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Ni Z, Li J, Qian X, Yong Y, Wu M, Wang Y, Lv W, Zhang S, Zhang Y, Shao Y, Chen A. Phellinus igniarius Polysaccharides Ameliorate Hyperglycemia by Modulating the Composition of the Gut Microbiota and Their Metabolites in Diabetic Mice. Molecules 2023; 28:7136. [PMID: 37894615 PMCID: PMC10609020 DOI: 10.3390/molecules28207136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/11/2023] [Accepted: 10/15/2023] [Indexed: 10/29/2023] Open
Abstract
Gut microbiota dysbiosis has been reported as a risk factor in the development of type 2 diabetes mellitus (T2DM). Polysaccharides from Phellinus igniarius (P. igniarius) possess various properties that help manage metabolic diseases; however, their underlying mechanism of action remains unclear. Therefore, in this study, we aimed to evaluate the effect of P. igniarius polysaccharides (SH-P) on improving hyperglycemia in mice with T2DM and clarified its association with the modulation of gut microbiota and their metabolites using 16S rDNA sequencing and liquid chromatography-mass spectrometry. Fecal microbiota transplantation (FMT) was used to verify the therapeutic effects of microbial remodeling. SH-P supplementation alleviated hyperglycemia symptoms in T2DM mice, ameliorated gut dysbiosis, and significantly increased the abundance of Lactobacillus in the gut. Pathway enrichment analysis indicated that SH-P treatment altered metabolic pathways associated with the occurrence and development of diabetes. Spearman's correlation analysis revealed that changes in the dominant bacterial genera were significantly correlated with metabolite levels closely associated with hyperglycemia. Additionally, FMT significantly improved insulin sensitivity and antioxidative capacity and reduced inflammation and tissue injuries, indicating improved glucose homeostasis. These results indicate that the ameliorative effects of SH-P on hyperglycemia are associated with the modulation of gut microbiota composition and its metabolites.
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Affiliation(s)
- Zaizhong Ni
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
| | - Jinting Li
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
| | - Xinyi Qian
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
| | - Yidan Yong
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
| | - Mengmeng Wu
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
| | - Yanan Wang
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
| | - Wendi Lv
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
| | - Simeng Zhang
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
| | - Yifei Zhang
- College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Ying Shao
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
| | - Anhui Chen
- College of Food and Bioengineering, Xuzhou University of Technology, Xuzhou 221018, China
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Schmich SKP, Keck J, Bonaterra GA, Bertoune M, Adam A, Wilhelm B, Slater EP, Schwarzbach H, Fendrich V, Kinscherf R, Hildebrandt W. Effects of Monoamino-Oxidase-A (MAO-A) Inhibition on Skeletal Muscle Inflammation and Wasting through Pancreatic Ductal Adenocarcinoma in Triple Transgenic Mice. Biomedicines 2023; 11:biomedicines11030912. [PMID: 36979889 PMCID: PMC10046345 DOI: 10.3390/biomedicines11030912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Cancer cachexia describes a syndrome of muscle wasting and lipolysis that is still largely untreatable and negatively impacts prognosis, mobility, and healthcare costs. Since upregulation of skeletal muscle monoamine-oxidase-A (MAO-A), a source of reactive oxygen species, may contribute to cachexia, we investigated the effects of the MAO-inhibitor harmine-hydrochloride (HH, intraperitoneal, 8 weeks) on muscle wasting in a triple-transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC) and wild type (WT) mice. Gastrocnemius and soleus muscle cryo-cross-sections were analyzed for fiber type-specific cross-sectional area (CSA), fraction and capillarization using ATPase- and lectin-stainings. Transcripts of pro-apoptotic, -atrophic, and -inflammatory signals were determined by RT-qPCR. Furthermore, we evaluated the integrity of neuromuscular junction (NMJ, pre-/post-synaptic co-staining) and mitochondrial ultrastructure (transmission electron microscopy). MAO-A expression in gastrocnemius muscle was increased with PDAC vs. WT (immunohistochemistry: p < 0.05; Western blot: by trend). PDAC expectedly reduced fiber CSA and upregulated IL-1β in both calf muscles, while MuRF1 expression increased in soleus muscle only. Although IL-1β decreased, HH caused an additional 38.65% (p < 0.001) decrease in gastrocnemius muscle (IIBX) fiber CSA. Moreover, soleus muscle CSA remained unchanged despite the downregulation of E3-ligases FBXO32 (p < 0.05) and MuRF1 (p < 0.01) through HH. Notably, HH significantly decreased the post-synaptic NMJ area (quadriceps muscle) and glutathione levels (gastrocnemius muscle), thereby increasing mitochondrial damage and centronucleation in soleus and gastrocnemius type IIBX fibers. Moreover, although pro-atrophic/-inflammatory signals are reversed, HH unfortunately fails to stop and rather promotes PDAC-related muscle wasting, possibly via denervation or mitochondrial damage. These differential adverse vs. therapeutic effects warrant studies regarding dose-dependent benefits and risks with consideration of other targets of HH, such as the dual-specificity tyrosine phosphorylation regulated kinases 1A and B (DYRK1A/B).
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Affiliation(s)
- Simon K. P. Schmich
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Jan Keck
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Gabriel A. Bonaterra
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Mirjam Bertoune
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Anna Adam
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Beate Wilhelm
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Emily P. Slater
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany
| | - Hans Schwarzbach
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Volker Fendrich
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany
| | - Ralf Kinscherf
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Wulf Hildebrandt
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
- Correspondence: ; Tel.: +49-6421-2864042; Fax: +49-6421-2868983
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Wang L, Gou X, Ding Y, Liu J, Wang Y, Wang Y, Zhang J, Du L, Peng W, Fan G. The interplay between herbal medicines and gut microbiota in metabolic diseases. Front Pharmacol 2023; 14:1105405. [PMID: 37033634 PMCID: PMC10079915 DOI: 10.3389/fphar.2023.1105405] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Accepted: 03/09/2023] [Indexed: 04/11/2023] Open
Abstract
Globally, metabolic diseases are becoming a major public health problem. Herbal medicines are medicinal materials or preparations derived from plants and are widely used in the treatment of metabolic diseases due to their good curative effects and minimal side effects. Recent studies have shown that gut microbiota plays an important role in the herbal treatment of metabolic diseases. However, the mechanisms involved are still not fully understood. This review provides a timely and comprehensive summary of the interactions between herbal medicines and gut microbiota in metabolic diseases. Mechanisms by which herbal medicines treat metabolic diseases include their effects on the gut microbial composition, the intestinal barrier, inflammation, and microbial metabolites (e.g., short-chain fatty acids and bile acids). Herbal medicines can increase the abundance of beneficial bacteria (e.g., Akkermansia and Blautia), reduce the abundance of harmful bacteria (e.g., Escherichia-Shigella), protect the intestinal barrier, and alleviate inflammation. In turn, gut microbes can metabolize herbal compounds and thereby increase their bioavailability and bioactivity, in addition to reducing their toxicity. These findings suggest that the therapeutic effects of herbal medicines on metabolic diseases are closely related to their interactions with the gut microbiota. In addition, some methods, and techniques for studying the bidirectional interaction between herbal medicines and gut microbiota are proposed and discussed. The information presented in this review will help with a better understanding of the therapeutic mechanisms of herbal medicines and the key role of gut microbiota.
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Affiliation(s)
- Lijie Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoling Gou
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yin Ding
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingye Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yue Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yaqian Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jing Zhang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Leilei Du
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Gang Fan, ; Wei Peng, ; Leilei Du,
| | - Wei Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Gang Fan, ; Wei Peng, ; Leilei Du,
| | - Gang Fan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
- *Correspondence: Gang Fan, ; Wei Peng, ; Leilei Du,
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Carpéné C, Viana P, Iffiú-Soltesz Z, Tapolcsányi P, Földi AÁ, Mátyus P, Dunkel P. Effects of Chemical Structures Interacting with Amine Oxidases on Glucose, Lipid and Hydrogen Peroxide Handling by Human Adipocytes. Molecules 2022; 27:6224. [PMID: 36234761 PMCID: PMC9571511 DOI: 10.3390/molecules27196224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 09/07/2022] [Accepted: 09/19/2022] [Indexed: 11/26/2022] Open
Abstract
Benzylamine is a natural molecule present in food and edible plants, capable of activating hexose uptake and inhibiting lipolysis in human fat cells. These effects are dependent on its oxidation by amine oxidases present in adipocytes, and on the subsequent hydrogen peroxide production, known to exhibit insulin-like actions. Virtually, other substrates interacting with such hydrogen peroxide-releasing enzymes potentially can modulate lipid accumulation in adipose tissue. Inhibition of such enzymes has also been reported to influence lipid deposition. We have therefore studied in human adipocytes the lipolytic and lipogenic activities of pharmacological entities designed to interact with amine oxidases highly expressed in this cell type: the semicarbazide-sensitive amine oxidase (SSAO also known as PrAO or VAP-1) and the monoamine oxidases (MAO). The results showed that SZV-2016 and SZV-2017 behaved as better substrates than benzylamine, releasing hydrogen peroxide once oxidized, and reproduced or even exceeded its insulin-like metabolic effects in fat cells. Additionally, several novel SSAO inhibitors, such as SZV-2007 and SZV-1398, have been evidenced and shown to inhibit benzylamine metabolic actions. Taken as a whole, our findings reinforce the list of molecules that influence the regulation of triacylglycerol assembly/breakdown, at least in vitro in human adipocytes. The novel compounds deserve deeper investigation of their mechanisms of interaction with SSAO or MAO, and constitute potential candidates for therapeutic use in obesity and diabetes.
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Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR1297, 31432 Toulouse, France
- Team Dinamix, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, 31432 Toulouse, France
| | - Pénélope Viana
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR1297, 31432 Toulouse, France
- Team Dinamix, Institute of Metabolic and Cardiovascular Diseases (I2MC), Paul Sabatier University, 31432 Toulouse, France
| | - Zsuzsa Iffiú-Soltesz
- Institut des Maladies Métaboliques et Cardiovasculaires, INSERM UMR1297, 31432 Toulouse, France
| | - Pál Tapolcsányi
- Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hungary
| | - Anna Ágota Földi
- Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hungary
| | - Péter Mátyus
- Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hungary
- E-Group ICT SOFTWARE, H-1027 Budapest, Hungary
| | - Petra Dunkel
- Department of Organic Chemistry, Semmelweis University, H-1092 Budapest, Hungary
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Carpéné C, Viana P, Fontaine J, Laurell H, Grolleau JL. Multiple Direct Effects of the Dietary Protoalkaloid N-Methyltyramine in Human Adipocytes. Nutrients 2022; 14:nu14153118. [PMID: 35956295 PMCID: PMC9370673 DOI: 10.3390/nu14153118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 07/23/2022] [Accepted: 07/27/2022] [Indexed: 02/06/2023] Open
Abstract
Dietary amines have been the subject of a novel interest in nutrition since the discovery of trace amine-associated receptors (TAARs), especially TAAR-1, which recognizes tyramine, phenethylamine, tryptamine, octopamine, N-methyltyramine (NMT), synephrine, amphetamine and related derivatives. Alongside the psychostimulant properties of TAAR-1 ligands, it is their ephedrine-like action on weight loss that drives their current consumption via dietary supplements advertised for ‘fat-burning’ properties. Among these trace amines, tyramine has recently been described, at high doses, to exhibit an antilipolytic action and activation of glucose transport in human adipocytes, i.e., effects that are facilitating lipid storage rather than mobilization. Because of its close structural similarity to tyramine, NMT actions on human adipocytes therefore must to be reevaluated. To this aim, we studied the lipolytic and antilipolytic properties of NMT together with its interplay with insulin stimulation of glucose transport along with amine oxidase activities in adipose cells obtained from women undergoing abdominal surgery. NMT activated 2-deoxyglucose uptake when incubated with freshly isolated adipocytes at 0.01–1 mM, reaching one-third of the maximal stimulation by insulin. However, when combined with insulin, NMT limited by half the action of the lipogenic hormone on glucose transport. The NMT-induced stimulation of hexose uptake was sensitive to inhibitors of monoamine oxidases (MAO) and of semicarbazide-sensitive amine oxidase (SSAO), as was the case for tyramine and benzylamine. All three amines inhibited isoprenaline-induced lipolysis to a greater extent than insulin, while they were poorly lipolytic on their own. All three amines—but not isoprenaline—interacted with MAO or SSAO. Due to these multiple effects on human adipocytes, NMT cannot be considered as a direct lipolytic agent, potentially able to improve lipid mobilization and fat oxidation in consumers of NMT-containing dietary supplements.
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Affiliation(s)
- Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM U1297), I2MC, CEDEX 4, 31432 Toulouse, France; (P.V.); (J.F.); (H.L.)
- CHU Rangueil, Université Paul Sabatier, I2MC, CEDEX 4, 31432 Toulouse, France
- Correspondence:
| | - Pénélope Viana
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM U1297), I2MC, CEDEX 4, 31432 Toulouse, France; (P.V.); (J.F.); (H.L.)
- CHU Rangueil, Université Paul Sabatier, I2MC, CEDEX 4, 31432 Toulouse, France
| | - Jessica Fontaine
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM U1297), I2MC, CEDEX 4, 31432 Toulouse, France; (P.V.); (J.F.); (H.L.)
- CHU Rangueil, Université Paul Sabatier, I2MC, CEDEX 4, 31432 Toulouse, France
| | - Henrik Laurell
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale (INSERM U1297), I2MC, CEDEX 4, 31432 Toulouse, France; (P.V.); (J.F.); (H.L.)
- CHU Rangueil, Université Paul Sabatier, I2MC, CEDEX 4, 31432 Toulouse, France
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Du L, Li Q, Yi H, Kuang T, Tang Y, Fan G. Gut microbiota-derived metabolites as key actors in type 2 diabetes mellitus. Biomed Pharmacother 2022; 149:112839. [PMID: 35325852 DOI: 10.1016/j.biopha.2022.112839] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/14/2022] [Accepted: 03/16/2022] [Indexed: 12/01/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most risk factors threatening human health. Although genetic and environmental factors contribute to the development of T2DM, gut microbiota has also been found to be involved. Gut microbiota-derived metabolites are a key factor in host-microbe crosstalk, and have been revealed to play a central role in the physiology and physiopathology of T2DM. In this review, we provide a timely and comprehensive summary of the microbial metabolites that are protective or causative for T2DM, including some amino acids-derived metabolites, short-chain fatty acids, trimethylamine N-oxide, and bile acids. The mechanisms by which metabolites affect T2DM have been elaborated. Knowing more about these processes will increase our understanding of the causal relationship between gut microbiota and T2DM. Moreover, some frontier therapies that target gut microbes and their metabolites to improve T2DM, including dietary intervention, fecal microbiota transplantation, probiotics, prebiotics or synbiotics intervention, and drugging microbial metabolism, have been critically discussed. This review may provide novel insights for the development of targeted and personalized treatments for T2DM based on gut microbial metabolites. More high-quality clinical trials are needed to accelerate the clinical translation of gut-targeted therapies for T2DM.
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Affiliation(s)
- Leilei Du
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Qi Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Huan Yi
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Tingting Kuang
- School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China
| | - Yi Tang
- Department of Endocrinology, Chengdu Fifth People's Hospital, Chengdu 611130, China.
| | - Gang Fan
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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High doses of tyramine stimulate glucose transport in human fat cells. J Physiol Biochem 2022; 78:543-556. [DOI: 10.1007/s13105-021-00864-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 12/09/2021] [Indexed: 01/13/2023]
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Morais TMF, Melo TS, Dantas MB, Ferreira JM, Sousa DFD, Magalhães EP, Menezes RRPPBD, Pessoa ODL, Feitosa ML, Sousa FCFD, Sampaio TL, Queiroz MGRD. Tyramine exerts hypolipidemic and anti-obesity effects in vivo. BRAZ J PHARM SCI 2022. [DOI: 10.1590/s2175-97902022e201191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
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Strassheim D, Sullivan T, Irwin DC, Gerasimovskaya E, Lahm T, Klemm DJ, Dempsey EC, Stenmark KR, Karoor V. Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases. Cells 2021; 10:3347. [PMID: 34943862 PMCID: PMC8699532 DOI: 10.3390/cells10123347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/10/2021] [Accepted: 11/18/2021] [Indexed: 12/15/2022] Open
Abstract
G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.
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Affiliation(s)
- Derek Strassheim
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Timothy Sullivan
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - David C. Irwin
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Evgenia Gerasimovskaya
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Tim Lahm
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health Denver, Denver, CO 80206, USA;
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
| | - Dwight J. Klemm
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Edward C. Dempsey
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kurt R. Stenmark
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Vijaya Karoor
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health Denver, Denver, CO 80206, USA;
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
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Fontaine J, Tavernier G, Morin N, Carpéné C. Vanadium-dependent activation of glucose transport in adipocytes by catecholamines is not mediated via adrenoceptor stimulation or monoamine oxidase activity. World J Diabetes 2020; 11:622-643. [PMID: 33384769 PMCID: PMC7754167 DOI: 10.4239/wjd.v11.i12.622] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/12/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Benzylamine and methylamine activate glucose uptake in adipocytes. For tyramine, this effect has even been extended to cardiomyocytes. AIM To investigate the effects of catecholamines and other amines on glucose uptake. METHODS A screening compared 25 biogenic amines on 2-deoxyglucose (2-DG) uptake activation in rat adipocytes. Pharmacological approaches and transgenic mouse models were then used to decipher the mode of action of several hits. RESULTS In rat adipocytes, insulin stimulation of 2-DG uptake was reproduced with catecholamines. 100 µmol/L or 1 mmol/L adrenaline, noradrenaline, dopamine and deoxyepinephrine, maximally activated hexose transport only when sodium orthovanadate was added at 100 µmol/L. Such activation was similar to that already reported for benzylamine, methylamine and tyramine, well-recognized substrates of semicarbazide-sensitive amine oxidase (SSAO) and monoamine oxidase (MAO). Several, but not all, tested agonists of β-adrenoreceptors (β-ARs) also activated glucose transport while α-AR agonists were inactive. Lack of blockade by α- and β-AR antagonists indicated that catecholamine-induced 2-DG uptake was not mediated by AR stimulation. Adipocytes from mice lacking β1-, β2- and β3-ARs (triple KO) also responded to millimolar doses of adrenaline or noradrenaline by activating hexose transport in the presence of 100 µmol/L vanadate. The MAO blocker pargyline, and SSAO inhibitors did not block the effects of adrenaline or noradrenaline plus vanadate, which were blunted by antioxidants. CONCLUSION Catecholamines exert unexpected insulin-like actions in adipocytes when combined with vanadium. For limiting insulin resistance by activating glucose consumption at least in fat stores, we propose that catecholamine derivatives combined with vanadium can generate novel complexes that may have low toxicity and promising anti-diabetic properties.
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Affiliation(s)
- Jessica Fontaine
- Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, INSERM UMR1048, Université Paul Sabatier Toulouse III, Toulouse 31432, France
| | - Geneviève Tavernier
- Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, INSERM UMR1048, Université Paul Sabatier Toulouse III, Toulouse 31432, France
| | - Nathalie Morin
- Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, INSERM UMR1048, Université Paul Sabatier Toulouse III, Toulouse 31432, France
- INSERM UMR 1139 Faculté de Pharmacie, Université de Paris, Paris 75006, France
| | - Christian Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires, Institut National de la Santé et de la Recherche Médicale, INSERM UMR1048, Université Paul Sabatier Toulouse III, Toulouse 31432, France
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11
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Effects of 3-Hydroxypyridine and Succinic Acid Derivatives on Monoamine Oxidase Activity In Vitro. Pharm Chem J 2018. [DOI: 10.1007/s11094-018-1760-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
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12
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Murgia M, Toniolo L, Nagaraj N, Ciciliot S, Vindigni V, Schiaffino S, Reggiani C, Mann M. Single Muscle Fiber Proteomics Reveals Fiber-Type-Specific Features of Human Muscle Aging. Cell Rep 2018; 19:2396-2409. [PMID: 28614723 DOI: 10.1016/j.celrep.2017.05.054] [Citation(s) in RCA: 198] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 04/10/2017] [Accepted: 05/17/2017] [Indexed: 12/20/2022] Open
Abstract
Skeletal muscle is a key tissue in human aging, which affects different muscle fiber types unequally. We developed a highly sensitive single muscle fiber proteomics workflow to study human aging and show that the senescence of slow and fast muscle fibers is characterized by diverging metabolic and protein quality control adaptations. Whereas mitochondrial content declines with aging in both fiber types, glycolysis and glycogen metabolism are upregulated in slow but downregulated in fast muscle fibers. Aging mitochondria decrease expression of the redox enzyme monoamine oxidase A. Slow fibers upregulate a subset of actin and myosin chaperones, whereas an opposite change happens in fast fibers. These changes in metabolism and sarcomere quality control may be related to the ability of slow, but not fast, muscle fibers to maintain their mass during aging. We conclude that single muscle fiber analysis by proteomics can elucidate pathophysiology in a sub-type-specific manner.
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Affiliation(s)
- Marta Murgia
- Max-Planck-Institute of Biochemistry, Martinsried 82152, Germany; Department of Biomedical Science, University of Padova, Padua 35121, Italy.
| | - Luana Toniolo
- Department of Biomedical Science, University of Padova, Padua 35121, Italy
| | | | - Stefano Ciciliot
- Venetian Institute of Molecular Medicine, Padua 35129, Italy; Department of Medicine, University of Padua, Padua 35128, Italy
| | - Vincenzo Vindigni
- Department of Neurosciences, University of Padova, Padua 35128, Italy
| | | | - Carlo Reggiani
- Department of Biomedical Science, University of Padova, Padua 35121, Italy
| | - Matthias Mann
- Max-Planck-Institute of Biochemistry, Martinsried 82152, Germany.
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13
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Laurino A, Raimondi L. Commentary: 3-Iodothyronamine Reduces Insulin Secretion In Vitro via a Mitochondrial Mechanism. Front Endocrinol (Lausanne) 2018. [PMID: 29541060 PMCID: PMC5835504 DOI: 10.3389/fendo.2018.00057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Affiliation(s)
- Annunziatina Laurino
- Section of Pharmacology and Toxicology, Department of Psychology, Neurology, Drug Sciences, Health of the Child, Pharmacology, University of Florence, Florence, Italy
| | - Laura Raimondi
- Section of Pharmacology and Toxicology, Department of Psychology, Neurology, Drug Sciences, Health of the Child, Pharmacology, University of Florence, Florence, Italy
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14
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Les F, Iffiú-Soltész Z, Mercarder J, Carpéné C. Tyramine activates lipid accumulation in rat adipocytes: influences of <em>in vitro</em> and <em>in vivo</em> administration. AIMS MOLECULAR SCIENCE 2017. [DOI: 10.3934/molsci.2017.3.339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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15
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High intake of dietary tyramine does not deteriorate glucose handling and does not cause adverse cardiovascular effects in mice. J Physiol Biochem 2015; 72:539-53. [DOI: 10.1007/s13105-015-0456-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 11/26/2015] [Indexed: 01/31/2023]
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16
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Carpéné C, Gomez-Zorita S, Gupta R, Grès S, Rancoule C, Cadoudal T, Mercader J, Gomez A, Bertrand C, Iffiu-Soltész Z. Combination of low dose of the anti-adipogenic agents resveratrol and phenelzine in drinking water is not sufficient to prevent obesity in very-high-fat diet-fed mice. Eur J Nutr 2014; 53:1625-35. [PMID: 24531732 DOI: 10.1007/s00394-014-0668-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Accepted: 02/05/2014] [Indexed: 02/07/2023]
Abstract
PURPOSE Resveratrol inhibits lipid accumulation but suffers from limited bioavailability. The anti-depressive agent phenelzine limits adipogenesis in various models of cultured preadipocytes, and this hydrazine derivative also inhibits de novo lipogenesis in mature adipocytes. It was therefore tested whether resveratrol effects on adiposity reduction and glucose tolerance improvement could be reinforced by co-administration with phenelzine. METHODS Mice fed a very-high-fat diet (VHFD, 60% calories as fat) were subjected to drinking solution containing low dose of resveratrol (0.003%) and/or 0.02% phenelzine for 12 weeks. Body fat content, glucose tolerance, food and water consumption were checked during treatment while fat depot mass was determined at the end of supplementation. Direct influence of the agents on lipogenesis and glucose uptake was tested in adipocytes. RESULTS Epididymal fat depots were reduced in mice drinking phenelzine alone or with resveratrol. No limitation of body weight gain or body fat content was observed in the groups drinking resveratrol or phenelzine, separately or in combination. The altered glucose tolerance and the increased fat body composition of VHFD-fed mice were not reversed by resveratrol and/or phenelzine. Such lack of potentiation between resveratrol and phenelzine prompted us to verify in vitro their direct effects on mouse adipocytes. Both molecules inhibited de novo lipogenesis, but did not potentiate each other at 10 or 100 μM. Only resveratrol inhibited hexose uptake in a manner that was not improved by phenelzine. CONCLUSIONS Phenelzine has no interest to be combined with low doses of resveratrol for treating/preventing obesity, when considering the VHFD mouse model.
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Affiliation(s)
- C Carpéné
- Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale, U 1048, Team 3, CHU Rangueil, Université de Toulouse, UPS, 31432, Toulouse Cedex 4, France,
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17
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Grès S, Bour S, Valet P, Carpéné C. Benzylamine antihyperglycemic effect is abolished by AOC3 gene invalidation in mice but not rescued by semicarbazide-sensitive amine oxidase expression under the control of aP2 promoter. J Physiol Biochem 2012; 68:651-62. [PMID: 22547093 DOI: 10.1007/s13105-012-0171-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2012] [Accepted: 04/10/2012] [Indexed: 12/25/2022]
Abstract
Semicarbazide-sensitive amine oxidase (SSAO) is a transmembrane enzyme that metabolizes primary amines from endogenous or dietary origin. SSAO is highly expressed in adipose, smooth muscle and endothelial cells. In each of these cell types, SSAO is implicated in different biological functions, such as glucose transport activation, extracellular matrix maturation and leucocyte extravasation, respectively. However, the physiological functions of SSAO and their involvement in pathogenesis remain uncompletely characterized. To better understand the role of adipose tissue SSAO, we investigated whether it was necessary and/or sufficient to produce the antihyperglycemic effect of the SSAO-substrate benzylamine, already reported in mice. Therefore, we crossed SSAO-deficient mice invalidated for AOC3 gene and transgenic mice expected to express human SSAO in an adipocyte-specific manner, under the control of aP2 promoter. The aP2-human AOC3 construct (aP2-hAOC3) was equally expressed in the adipose tissue of mice expressing or not the native murine form and almost absent in other tissues. However, the corresponding SSAO activity found in adipose tissue represented only 20 % that of control mice. As a consequence, the benzylamine antihyperglycemic effect observed during glucose tolerance test in control was abolished in AOC3-KO mice but not rescued in mice expressing aP2-hAOC3. The capacity of benzylamine or methylamine to activate glucose uptake in adipocytes exhibited parallel variations in the corresponding genotypes. Although the aP2-hAOC3 construct did not allow a total rescue of SSAO activity in adipose tissue, it could be assessed from our observations that adipocyte SSAO plays a pivotal role in the increased glucose tolerance promoted by pharmacological doses of benzylamine.
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Affiliation(s)
- Sandra Grès
- Institut National de la Santé et de la Recherche Médicale (INSERM) U1048, I2MC, CHU Rangueil, 31432 Toulouse, France
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18
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Olivieri A, Rico D, Khiari Z, Henehan G, O'Sullivan J, Tipton K. From caffeine to fish waste: amine compounds present in food and drugs and their interactions with primary amine oxidase. J Neural Transm (Vienna) 2011; 118:1079-89. [PMID: 21373760 DOI: 10.1007/s00702-011-0611-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Accepted: 02/16/2011] [Indexed: 12/29/2022]
Abstract
Tissue bound primary amine oxidase (PrAO) and its circulating plasma-soluble form are involved, through their catalytic activity, in important cellular roles, including the adhesion of lymphocytes to endothelial cells during various inflammatory conditions, the regulation of cell growth and maturation, extracellular matrix deposition and maturation and glucose transport. PrAO catalyses the oxidative deamination of several xenobiotics and has been linked to vascular toxicity, due to the generation of cytotoxic aldehydes. In this study, a series of amines and aldehydes contained in food and drugs were tested via a high-throughput assay as potential substrates or inhibitors of bovine plasma PrAO. Although none of the compounds analyzed were found to be substrates for the enzyme, a series of molecules, including caffeine, the antidiabetics phenformin and tolbutamide and the antimicrobial pentamidine, were identified as PrAO inhibitors. Although the inhibition observed was in the millimolar and micromolar range, these data show that further work will be necessary to elucidate whether the interaction of ingested biogenic or xenobiotic amines with PrAO might adversely affect its biological roles.
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Affiliation(s)
- Aldo Olivieri
- School of Biochemistry and Immunology, Trinity College, Dublin 2, Ireland.
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19
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Grilli E, Messina M, Tedeschi M, Piva A. Feeding a microencapsulated blend of organic acids and nature identical compounds to weaning pigs improved growth performance and intestinal metabolism. Livest Sci 2010. [DOI: 10.1016/j.livsci.2010.06.056] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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20
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Chronic benzylamine administration in the drinking water improves glucose tolerance, reduces body weight gain and circulating cholesterol in high-fat diet-fed mice. Pharmacol Res 2010; 61:355-63. [PMID: 20045461 DOI: 10.1016/j.phrs.2009.12.014] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Revised: 12/23/2009] [Accepted: 12/23/2009] [Indexed: 12/27/2022]
Abstract
Benzylamine is found in Moringa oleifera, a plant used to treat diabetes in traditional medicine. In mammals, benzylamine is metabolized by semicarbazide-sensitive amine oxidase (SSAO) to benzaldehyde and hydrogen peroxide. This latter product has insulin-mimicking action, and is involved in the effects of benzylamine on human adipocytes: stimulation of glucose transport and inhibition of lipolysis. This study examined whether chronic, oral administration of benzylamine could improve glucose tolerance and the circulating lipid profile without increasing oxidative stress in overweight and pre-diabetic mice. The benzylamine diffusion across the intestine was verified using everted gut sacs. Then, glucose handling and metabolic markers were measured in mice rendered insulin-resistant when fed a high-fat diet (HFD) and receiving or not benzylamine in their drinking water (3600micromol/(kgday)) for 17 weeks. HFD-benzylamine mice showed lower body weight gain, fasting blood glucose, total plasma cholesterol and hyperglycaemic response to glucose load when compared to HFD control. In adipocytes, insulin-induced activation of glucose transport and inhibition of lipolysis remained unchanged. In aorta, benzylamine treatment partially restored the nitrite levels that were reduced by HFD. In liver, lipid peroxidation markers were reduced. Resistin and uric acid, surrogate plasma markers of metabolic syndrome, were decreased. In spite of the putative deleterious nature of the hydrogen peroxide generated during amine oxidation, and in agreement with its in vitro insulin-like actions found on adipocytes, the SSAO-substrate benzylamine could be considered as a potential oral agent to treat metabolic syndrome.
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21
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Influence of prolonged fasting on monoamine oxidase and semicarbazide-sensitive amine oxidase activities in rat white adipose tissue. J Physiol Biochem 2009; 65:11-23. [PMID: 19588727 DOI: 10.1007/bf03165965] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO) activities are very high in white adipose tissue (WAT). SSAO, also known as Vascular Adhesion Protein-1 in vessels, is present at the surface of fat cells and independent approaches have evidenced its impressive increase during adipogenesis. However, the factors that might regulate the expression SSAO and MAO in adipose tissue are still poorly defined. Here, we report the influence of fasting on MAO and SSAO activities in adipose depots. A decrease of MAO activity occurred after three days of starvation in the intra-abdominal adipose tissue (INWAT) of male Wistar rats, regardless of their initial adiposity or fat loss. The reduced fat stores of seven-week old rats, loosing 59 % of INWAT mass during fasting, contained only one half of the MAO activity found in fed control. The same reduction of MAO was observed after prolonged fasting in older rats which lose only 26% of their INWAT during the same starvation duration, leading to a fat mass comparable to that of younger fed control rats. It was therefore the endocrine and metabolic changes occurring during fasting that were responsible for the reduced MAO activity and not the amount of INWAT. Surprisingly, SSAO activity remained unchanged during starvation. In subcutaneous WAT, the changes in MAO and SSAO activities exhibited the same tendencies than those found in INWAT. Taken together, these data show that both MAO and SSAO activities increase in INWAT with age-dependent fattening, and indicate that only MAO diminishes during fasting.
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22
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Yraola F, Zorzano A, Albericio F, Royo M. Structure-activity relationships of SSAO/VAP-1 arylalkylamine-based substrates. ChemMedChem 2009; 4:495-503. [PMID: 19266512 DOI: 10.1002/cmdc.200800393] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) substrates show insulin-mimetic effects and are therefore potentially valuable molecules for the treatment of diabetes mellitus. Herein we review several structural and electronic aspects of SSAO arylalkylamine-based substrates. Two main modifications directly affect amine oxidase (AO) activity: 1) variation in ring substitution modulates the biological activity of the arylalkylamine ligand by converting a substrate into a substrate-like inhibitor, and 2) variation in the number of methylene units between the aromatic ring and the ammonium groups of the arylalkylamine substrates dramatically alters the oxidation rate between species. Furthermore, we review relevant information about mammalian SSAO/VAP-1 substrate selectivity and specificity over monoamine oxidases (MAOs).
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23
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Zorzano A, Palacín M, Marti L, García-Vicente S. Arylalkylamine vanadium salts as new anti-diabetic compounds. J Inorg Biochem 2009; 103:559-66. [PMID: 19246098 DOI: 10.1016/j.jinorgbio.2009.01.015] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2008] [Revised: 12/24/2008] [Accepted: 01/16/2009] [Indexed: 01/27/2023]
Abstract
Vanadium compounds show insulin-like effects in vivo and in vitro. Several clinical studies have shown the efficacy of vanadium compounds in type 2 diabetic subjects. However, a major concern is safety, which calls for the development of more potent vanadium compounds. For that reason different laboratories develop strategies to decrease the therapeutic dose of vanadate. One of these strategies use substrates of semicarbazide-sensitive amine oxidase (SSAO)/vascular adhesion protein-1 (VAP-1), a bifunctional protein with amine oxidase activity and adhesive properties implicated in lymphocyte homing at inflammation sites. Substrates of SSAO combined with low concentrations of vanadate strongly stimulate glucose transport and GLUT4 glucose transporter recruitment to the plasma membrane in 3T3-L1 adipocytes and in rat adipocytes. This combination also shows anti-diabetic effects in various animal models of type 1 and type 2 diabetes. Benzylamine/vanadate administration generates peroxovanadium locally in pancreatic islets, which stimulates insulin secretion, and also produces peroxovanadium in adipose tissue, thereby activating glucose metabolism in adipocytes and in neighboring muscle. This opens up the possibility of using the SSAO/VAP-1 activity as a local generator of protein tyrosine phosphatase inhibitors in anti-diabetic therapy. More recently a novel class of arylalkylaminevanadium salts have shown potent insulin-mimetic effects downstream of the insulin receptor. Administration of these compounds lowers glycemia and normalizes the plasma lipid profile in type 1 and type 2 models of diabetes. The combination of different approaches to decrease vanadium doses, among them chelating agents and SSAO substrates, should permit to develop safe and efficient vanadium based agents safe for diabetes treatment.
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Affiliation(s)
- Antonio Zorzano
- Institute for Research in Biomedicine (IRB Barcelona), C/Baldiri Reixac 10, Barcelona, Spain.
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24
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Iffiú-Soltész Z, Prévot D, Grès S, Bour S, Szökö E, Knauf C, Burcelin R, Fernández-Quintela A, Lomba A, Milagro FI, Carpéné C. Influence of acute and chronic administration of benzylamine on glucose tolerance in diabetic and obese mice fed on very high-fat diet. J Physiol Biochem 2007; 63:305-15. [DOI: 10.1007/bf03165762] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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Role of myotonic dystrophy protein kinase (DMPK) in glucose homeostasis and muscle insulin action. PLoS One 2007; 2:e1134. [PMID: 17987120 PMCID: PMC2043489 DOI: 10.1371/journal.pone.0001134] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2007] [Accepted: 10/14/2007] [Indexed: 11/19/2022] Open
Abstract
Myotonic dystrophy 1 (DM1) is caused by a CTG expansion in the 3′-unstranslated region of the DMPK gene, which encodes a serine/threonine protein kinase. One of the common clinical features of DM1 patients is insulin resistance, which has been associated with a pathogenic effect of the repeat expansions. Here we show that DMPK itself is a positive modulator of insulin action. DMPK-deficient (dmpk−/−) mice exhibit impaired insulin signaling in muscle tissues but not in adipocytes and liver, tissues in which DMPK is not expressed. Dmpk−/− mice display metabolic derangements such as abnormal glucose tolerance, reduced glucose uptake and impaired insulin-dependent GLUT4 trafficking in muscle. Using DMPK mutants, we show that DMPK is required for a correct intracellular trafficking of insulin and IGF-1 receptors, providing a mechanism to explain the molecular and metabolic phenotype of dmpk−/− mice. Taken together, these findings indicate that reduced DMPK expression may directly influence the onset of insulin-resistance in DM1 patients and point to dmpk as a new candidate gene for susceptibility to type 2-diabetes.
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Gilliam LK, Palmer JP, Taborsky GJ. Tyramine-mediated activation of sympathetic nerves inhibits insulin secretion in humans. J Clin Endocrinol Metab 2007; 92:4035-8. [PMID: 17684049 PMCID: PMC4012611 DOI: 10.1210/jc.2007-0536] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Older studies have shown that high doses of norepinephrine infused into human subjects can inhibit insulin secretion. Similar inhibition during electrical stimulation of sympathetic nerves in animals raises the possibility that the suppression of insulin secretion seen in humans could reflect a physiological effect of sympathetic nerves on islet beta-cells. However, a direct test of the hypothesis that moderate and selective activation of these nerves is sufficient to inhibit insulin secretion in humans is lacking. OBJECTIVE We sought to test this hypothesis by releasing moderate amounts of endogenous norepinephrine selectively from the sympathetic nerves of normal human subjects by infusing them with low doses of the indirect sympathomimetic agent tyramine. METHODS During a single study visit, 11 healthy subjects received iv injections of arginine either alone or in combination with a low-dose tyramine infusion. Physiological (blood pressure) and biochemical (insulin, glucose, and norepinephrine) parameters were measured. RESULTS The acute insulin response to arginine was significantly reduced during tyramine compared with that seen in the absence of tyramine (P = 0.036). CONCLUSIONS These data suggest that moderate and selective activation of sympathetic nerves inhibits insulin release in humans.
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Affiliation(s)
- Lisa K Gilliam
- Department of Medicine, University of Washington, 1959 N.E. Pacific Street, Box 357710, Seattle, Washington 98195, USA.
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27
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Bour S, Prévot D, Guigné C, Stolen C, Jalkanen S, Valet P, Carpéné C. Semicarbazide-sensitive amine oxidase substrates fail to induce insulin-like effects in fat cells from AOC3 knockout mice. J Neural Transm (Vienna) 2007; 114:829-33. [PMID: 17406965 DOI: 10.1007/s00702-007-0671-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2006] [Accepted: 11/15/2006] [Indexed: 01/04/2023]
Abstract
Substrates of semicarbazide-sensitive amine oxidases (SSAO) stimulate glucose transport in adipocytes. To definitively demonstrate the involvement of SSAO in this insulin-like effect, glucose transport has been studied in fat cells from mice with a targeted deletion of AOC3, a gene encoding a SSAO called vascular adhesion protein-1. SSAO activity was present in white adipose tissues of wild type (WT) but was absent in AOC3KO mice. The SSAO-substrates benzylamine and methylamine were unable to stimulate hexose transport in adipocytes isolated from AOC3KO mice while they were active in WT adipocytes, especially in combination with vanadate. Impairment of amine-dependent glucose uptake was also observed with tyramine while there was no change in insulin responsiveness. These observations prove that the effects of exogenous or biogenic amines on glucose transport are not receptor-mediated but are oxidation-dependent. They also confirm that the major SSAO form expressed in mouse adipocytes is encoded by the AOC3 gene.
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Affiliation(s)
- S Bour
- Institut National de la Santé et de la Recherche Médicale, U586 INSERM, IFR 31, CHU Rangueil, Toulouse, France
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28
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Bour S, Daviaud D, Gres S, Lefort C, Prévot D, Zorzano A, Wabitsch M, Saulnier-Blache JS, Valet P, Carpéné C. Adipogenesis-related increase of semicarbazide-sensitive amine oxidase and monoamine oxidase in human adipocytes. Biochimie 2007; 89:916-25. [PMID: 17400359 DOI: 10.1016/j.biochi.2007.02.013] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2006] [Accepted: 02/16/2007] [Indexed: 02/08/2023]
Abstract
A strong induction of semicarbazide-sensitive amine oxidase (SSAO) has previously been reported during murine preadipocyte lineage differentiation but it remains unknown whether this emergence also occurs during adipogenesis in man. Our aim was to compare SSAO and monoamine oxidase (MAO) expression during in vitro differentiation of human preadipocytes and in adipose and stroma-vascular fractions of human fat depots. A human preadipocyte cell strain from a patient with Simpson-Golabi-Behmel syndrome was first used to follow amine oxidase expression during in vitro differentiation. Then, human preadipocytes isolated from subcutaneous adipose tissues were cultured under conditions promoting ex vivo adipose differentiation and tested for MAO and SSAO expression. Lastly, human adipose tissue was separated into mature adipocyte and stroma-vascular fractions for analyses of MAO and SSAO at mRNA, protein and activity levels. Both SSAO and MAO were increased from undifferentiated preadipocytes to lipid-laden cells in all the models: 3T3-F442A and 3T3-L1 murine lineages, human SGBS cell strain or human preadipocytes in primary culture. In human subcutaneous adipose tissue, the adipocyte-enriched fraction exhibited seven-fold higher amine oxidase activity and contained three- to seven-fold higher levels of mRNAs encoded by MAO-A, MAO-B, AOC3 and AOC2 genes than the stroma-vascular fraction. MAO-A and AOC3 genes accounted for the majority of their respective MAO and SSAO activities in human adipose tissue. Most of the SSAO and MAO found in adipose tissue originated from mature adipocytes. Although the mechanism and role of adipogenesis-related increase in amine oxidase expression remain to be established, the resulting elevated levels of amine oxidase activities found in human adipocytes may be of potential interest for therapeutic intervention in obesity.
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Affiliation(s)
- Sandy Bour
- U858 INSERM, I2MR, IFR 31, CHU Rangueil, BP 84225, 31432 Toulouse Cedex 4, France
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Zucchi R, Chiellini G, Scanlan TS, Grandy DK. Trace amine-associated receptors and their ligands. Br J Pharmacol 2006; 149:967-78. [PMID: 17088868 PMCID: PMC2014643 DOI: 10.1038/sj.bjp.0706948] [Citation(s) in RCA: 217] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Classical biogenic amines (adrenaline, noradrenaline, dopamine, serotonin and histamine) interact with specific families of G protein-coupled receptors (GPCRs). The term 'trace amines' is used when referring to p-tyramine, beta-phenylethylamine, tryptamine and octopamine, compounds that are present in mammalian tissues at very low (nanomolar) concentrations. The pharmacological effects of trace amines are usually attributed to their interference with the aminergic pathways, but in 2001 a new gene was identified, that codes for a GPCR responding to p-tyramine and beta-phenylethylamine but not to classical biogenic amines. Several closely related genes were subsequently identified and designated as the trace amine-associated receptors (TAARs). Pharmacological investigations in vitro show that many TAAR subtypes may not respond to p-tyramine, beta-phenylethylamine, tryptamine or octopamine, suggesting the existence of additional endogenous ligands. A novel endogenous thyroid hormone derivative, 3-iodothyronamine, has been found to interact with TAAR1 and possibly other TAAR subtypes. In vivo, micromolar concentrations of 3-iodothyronamine determine functional effects which are opposite to those produced on a longer time scale by thyroid hormones, including reduction in body temperature and decrease in cardiac contractility. Expression of all TAAR subtypes except TAAR1 has been reported in mouse olfactory epithelium, and several volatile amines were shown to interact with specific TAAR subtypes. In addition, there is evidence that TAAR1 is targeted by amphetamines and other psychotropic agents, while genetic linkage studies show a significant association between the TAAR gene family locus and susceptibility to schizophrenia or bipolar affective disorder.
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Affiliation(s)
- R Zucchi
- Dipartimento di Scienze dell'Uomo e dell'Ambiente, University of Pisa, Pisa, Italy.
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Bour S, Iglesias-Osma MC, Marti L, Duro P, Garcia-Barrado MJ, Pastor MF, Prévot D, Visentin V, Valet P, Moratinos J, Carpéné C. The imidazoline I2-site ligands BU 224 and 2-BFI inhibit MAO-A and MAO-B activities, hydrogen peroxide production, and lipolysis in rodent and human adipocytes. Eur J Pharmacol 2006; 552:20-30. [PMID: 17056035 DOI: 10.1016/j.ejphar.2006.09.021] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2006] [Revised: 09/07/2006] [Accepted: 09/11/2006] [Indexed: 12/31/2022]
Abstract
Numerous imidazolinic agents exhibit antihyperglycaemic properties and have been described to promote insulin secretion, however their effects on adipose tissue development have been poorly investigated. Since white adipose tissue (WAT) plays an important role in glucose homeostasis and expresses imidazoline (I(2)) binding sites abundantly, this work aimed at studying extrapancreatic actions of two I(2)-site ligands, BU 224 and 2-BFI in adipocytes. Interaction with monoamine oxidase (MAO) was investigated by measuring the ability to modulate [(14)C]tyramine oxidation and hydrogen peroxide production. Direct influence on glucose uptake or on lipolytic activity was tested on mouse, rat, rabbit and human adipocytes. BU 224 and 2-BFI behaved as reversible inhibitors of both MAO-A and -B, as demonstrated by total inhibition of tyramine oxidation in human adipocytes and platelets or in liver from rats previously treated with selective MAO-inhibitors. Moreover, they weakly inhibited semicarbazide-sensitive amine oxidase. Like classical MAO-inhibitors, they were unable to produce hydrogen peroxide and to activate glucose uptake but prevented tyramine to do so in rodent or human adipocytes. BU 224 and 2-BFI also differed from MAO-inhibitors since they inhibited lipolysis at millimolar concentrations via a still undefined pathway independent of alpha(2)-adrenoceptor stimulation, beta-adrenergic antagonism and MAO activation. However, chronic treatment of obese Zucker rats with 2-BFI did not modify the maximal lipolytic capacity or the mild insulin resistance status of their adipocytes. Taken together, our observations demonstrate on WAT novel effects of BU 224 and 2-BFI different from their already reported actions on brain or endocrine pancreas.
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Affiliation(s)
- Sandy Bour
- Inserm, U586, Unité de Recherches sur les Obésités, Université Paul Sabatier, IFR31, CHU Rangueil, Toulouse, F-31432, France
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Yraola F, García-Vicente S, Fernandez-Recio J, Albericio F, Zorzano A, Marti L, Royo M. New Efficient Substrates for Semicarbazide-Sensitive Amine Oxidase/VAP-1 Enzyme: Analysis by SARs and Computational Docking. J Med Chem 2006; 49:6197-208. [PMID: 17034126 DOI: 10.1021/jm051076e] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Structure activity relationships for semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) were studied using a library of arylalkylamine substrates, with the aim of contributing to the discovery of more efficient SSAO substrates. Experimental data were contrasted with computational docking studies, thereby allowing us to examine the mechanism and substrate-binding affinity of SSAO and thus contribute to the discovery of more efficient SSAO substrates and provide a structural basis for their interactions. We also built a model of the mouse SSAO structure, which provides several structural rationales for interspecies differences in SSAO substrate selectivity and reveals new trends in SSAO substrate recognition. In this context, we identified novel efficient substrates for human SSAO that can be used as a lead for the discovery of antidiabetic agents.
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Affiliation(s)
- Francesc Yraola
- Combinatorial Chemistry Unit and Institute for Research in Biomedicine, Barcelona Science Park, Josep Samitier 1, E-08028-Barcelona, Spain
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Salmi M, Jalkanen S. Developmental regulation of the adhesive and enzymatic activity of vascular adhesion protein-1 (VAP-1) in humans. Blood 2006; 108:1555-61. [PMID: 16556889 DOI: 10.1182/blood-2005-11-4599] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Vascular adhesion protein-1 (VAP-1) is a homodimeric glycoprotein that belongs to a unique subgroup of cell-surface-expressed oxidases. In adults, endothelial VAP-1 supports leukocyte rolling, firm adhesion, and transmigration in both enzyme activity-dependent and enzyme activity-independent manner. Here we studied the induction and function of VAP-1 during human ontogeny. We show that VAP-1 is already found in the smooth muscle at embryonic week 7. There are marked time-dependent switches in VAP-1 expression in the sinusoids of the liver, in the peritubular capillaries of the kidney, in the capillaries of the heart, and in the venules in the lamina propria of the gut. Fetal VAP-1 is dimerized, and it is enzymatically active. VAP-1 in fetal-type venules is able to bind cord blood lymphocytes. Also, adenovirally transfected VAP-1 on human umbilical vein endothelial cells is involved in rolling and firm adhesion of cord blood lymphocytes under conditions of physiologic shear stress. We conclude that VAP-1 is synthesized from early on in human vessels and it is functionally intact already before birth. Thus, VAP-1 may contribute critically to the oxidase activities in utero, and prove important for lymphocyte trafficking during human ontogeny.
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Affiliation(s)
- Marko Salmi
- National Public Health Institute, Turku, Finland.
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Visentin V, Boucher J, Bour S, Prévot D, Castan I, Carpéné C, Valet P. Influence of high-fat diet on amine oxidase activity in white adipose tissue of mice prone or resistant to diet-induced obesity. J Physiol Biochem 2005; 61:343-52. [PMID: 16180332 DOI: 10.1007/bf03167051] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Decreased monoamine oxidase (MAO) activity has been observed in adipose tissue of obese patients. Since substrates of MAO and semicarbazide-sensitive amine oxidase (SSAO) can modify adipocyte metabolism, this work investigates whether changes in amine oxidase activity may occur during white adipose tissue (WAT) development. We evaluated MAO and SSAO activities in WAT of high-fat diet (HFD) and low-fat diet fed mice. To distinguish the effect of HFD on its own from the effect of fat mass enlargement, obesity-prone transgenic line of the FVBn strain lacking beta3-adrenergic receptors (AR) but expressing human beta3-AR and alpha2-AR (mbeta3-/-, hbeta3+/+, halpha2+/-) was compared to its obesity-resistant control (mbeta3-/-, hbeta3+/+). As already reported, the former mice became obese while the latter resisted to HFD. No significant change in SSAO or MAO activity was found in WAT of both strains after HFD when expressing oxidase activity per milligram of protein. However, when considering the overall capacity of the fat depots to oxidize tyramine or benzylamine, there was an increase in MAO and SSAO activity only in the enlarged WAT of HFD-induced obese mice. Therefore, the comparison of these models allowed to demonstrate that the higher amine oxidase capacity hold in enlarged fat stores of obese mice is more likely the consequence of increased fat cell number rather than the result of an increased expression of MAO or SSAO in the adipocyte.
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Affiliation(s)
- V Visentin
- Institut National de la Santé et de la Recherche Médicale, U586, IFR 31, Bat. L3, CHU Rangueil, Université Paul Sabatier, 31432 Toulouse, France
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Carpéné C, Bour S, Visentin V, Pellati F, Benvenuti S, Iglesias-Osma MC, García-Barrado MJ, Valet P. Amine oxidase substrates for impaired glucose tolerance correction. J Physiol Biochem 2005; 61:405-19. [PMID: 16180339 DOI: 10.1007/bf03167058] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Amine oxidases are widely distributed from microorganisms to vertebrates and produce hydrogen peroxide plus aldehyde when catabolizing endogenous or xenobiotic amines. Novel roles have been attributed to several members of the amine oxidase families, which cannot be anymore considered as simple amine scavengers. Semicarbazide-sensitive amine oxidase (SSAO) is abundantly expressed in mammalian endothelial, smooth muscle, and fat cells, and plays a role in lymphocyte adhesion to vascular wall, arterial fiber elastic maturation, and glucose transport, respectively. This latter role was studied in detail and the perspectives of insulin-like actions of amine oxidase substrates are discussed in the present review. Independent studies have demonstrated that SSAO substrates and monoamine oxidase substrates mimic diverse insulin effects in adipocytes: glucose transport activation, lipogenesis stimulation and lipolysis inhibition. These substrates also stimulate in vitro adipogenesis. Acute in vivo administration of amine oxidase substrates improves glucose tolerance in rats, mice and rabbits, while chronic treatments with benzylamine plus vanadate exert an antihyperglycaemic effect in diabetic rats. Dietary supplementations with methylamine, benzylamine or tyramine have been proven to influence metabolic control in rodents by increasing glucose tolerance or decreasing lipid mobilisation, without noticeable changes in the plasma markers of lipid peroxidation or protein glycation, despite adverse effects on vasculature. Thus, the ingested amines are not totally metabolized at the intestinal level and can act on adipose and vascular tissues. In regard with this influence on metabolic control, more attention must be paid to the composition or supplementation in amines in foods and nutraceutics.
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Affiliation(s)
- C Carpéné
- INSERM U586, IFR 31, Bat L3, CHU Rangueil, Université P. Sabatier, BP 84225, 31342 Toulouse, France.
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Visentin V, Bour S, Boucher J, Prévot D, Valet P, Ordener C, Parini A, Carpéné C. Glucose handling in streptozotocin-induced diabetic rats is improved by tyramine but not by the amine oxidase inhibitor semicarbazide. Eur J Pharmacol 2005; 522:139-46. [PMID: 16202994 DOI: 10.1016/j.ejphar.2005.08.051] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2005] [Revised: 08/08/2005] [Accepted: 08/15/2005] [Indexed: 01/27/2023]
Abstract
A soluble form of semicarbazide-sensitive amine oxidase (SSAO) circulating in plasma is known to increase in type 1 and 2 diabetes. This cuproenzyme generates hydrogen peroxide, ammonia, and aldehydes when oxidizing circulating biogenic or exogenous amines. Based on the angiotoxicity of these products, inhibition of SSAO has been proposed to prevent vascular complications of diabetes. However, substrates of SSAO and monoamine oxidase (MAO) have been recently evidenced to activate glucose utilisation in insulin-sensitive tissues and to exhibit antihyperglycemic actions. To determine whether amine oxidase blockade or activation could be beneficial for diabetes, we aimed at comparing the influence of prolonged treatments with semicarbazide (SSAO-inhibitor), pargyline (MAO-inhibitor), or tyramine (amine oxidase substrate) on amine oxidase activities and glycemic control in streptozotocin-induced diabetic rats. The increase in plasma SSAO was confirmed in diabetic rats, while MAO and SSAO were decreased in subcutaneous adipose tissue when compared with normoglycemic controls. Among the diabetic rats, only those receiving tyramine exhibited slightly decreased hyperglycemia and improved glucose tolerance. Adipocytes from untreated or treated diabetic rats shared similar sensitivity to insulin. However glucose uptake activation and lipolysis inhibition in response to amine oxidase substrates combined with vanadate were impaired in rats treated with amine oxidase inhibitors. Thus, amine oxidase inhibition does not improve metabolic control while prolonged administration of tyramine slightly improves glucose disposal. It is therefore concluded that amine oxidase activation by increased substrate supply elicits insulin-like actions that may be more beneficial in diabetes than SSAO inhibition formerly proposed to prevent vascular complications.
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Affiliation(s)
- Virgile Visentin
- Institut National de la Santé et de la Recherche Médicale, U586, IFR 31, Bat. L3, CHU Rangueil, Toulouse, France
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Marti L, Abella A, De La Cruz X, García-Vicente S, Unzeta M, Carpéné C, Palacín M, Testar X, Orozco M, Zorzano A. Exploring the binding mode of semicarbazide-sensitive amine oxidase/VAP-1: identification of novel substrates with insulin-like activity. J Med Chem 2004; 47:4865-74. [PMID: 15369390 DOI: 10.1021/jm0499211] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We previously reported that substrates of semicarbazide-sensitive amine oxidase in combination with low concentrations of vanadate exert potent insulin-like effects. Here we performed homology modeling of the catalytic domain of mouse SSAO/VAP-1 and searched through chemical databases to identify novel SSAO substrates. The modeling of the catalytic domain revealed that aromatic residues Tyr384, Phe389, and Tyr394 define a pocket of stable size that may participate in the binding of apolar substrates. We identified a number of amines as substrates of human, rat, and mouse SSAO. The compounds PD0119035, 2,3-dimethoxy-benzylamine, and C-naphthalen-1-yl-methylamine showed high affinity as substrates of rat SSAO. C-Naphthalen-1-yl-methylamine was the only substrate that showed high affinity for human SSAO. C-Naphthalen-1-yl-methylamine and 4-aminomethyl-benzenesulfonamide showed the highest capacity to stimulate glucose transport in isolated rat adipocytes. The impact of these findings on the development of new treatments for diabetes is discussed.
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Affiliation(s)
- Luc Marti
- Parc Científic de Barcelona and Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Avda. Diagonal 645, E-08028 Barcelona, Spain
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Visentin V, Prévot D, De Saint Front VD, Morin-Cussac N, Thalamas C, Galitzky J, Valet P, Zorzano A, Carpéné C. Alteration of amine oxidase activity in the adipose tissue of obese subjects. ACTA ACUST UNITED AC 2004; 12:547-55. [PMID: 15044673 DOI: 10.1038/oby.2004.62] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE To explore the activity of monoamine oxidases (MAOs) and semicarbazide-sensitive amine oxidases (SSAOs) in adipose tissue and blood of lean and moderately obese subjects and to study whether there is a link between these hydrogen peroxide-generating enzymes and blood markers of oxidative stress. RESEARCH METHODS AND PROCEDURES Nine obese male subjects (BMI 32.6 +/- 0.4 kg/m(2)) and nine controls (BMI 23.4 +/- 0.5) of 24- to 40-year-old subjects were included in the study. MAO and SSAO activities were measured on microbiopsies of abdominal subcutaneous adipose tissue by quantifying (14)C-tyramine and (14)C-benzylamine oxidation. Levels of soluble SSAO, lipid peroxidation products, and antioxidant agents were measured in plasma, whereas cytoprotective enzymes were determined in blood lysates. RESULTS The high MAO activity found in adipose tissue was diminished by one-half in obese subjects (maximum initial velocity of 1.2 vs. 2.3 nmol tyramine oxidized/mg protein/min). There was no change in SSAO activity, either under its adipose tissue-bound or plasma-soluble form. Plasma levels of lipid peroxidation products and antioxidant vitamins remained unmodified, as well as erythrocyte antioxidant enzymes, whereas circulating triglycerides, insulin, and leptin were increased. DISCUSSION Although they already exhibited several signs of endocrino-metabolic disorders, the obese men did not exhibit the increase in blood markers of oxidative stress or the decrease in antioxidant defenses reported to occur in very obese or diabetic subjects. The reduced MAO and the unchanged SSAO activities found in obesity suggest that these hydrogen peroxide-generating enzymes expressed in adipocytes are probably not involved in the onset of the oxidative stress found in severe obesity and/or in its complications.
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Affiliation(s)
- Virgile Visentin
- Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire Rangueil, Toulouse, France
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Iglesias-Osma MC, Garcia-Barrado MJ, Visentin V, Pastor-Mansilla MF, Bour S, Prévot D, Valet P, Moratinos J, Carpéné C. Benzylamine exhibits insulin-like effects on glucose disposal, glucose transport, and fat cell lipolysis in rabbits and diabetic mice. J Pharmacol Exp Ther 2004; 309:1020-8. [PMID: 14978192 DOI: 10.1124/jpet.103.063636] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Benzylamine, a substrate of semicarbazide-sensitive amine oxidase (SSAO), stimulates glucose transport in rat adipocytes and improves glucose disposal in diabetic rats only in the presence of vanadate. These effects have been described to result from a synergism between the hydrogen peroxide formed during amine oxidation and vanadate, via the generation of pervanadate, a powerful insulin mimicker. However, it has also been reported that benzylamine alone can stimulate glucose uptake and inhibit lipolysis in human fat cells. In this work, we therefore investigated whether benzylamine on its own was able to induce both in vivo and in vitro insulin-like responses in animal models other than rat. In rabbits, the i.v. infusion of 7 micromol/kg benzylamine before a glucose tolerance test resulted in a net reduction of the hyperglycemic response without a change in insulin secretion. Benzylamine also improved glucose tolerance and reduced lipid mobilization in hyperglycemic/obese mice. In vitro, 0.1 mM benzylamine stimulated glucose transport and inhibited lipolysis in mouse and rabbit adipocytes. These effects were blocked by previous treatments with semicarbazide, a SSAO inhibitor. Levels of benzylamine oxidation were more elevated in mouse than in rabbit adipose tissues, whereas the reverse was observed for skeletal muscles. Finally, benzylamine was unable to stimulate insulin secretion by isolated pancreatic islets from both species and SSAO activity was hardly detectable in pancreas. Together, our results bring evidence that benzylamine on its own can improve glucose tolerance in rabbit and mouse, likely by stimulating glucose uptake via amine oxidase activation in insulin-sensitive tissues.
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Affiliation(s)
- María Carmen Iglesias-Osma
- Unité de recherches sur les obésités, Institut National de la Santé et de la Recherche Médicale U586, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, France
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Bairras C, Ferrand C, Atgié C. Effect of tyramine, a dietary amine, on glycerol and lactate release by isolated adipocytes from old rats. J Physiol Biochem 2004; 59:161-7. [PMID: 15000446 DOI: 10.1007/bf03179911] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Amine degradation by adipocyte amine oxidases leads to the production of metabolites that interact with lipid and glucose metabolisms and their hormonal regulations. To further investigate these interactions, we determined the effect of a dietary amine, tyramine (TYR), on glycerol and lactate releases, respectively taken as indices of lipolytic and glycolytic activities of isolated adipocytes. Old male Wistar rats were used to prepare adipocytes by collagenase dissociation of retroperitoneal fat pads. The two tested doses of tyramine (10 microM and 1 mM) had no effect on basal glycerol release. On the other hand, TYR, at the highest dose tested (1 mM), weakly but significantly increased basal lactate release, which was elevated in adipocytes from old rats. Norepinephrine (NE), highly stimulated adipocyte lipolysis with a submaximal effect at 1 microM which was slightly but significantly inhibited by TYR 1 mM. Insulin 1 nM (INS) also poorly inhibited the NE-stimulated lipolysis in adipocytes isolated from old rats. TYR was able to potentiate the poor antilipolytic efficiency of INS. Under similar conditions, a high dose of NE greatly reduced lactate production and TYR (1 mM) reversed this inhibition of lactate release. INS was also able to totally reverse the inhibitory effect of NE on lactate release, but there was no potentiation between insulin and tyramine effects. It can be concluded that high doses of TYR interact with norepinephrine and insulin, at least on the control of glycerol and lactate release, by counteracting catecholamine effects and by mimicking insulin actions.
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Affiliation(s)
- C Bairras
- Unité de Nutrition et Signalisation Cellulaire (site d'Agen), Université Bordeaux 1--DUSA, Avenue Michel Serres, 47000 Agen, France
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Visentin V, Marq P, Bour S, Subra C, Prévot D, Morin N, Valet P, Monje MC, Nepveu F, Carpéné C. Effect of prolonged treatment with tyramine on glucose tolerance in streptozotocin-induced diabetic rats. J Physiol Biochem 2004; 59:225-32. [PMID: 15000454 DOI: 10.1007/bf03179919] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The biogenic amine tyramine has been reported to stimulate in vitro glucose transport in adipocytes, cardiomyocytes and skeletal muscle, and to improve in vivo glucose utilization in rats. These effects were dependent on amine oxidation, since they were blocked by inhibitors of monoamine oxidase (MAO) and semicarbazide-sensitive amine oxidase (SSAO). We thus tested in this work whether a prolonged treatment with tyramine could improve glucose tolerance in streptozotocin-induced diabetic rats. First, tyramine content of standard rodent chow was determined by HPLC and daily tyramine intake of control rats was estimated to be around 26 micromol/kg body weight. Then, tyramine was administred during 3 weeks in streptozotocin-induced diabetic rats at 29 micromol/kg by daily i.p. injection alone or together with vanadate 0.02 micromol/kg. In another group of diabetic rats, tyramine was subcutaneously delivered at 116 micromol/kg/day by osmotic minipumps. All tyramine treatments resulted in a decrease of the hyperglycemic responses to an i.p. glucose load. Adipocytes isolated from either untreated or treated diabetic rats were sensitive to the stimulation of glucose uptake by tyramine. However, diabetic animals receiving tyramine for three weeks did not recover from their hyperglycemia, hypoinsulinemia and glucosuria. These results show that the improvement of glucose tolerance induced by prolonged tyramine administration occurs in an insulin-depleted model and probably results from peripheral insulin-like actions of the oxidation of MAO/SSAO substrates, such as the stimulation of glucose uptake into adipocytes.
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Affiliation(s)
- V Visentin
- Institut National de la Santé et de la Recherche Médicale, U586, CHU Rangueil, Toulouse, France
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Bour S, Visentin V, Prévot D, Carpéné C. Moderate weight-lowering effect of octopamine treatment in obese Zucker rats. J Physiol Biochem 2004; 59:175-82. [PMID: 15000448 DOI: 10.1007/bf03179913] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Octopamine is proposed as a substitution product of synephrine by diverse drug industries that advertise new weight-lowering products or medicinal plants enriched in this biogenic amine. We have already reported that octopamine is able to activate in vitro lipolysis in rat adipocytes via beta3-adrenergic receptor activation, while it activates glucose uptake in human fat cells via its oxidation by amine oxidases. In this work, we tested whether a chronic challenge with octopamine could exert anti-obesity effects. A treatment consisting in daily i.p. administration of octopamine (81 micromol/kg) was compared on a four-week period with calorie restriction in the genetically obese Zucker rat. Octopamine treatment resulted in a 19% decrease in body weight gain, when compared to the 177 g gained by controls during the same period. The decrease in body weight gain was detectable only after three weeks of treatment and was apparently not due to a pronounced and sustainable anorectic effect of octopamine since: 1) cumulated food consumption was only reduced by 10%; 2) the experimental 18% reduction of food intake provoked a rapid decrease in body weight gain, significant in less than two weeks. The lipolytic responses to isoprenaline or octopamine and the stimulation of glucose transport by insulin or by the amine oxidase substrate tyramine were unmodified by the treatments. Noteworthy, the elevated plasma insulin of obese rats was lowered by octopamine. This study shows that octopamine can reduce body weight gain in obese rats, without apparent adverse effects, but with less efficacy than beta3-AR agonists.
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Affiliation(s)
- S Bour
- Institut National de la Santé et de la Recherche Médicale, U586, CHU Rangueil, Université Paul Sabatier, 31043 Toulouse, France
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Subra C, Fontana E, Visentin V, Testar X, Carpéné C. Tyramine and benzylamine partially but selectively mimic insulin action on adipose differentiation in 3T3-L1 cells. J Physiol Biochem 2004; 59:209-16. [PMID: 15000452 DOI: 10.1007/bf03179917] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Biogenic amines like tyramine, methylamine and the non-naturally occuring amine, benzylamine, have been described to promote adipose conversion of murine 3T3 preadipocytes. To further investigate these novel effects of amines, we studied whether they selectively mimic the long-term adipogenic action of insulin. To this aim, we decided to use the 3T3-L1 cell line since this model needs a complex combination of inducers to trigger the differentiation programme: insulin, isobutylmethylxanthine (IBMX, an activator of cAMP-signal transduction pathway) and the synthetic glucocorticoid, dexamethasone. A cell culture protocol was designed, by which each component of the differentiation cocktail was replaced with either benzylamine or tyramine, in order to determine whether these amine oxidase substrates could substitute any of the differentiation inducers in 3T3-L1 cells. The incomplete lipid accumulation found in cells grown under IBMX- or dexamethasone-free conditions was not improved by the daily addition of amines to the culture medium. Insulin was the only component of adipose differentiation cocktail of 3T3-L1 that could be replaced, although partially, by tyramine or benzylamine. When used at 0.5 mM, these amines resulted in a significant increase of triacylglycerol accumulated eight days after confluence, when compared to cells kept without insulin. This partial insulin replacement was totally abolished by SSAO-inhibitors, while MAO-blockade did not reduce lipid accumulation. As previously reported for other insulin-sensitive processes, such as stimulation of glucose transport or lipolysis inhibition in mature adipocytes, the stimulation of adipogenesis by tyramine and benzylamine was an SSAO-dependent mechanism that apparently shared common signaling pathways with insulin.
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Affiliation(s)
- C Subra
- Institut National de la Santé et de la Recherche Médicale, U586, CHU Rangueil, 31043 Toulouse, France
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Abella A, García-Vicente S, Viguerie N, Ros-Baró A, Camps M, Palacín M, Zorzano A, Marti L. Adipocytes release a soluble form of VAP-1/SSAO by a metalloprotease-dependent process and in a regulated manner. Diabetologia 2004; 47:429-438. [PMID: 14968297 DOI: 10.1007/s00125-004-1346-2] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2003] [Revised: 12/15/2003] [Indexed: 11/30/2022]
Abstract
AIMS/HYPOTHESIS Vascular adhesion protein-1 (VAP-1), which is identical to semicarbazide-sensitive amine oxidase (SSAO), is a dual-function membrane protein with adhesion properties and amine oxidase activity. A soluble form of VAP-1 is found in serum, where concentrations are enhanced in diabetes and obesity. In vitro, soluble VAP-1 enhances lymphocyte adhesion to endothelial cells, thus possibly participating in the enhanced lymphocyte adhesion capacity that is implicated in the cardiovascular complications associated with diabetes or obesity. In both, the tissue origin of the soluble VAP-1/SSAO is unknown. We examined whether adipose tissue, which has abundant expression of VAP-1/SSAO, is a source of soluble VAP-1. METHODS We detected VAP-1/SSAO in plasma of diabetic animals, with or without VAP-1 immunoprecipitation, and in culture medium from 3T3-L1 adipocytes and human adipose tissue explants. VAP-1 protein glycosylation was measured. RESULTS Diabetic and obese animals have increased plasma SSAO activity associated with VAP-1 protein. We also found that 3T3-L1 adipocytes and human adipose tissue explants release a soluble form of VAP-1/SSAO, which derives from the membrane. The release of soluble VAP-1 was enhanced by exposure of murine and human adipocytes to TNF-alpha and blocked by batimastat, a metalloprotease inhibitor. Partial ablation of adipose tissue reduced plasma SSAO activity in normal and diabetic rats. CONCLUSIONS/INTERPRETATION Adipose cells are a source of soluble VAP-1/SSAO released by shedding of the membrane form. The release of SSAO is regulated by TNF-alpha and insulin. By releasing VAP-1/SSAO, adipose cells could contribute to the atherogenesis and vascular dysfunction associated with diabetes and obesity.
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Affiliation(s)
- A Abella
- Barcelona Science Parc and Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Josep Samitier, 1-5, 08028, Barcelona, Spain
| | - S García-Vicente
- Barcelona Science Parc and Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Josep Samitier, 1-5, 08028, Barcelona, Spain
| | - N Viguerie
- Research Unit on Obesity, French Institute of Health and Medical Research Unit 586, Louis Bugnard Institut, Rangueil Hospital, Université Paul Sabatier, Toulouse, France
| | - A Ros-Baró
- Barcelona Science Parc and Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Josep Samitier, 1-5, 08028, Barcelona, Spain
| | - M Camps
- Barcelona Science Parc and Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Josep Samitier, 1-5, 08028, Barcelona, Spain
| | - M Palacín
- Barcelona Science Parc and Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Josep Samitier, 1-5, 08028, Barcelona, Spain
| | - A Zorzano
- Barcelona Science Parc and Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Josep Samitier, 1-5, 08028, Barcelona, Spain
| | - L Marti
- Barcelona Science Parc and Department of Biochemistry and Molecular Biology, Faculty of Biology, Universitat de Barcelona, Josep Samitier, 1-5, 08028, Barcelona, Spain.
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Fowler JS, Logan J, Wang GJ, Franceschi D, Volkow ND, Telang F, Pappas N, Ferrieri R, Shea C, Garza V, Xu Y, King P, Schlyer D, Gatley SJ, Ding YS, Warner D, Netusil N, Carter P, Jayne M, Alexoff D, Zhu W, Vaska P. Monoamine oxidase A imaging in peripheral organs in healthy human subjects. Synapse 2003; 49:178-87. [PMID: 12774302 DOI: 10.1002/syn.10231] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Monoamine oxidase (MAO) catalyzes the oxidative deamination of many biogenic and dietary amines. Though studies of MAO have focused mainly on its regulatory role in the brain, MAO in peripheral organs also represents a vast mechanism for detoxifying vasoactive compounds as well as for terminating the action of physiologically active amines, which can cross the blood brain barrier. Indeed, robust central and peripheral MAO activity is a major requirement in the safe use of many CNS drugs, particularly antidepressants, and thus an awareness of the MAO inhibitory potential of drugs is essential in therapeutics. In this study, we examined the feasibility of quantifying MAO A in peripheral organs in healthy human subjects using comparative positron emission tomography (PET) imaging with carbon-11 (t(1/2): 20.4 min) labeled clorgyline ([(11)C]clorgyline) a suicide inactivator of MAO A and its deuterium labeled counterpart ([(11)C]clorgyline-D2). Heart, lungs, kidneys, thyroid, and spleen showed a robust deuterium isotope effect characteristic of MAO and the magnitude of the effect was similar to that of trancylcypromine, an irreversible MAO inhibitor used in the treatment of depression. Liver time-activity curves were not affected by deuterium substitution precluding the estimation of liver MAO in vivo. In organs showing an isotope effect, MAO A is greatest in the lungs and kidneys followed by the thyroid and heart. This method, which has been previously applied in the human brain, opens the possibility to also directly assess the effects of different variables including smoking, dietary substances, drugs, disease, and genetics on peripheral MAO A in humans.
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Affiliation(s)
- Joanna S Fowler
- Chemistry Department, Brookhaven National Laboratory, Upton, New York 11973, USA.
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Visentin V, Prévot D, Marti L, Carpéné C. Inhibition of rat fat cell lipolysis by monoamine oxidase and semicarbazide-sensitive amine oxidase substrates. Eur J Pharmacol 2003; 466:235-43. [PMID: 12694806 DOI: 10.1016/s0014-2999(03)01562-0] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
It has been demonstrated that amine oxidase substrates stimulate glucose transport in cardiomyocytes and adipocytes, promote adipogenesis in pre-adipose cell lines and lower blood glucose in diabetic rats. These insulin-like effects are dependent on amine oxidation by semicarbazide-sensitive amine oxidase or by monoamine oxidase. The present study aimed to investigate whether amine oxidase substrates also exhibit another insulin-like property, the inhibition of lipolysis. We therefore tested the influence of tyramine and benzylamine on lipolytic activity in rat adipocytes. These amines did not modify basal lipolysis but dose-dependently counteracted the stimulation induced by lipolytic agents. The response to 10 nM isoprenaline was totally inhibited by tyramine 1 mM. The blockade produced by inhibition of amine oxidase activity or by 1 mM glutathione suggested that the generation of oxidative species, which occurs during amine oxidation, was involved in tyramine antilipolytic effect. Among the products resulting from amine oxidation, only hydrogen peroxide was antilipolytic in a manner that was potentiated by vanadate, as for tyramine or benzylamine. Antilipolytic responses to tyramine and to insulin were sensitive to wortmannin. These data suggest that inhibition of lipolysis is a novel insulin-like effect of amine oxidase substrates which is mediated by hydrogen peroxide generated during amine oxidation.
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Affiliation(s)
- Virgile Visentin
- Institut Louis Bugnard, Institut National de la Santé et de la Recherche Médicale, Unité 586, C.H.U. Rangueil, Toulouse Cedex F-31403, France
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Abella A, Marti L, Camps M, Claret M, Fernández-Alvarez J, Gomis R, Gumà A, Viguerie N, Carpéné C, Palacín M, Testar X, Zorzano A. Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 activity exerts an antidiabetic action in Goto-Kakizaki rats. Diabetes 2003; 52:1004-13. [PMID: 12663473 DOI: 10.2337/diabetes.52.4.1004] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
In this study we have explored whether the bifunctional protein semicarbazide-sensitive amine oxidase (SSAO)/vascular adhesion protein-1 (VAP-1) represents a novel target for type 2 diabetes. To this end, Goto-Kakizaki (GK) diabetic rats were treated with the SSAO substrate benzylamine and with low ineffective doses of vanadate previously shown to have antidiabetic effects in streptozotocin-induced diabetic rats. The administration of benzylamine in combination with vanadate in type 2 diabetic rats acutely stimulated glucose tolerance, and the chronic treatment normalized hyperglycemia, stimulated glucose transport in adipocytes, and reversed muscle insulin resistance. Acute in vivo administration of benzylamine and vanadate stimulated skeletal muscle glucose transport, an effect that was also observed in incubated muscle preparations coincubated with adipose tissue explants or with human recombinant SSAO. Acute administration of benzylamine/vanadate also ameliorated insulin secretion in diabetic GK rats, and this effect was also observed in incubated pancreatic islets. In keeping with these observations, we also demonstrate that pancreatic islets express SSAO/VAP-1. As far as mechanisms of action, we have found that benzylamine/vanadate causes enhanced tyrosine phosphorylation of proteins and reduced protein tyrosine phosphatase activity in adipocytes. In addition, incubation of human recombinant SSAO, benzylamine, and vanadate generates peroxovanadium compounds in vitro. Based on these data, we propose that benzylamine/vanadate administration generates peroxovanadium locally in pancreatic islets, which stimulates insulin secretion and also produces peroxovanadium in adipose tissue, activating glucose metabolism in adipocytes and in neighboring muscle. This opens the possibility of using the SSAO/VAP-1 activity as a local generator of protein tyrosine phosphatase inhibitors in antidiabetic therapy.
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Affiliation(s)
- Anna Abella
- Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain
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