 75% of the protein was from either plant-based sources (HPP) or animal sources (HPA). For both diets, 30% and 35% of the total calories were from fat and carbohydrates, respectively. The dietary intervention lasted 6 months. RESULTS Both diets improved body composition to a similar extent, including weight loss (-8.05 ± 5.12 kg for the HPA diet and -7.70 ± 5.47 kg for the HPP diet at 6 months) and fat mass, mainly visceral fat. Both diets had a similar beneficial effect on glucose metabolism, including fasting glucose, insulin, homeostasis model assessment of insulin resistance index and glycated haemoglobin. Other biochemical parameters, including lipid profiles, liver enzymes, adipokines and inflammatory biomarkers, similarly improved in both groups. Fasting incretins, mainly glucagon-like peptide 1, decreased significantly in both groups, and this effect correlated with weight loss. CONCLUSIONS Low-calorie HP diets improved body composition, glucose metabolism and other cardiometabolic outcomes, regardless of protein source (either animal or plant sources), in outpatients with prediabetes or T2DM. CLINICAL TRIAL REGISTRATION The clinical trial was registered in ClinicalTrials.gov (identifier: NCT05456347) https://clinicaltrials.gov/study/NCT05456347?term=NCT05456347&rank=1.
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Affiliation(s)
- Carmen Rodrigo‐Carbó
- Miguel Servet University Hospital, Aragon Health Research Institute, CIBERCVZaragozaSpain
- Departament of Physiatry and Nursing, Faculty of Health and Sport ScienceUniversity of ZaragozaHuescaSpain
| | | | - Sofía Pérez‐Calahorra
- Departament of Physiatry and Nursing, Faculty of Health ScienceUniversity of ZaragozaZaragozaSpain
| | - Irene Gracia‐Rubio
- Miguel Servet University Hospital, Aragon Health Research Institute, CIBERCVZaragozaSpain
- Department of Human Anatomy and Histology, Faculty of MedicineUniversity of ZaragozaZaragozaSpain
| | | | - Carlos Galindo‐Lalana
- Miguel Servet University Hospital, Aragon Health Research Institute, CIBERCVZaragozaSpain
| | - Rocío Mateo‐Gallego
- Miguel Servet University Hospital, Aragon Health Research Institute, CIBERCVZaragozaSpain
- Departament of Physiatry and Nursing, Faculty of Health and Sport ScienceUniversity of ZaragozaHuescaSpain
| | - Itziar Lamiquiz‐Moneo
- Miguel Servet University Hospital, Aragon Health Research Institute, CIBERCVZaragozaSpain
- Department of Human Anatomy and Histology, Faculty of MedicineUniversity of ZaragozaZaragozaSpain
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Abdelhafez YG, Wang G, Li S, Pellegrinelli V, Chaudhari AJ, Ramirez A, Sen F, Vidal-Puig A, Sidossis LS, Klein S, Badawi RD, Chondronikola M. The role of brown adipose tissue in branched-chain amino acid clearance in people. iScience 2024; 27:110559. [PMID: 39175781 PMCID: PMC11340589 DOI: 10.1016/j.isci.2024.110559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 06/24/2024] [Accepted: 07/17/2024] [Indexed: 08/24/2024] Open
Abstract
Brown adipose tissue (BAT) in rodents appears to be an important tissue for the clearance of plasma branched-chain amino acids (BCAAs) contributing to improved metabolic health. However, the role of human BAT in plasma BCAA clearance is poorly understood. Here, we evaluate patients with prostate cancer who underwent positron emission tomography-computed tomography imaging after an injection of 18F-fluciclovine (L-leucine analog). Supraclavicular adipose tissue (AT; primary location of human BAT) has a higher net uptake rate for 18F-fluciclovine compared to subcutaneous abdominal and upper chest AT. Supraclavicular AT 18F-fluciclovine net uptake rate is lower in patients with obesity and type 2 diabetes. Finally, the expression of genes involved in BCAA catabolism is higher in the supraclavicular AT of healthy people with high BAT volume compared to those with low BAT volume. These findings support the notion that BAT can potentially function as a metabolic sink for plasma BCAA clearance in people.
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Affiliation(s)
- Yasser G. Abdelhafez
- Department of Radiology, University of California Davis, Sacramento, CA 95817, USA
- Nuclear Medicine Unit, South Egypt Cancer Institute, Assiut University, El Fateh 71111, Egypt
| | - Guobao Wang
- Department of Radiology, University of California Davis, Sacramento, CA 95817, USA
| | - Siqi Li
- Department of Radiology, University of California Davis, Sacramento, CA 95817, USA
| | - Vanessa Pellegrinelli
- Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Abhijit J. Chaudhari
- Department of Radiology, University of California Davis, Sacramento, CA 95817, USA
| | - Anthony Ramirez
- Department of Nutrition, University of California Davis, Davis, CA 95616, USA
| | - Fatma Sen
- Department of Radiology, University of California Davis, Sacramento, CA 95817, USA
| | - Antonio Vidal-Puig
- Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Labros S. Sidossis
- Department of Kinesiology and Health, Rutgers University, New Brunswick, NJ 08901, USA
| | - Samuel Klein
- Center for Human Nutrition, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Ramsey D. Badawi
- Department of Radiology, University of California Davis, Sacramento, CA 95817, USA
| | - Maria Chondronikola
- Department of Radiology, University of California Davis, Sacramento, CA 95817, USA
- Institute of Metabolic Science-Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK
- Department of Nutrition, University of California Davis, Davis, CA 95616, USA
- Department of Nutrition and Dietetics, Harokopio University of Athens, 17778 Athens, Greece
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Shen R, Pan C, Yi G, Li Z, Dong C, Yu J, Zhang J, Dong Q, Yu K, Zeng Q. Type 2 Diabetes, Circulating Metabolites, and Calcific Aortic Valve Stenosis: A Mendelian Randomization Study. Metabolites 2024; 14:385. [PMID: 39057708 PMCID: PMC11278608 DOI: 10.3390/metabo14070385] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 06/26/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Epidemiological studies have shown an association between type 2 diabetes (T2D) and calcific aortic valve stenosis (CAVS), but the potential causal relationship and underlying mechanisms remain unclear. Therefore, we conducted a two-sample and two-step Mendelian randomization (MR) analysis to evaluate the association of T2D with CAVS and the mediating effects of circulating metabolites and blood pressure using genome-wide association study (GWAS) summary statistics. The inverse variance weighted (IVW) method was used for the primary MR analysis, and comprehensive sensitivity analyses were performed to validate the robustness of the results. Our results showed that genetically predicted T2D was associated with increased CAVS risk (OR 1.153, 95% CI 1.096-1.214, p < 0.001), and this association persisted even after adjusting for adiposity traits in multivariable MR analysis. Furthermore, the two-step MR analysis identified 69 of 251 candidate mediators that partially mediated the effect of T2D on CAVS, including total branched-chain amino acids (proportion mediated: 23.29%), valine (17.78%), tyrosine (9.68%), systolic blood pressure (8.72%), the triglyceride group (6.07-11.99%), the fatty acid group (4.78-12.82%), and the cholesterol group (3.64-11.56%). This MR study elucidated the causal impact of T2D on CAVS risk independently of adiposity and identified potential mediators in this association pathways. Our findings shed light on the pathogenesis of CAVS and suggest additional targets for the prevention and intervention of CAVS attributed to T2D.
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Affiliation(s)
- Rui Shen
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chengliang Pan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Guiwen Yi
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhiyang Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chen Dong
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jian Yu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jiangmei Zhang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qian Dong
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kunwu Yu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qiutang Zeng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; (R.S.); (C.P.); (G.Y.); (Z.L.); (C.D.); (J.Y.); (J.Z.); (Q.D.)
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
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Del Carmen Fernández-Fígares Jiménez M. Plant foods, healthy plant-based diets, and type 2 diabetes: a review of the evidence. Nutr Rev 2024; 82:929-948. [PMID: 37550262 DOI: 10.1093/nutrit/nuad099] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/09/2023] Open
Abstract
Type 2 diabetes (T2D) is a metabolic chronic disease in which insulin resistance and insufficient insulin production lead to elevated blood glucose levels. The prevalence of T2D is growing worldwide, mainly due to obesity and the adoption of Western diets. Replacing animal foods with healthy plant foods is associated with a lower risk of T2D in prospective studies. In randomized controlled trials, the consumption of healthy plant foods in place of animal foods led to cardiometabolic improvements in patients with T2D or who were at high risk of the disease. Dietary patterns that limit or exclude animal foods and focus on healthy plant foods (eg, fruits, vegetables, whole grains, nuts, legumes), known as healthy, plant-based diets, are consistently associated with a lower risk of T2D in cohort studies. The aim of this review is to examine the differential effects of plant foods and animal foods on T2D risk and to describe the existing literature about the role of healthy, plant-based diets, particularly healthy vegan diets, in T2D prevention and management. The evidence from cohort studies and randomized controlled trials will be reported, in addition to the potential biological mechanisms that seem to be involved.
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11
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Tang N, Liu Y, Yang S, Zhong M, Cui D, Chai O, Wang Y, Liu Y, Zhang X, Hou Z, Sun H. Correlation between newborn weight and serum BCAAs in pregnant women with diabetes. Nutr Diabetes 2024; 14:38. [PMID: 38839749 PMCID: PMC11153640 DOI: 10.1038/s41387-024-00301-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 05/28/2024] [Accepted: 05/30/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND Branched-chain amino acids (BCAAs), including leucine, isoleucine, and valine, are essential amino acids for mammals. Maternal BCAAs during pregnancy have been associated with newborn development. Meanwhile, BCAAs have been tightly linked with insulin resistance and diabetes in recent years. Diabetes in pregnancy is a common metabolic disorder. The current study aims to assess the circulating BCAA levels in pregnant women with diabetes and their relationship with neonatal development. METHODS The serum concentrations of BCAAs and their corresponding branched-chain α-keto acids (BCKAs) catabolites in 33 pregnant women with normal glucose tolerance, 16 pregnant women with type 2 diabetes before pregnancy (PDGM), and 15 pregnant women with gestational diabetes mellitus (GDM) were determined using a liquid chromatography system coupled to a mass spectrometer. The data were tested for normal distribution and homogeneity of variance before statistical analysis. Correlations were computed with the Pearson correlation coefficient. RESULTS The maternal serum BCAAs and BCKAs levels during late pregnancy were higher in women with PGDM than those in healthy women. Meanwhile, the circulating BCAAs and BCKAs showed no significant changes in women with GDM compared with those in healthy pregnant women. Furthermore, the circulating BCAA and BCKA levels in women with PGDM were positively correlated with the weight of the newborn. The circulating leucine level in women with GDM was positively correlated with the weight of the newborn. BCAA and BCKA levels in healthy pregnant women showed no correlation with newborn weight. CONCLUSIONS The serum BCAAs in pregnant women with diabetes, which was elevated in PGDM but not GDM, were positively correlated with newborn weight. These findings highlight potential approaches for early identification of high-risk individuals and interventions to reduce the risk of adverse pregnancy outcomes.
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Affiliation(s)
- Na Tang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Yajin Liu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Sa Yang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Mengyu Zhong
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Dongqing Cui
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Ou Chai
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Yurong Wang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Yunwei Liu
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Xuejiao Zhang
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
| | - Zhimin Hou
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
| | - Haipeng Sun
- NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
- Center for Cardiovascular Diseases, The Province and Ministry Co-Sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
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12
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Yuan Z, Qiao H, Wang Z, Wang H, Han M, Zhang W, Zhou Y, Hassan HM, Zhao W, Qin T. Taohe Chengqi decoction alleviated metabolic-associated fatty liver disease by boosting branched chain amino acids catabolism in the skeletal muscles of type 2 diabetes mellitus. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155315. [PMID: 38387274 DOI: 10.1016/j.phymed.2023.155315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 12/03/2023] [Accepted: 12/25/2023] [Indexed: 02/24/2024]
Abstract
OBJECTIVE Metabolic-associated fatty liver disease (MAFLD) is the most prevalent liver disease, whereas type 2 diabetes mellitus (T2DM) is considered an independent risk factor for MAFLD incidence. Taohe Chengqi decoction (THCQ) is clinically prescribed for T2DM treatment; however, the hepatoprotective effect of THCQ against MAFLD is still unknown. This study intended to elucidate the therapeutic effect of THCQ on T2DM-associated MAFLD and to investigate the underlying mechanisms. METHODS THCQ lyophilized powder was prepared and analyzed by UHPLC-MS/MS. A stable T2DM mouse model was established by high-fat diet (HFD) feeding combined with streptozotocin (STZ) injection. The T2DM mice were administered THCQ (2.5 g/kg or 5 g/kg) to explore the pharmacological effects of THCQ on T2DM-associated MAFLD. Liver tissue transcriptome was analyzed and the participatory roles of PPARα/γ pathways were verified both in vivo and in vitro. Serum metabolome analysis was used to explore the metabolome changes and skeletal muscle branched chain amino acid (BCAA) catabolic enzymes were further detected. Moreover, an AAV carrying BCKDHA shRNA was intramuscularly injected to verify the impact of THCQ on skeletal muscle BCAA catabolism and the potential therapeutic outcome on hepatic steatosis. RESULTS THCQ improved hepatic steatosis in MAFLD. RNA-sequencing analysis showed dysregulation in the hepatic PPARγ-related fatty acid synthesis, while PPARα-dependent fatty acid oxidation was elevated following THCQ treatment. Interestingly, in vitro analyses of these findings showed that THCQ had minor effects on fatty acid oxidation and/or synthesis. The metabolomic study revealed that THCQ accelerated BCAA catabolism in the skeletal muscles, in which knockdown of the BCAA catabolic enzyme BCKDHA diminished the THCQ therapeutic effect on hepatic steatosis. CONCLUSION This study highlighted the potential therapeutic effect of THCQ on hepatic steatosis in MALFD. THCQ upregulated fatty acid oxidation and reduced its synthesis via restoration of PPARα/γ pathways in HFD/STZ-induced T2DM mice, which is mediated through augmenting BCKDH activity and accelerating BCAA catabolism in the skeletal muscles. Overall, this study provided in-depth clues for "skeletal muscles-liver communication" in the therapeutic effect of THCQ against hepatic steatosis. These findings suggested THCQ might be a potential candidate against T2DM-associated MAFLD.
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Affiliation(s)
- Ziqiao Yuan
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450018, China
| | - Hui Qiao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Ziwei Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Haoran Wang
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Mingru Han
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Yang Zhou
- Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Zhengzhou Children's Hospital, Zhengzhou 450018, China
| | - Hozeifa Mohamed Hassan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou 318000, China.
| | - Wen Zhao
- Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China; State Key Laboratory of Esophageal Cancer Prevention and Treatment; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
| | - Tingting Qin
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.
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Chen L, Wang J, Ren Y, Ma Y, Liu J, Jiang H, Liu C. Artesunate improves glucose and lipid metabolism in db/db mice by regulating the metabolic profile and the MAPK/PI3K/Akt signalling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 126:155382. [PMID: 38382280 DOI: 10.1016/j.phymed.2024.155382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 12/23/2023] [Accepted: 01/20/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND Diabetes is a metabolic disorder characterized by chronic hyperglycaemia. Chronic metabolic abnormalities and long-term hyperglycaemia may result in a wide range of acute and chronic consequences. Previous studies have demonstrated that artesunate(ART) has antidiabetic, anti-inflammatory, antiatherosclerotic, and other beneficial effects, but the specific regulatory mechanism is not completely clear. AIM This study investigated the effects of ART on metabolic disorders in type 2 diabetes mellitus (T2DM) model db/db mice and explored the underlying mechanisms involved. METHODS C57BL/KsJ-db/db mice were used to identify the targets and molecular mechanism of ART. Metabolomic methods were used to evaluate the efficacy of ART in improving T2DM-related metabolic disorders. Network pharmacology and transcriptomic sequencing were used to analyse the targets and pathways of ART in T2DM. Finally, molecular biology experiments were performed to verify the key targets and pathways selected by network pharmacology and transcriptomic analyses. RESULTS After a 7-week ART intervention (160 mg/kg), the glucose and lipid metabolism levels of the db/db mice improved. Additionally, the oxidative stress indices, namely, the MDA and SOD levels, significantly improved (p<0.01). Linoleic acid and glycerophospholipid metabolism, amino acid metabolism, bile acid synthesis, and purine metabolism disorders in db/db mice were partially corrected after ART treatment. Network pharmacology analysis identified important targets of ART for the treatment of metabolic disorders in T2DM . These targets are involved in key signalling pathways, including the highest scores observed for the PI3K/Akt signalling pathway. Transcriptomic analysis revealed that ART could activate the MAPK signalling pathway and two key gene targets, HGK and GADD45. Immunoblotting revealed that ART increases p-PI3K, p-AKT, Glut2, and IRS1 protein expression and suppresses the phosphorylation of p38, ERK1/2, and JNK, returning HGK and GADD45 to their preartesunate levels. CONCLUSION Treatment of db/db mice with 160 mg/kg ART for 7 weeks significantly reduced fasting blood glucose and lipid levels. It also improved metabolic imbalances in amino acids, lipids, purines, and bile acids, thereby improving metabolic disorders. These effects are achieved by activating the PI3K/AKT pathway and inhibiting the MAPK pathway, thus demonstrating the efficacy of the drug.
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Affiliation(s)
- Lulu Chen
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Department of Clinical Laboratory, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Jialin Wang
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Yanshuang Ren
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Yujin Ma
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Jie Liu
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
| | - Hongwei Jiang
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China.
| | - Chuanxin Liu
- Luoyang Key Laboratory of Clinical Multiomics and Translational Medicine, Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China.
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Huang C, Luo Y, Zeng B, Chen Y, Liu Y, Chen W, Liao X, Liu Y, Wang Y, Wang X. Branched-chain amino acids prevent obesity by inhibiting the cell cycle in an NADPH-FTO-m 6A coordinated manner. J Nutr Biochem 2023; 122:109437. [PMID: 37666478 DOI: 10.1016/j.jnutbio.2023.109437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 08/15/2023] [Accepted: 08/30/2023] [Indexed: 09/06/2023]
Abstract
Obesity has become a major health crisis in the past decades. Branched-chain amino acids (BCAA), a class of essential amino acids, exerted beneficial health effects with regard to obesity and its related metabolic dysfunction, although the underlying reason is unknown. Here, we show that BCAA supplementation alleviates high-fat diet (HFD)-induced obesity and insulin resistance in mice and inhibits adipogenesis in 3T3-L1 cells. Further, we find that BCAA prevent the mitotic clonal expansion (MCE) of preadipocytes by reducing cyclin A2 (CCNA2) and cyclin-dependent kinase 2 (CDK2) expression. Mechanistically, BCAA decrease the concentration of nicotinamide adenine dinucleotide phosphate (NADPH) in adipose tissue and 3T3-L1 cells by reducing glucose-6-phosphate dehydrogenase (G6PD) expression. The reduced NADPH attenuates the expression of fat mass and obesity-associated (FTO) protein, a well-known m6A demethylase, to increase the N6-methyladenosine (m6A) levels of Ccna2 and Cdk2 mRNA. Meanwhile, the high m6A levels of Ccna2 and Cdk2 mRNA are recognized by YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), which results in mRNA decay and reduction of their protein expressions. Overall, our data demonstrate that BCAA inhibit obesity and adipogenesis by reducing CDK2 and CCNA2 expression via an NADPH-FTO-m6A coordinated manner in vivo and in vitro, which raises a new perspective on the role of m6A in the BCAA regulation of obesity and adipogenesis.
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Affiliation(s)
- Chaoqun Huang
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Yaojun Luo
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Botao Zeng
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Yushi Chen
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Youhua Liu
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Wei Chen
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Xing Liao
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Yuxi Liu
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Yizhen Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China
| | - Xinxia Wang
- College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang province, China; Key Laboratory of Molecular Animal Nutrition (Zhejiang University), Ministry of Education, Hangzhou, China; Key Laboratory of Animal Nutrition and Feed Science (Eastern of China), Ministry of Agriculture and Rural Affairs, Hangzhou, China; Key Laboratory of Animal Feed and Nutrition of Zhejiang Province, Hangzhou, China.
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15
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Yang W, Jiang W, Guo S. Regulation of Macronutrients in Insulin Resistance and Glucose Homeostasis during Type 2 Diabetes Mellitus. Nutrients 2023; 15:4671. [PMID: 37960324 PMCID: PMC10647592 DOI: 10.3390/nu15214671] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 10/30/2023] [Accepted: 11/02/2023] [Indexed: 11/15/2023] Open
Abstract
Insulin resistance is an important feature of metabolic syndrome and a precursor of type 2 diabetes mellitus (T2DM). Overnutrition-induced obesity is a major risk factor for the development of insulin resistance and T2DM. The intake of macronutrients plays a key role in maintaining energy balance. The components of macronutrients distinctly regulate insulin sensitivity and glucose homeostasis. Precisely adjusting the beneficial food compound intake is important for the prevention of insulin resistance and T2DM. Here, we reviewed the effects of different components of macronutrients on insulin sensitivity and their underlying mechanisms, including fructose, dietary fiber, saturated and unsaturated fatty acids, and amino acids. Understanding the diet-gene interaction will help us to better uncover the molecular mechanisms of T2DM and promote the application of precision nutrition in practice by integrating multi-omics analysis.
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Affiliation(s)
| | | | - Shaodong Guo
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX 77843, USA; (W.Y.); (W.J.)
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16
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Liu Y, Wang D, Liu YP. Metabolite profiles of diabetes mellitus and response to intervention in anti-hyperglycemic drugs. Front Endocrinol (Lausanne) 2023; 14:1237934. [PMID: 38027178 PMCID: PMC10644798 DOI: 10.3389/fendo.2023.1237934] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2023] [Accepted: 10/16/2023] [Indexed: 12/01/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) has become a major health problem, threatening the quality of life of nearly 500 million patients worldwide. As a typical multifactorial metabolic disease, T2DM involves the changes and interactions of various metabolic pathways such as carbohydrates, amino acid, and lipids. It has been suggested that metabolites are not only the endpoints of upstream biochemical processes, but also play a critical role as regulators of disease progression. For example, excess free fatty acids can lead to reduced glucose utilization in skeletal muscle and induce insulin resistance; metabolism disorder of branched-chain amino acids contributes to the accumulation of toxic metabolic intermediates, and promotes the dysfunction of β-cell mitochondria, stress signal transduction, and apoptosis. In this paper, we discuss the role of metabolites in the pathogenesis of T2DM and their potential as biomarkers. Finally, we list the effects of anti-hyperglycemic drugs on serum/plasma metabolic profiles.
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Affiliation(s)
| | | | - Yi-Ping Liu
- Provincial University Key Laboratory of Sport and Health Science, School of Physical Education and Sport Sciences, Fujian Normal University, Fuzhou, China
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17
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Moreno-Vedia J, Llop D, Rodríguez-Calvo R, Plana N, Amigó N, Rosales R, Esteban Y, Girona J, Masana L, Ibarretxe D. Serum branch-chained amino acids are increased in type 2 diabetes and associated with atherosclerotic cardiovascular disease. Cardiovasc Diabetol 2023; 22:249. [PMID: 37710233 PMCID: PMC10503204 DOI: 10.1186/s12933-023-01958-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2023] [Accepted: 08/12/2023] [Indexed: 09/16/2023] Open
Abstract
BACKGROUND AND AIM Circulating biomarkers of metabolic and cardiovascular diseases can help in the early detection and prevention of those diseases. Using proton nuclear magnetic resonance (1H-NMR), we aimed to study the plasma levels of low-molecular-weight metabolites (LMWMs) in a cohort of 307 patients with metabolic diseases to assess their relationships with type-2 diabetes (T2D) and incident atherosclerotic cardiovascular disease (ASCVD). METHODS We conducted a cross-sectional and prospective study. We included 307 patients attending the Lipid Unit of our University Hospital for the treatment of the following metabolic disturbances and associated disorders: T2D (73.9%), obesity (58.7%), and hypertension (55.1%). 1H-NMR was used to study the plasma levels of 13 LMWMs. LMWM serum concentrations were evaluated in patients with and without T2D. and the correlations with several parameters and their associations with T2D were analyzed. The association between LMWM levels at baseline and the development of ASCVD in patients with T2D after 10 years of follow-up was also evaluated. RESULTS Among the LMWMs measured, the branched-chain amino acids (BCAAs) valine, leucine and isoleucine showed a positive association with several clinical and lipid-related biochemical parameters and inflammatory markers (p < 0.05). Likewise, these three BCAAS were associated with diabetes even after adjusting for covariates (p < 0.05). During the follow-up period of 10 years, 29 of the 185 patients with diabetes at baseline (15.68%) developed ASCVD. After adjusting for clinical covariates, baseline levels of valine and alanine were associated with the development of ASCVD (p < 0.05). CONCLUSION Overall, our results indicated that plasma levels of LMWMs measured by 1H-NMR could be potential biomarkers associated with T2D. Moreover, alanine and valine can help in the early detection of the cardiovascular risk associated with this metabolic disease.
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Affiliation(s)
- Juan Moreno-Vedia
- Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira I Virgili, Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Dídac Llop
- Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira I Virgili, Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Ricardo Rodríguez-Calvo
- Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira I Virgili, Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Núria Plana
- Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira I Virgili, Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | | | - Roser Rosales
- Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira I Virgili, Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Yaiza Esteban
- Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira I Virgili, Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Josefa Girona
- Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira I Virgili, Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Lluís Masana
- Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira I Virgili, Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain.
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
| | - Daiana Ibarretxe
- Vascular Medicine and Metabolism Unit, Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, Universitat Rovira I Virgili, Institut Investigació Sanitaria Pere Virgili (IISPV), Reus, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
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18
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Becetti I, Lauze M, Lee H, Bredella MA, Misra M, Singhal V. Changes in Branched-Chain Amino Acids One Year after Sleeve Gastrectomy in Youth with Obesity and Their Association with Changes in Insulin Resistance. Nutrients 2023; 15:3801. [PMID: 37686833 PMCID: PMC10489782 DOI: 10.3390/nu15173801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 08/25/2023] [Accepted: 08/28/2023] [Indexed: 09/10/2023] Open
Abstract
Adults with obesity have a reduction in branched-chain amino acid (BCAA) levels following metabolic and bariatric surgery (MBS), which is hypothesized to contribute to the metabolic advantages of MBS. We examined this relationship in 62 youth 13-24 years old with severe obesity (47 female) over 12 months. Thirty had sleeve gastrectomy (SG) and 32 were non-surgical controls (NS). We measured fasting insulin, glucose, glycated hemoglobin (HbA1c), isoleucine, leucine, and valine concentrations, and post-prandial insulin and glucose, following a mixed meal tolerance test. Twenty-four-hour food recalls were collected. At baseline, groups did not differ in the intake or the serum levels of BCAAs, HbA1C, HOMA-IR, Matsuda index, insulinogenic index, or oral Disposition index (oDI). Over 12 months, SG vs. NS had greater reductions in serum BCAAs, and SG had significant reductions in BCAA intake. SG vs. NS had greater reductions in HbA1c and HOMA-IR, with increases in the Matsuda index and oDI. In SG, baseline leucine and total BCAA concentrations were negatively correlated with the baseline Matsuda index. Reductions in serum leucine were positively associated with the reductions in HOMA-IR over 12 months. These associations suggest a potential role of BCAA in regulating metabolic health. Reducing dietary intake and serum BCAA concentrations may reduce insulin resistance.
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Affiliation(s)
- Imen Becetti
- Division of Pediatric Endocrinology, Mass General for Children and Harvard Medical School, Boston, MA 02114, USA; (M.M.); (V.S.)
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Meghan Lauze
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Hang Lee
- Biostatistics Center, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Miriam A. Bredella
- Department of Radiology, Musculoskeletal Imaging and Interventions, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Madhusmita Misra
- Division of Pediatric Endocrinology, Mass General for Children and Harvard Medical School, Boston, MA 02114, USA; (M.M.); (V.S.)
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Vibha Singhal
- Division of Pediatric Endocrinology, Mass General for Children and Harvard Medical School, Boston, MA 02114, USA; (M.M.); (V.S.)
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Pediatric Program, MGH Weight Center, Massachusetts General Hospital, Boston, MA 02114, USA
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19
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Zheng XX, Li DX, Li YT, Chen YL, Zhao YL, Ji S, Guo MZ, Du Y, Tang DQ. Mulberry leaf water extract alleviates type 2 diabetes in mice via modulating gut microbiota-host co-metabolism of branched-chain amino acid. Phytother Res 2023; 37:3195-3210. [PMID: 37013717 DOI: 10.1002/ptr.7822] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/21/2023] [Accepted: 03/24/2023] [Indexed: 04/05/2023]
Abstract
Elevations in circling branched-chain amino acids (BCAAs) levels associated with insulin resistance and type 2 diabetes mellitus (T2DM). Morus alba L. water extracts (MLE) show hypoglycemic function, but the precise mechanism remains obscure. This study is designed to investigate the association of the antidiabetes effect of MLE with the BCAAs co-metabolism modulated by host and gut microbiota. Tissue-specific expressions of BCAA-catabolizing enzymes were detected by RT-PCR and western blot, respectively. The components of the intestinal microflora were analyzed by high-throughput 16S rRNA gene sequencing. The results showed that MLE administration improved blood glucose and insulin level, decreased inflammatory cytokines expression, and lowered serum and feces BCAAs levels. Furthermore, MLE reversed the abundance changes of the bacterial genera correlated with serum and feces BCAAs, such as Anaerovorax, Bilophila, Blautia, Colidextribacter, Dubosiella, Intestinimonas, Lachnoclostridium, Lachnospiraceae_NK4A136, Oscillibacter, and Roseburia. Functionality prediction indicated that MLE potentially inhibited bacterial BCAAs biosynthesis, and promoted the tissue-specific expression of BCAAs catabolic enzyme. More importantly, MLE had obvious impacts on BCAA catabolism in germ-free-mimic T2DM mice. Those results indicated that MLE improving T2DM-related biochemical abnormalities is associated with not only gut microbiota modification but also the tissue-specific expression of BCAAs catabolic enzyme.
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Affiliation(s)
- Xiao-Xiao Zheng
- Department of Pharmacy, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, 221116, China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China
| | - Ding-Xiang Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China
| | - Ya-Ting Li
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China
| | - Yu-Lang Chen
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China
| | - Yan-Lin Zhao
- Department of Pharmaceutical Analysis, Xuzhou Medical University, Xuzhou, 221204, China
| | - Shuai Ji
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China
- Department of Pharmacy, Suining People's Hospital Affiliated to Xuzhou Medical University, Suining, 221202, China
| | - Meng-Zhe Guo
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China
- Department of Pharmacy, Suining People's Hospital Affiliated to Xuzhou Medical University, Suining, 221202, China
| | - Yan Du
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China
- State Key Laboratory of Pharmaceutical Biotechnology, Chemistry and Biomedicine Innovation Center (ChemBIC), Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, 210093, China
| | - Dao-Quan Tang
- Department of Pharmacy, Xuzhou Municipal Hospital Affiliated to Xuzhou Medical University, Xuzhou, 221116, China
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, 221004, China
- Department of Pharmaceutical Analysis, Xuzhou Medical University, Xuzhou, 221204, China
- Department of Pharmacy, Suining People's Hospital Affiliated to Xuzhou Medical University, Suining, 221202, China
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20
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Yao H, Li K, Wei J, Lin Y, Liu Y. The contradictory role of branched-chain amino acids in lifespan and insulin resistance. Front Nutr 2023; 10:1189982. [PMID: 37408986 PMCID: PMC10318341 DOI: 10.3389/fnut.2023.1189982] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Accepted: 05/26/2023] [Indexed: 07/07/2023] Open
Abstract
Branched-chain amino acids (BCAAs; a mixture of leucine, valine and isoleucine) have important regulatory effects on glucose and lipid metabolism, protein synthesis and longevity. Many studies have reported that circulating BCAA levels or dietary intake of BCAAs is associated with longevity, sarcopenia, obesity, and diabetes. Among them, the influence of BCAAs on aging and insulin resistance often present different benefits or harmful effects in the elderly and in animals. Considering the nonobvious correlation between circulating BCAA levels and BCAA uptake, as well as the influence of diseases, diet and aging on the body, some of the contradictory conclusions have been drawn. The regulatory mechanism of the remaining contradictory role may be related to endogenous branched-chain amino acid levels, branched-chain amino acid metabolism and mTOR-related autophagy. Furthermore, the recent discovery that insulin resistance may be independent of longevity has expanded the research thinking related to the regulatory mechanism among the three. However, the negative effects of BCAAs on longevity and insulin resistance were mostly observed in high-fat diet-fed subjects or obese individuals, while the effects in other diseases still need to be studied further. In conclusion, there is still no definite conclusion on the specific conditions under which BCAAs and insulin resistance extend life, shorten life, or do not change lifespan, and there is still no credible and comprehensive explanation for the different effects of BCAAs and insulin resistance on lifespan.
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Affiliation(s)
- He Yao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Kai Li
- Department of General Surgery, The First People’s Hospital of Taian, Taian, Shandong, China
| | - Jie Wei
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yajun Lin
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Yinghua Liu
- Department of Nutrition, National Clinical Research Center for Geriatric Diseases, The First Medical Center of Chinese PLA General Hospital, Beijing, China
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21
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Cai D, Hou B, Xie SL. Amino acid analysis as a method of discovering biomarkers for diagnosis of diabetes and its complications. Amino Acids 2023:10.1007/s00726-023-03255-8. [PMID: 37067568 DOI: 10.1007/s00726-023-03255-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 02/21/2023] [Indexed: 04/18/2023]
Abstract
Diabetes mellitus (DM) is a severe chronic diseases with a global prevalence of 9%, leading to poor health and high health care costs, and is a direct cause of millions of deaths each year. The rising epidemic of diabetes and its complications, such as retinal and peripheral nerve disease, is a huge burden globally. A better understanding of the molecular pathways involved in the development and progression of diabetes and its complications can facilitate individualized prevention and treatment. High diabetes mellitus incidence rate is caused mainly by lack of non-invasive and reliable methods for early diagnosis, such as plasma biomarkers. The incidence of diabetes and its complications in the world still grows so it is crucial to develop a new, faster, high specificity and more sensitive diagnostic technologies. With the advancement of analytical techniques, metabolomics can identify and quantify multiple biomarkers simultaneously in a high-throughput manner, and effective biomarkers can greatly improve the efficiency of diabetes and its complications. By providing information on potential metabolic pathways, metabolomics can further define the mechanisms underlying the progression of diabetes and its complications, help identify potential therapeutic targets, and improve the prevention and management of T2D and its complications. The application of amino acid metabolomics in epidemiological studies has identified new biomarkers of diabetes mellitus (DM) and its complications, such as branched-chain amino acids, phenylalanine and arginine metabolites. This study focused on the analysis of metabolic amino acid profiling as a method for identifying biomarkers for the detection and screening of diabetes and its complications. The results presented are all from recent studies, and in all cases analyzed, there were significant changes in the amino acid profile of patients in the experimental group compared to the control group. This study demonstrates the potential of amino acid profiles as a detection method for diabetes and its complications.
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Affiliation(s)
- Dan Cai
- The Affiliated Nanhua Hospital, Department of Hand and Foot Surgery, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Biao Hou
- The Affiliated Nanhua Hospital, Department of Hand and Foot Surgery, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China
| | - Song Lin Xie
- The Affiliated Nanhua Hospital, Department of Hand and Foot Surgery, Hengyang Medical School, University of South China, Hengyang, 421001, Hunan, China.
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22
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Liu Y, Gan L, Zhao B, Yu K, Wang Y, Männistö S, Weinstein SJ, Huang J, Albanes D. Untargeted metabolomic profiling identifies serum metabolites associated with type 2 diabetes in a cross-sectional study of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Am J Physiol Endocrinol Metab 2023; 324:E167-E175. [PMID: 36516224 PMCID: PMC9925157 DOI: 10.1152/ajpendo.00287.2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/07/2022] [Accepted: 12/10/2022] [Indexed: 12/15/2022]
Abstract
Type 2 diabetes (T2D) is a complex chronic disease with substantial phenotypic heterogeneity affecting millions of individuals. Yet, its relevant metabolites and etiological pathways are not fully understood. The aim of this study is to assess a broad spectrum of metabolites related to T2D in a large population-based cohort. We conducted a metabolomic analysis of 4,281 male participants within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. The serum metabolomic analysis was performed using an LC-MS/GC-MS platform. Associations between 1,413 metabolites and T2D were examined using linear regression, controlling for important baseline risk factors. Standardized β-coefficients and standard errors (SEs) were computed to estimate the difference in metabolite concentrations. We identified 74 metabolites that were significantly associated with T2D based on the Bonferroni-corrected threshold (P < 3.5 × 10-5). The strongest signals associated with T2D were of carbohydrates origin, including glucose, 1,5-anhydroglucitol (1,5-AG), and mannose (β = 0.34, -0.91, and 0.41, respectively; all P < 10-75). We found several chemical class pathways that were significantly associated with T2D, including carbohydrates (P = 1.3 × 10-11), amino acids (P = 2.7 × 10-6), energy (P = 1.5 × 10-4), and xenobiotics (P = 1.2 × 10-3). The strongest subpathway associations were seen for fructose-mannose-galactose metabolism, glycolysis-gluconeogenesis-pyruvate metabolism, fatty acid metabolism (acyl choline), and leucine-isoleucine-valine metabolism (all P < 10-8). Our findings identified various metabolites and candidate chemical class pathways that can be characterized by glycolysis and gluconeogenesis metabolism, fructose-mannose-galactose metabolism, branched-chain amino acids, diacylglycerol, acyl cholines, fatty acid oxidation, and mitochondrial dysfunction.NEW & NOTEWORTHY These metabolomic patterns may provide new additional evidence and potential insights relevant to the molecular basis of insulin resistance and the etiology of T2D.
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Affiliation(s)
- Yuzhao Liu
- Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Lu Gan
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Bin Zhao
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Kai Yu
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, NIH, Bethesda, Maryland
| | - Yangang Wang
- Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Satu Männistö
- Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland
| | - Stephanie J Weinstein
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, NIH, Bethesda, Maryland
| | - Jiaqi Huang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
- Xiangya School of Public Health, Central South University, Changsha, China
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, NIH, Bethesda, Maryland
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23
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Role of Skeletal Muscle in the Pathogenesis and Management of Type 2 Diabetes: A Special Focus on Asian Indians. J Indian Inst Sci 2023. [DOI: 10.1007/s41745-022-00349-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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24
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van Beek SMM, Bruls YMH, Vanweert F, Fealy CE, Connell NJ, Schaart G, Moonen-Kornips E, Jörgensen JA, Vaz FM, Smeets ETHC, Joris PJ, Gemmink A, Houtkooper RH, Hesselink MKC, Bengtsson T, Havekes B, Schrauwen P, Hoeks J. Effect of β2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial. Nat Commun 2023; 14:173. [PMID: 36635304 PMCID: PMC9835033 DOI: 10.1038/s41467-023-35798-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 01/03/2023] [Indexed: 01/13/2023] Open
Abstract
β2-agonist treatment improves skeletal muscle glucose uptake and whole-body glucose homeostasis in rodents, likely via mTORC2-mediated signalling. However, human data on this topic is virtually absent. We here investigate the effects of two-weeks treatment with the β2-agonist clenbuterol (40 µg/day) on glucose control as well as energy- and substrate metabolism in healthy young men (age: 18-30 years, BMI: 20-25 kg/m2) in a randomised, placebo-controlled, double-blinded, cross-over study (ClinicalTrials.gov-identifier: NCT03800290). Randomisation occurred by controlled randomisation and the final allocation sequence was seven (period 1: clenbuterol, period 2: placebo) to four (period 1: placebo, period 2: clenbuterol). The primary and secondary outcome were peripheral insulin-stimulated glucose disposal and skeletal muscle GLUT4 translocation, respectively. Primary analyses were performed on eleven participants. No serious adverse events were reported. The study was performed at Maastricht University, Maastricht, The Netherlands, between August 2019 and April 2021. Clenbuterol treatment improved peripheral insulin-stimulated glucose disposal by 13% (46.6 ± 3.5 versus 41.2 ± 2.7 µmol/kg/min, p = 0.032), whereas skeletal muscle GLUT4 translocation assessed in overnight fasted muscle biopsies remained unaffected. These results highlight the potential of β2-agonist treatment in improving skeletal muscle glucose uptake and underscore the therapeutic value of this pathway for the treatment of type 2 diabetes. However, given the well-known (cardiovascular) side-effects of systemic β2-agonist treatment, further exploration on the underlying mechanisms is needed to identify viable therapeutic targets.
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Affiliation(s)
- Sten M M van Beek
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Yvonne M H Bruls
- Department of Radiology and Nuclear Medicine, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, the Netherlands
| | - Froukje Vanweert
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Ciarán E Fealy
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Niels J Connell
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Gert Schaart
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Esther Moonen-Kornips
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Johanna A Jörgensen
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Frédéric M Vaz
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands.,Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands.,Core Facility Metabolomics, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
| | - Ellen T H C Smeets
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Peter J Joris
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Anne Gemmink
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Riekelt H Houtkooper
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC location University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands.,Amsterdam Gastroenterology, Endocrinology, and Metabolism, Amsterdam, The Netherlands.,Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Matthijs K C Hesselink
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Tore Bengtsson
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Bas Havekes
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.,Department of Internal Medicine, Division of Endocrinology and Metabolic Disease, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Patrick Schrauwen
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands
| | - Joris Hoeks
- Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands.
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25
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Branched-Chain Amino Acids and Insulin Resistance, from Protein Supply to Diet-Induced Obesity. Nutrients 2022; 15:nu15010068. [PMID: 36615726 PMCID: PMC9824001 DOI: 10.3390/nu15010068] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/30/2022] [Accepted: 12/09/2022] [Indexed: 12/28/2022] Open
Abstract
For more than a decade, there has been a wide debate about the branched-chain amino acids (BCAA) leucine, valine, and isoleucine, with, on the one hand, the supporters of their anabolic effects and, on the other hand, those who suspect them of promoting insulin resistance. Indeed, the role of leucine in the postprandial activation of protein synthesis has been clearly established, even though supplementation studies aimed at taking advantage of this property are rather disappointing. Furthermore, there is ample evidence of an association between the elevation of their plasma concentrations and insulin resistance or the risk of developing type 2 diabetes, although there are many confounding factors, starting with the level of animal protein consumption. After a summary of their metabolism and anabolic properties, we analyze in this review the factors likely to increase the plasma concentrations of BCAAs, including insulin-resistance. After an analysis of supplementation or restriction studies in search of a direct role of BCAAs in insulin resistance, we discuss an indirect role through some of their metabolites: branched-chain keto acids, C3 and C5 acylcarnitines, and hydroxyisobutyrate. Overall, given the importance of insulin in the metabolism of these amino acids, it is very likely that small alterations in insulin sensitivity are responsible for a reduction in their catabolism long before the onset of impaired glucose tolerance.
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26
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Ademolu AB. Branched Chain Amino Acids and Gestational Diabetes Mellitus. J Clin Endocrinol Metab 2022; 107:e4322-e4323. [PMID: 35994362 DOI: 10.1210/clinem/dgac481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Indexed: 11/19/2022]
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27
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Vanweert F, Schrauwen P, Phielix E. Role of branched-chain amino acid metabolism in the pathogenesis of obesity and type 2 diabetes-related metabolic disturbances BCAA metabolism in type 2 diabetes. Nutr Diabetes 2022; 12:35. [PMID: 35931683 PMCID: PMC9356071 DOI: 10.1038/s41387-022-00213-3] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 06/15/2022] [Accepted: 07/05/2022] [Indexed: 12/23/2022] Open
Abstract
Branched-chain amino acid (BCAA) catabolism has been considered to have an emerging role in the pathogenesis of metabolic disturbances in obesity and type 2 diabetes (T2D). Several studies showed elevated plasma BCAA levels in humans with insulin resistance and patients with T2D, although the underlying reason is unknown. Dysfunctional BCAA catabolism could theoretically be an underlying factor. In vitro and animal work collectively show that modulation of the BCAA catabolic pathway alters key metabolic processes affecting glucose homeostasis, although an integrated understanding of tissue-specific BCAA catabolism remains largely unknown, especially in humans. Proof-of-concept studies in rodents -and to a lesser extent in humans – strongly suggest that enhancing BCAA catabolism improves glucose homeostasis in metabolic disorders, such as obesity and T2D. In this review, we discuss several hypothesized mechanistic links between BCAA catabolism and insulin resistance and overview current available tools to modulate BCAA catabolism in vivo. Furthermore, this review considers whether enhancing BCAA catabolism forms a potential future treatment strategy to promote metabolic health in insulin resistance and T2D.
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Affiliation(s)
- Froukje Vanweert
- Department of Nutrition and Movement Sciences, NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Patrick Schrauwen
- Department of Nutrition and Movement Sciences, NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Esther Phielix
- Department of Nutrition and Movement Sciences, NUTRIM, School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, The Netherlands.
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28
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Meyer RK, Bime MA, Duca FA. Small intestinal metabolomics analysis reveals differentially regulated metabolite profiles in obese rats and with prebiotic supplementation. Metabolomics 2022; 18:60. [PMID: 35871176 PMCID: PMC10234511 DOI: 10.1007/s11306-022-01920-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 07/07/2022] [Indexed: 10/16/2022]
Abstract
INTRODUCTION Obesity occurs partly due to consumption of a high-fat, high-sugar and low fiber diet and is associated with an altered gut microbiome. Prebiotic supplementation can reverse obesity and beneficially alter the gut microbiome, evidenced by previous studies in rodents. However, the role of the small intestinal metabolome in obese and prebiotic supplemented rodents has never been investigated. OBJECTIVES To investigate and compare the small intestinal metabolome of healthy and obese rats, as well as obese rats supplemented with the prebiotic oligofructose (OFS). METHODS Untargeted metabolomics was performed on small intestinal contents of healthy chow-fed, high fat diet-induced obese, and obese rats supplemented with oligofructose using UPLC-MS/MS. Quantification of enterohepatic bile acids was performed with UPLC-MS to determine specific effects of obesity and fiber supplementation on the bile acid pool composition. RESULTS The small intestinal metabolome of obese rats was distinct from healthy rats. OFS supplementation did not significantly alter the small intestinal metabolome but did alter levels of several metabolites compared to obese rats, including bile acid metabolites, amino acid metabolites, and metabolites related to the gut microbiota. Further, obese rats had lower total bile acids and increased taurine-conjugated bile acid species in enterohepatic circulation; this effect was reversed with OFS supplementation in high fat-feeding. CONCLUSION Obesity is associated with a distinct small intestinal metabolome, and OFS supplementation reverses some metabolite levels that were altered in obese rats. Future research into the effects of specific metabolites identified in this study will provide deeper insight into the mechanism of fiber supplementation on improved body weight.
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Affiliation(s)
- Rachel K Meyer
- School of Nutritional Sciences and Wellness, University of Arizona, ACBS Building, 1117 E Lowell Street, Tucson, AZ, 85711, USA
| | - Megan A Bime
- KEYS Program, BIO5 Institute, University of Arizona, Tucson, USA
| | - Frank A Duca
- BIO5 Institute, University of Arizona, Tucson, USA.
- Department of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, USA.
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29
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Vanweert F, Neinast M, Tapia EE, van de Weijer T, Hoeks J, Schrauwen-Hinderling VB, Blair MC, Bornstein MR, Hesselink MKC, Schrauwen P, Arany Z, Phielix E. A randomized placebo-controlled clinical trial for pharmacological activation of BCAA catabolism in patients with type 2 diabetes. Nat Commun 2022; 13:3508. [PMID: 35717342 PMCID: PMC9206682 DOI: 10.1038/s41467-022-31249-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 06/06/2022] [Indexed: 01/07/2023] Open
Abstract
Elevations in plasma branched-chain amino acid (BCAA) levels associate with insulin resistance and type 2 diabetes (T2D). Pre-clinical models suggest that lowering BCAA levels improve glucose tolerance, but data in humans are lacking. Here, we used sodium phenylbutyrate (NaPB), an accelerator of BCAA catabolism, as tool to lower plasma BCAA levels in patients with T2D, and evaluate its effect on metabolic health. This trial (NetherlandsTrialRegister: NTR7426) had a randomized, placebo-controlled, double-blind cross-over design and was performed in the Maastricht University Medical Center (MUMC+), the Netherlands, between February 2019 and February 2020. Patients were eligible for the trial if they were 40-75years, BMI of 25-38 kg/m², relatively well-controlled T2D (HbA1C < 8.5%) and treated with oral glucose-lowering medication. Eighteen participants were randomly assigned to receive either NaPB 4.8 g/m²/day and placebo for 2 weeks via controlled randomization and sixteen participants completed the study. The primary outcome was peripheral insulin sensitivity. Secondary outcomes were ex vivo muscle mitochondrial oxidative capacity, substrate oxidation and ectopic fat accumulation. Fasting blood samples were collected to determine levels of BCAA, their catabolic intermediates, insulin, triglycerides, free fatty acids (FFA) and glucose. NaPB led to a robust 27% improvement in peripheral insulin sensitivity compared to placebo (ΔRd:13.2 ± 1.8 vs. 9.6 ± 1.8 µmol/kg/min, p = 0.02). This was paralleled by an improvement in pyruvate-driven muscle mitochondrial oxidative capacity and whole-body insulin-stimulated carbohydrate oxidation, and a reduction in plasma BCAA and glucose levels. No effects were observed on levels of insulin, triglycerides and FFA, neither did fat accumulation in muscle and liver change. No adverse events were reported. These data establish the proof-of-concept in humans that modulating the BCAA oxidative pathway may represent a potential treatment strategy for patients with T2D.
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Affiliation(s)
- Froukje Vanweert
- grid.5012.60000 0001 0481 6099Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, 6229 ER The Netherlands
| | - Michael Neinast
- grid.25879.310000 0004 1936 8972Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA 19104 USA
| | - Edmundo Erazo Tapia
- grid.5012.60000 0001 0481 6099Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, 6229 ER The Netherlands
| | - Tineke van de Weijer
- grid.5012.60000 0001 0481 6099Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, 6229 ER The Netherlands ,grid.412966.e0000 0004 0480 1382Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, 6229 ER The Netherlands
| | - Joris Hoeks
- grid.5012.60000 0001 0481 6099Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, 6229 ER The Netherlands
| | - Vera B. Schrauwen-Hinderling
- grid.5012.60000 0001 0481 6099Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, 6229 ER The Netherlands ,grid.412966.e0000 0004 0480 1382Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, 6229 ER The Netherlands
| | - Megan C. Blair
- grid.25879.310000 0004 1936 8972Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA 19104 USA
| | - Marc R. Bornstein
- grid.25879.310000 0004 1936 8972Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA 19104 USA
| | - Matthijs K. C. Hesselink
- grid.5012.60000 0001 0481 6099Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, 6229 ER The Netherlands
| | - Patrick Schrauwen
- grid.5012.60000 0001 0481 6099Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, 6229 ER The Netherlands
| | - Zoltan Arany
- grid.25879.310000 0004 1936 8972Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, PA 19104 USA
| | - Esther Phielix
- grid.5012.60000 0001 0481 6099Department of Nutrition and Movement Sciences, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, 6229 ER The Netherlands
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Immunometabolic Reprogramming in Response to HIV Infection Is Not Fully Normalized by Suppressive Antiretroviral Therapy. Viruses 2022; 14:v14061313. [PMID: 35746785 PMCID: PMC9228482 DOI: 10.3390/v14061313] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/07/2022] [Accepted: 06/09/2022] [Indexed: 11/25/2022] Open
Abstract
Background: HIV infection results in immunometabolic reprogramming. While we are beginning to understand how this metabolic reprogramming regulates the immune response to HIV infection, we do not currently understand the impact of ART on immunometabolism in people with HIV (PWH). Methods: Serum obtained from HIV-infected (n = 278) and geographically matched HIV seronegative control subjects (n = 300) from Rakai Uganda were used in this study. Serum was obtained before and ~2 years following the initiation of ART from HIV-infected individuals. We conducted metabolomics profiling of the serum and focused our analysis on metabolic substrates and pathways assocaited with immunometabolism. Results: HIV infection was associated with metabolic adaptations that implicated hyperactive glycolysis, enhanced formation of lactate, increased activity of the pentose phosphate pathway (PPP), decreased β-oxidation of long-chain fatty acids, increased utilization of medium-chain fatty acids, and enhanced amino acid catabolism. Following ART, serum levels of ketone bodies, carnitine, and amino acid metabolism were normalized, however glycolysis, PPP, lactate production, and β-oxidation of long-chain fatty acids remained abnormal. Conclusion: Our findings suggest that HIV infection is associated with an increased immunometabolic demand that is satisfied through the utilization of alternative energetic substrates, including fatty acids and amino acids. ART alone was insufficient to completely restore this metabolic reprogramming to HIV infection, suggesting that a sustained impairment of immunometabolism may contribute to chronic immune activation and comorbid conditions in virally suppressed PWH.
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31
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Cuomo P, Capparelli R, Iannelli A, Iannelli D. Role of Branched-Chain Amino Acid Metabolism in Type 2 Diabetes, Obesity, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:ijms23084325. [PMID: 35457142 PMCID: PMC9030262 DOI: 10.3390/ijms23084325] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/06/2022] [Accepted: 04/11/2022] [Indexed: 12/17/2022] Open
Abstract
Branched-chain amino acids (BCAAs) include leucine, isoleucine, and valine. Mammalians cannot synthesize these amino acids de novo and must acquire them through their diet. High levels of BCAAs are associated with insulin resistance; type 2 diabetes; obesity; and non-metabolic diseases, including several forms of cancer. BCAAs—in particular leucine—activate the rapamycin complex1 mTORC1, which regulates cell growth and metabolism, glucose metabolism and several more essential physiological processes. Diets rich in BCAAs are associated with metabolic diseases (listed above), while diets low in BCAAs are generally reported to promote metabolic health. As for the dysregulation of the metabolism caused by high levels of BCAAs, recent studies propose that the accumulation of acyl-carnitine and diacyl-CoA in muscles alters lipid metabolism. However, this suggestion is not broadly accepted. On clinical grounds, pre- and post-operative metabolic profiles of candidate patients for bariatric surgery are being used to select the optimal procedure for each individual patient.
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Affiliation(s)
- Paola Cuomo
- Department of Agricultural Sciences, University of Naples “Federico II”, Via Università, 100-Portici, 80055 Naples, Italy;
| | - Rosanna Capparelli
- Department of Agricultural Sciences, University of Naples “Federico II”, Via Università, 100-Portici, 80055 Naples, Italy;
- Correspondence: (R.C.); (D.I.)
| | - Antonio Iannelli
- Department of Digestive Surgery, Université Côte d’ Azur, F-06108 Nice, France;
- Centre Hospitalier Universitaire de Nice-Digestive Surgery and Liver Transplantation Unit, Archet 2 Hospital, 151 Route de Saint Antoine de Ginestiere, F-062024 Nice, France
- Inserm, U1065, Team 8 “Hepatic Complications of Obesity and Alcohol”, F-062024 Nice, France
| | - Domenico Iannelli
- Department of Agricultural Sciences, University of Naples “Federico II”, Via Università, 100-Portici, 80055 Naples, Italy;
- Correspondence: (R.C.); (D.I.)
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Zhou Z, Sun B, Yu D, Zhu C. Gut Microbiota: An Important Player in Type 2 Diabetes Mellitus. Front Cell Infect Microbiol 2022; 12:834485. [PMID: 35242721 PMCID: PMC8886906 DOI: 10.3389/fcimb.2022.834485] [Citation(s) in RCA: 127] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/24/2022] [Indexed: 01/10/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the common metabolic diseases in the world. Due to the rise in morbidity and mortality, it has become a global health problem. To date, T2DM still cannot be cured, and its intervention measures mainly focus on glucose control as well as the prevention and treatment of related complications. Interestingly, the gut microbiota plays an important role in the development of metabolic diseases, especially T2DM. In this review, we introduce the characteristics of the gut microbiota in T2DM population, T2DM animal models, and diabetic complications. In addition, we describe the molecular mechanisms linking host and the gut microbiota in T2DM, including the host molecules that induce gut microbiota dysbiosis, immune and inflammatory responses, and gut microbial metabolites involved in pathogenesis. These findings suggest that we can treat T2DM and its complications by remodeling the gut microbiota through interventions such as drugs, probiotics, prebiotics, fecal microbiota transplantation (FMT) and diets.
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Affiliation(s)
- Zheng Zhou
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Bao Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institution of Clinical Pharmacy, Central South University, Changsha, China
| | - Dongsheng Yu
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Dongsheng Yu, ; Chunsheng Zhu,
| | - Chunsheng Zhu
- Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Dongsheng Yu, ; Chunsheng Zhu,
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33
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Ten Have GAM, Engelen MPKJ, Deutz NEP. In-vivo production of branched-chain amino acids, branched-chain keto acids, and β-hydroxy β-methylbutyric acid. Curr Opin Clin Nutr Metab Care 2022; 25:43-49. [PMID: 34798641 DOI: 10.1097/mco.0000000000000800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW The branched-chain amino acids (BCAA), branched-chain keto acids (BCKA), and β-hydroxy β-methylbutyric acid (HMB) have regained interest as food ingredients in health and disease. To support nutritional strategies, it is critical to gain insight into the whole body and transorgan kinetics of these components. We, therefore, reviewed the most recent literature in this field on in vivo analysis of BCAA, BCKA, and HMB kinetics in health and disease. RECENT FINDINGS With a new comprehensive metabolic flux analysis BCAA, BCKA, and HMB whole body production, interconversion and disposal rates can be measured simultaneously. Recent studies have provided us with a better understanding of whole-body and transorgan kinetics under postabsorptive, postprandial, hibernating, and lactating conditions. In human pathophysiological conditions like COPD, obesity, and diabetes, the added value of BCAA kinetic measurements over the commonly used concentration measurements only, is discussed. SUMMARY This article highlights the importance of implementing BCAA, BCKA, and HMB kinetic studies to further advance the field by gaining more mechanistic insights and providing direction to the development of new targeted (nutritional) strategies.
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Affiliation(s)
- Gabriella A M Ten Have
- Center for Translational Research in Aging & Longevity, Department of Health & Kinesiology, Texas A&M University, College Station, Texas, USA
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Ikeda H. The Effect of Mild Renal Dysfunction on the Assessment of Plasma Amino Acid Concentration and Insulin Resistance in Patients with Type 2 Diabetes Mellitus. J Diabetes Res 2022; 2022:2048300. [PMID: 35734236 PMCID: PMC9208954 DOI: 10.1155/2022/2048300] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/23/2022] [Accepted: 05/25/2022] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND An increase in the levels of branched-chain amino acids (BCAAs) and certain aromatic amino acids, such as alanine, in plasma is correlated with insulin resistance (IR) in type 2 diabetes mellitus (T2DM). T2DM is a leading risk factor for chronic kidney disease. Meanwhile, renal dysfunction causes changes in plasma amino acid levels. To date, no study has examined how mild renal dysfunction and IR interact with plasma amino acid levels. This study examines the effects of IR and renal dysfunction on plasma amino acid concentrations in T2DM. METHODS Data were collected from healthy male participants (controls) and male patients with T2DM between May 2018 and February 2022. Blood samples were collected after overnight fasting. IR and renal function were evaluated using the homeostasis model assessment of IR (HOMA-IR) and serum cystatin C (CysC), respectively. RESULTS A total of 49 and 93 participants were included in the control and T2DM groups, respectively. In the T2DM group, eight amino acids (alanine, glutamic acid, glutamine, glycine, isoleucine, leucine, tyrosine, and valine) and total BCAA showed a significant correlation with HOMA-IR (p < 0.01), whereas six amino acids (γ-aminobutyric acid, citrulline, cysteine, glycine, methionine, and valine) and total BCAA showed a significant correlation with 1/CysC (p < 0.02). However, only alanine, glutamic acid, and each BCAA showed significant differences between the control group and the IR T2DM subgroup. Increases in the BCAA levels with T2DM were canceled by renal dysfunction (CysC ≥ 0.93) in patients with intermediate IR. CONCLUSION To use plasma BCAA concentration as a marker of IR, renal function must be considered, even in mild renal dysfunction. Increased alanine and glutamic acid levels indicate IR, regardless of mild renal dysfunction.
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Affiliation(s)
- Hideki Ikeda
- Department of Internal Medicine, Sanyudo Hospital, Chuo 6 Chome-1-219, Yonezawa, Yamagata 992-0045, Japan
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35
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Zhang Y, Zhang Z, Li C, Tang D, Dai Y. Metabolomics Study Reveals the Alteration of Fatty Acid Oxidation in the Heart of Diabetic Mice by Empagliflozin. Mol Omics 2022; 18:643-651. [PMID: 35587588 DOI: 10.1039/d2mo00036a] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Empagliflozin (Empa, SGLT2 inhibitor), is widely used in clinical situation for the management of diabetes. It has beneficial effects in reducing cardiac dysfunction and heart failure. However, rare studies had...
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Affiliation(s)
- Yingwei Zhang
- Department of Neurology, Shenzhen Longhua District Central Hospital, Shenzhen 518000, China.
| | - Zeyu Zhang
- The Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China.
| | - Chundi Li
- Department of Neurology, Shenzhen Longhua District Central Hospital, Shenzhen 518000, China.
| | - Donge Tang
- The Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China.
| | - Yong Dai
- The Clinical Medical Research Center, Guangdong Provincial Engineering Research Center of Autoimmune Disease Precision Medicine, Shenzhen Engineering Research Center of Autoimmune Disease, The Second Clinical Medical College of Jinan University, Shenzhen People's Hospital, Shenzhen 518020, China.
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Mann G, Mora S, Madu G, Adegoke OAJ. Branched-chain Amino Acids: Catabolism in Skeletal Muscle and Implications for Muscle and Whole-body Metabolism. Front Physiol 2021; 12:702826. [PMID: 34354601 PMCID: PMC8329528 DOI: 10.3389/fphys.2021.702826] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 06/24/2021] [Indexed: 12/20/2022] Open
Abstract
Branched-chain amino acids (BCAAs) are critical for skeletal muscle and whole-body anabolism and energy homeostasis. They also serve as signaling molecules, for example, being able to activate mammalian/mechanistic target of rapamycin complex 1 (mTORC1). This has implication for macronutrient metabolism. However, elevated circulating levels of BCAAs and of their ketoacids as well as impaired catabolism of these amino acids (AAs) are implicated in the development of insulin resistance and its sequelae, including type 2 diabetes, cardiovascular disease, and of some cancers, although other studies indicate supplements of these AAs may help in the management of some chronic diseases. Here, we first reviewed the catabolism of these AAs especially in skeletal muscle as this tissue contributes the most to whole body disposal of the BCAA. We then reviewed emerging mechanisms of control of enzymes involved in regulating BCAA catabolism. Such mechanisms include regulation of their abundance by microRNA and by post translational modifications such as phosphorylation, acetylation, and ubiquitination. We also reviewed implications of impaired metabolism of BCAA for muscle and whole-body metabolism. We comment on outstanding questions in the regulation of catabolism of these AAs, including regulation of the abundance and post-transcriptional/post-translational modification of enzymes that regulate BCAA catabolism, as well the impact of circadian rhythm, age and mTORC1 on these enzymes. Answers to such questions may facilitate emergence of treatment/management options that can help patients suffering from chronic diseases linked to impaired metabolism of the BCAAs.
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Affiliation(s)
| | | | | | - Olasunkanmi A. J. Adegoke
- Muscle Health Research Centre, School of Kinesiology and Health Science, York University, Toronto, ON, Canada
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