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Patel A, Rajgopal B, Jaiswal M. Various strategies to induce beta cell neogenesis: a comprehensive review for unravelling the potential future therapy for curing diabetes. Growth Factors 2025:1-28. [PMID: 40400239 DOI: 10.1080/08977194.2025.2508723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 05/12/2025] [Indexed: 05/23/2025]
Abstract
Pancreatic endocrine cells are categorized in to 5 types (alpha, beta, delta, pancreatic polypeptide cells and epsilon), which expresses glucagon, insulin, somatostatin, pancreatic polypeptide, and ghrelin, respectively. Several studies including lineage tracing in Ins2Akita diabetic mice have been done to investigate the identities of pancreatic endocrine cells which concludes, alpha cells have enormous plasticity, which enables them to be reprogrammed by specific transcription factors into insulin secreting beta like cells. Gene therapy has provided the beneficial outcome. Pdx1, MaFA and PAX4 (the transcription factors) in alpha cells can be over expressed which results in reprogramming the targeted alpha cells into beta cells. This trans-differentiation may be induced by infusing an adeno-associated virus (AAV) loaded with distinct transcription factors in the duct of pancreas. Several researches have demonstrated the successful restoration of enhanced insulin secretion in diabetes induced mice. Additionally ductal neurogenin3 (Ngn3), Sglt2 inhibitors, Igfbp1, GLP1 and several clinical and non-clinical agents has been postulated as a basis of beta cell neogenesis. Alpha cell owing to its high plasticity, on prolonged exposure to GABA reprogrammed into beta-like cell due to downregulation of Arx expression by GABA. The various approaches for beta cell neogenesis open a new window towards the establishment of novel gene therapy accession to treat diabetes. However, broad studies are still needed to improve and optimize this treatment methodology. The potentiality of endogenous pancreatic alpha cell to beta cell conversion methods and its outcomes are invigorating. This accomplishment is presently being under trial in non-human primates.
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Affiliation(s)
- Anjali Patel
- Rungta College of Pharmaceutical Sciences and Research, Bhilai, India
| | - B Rajgopal
- Rungta College of Pharmaceutical Sciences and Research, Bhilai, India
| | - Manisha Jaiswal
- Rungta Institute of Pharmaceutical Education and Research, Bhilai, India
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2
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Hill H, Lundkvist P, Tsatsaris G, Birnir B, Espes D, Carlsson PO. Long-term gamma-aminobutyric acid (GABA) treatment fails to regain beta-cell function in longstanding type 1 diabetes in a randomized trial. Sci Rep 2025; 15:11530. [PMID: 40185824 PMCID: PMC11971400 DOI: 10.1038/s41598-025-95751-y] [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: 01/09/2025] [Accepted: 03/24/2025] [Indexed: 04/07/2025] Open
Abstract
Gamma-amino butyric acid (GABA) has in experimental studies been found to promote beta-cell proliferation, enhance insulin secretion and reduce inflammation, positioning it as a candidate drug for type 1 diabetes (T1D) therapy. This phase I/II randomized controlled trial assessed the safety and efficacy of long-term treatment with Remygen® (Diamyd Medical), a controlled-release oral GABA formulation, as a potential beta-cell regenerative therapy in adults with long-standing T1D. Thirty-five male subjects with T1D (≥ 5 years) were randomized into three arms receiving the study drug(s) once daily for 6 months: GABA 200 mg (Arm 1), GABA 600 mg (Arm 2) and GABA 600 mg + alprazolam 0.5 mg for 3 months followed by GABA 600 mg alone for 3 months (Arm 3). Safety measures, hormonal counter-regulation during hypoglycemic clamps, fasting- and stimulated C-peptide levels, were assessed at multiple timepoints. Safety concerns included elevated aspartate aminotransferase (AST) in nine subjects, leading to the withdrawal of two subjects. Most elevations were, however, transient with no dose-differences. No effects were observed on fasting- or stimulated C-peptide levels, CGM metrics or HbA1c. Hypoglycemic hormonal counter-regulation was unaltered. To conclude, we found no clinical evidence of a beta-cell regenerative effect of GABA, but side effects were commonly observed.
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Affiliation(s)
- Henrik Hill
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Per Lundkvist
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | | | - Bryndis Birnir
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Daniel Espes
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Per-Ola Carlsson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
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Łaszczych D, Czernicka A, Łaszczych K. Targeting GABA signaling in type 1 diabetes and its complications- an update on the state of the art. Pharmacol Rep 2025; 77:409-424. [PMID: 39833509 DOI: 10.1007/s43440-025-00697-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 01/04/2025] [Accepted: 01/13/2025] [Indexed: 01/22/2025]
Abstract
Type 1 diabetes (T1D) is an autoimmune disease that leads to the progressive destruction of insulin-producing β cells, resulting in lifelong insulin dependence and a range of severe complications. Beyond conventional glycemic control, innovative therapeutic strategies are needed to address the underlying disease mechanisms. Recent research has highlighted gamma-aminobutyric acid (GABA) as a promising therapeutic target for T1D due to its dual role in modulating both β cell survival and immune response within pancreatic islets. GABA signaling supports β cell regeneration, inhibits α cell hyperactivity, and promotes α-to-β cell transdifferentiation, contributing to improved islet function. Moreover, GABA's influence extends to mitigating T1D complications, including nephropathy, neuropathy, and retinopathy, as well as regulating central nervous system pathways involved in glucose metabolism. This review consolidates the latest advances in GABA-related T1D therapies, covering animal preclinical and human clinical studies and examining the therapeutic potential of GABA receptor modulation, combination therapies, and dietary interventions. Emphasis is placed on the translational potential of GABA-based approaches to enhance β cell viability and counteract autoimmune processes in T1D. Our findings underscore the therapeutic promise of GABA signaling modulation as a novel approach for T1D treatment and encourage further investigation into this pathway's role in comprehensive diabetes management.
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Affiliation(s)
- Dariusz Łaszczych
- Faculty of Medicine, Collegium Medicum, Nicolaus Copernicus University in Torun, Jagiellońska 13, 85-067, Bydgoszcz, Poland.
| | | | - Katarzyna Łaszczych
- Faculty of Pharmaceutical Sciences, Medical University of Silesia in Katowice, Jedności 8, Sosnowiec, 41-200, Poland
- Ziko Pharmacy, Plebiscytowa 39, Katowice, Poland
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Jagomäe T, Velling S, Tikva TB, Maksimtšuk V, Gaur N, Reimets R, Kaasik A, Vasar E, Plaas M. GABA and GLP-1 receptor agonist combination therapy modifies diabetes and Langerhans islet cytoarchitecture in a rat model of Wolfram syndrome. Diabetol Metab Syndr 2025; 17:82. [PMID: 40050934 PMCID: PMC11887366 DOI: 10.1186/s13098-025-01651-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 02/25/2025] [Indexed: 03/09/2025] Open
Abstract
BACKGROUND AND AIM Wolfram syndrome (WS) is a rare autosomal disorder caused by WFS1 gene mutations, currently lacking approved treatments. Preclinical and clinical reports suggest that diabetes medications, such as glucagon-like peptide-1 receptor agonist (GLP1-RA), slow WS-related diabetes and neurodegeneration, improving patient outcomes. Gamma-aminobutyric acid (GABA) has crucial role in pancreatic islet function and blood glucose regulation. However, its specific role in WS diabetic pathophysiology has never been explored. The aim of this study was to enhance the therapeutic efficacy of liraglutide in mitigating the progression of diabetes associated with WS through supplementation with GABA. METHODS In this study, 5-month-old glucose intolerant WS rats and their wild-type littermates where daily treated with GABA (1 g/kg/day), liraglutide (0.4 mg/kg/day), or a combination of both. During the four-month experimental period, the diabetic phenotype was closely monitored using intraperitoneal glucose tolerance tests (IPGTT) and corresponding hormone measurements via enzyme-linked immunoassay. Following the treatments, immunohistochemical staining was performed to examine the morphology, cellular distribution, and health of Langerhans islets. RESULTS Unlike in conventional diabetes models, GABA monotherapy alone had no significant effect on the diabetic phenotype in WS rats. In contrast, liraglutide monotherapy effectively delayed diabetes progression. Remarkably, the combined therapy of GABA and liraglutide reversed the diabetic phenotype, significantly enhancing glucose homeostasis, as well as insulin and C-peptide secretion. The combined treatment also increased β-cell mass and corrected the pancreatic Langerhans intra-islet ratio of α-, β-, and δ-cells. As a result, the overall morphology and cytoarchitecture of the pancreatic islets were fully restored, suggesting a potential role for these agents in preserving islet integrity. Additionally, both liraglutide and combination therapy increased the number of GAD (glutamic acid decarboxylase) 65/67-positive β-cells in WS rats, indicating an improvement in general β-cell health. CONCLUSION GABA monotherapy had no significant effect on the diabetic phenotype in WS rats, while liraglutide monotherapy effectively delayed diabetes progression. However, the combination therapy of GABA and liraglutide demonstrated a markedly superior effect, not only reversing the diabetic phenotype but also significantly enhancing glucose homeostasis, insulin and C-peptide secretion, and β-cell mass. This combined treatment led to a restoration of Langerhans islet architecture, correction of the endocrine cell proportions, and a notable increase in GAD65/67-positive β-cells, indicating improved β-cell health and function. These findings provide strong evidence supporting the evaluation of GABA and GLP-1 RAs as a combination therapy in clinical trials. Their synergistic effects may offer enhanced β-cell protection, promote functional recovery, and uncover novel therapeutic pathways for treating patients with WS.
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Affiliation(s)
- Toomas Jagomäe
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14b Ravila Street, 50411, Tartu, Estonia.
| | - Sandra Velling
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14b Ravila Street, 50411, Tartu, Estonia
| | - Tessa Britt Tikva
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14b Ravila Street, 50411, Tartu, Estonia
| | - Varvara Maksimtšuk
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14b Ravila Street, 50411, Tartu, Estonia
| | - Nayana Gaur
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14b Ravila Street, 50411, Tartu, Estonia
| | - Riin Reimets
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14b Ravila Street, 50411, Tartu, Estonia
| | - Allen Kaasik
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
| | - Eero Vasar
- Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, 19 Ravila Street, 50411, Tartu, Estonia
| | - Mario Plaas
- Laboratory Animal Centre, Institute of Biomedicine and Translational Medicine, University of Tartu, 14b Ravila Street, 50411, Tartu, Estonia.
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Guan F, Fu B, Wang P, Yan C, Wu M, Xu X, Wang H, Yu P. Directed evolution of glutamate decarboxylase B for enhancing its enzyme activity towards nearly neutral pHs based on error-prone PCR. Int J Biol Macromol 2025; 292:139283. [PMID: 39736285 DOI: 10.1016/j.ijbiomac.2024.139283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/16/2024] [Accepted: 12/27/2024] [Indexed: 01/01/2025]
Abstract
Glutamate decarboxylases (GADs) can catalyze the conversion of l-glutamate to γ-aminobutyric acid (GABA), while consuming one H+. However, the GADs found so far are catalytically active in the pHs of 3.8-5.0, and are inactivated at nearly neutral pHs (>5.0). In order to obtain GADs with a high activity at nearly neutral pHs, the directed evolution of GadB was performed. The gadB gene was amplified by error-prone PCR, and was transformed into E. coli BL21(DE3) to establish a random mutagenesis library. A high throughput screening based on the changes in the color of bromothymol blue was used to screen the mutated strain whose GadB was active at nearly neutral pHs. The mutated GadB was purified to investigate enzymatic properties and the mechanism of pH adaption by molecular docking. The results indicated that the mutated GadBD304G/F433L was screened and its activities were respectively increased by 935.90 % and 984.31 % at pHs 5.8 and 6.6 as compared to those of GadB(WT). By simulating the molecular docking, GadBD304G/F433L could form more hydrogen bonds with the substrate and had a lower binding energy, thus increasing the affinity for the substrate. This study contributes to a basis for the use of GadB at nearly neutral pHs.
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Affiliation(s)
- Fuyao Guan
- College of Food Science and Biotechnology, Zhejiang Gongshang University, 149 Jiaogong Road, Hangzhou, Zhejiang Province 310035, People's Republic of China
| | - Bing Fu
- College of Food Science and Biotechnology, Zhejiang Gongshang University, 149 Jiaogong Road, Hangzhou, Zhejiang Province 310035, People's Republic of China; College of Forestry Science and Technology, Lishui Vocational and Technical College, 357 Zhongshan Street North, Lishui, Zhejiang Province 323000, People's Republic of China
| | - Peize Wang
- College of Food Science and Biotechnology, Zhejiang Gongshang University, 149 Jiaogong Road, Hangzhou, Zhejiang Province 310035, People's Republic of China
| | - Chuyang Yan
- College of Food Science and Biotechnology, Zhejiang Gongshang University, 149 Jiaogong Road, Hangzhou, Zhejiang Province 310035, People's Republic of China
| | - Min Wu
- College of Food Science and Biotechnology, Zhejiang Gongshang University, 149 Jiaogong Road, Hangzhou, Zhejiang Province 310035, People's Republic of China
| | - Xin Xu
- College of Food Science and Biotechnology, Zhejiang Gongshang University, 149 Jiaogong Road, Hangzhou, Zhejiang Province 310035, People's Republic of China
| | - Haoju Wang
- College of Food Science and Biotechnology, Zhejiang Gongshang University, 149 Jiaogong Road, Hangzhou, Zhejiang Province 310035, People's Republic of China
| | - Ping Yu
- College of Food Science and Biotechnology, Zhejiang Gongshang University, 149 Jiaogong Road, Hangzhou, Zhejiang Province 310035, People's Republic of China.
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Kosheleva L, Koshelev D, Lagunas-Rangel FA, Levit S, Rabinovitch A, Schiöth HB. Disease-modifying pharmacological treatments of type 1 diabetes: Molecular mechanisms, target checkpoints, and possible combinatorial treatments. Pharmacol Rev 2025; 77:100044. [PMID: 40014914 PMCID: PMC11964952 DOI: 10.1016/j.pharmr.2025.100044] [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: 10/05/2024] [Accepted: 01/10/2025] [Indexed: 03/01/2025] Open
Abstract
After a century of extensive scientific investigations, there is still no curative or disease-modifying treatment available that can provide long-lasting remission for patients diagnosed with type 1 diabetes (T1D). Although T1D has historically been regarded as a classic autoimmune disorder targeting and destroying pancreatic islet β-cells, significant research has recently demonstrated that β-cells themselves also play a substantial role in the disease's progression, which could explain some of the unfavorable clinical outcomes. We offer a thorough review of scientific and clinical insights pertaining to molecular mechanisms behind pathogenesis and the different therapeutic interventions in T1D covering over 20 possible pharmaceutical intervention treatments. The interventions are categorized as immune therapies, treatments targeting islet endocrine dysfunctions, medications with dual modes of action in immune and islet endocrine cells, and combination treatments with a broader spectrum of activity. We suggest that these collective findings can provide a valuable platform to discover new combinatorial synergies in search of the curative disease-modifying intervention for T1D. SIGNIFICANCE STATEMENT: This research delves into the underlying causes of T1D and identifies critical mechanisms governing β-cell function in both healthy and diseased states. Thus, we identify specific pathways that could be manipulated by existing or new pharmacological interventions. These interventions fall into several categories: (1) immunomodifying therapies individually targeting immune cell processes, (2) interventions targeting β-cells, (3) compounds that act simultaneously on both immune cell and β-cell pathways, and (4) combinations of compounds simultaneously targeting immune and β-cell pathways.
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Affiliation(s)
- Liudmila Kosheleva
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Daniil Koshelev
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden
| | - Francisco Alejandro Lagunas-Rangel
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden; Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia
| | - Shmuel Levit
- Diabetes and Metabolism Institute, Assuta Medical Centers, Tel Aviv, Israel
| | | | - Helgi B Schiöth
- Department of Surgical Sciences, Functional Pharmacology and Neuroscience, Uppsala University, Uppsala, Sweden; Laboratory of Pharmaceutical Pharmacology, Latvian Institute of Organic Synthesis, Riga, Latvia.
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7
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Gajić Bojić M, Aranđelović J, Škrbić R, Savić MM. Peripheral GABA A receptors - Physiological relevance and therapeutic implications. Pharmacol Ther 2025; 266:108759. [PMID: 39615599 DOI: 10.1016/j.pharmthera.2024.108759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 11/04/2024] [Accepted: 11/22/2024] [Indexed: 12/13/2024]
Abstract
The role of γ- aminobutyric acid (GABA) and GABAA receptors is not only essential for neurotransmission in the central nervous system (CNS), but they are also involved in communication in various peripheral tissues such as the pancreas, liver, kidney, gastrointestinal tract, trachea, immune cells and blood vessels. GABAA receptors located outside the CNS ("peripheral GABAA receptors") enable both neuronal and non-neuronal GABA-ergic signaling in various physiological processes and are generally thought to have similar properties to the extrasynaptic receptors in the CNS. By activating these peripheral receptors, GABA and various GABAA receptor modulators, including drugs such as benzodiazepines and general anesthetics, may contribute to or otherwise affect the maintenance of general body homeostasis. However, the existing data in the literature on the role of non-neuronal GABA-ergic signaling in insulin secretion, glucose metabolism, renal function, intestinal motility, airway tone, immune response and blood pressure regulation are far from complete. In fact, they mainly focus on the identification of components for the local synthesis and utilization of GABA and on the expression repertoire of GABAA receptor subunits rather than on subunit composition, activation effects and (sub)cellular localization. A deeper understanding of how modulation of peripheral GABAA receptors can have significant therapeutic effects on a range of pathological conditions such as multiple sclerosis, diabetes, irritable bowel syndrome, asthma or hypertension could contribute to the development of more specific pharmacological strategies that would provide an alternative or complement to existing therapies. Selective GABAA receptor modulators with improved peripheral efficacy and reduced central side effects would therefore be highly desirable first-in-class drug candidates. This review updates recent advances unraveling the molecular components and cellular determinants of the GABA signaling machinery in peripheral organs, tissues and cells of both, humans and experimental animals.
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Affiliation(s)
- Milica Gajić Bojić
- Faculty of Medicine, Center for Biomedical Research, University of Banja Luka, Banja Luka 78000, Republic of Srpska, Bosnia and Herzegovina; Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Banja Luka - Faculty of Medicine, Banja Luka 78000, Republic of Srpska, Bosnia and Herzegovina
| | - Jovana Aranđelović
- Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Belgrade 11000, Serbia
| | - Ranko Škrbić
- Faculty of Medicine, Center for Biomedical Research, University of Banja Luka, Banja Luka 78000, Republic of Srpska, Bosnia and Herzegovina; Department of Pharmacology, Toxicology and Clinical Pharmacology, University of Banja Luka - Faculty of Medicine, Banja Luka 78000, Republic of Srpska, Bosnia and Herzegovina
| | - Miroslav M Savić
- Department of Pharmacology, University of Belgrade - Faculty of Pharmacy, Belgrade 11000, Serbia.
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He J, Liu F, Xu P, Xu T, Yu H, Wu B, Wang H, Chen J, Zhang K, Zhang J, Meng K, Yan X, Yang Q, Zhang X, Sun D, Chen X. Aerobic Exercise Improves the Overall Outcome of Type 2 Diabetes Mellitus Among People With Mental Disorders. Depress Anxiety 2024; 2024:6651804. [PMID: 40226688 PMCID: PMC11918971 DOI: 10.1155/da/6651804] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 12/09/2024] [Indexed: 04/15/2025] Open
Abstract
The escalating global prevalence of type 2 diabetes mellitus (T2DM) and mental disorder (MD) including schizophrenia, bipolar disorder, major depressive disorder, and anxiety highlights the urgency for comprehensive therapeutic strategies. Aerobic exercise (AE) is a viable adjunct therapy, providing significant benefits for individuals dealing with both T2DM and MD. This review consolidates evidence on AE's role in alleviating the physiological and psychological effects of these comorbid conditions. It delves into the pathophysiological connections between T2DM and various MD, including depression, schizophrenia, anxiety, and bipolar disorder-emphasizing their reciprocal exacerbation. Key neurophysiological mechanisms through which AE confers benefits are explored, including neuroinflammation modulation, brain structure and neuroplasticity enhancement, growth factor expression regulation, and hypothalamic-pituitary-adrenal (HPA)/microbiota-gut-brain (MGB) axis normalization. Clinical results indicate that AE significantly improves both metabolic and psychological parameters in patients with T2DM and MD, providing a substantial argument for integrating AE into comprehensive treatment plans. Future research should aim to establish detailed, personalized exercise prescriptions and explore the long-term benefits of AE in this population. This review underscores the potential of AE to complement existing therapeutic modalities and enhance the management of patients with T2DM and MD.
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Affiliation(s)
- Jiaxuan He
- Institute of Life Sciences and Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Fan Liu
- Institute of Life Sciences and Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Peiye Xu
- Institute of Life Sciences and Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Ting Xu
- Institute of Life Sciences and Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Haiyang Yu
- Institute of Life Sciences and Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Baihui Wu
- Institute of Life Sciences and Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
| | - Hanbing Wang
- Department of Biotechnology, The University of Hong Kong, Hong Kong SAR 999077, China
| | - Jia Chen
- Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 611100, China
| | - Kun Zhang
- Chongqing Municipality Clinical Research Center for Endocrinology and Metabolic Diseases, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Junbei Zhang
- Department of Endocrinology, Yiwu Central Hospital, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu 322000, China
| | - Kaikai Meng
- Department of Endocrinology, Yiwu Central Hospital, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu 322000, China
| | - Xiaoqing Yan
- The Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China
| | - Qinsi Yang
- Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325000, China
| | - Xingxing Zhang
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China
| | - Da Sun
- Institute of Life Sciences and Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325035, China
- Department of Endocrinology, Yiwu Central Hospital, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu 322000, China
| | - Xia Chen
- Department of Endocrinology, Yiwu Central Hospital, The Affiliated Yiwu Hospital of Wenzhou Medical University, Yiwu 322000, China
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Mick GJ, McCormick KL. The role of GABA in type 1 diabetes. Front Endocrinol (Lausanne) 2024; 15:1453396. [PMID: 39619323 PMCID: PMC11604429 DOI: 10.3389/fendo.2024.1453396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 10/22/2024] [Indexed: 12/13/2024] Open
Abstract
Gamma aminobutyric acid (GABA) is synthesized from glutamate by glutamic decarboxylase (GAD). The entero-pancreatic biology of GABA, which is produced by pancreatic islets, GAD-expressing microbiota, enteric immune cells, or ingested through diet, supports an essential physiologic role of GABA in the health and disease. Outside the central nervous system (CNS), GABA is uniquely concentrated in pancreatic β-cells. They express GAD65, which is a type 1 diabetes (T1D) autoantigen. Glutamate constitutes 10% of the amino acids in dietary protein and is preeminently concentrated in human milk. GABA is enriched in many foods, such as tomato and fermented cheese, and is an over-the-counter supplement. Selected microbiota in the midgut have the enzymatic capacity to produce GABA. Intestinal microbiota interact with gut-associated lymphoid tissue to maintain host defenses and immune tolerance, which are implicated in autoimmune disease. Although GABA is a widely known inhibitory neurotransmitter, oral GABA does not cross the blood brain barrier. Three diabetes-related therapeutic actions are ascribed to GABA, namely, increasing pancreatic β-cell content, attenuating excess glucagon and tamping down T-cell immune destruction. These salutary actions have been observed in numerous rodent diabetes models that usually employed high or near-continuous GABA doses. Clinical studies, to date, have identified positive effects of oral GABA on peripheral blood mononuclear cell cytokine release and plasma glucagon. Going forward, it is reassuring that oral GABA therapy has been well-tolerated and devoid of serious adverse effects.
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Affiliation(s)
- Gail J. Mick
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, United States
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Wu W, Zhang J, Qiao Y, Ren L, Chen Z, Fu Y, Yang Z. Association of long-term benzodiazepine hypnotic use and prediabetes in US population: A cross-sectional analysis of national health and nutrition examination survey data. Medicine (Baltimore) 2023; 102:e35705. [PMID: 37960777 PMCID: PMC10637564 DOI: 10.1097/md.0000000000035705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Accepted: 09/28/2023] [Indexed: 11/15/2023] Open
Abstract
Benzodiazepine hypnotics' effects on glucose metabolism are seldom reported, and the association between long-term (≥4 weeks) benzodiazepine usage and prediabetes has not been studied. This study was aimed to investigate the association between benzodiazepine hypnotic usage for ≥ 3 months and the prevalence of prediabetes. We analyzed cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) during 2005 to 2008, selecting adult participants without diabetes who used benzodiazepine hypnotics for at least 3 months or did not take any hypnotics. Individuals taking other hypnotics, antipsychotics, glucocorticoids, or hypoglycemic drugs were excluded. We defined prediabetes as an hemoglobin A1C (HbA1C) 5.7-6.4%, as suggested by the American Diabetes Association. Prescribed drug information was self-reported and checked by official interviewers, and HbA1C data in NHANES was recognized by the National Glycohemoglobin Standardization Program. We calculated the propensity score according to the covariates and adjusted it using multivariate logistic regression. Lower thresholds of HbA1C ≥ 5.5% or ≥ 5.3% were also analyzed. Among 4694 eligible participants, 38 received benzodiazepine hypnotics; using these hypnotics for ≥ 3 months was not significantly associated with the prevalence of prediabetes, as well as HbA1C ≥ 5.5% or ≥ 5.3%. Adjusted for propensity score, the respective odds ratios for prediabetes, HbA1C ≥ 5.5%, and HbA1C ≥ 5.3% were 1.09 (95% confidence interval [CI] 0.19-6.32), 0.83 (95% CI 0.22-3.13), and 1.22 (95% CI 0.3-4.93). No significant association was found between benzodiazepine hypnotic usage ≥ 3 months and the prevalence of prediabetes.
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Affiliation(s)
- Weizhen Wu
- Graduate School, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Junning Zhang
- Graduate School, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Yizhuo Qiao
- Graduate School, China Academy of Chinese Medical Science, Beijing, P.R. China
| | - Lijiang Ren
- Graduate School, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Zhe Chen
- Graduate School, Beijing University of Chinese Medicine, Beijing, P.R. China
| | - Yan Fu
- Xiyuan Hospital of China Academy of Chinese Medical Science, Beijing, P.R. China
| | - Zhixu Yang
- Xiyuan Hospital of China Academy of Chinese Medical Science, Beijing, P.R. China
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11
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Sionov RV, Ahdut-HaCohen R. A Supportive Role of Mesenchymal Stem Cells on Insulin-Producing Langerhans Islets with a Specific Emphasis on The Secretome. Biomedicines 2023; 11:2558. [PMID: 37761001 PMCID: PMC10527322 DOI: 10.3390/biomedicines11092558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/06/2023] [Accepted: 09/14/2023] [Indexed: 09/29/2023] Open
Abstract
Type 1 Diabetes (T1D) is a chronic autoimmune disease characterized by a gradual destruction of insulin-producing β-cells in the endocrine pancreas due to innate and specific immune responses, leading to impaired glucose homeostasis. T1D patients usually require regular insulin injections after meals to maintain normal serum glucose levels. In severe cases, pancreas or Langerhans islet transplantation can assist in reaching a sufficient β-mass to normalize glucose homeostasis. The latter procedure is limited because of low donor availability, high islet loss, and immune rejection. There is still a need to develop new technologies to improve islet survival and implantation and to keep the islets functional. Mesenchymal stem cells (MSCs) are multipotent non-hematopoietic progenitor cells with high plasticity that can support human pancreatic islet function both in vitro and in vivo and islet co-transplantation with MSCs is more effective than islet transplantation alone in attenuating diabetes progression. The beneficial effect of MSCs on islet function is due to a combined effect on angiogenesis, suppression of immune responses, and secretion of growth factors essential for islet survival and function. In this review, various aspects of MSCs related to islet function and diabetes are described.
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Affiliation(s)
- Ronit Vogt Sionov
- The Institute of Biomedical and Oral Research (IBOR), Faculty of Dental Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel
| | - Ronit Ahdut-HaCohen
- Department of Medical Neurobiology, Institute of Medical Research, Hadassah Medical School, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel;
- Department of Science, The David Yellin Academic College of Education, Jerusalem 9103501, Israel
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12
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Sun Y, Mehmood A, Giampieri F, Battino MA, Chen X. Insights into the cellular, molecular, and epigenetic targets of gamma-aminobutyric acid against diabetes: a comprehensive review on its mechanisms. Crit Rev Food Sci Nutr 2023; 64:12620-12637. [PMID: 37694998 DOI: 10.1080/10408398.2023.2255666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Diabetes is a metabolic disease due to impaired or defective insulin secretion and is considered one of the most serious chronic diseases worldwide. Gamma-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid commonly present in a wide range of foods. A number of studies documented that GABA has good anti-diabetic potential. This review summarized the available dietary sources of GABA as well as animal and human studies on the anti-diabetic properties of GABA, while also discussing the underlying mechanisms. GABA may modulate diabetes through various pathways such as inhibiting the activities of α-amylase and α-glucosidase, promoting β-cell proliferation, stimulating insulin secretion from β-cells, inhibiting glucagon secretion from α-cells, improving insulin resistance and glucose tolerance, and increasing antioxidant and anti-inflammatory activities. However, further mechanistic studies on animals and human are needed to confirm the therapeutic effects of GABA against diabetes.
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Affiliation(s)
- Yu Sun
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- Institute of Food Physical Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
| | - Arshad Mehmood
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- Institute of Food Physical Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
| | - Francesca Giampieri
- Research Group on Food, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
| | - Maurizio Antonio Battino
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- Research Group on Food, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Santander, Spain
- Department of Clinical Sciences, Università Politecnica delle Marche, Ancona, Italy
| | - Xiumin Chen
- School of Food and Biological Engineering, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- Institute of Food Physical Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
- International Joint Research Laboratory of Intelligent Agriculture and Agri-products Processing, Jiangsu University, Zhenjiang, Jiangsu, P.R. China
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13
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Kovaříková V, Špirková A, Šefčíková Z, Pisko J, Kalatová L, Koppel J, Fabian D, Čikoš Š. Gamma-aminobutyric acid (GABA) can affect physiological processes in preimplantation embryos via GABA A and GABA B receptors. Reprod Med Biol 2023; 22:e12528. [PMID: 37476368 PMCID: PMC10354355 DOI: 10.1002/rmb2.12528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 06/08/2023] [Accepted: 07/07/2023] [Indexed: 07/22/2023] Open
Abstract
Purpose Several widely used substances (e.g., some therapeutics or food supplements) can act on gamma-aminobutyric acid (GABA) receptors, and we investigated whether the activation of these receptors could affect the preimplantation embryo. Methods Transcripts of all GABA receptor subunits and selected proteins were examined using quantitative RT-PCR and immunohistochemistry. To analyze the effects of receptor activation, in vitro culture of mouse preimplantation embryos with natural and synthetic GABA receptor ligands was used. Results We detected nine GABA receptor transcripts in mouse blastocysts and 14 GABA receptor transcripts in ovulated oocytes. The results of this study indicate that ionotropic GABAA receptors can be formed from α5, β3, and γ3 (or δ, π) subunits, GABAA-ρ receptors can be formed from ρ2 subunits and metabotropic GABA receptors can be formed from GABAB1b and GABAB2 subunits in mouse blastocysts. Supplementing the culture medium with GABA at concentrations of 2-10 mM or with specific GABAA and GABAB receptor agonists (at concentrations of 10-100 μM) significantly increased the proportion of dead cells in blastocysts. The GABA-induced effects were prevented by pretreatment of embryos with GABAA and GABAB receptor antagonists. Conclusion The results of this study indicate that GABA and synthetic GABA receptor ligands can negatively affect preimplantation embryos via GABAA and GABAB receptors.
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Affiliation(s)
- Veronika Kovaříková
- Institute of Animal PhysiologyCentre of Biosciences of the Slovak Academy of SciencesKošiceSlovakia
| | - Alexandra Špirková
- Institute of Animal PhysiologyCentre of Biosciences of the Slovak Academy of SciencesKošiceSlovakia
| | - Zuzana Šefčíková
- Institute of Animal PhysiologyCentre of Biosciences of the Slovak Academy of SciencesKošiceSlovakia
| | - Jozef Pisko
- Institute of Animal PhysiologyCentre of Biosciences of the Slovak Academy of SciencesKošiceSlovakia
| | - Laura Kalatová
- Institute of Animal PhysiologyCentre of Biosciences of the Slovak Academy of SciencesKošiceSlovakia
| | - Juraj Koppel
- Institute of Animal PhysiologyCentre of Biosciences of the Slovak Academy of SciencesKošiceSlovakia
| | - Dušan Fabian
- Institute of Animal PhysiologyCentre of Biosciences of the Slovak Academy of SciencesKošiceSlovakia
| | - Štefan Čikoš
- Institute of Animal PhysiologyCentre of Biosciences of the Slovak Academy of SciencesKošiceSlovakia
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14
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Abstract
The pancreatic islets are essential microorgans controlling the glucose level in the blood. The islets consist of different cell types which communicate with each other by means of auto- and paracrine interactions. One of the communication molecules produced by and released within the islets is γ-aminobutyric acid (GABA), a well-known inhibitor of neuronal excitability in the mammalian nervous system. Interestingly, GABA is also present in the blood in the nanomolar concentration range. Thus, GABA can affect not only islet function per se (e.g. hormone secretion) but also interactions between immune cells and the pancreatic islet cells in physiological conditions and in pathological states (particularly in type 1 diabetes). In the last decade the interest in GABA signalling in islets has increased. The broad research scope ranges from fundamental physiological studies at the molecular and cellular level to pathological implications and clinical trials. The aim of this mini-review is to outline the current status of the islet GABA field mostly in relation to human islets, to identify the gaps in the current knowledge and what clinical implications GABA signalling may have in islets.
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15
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Chen Z, Sun Y, Chen L, Zhang Y, Wang J, Li H, Yan X, Xia L, Yao G. Differences in meat quality between Angus cattle and Xinjiang brown cattle in association with gut microbiota and its lipid metabolism. Front Microbiol 2022; 13:988984. [PMID: 36560955 PMCID: PMC9763702 DOI: 10.3389/fmicb.2022.988984] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 11/14/2022] [Indexed: 12/12/2022] Open
Abstract
Gut microbiota plays important roles in mediating fat metabolic events in humans and animals. However, the differences of meat quality traits related to the lipid metabolism (MQT-LM) in association with gut microbiota involving in lipid metabolism have not been well explored between Angus cattle (AG) and Xinjiang brown cattle (BC). Ten heads of 18-month-old uncastrated male AG and BC (5 in each group) raised under the identical conditions were selected to test MQT-LM, i.e., the backfat thickness (BFT), the intramuscular fat (IMF) content, the intramuscular adipocyte areas (IAA), the eye muscle area (EMA), the muscle fiber sectional area (MFSA) and the muscle shear force after sacrifice. The gut microbiota composition and structure with its metabolic function were analyzed by means of metagenomics and metabolomics with rectal feces. The correlation of MQT-LM with the gut microbiota and its metabolites was analyzed. In comparison with AG, BC had significant lower EMA, IMF content and IAA but higher BFT and MFSA. Chao1 and ACE indexes of α-diversity were lower. β-diversity between AG and BC were significantly different. The relative abundance of Bacteroidetes, Prevotella and Blautia and Prevotella copri, Blautia wexlerae, and Ruminococcus gnavus was lower. The lipid metabolism related metabolites, i.e., succinate, oxoglutaric acid, L-aspartic acid and L-glutamic acid were lower, while GABA, L-asparagine and fumaric acid were higher. IMF was positively correlated with Prevotella copri, Blautia wexlerae and Ruminococcus gnavus, and the metabolites succinate, oxoglutaric acid, L-aspartic acid and L-glutamic acid, while negatively with GABA, L-asparagine and fumaric acid. BFT was negatively correlated with Blautia wexlerae and the metabolites succinate, L-aspartic acid and L-glutamic acid, while positively with GABA, L-asparagine and fumaric acid. Prevotella Copri, Blautia wexlerae, and Ruminococcus gnavus was all positively correlated with succinate, oxoglutaric acid, while negatively with L-asparagine and fumaric acid. In conclusion, Prevotella copri, Prevotella intermedia, Blautia wexlerae, and Ruminococcus gnavus may serve as the potential differentiated bacterial species in association with MQT-LM via their metabolites of oxoglutaric acid, succinate, fumaric acid, L-aspartic acid, L-asparagine, L-glutamic acid and GABA between BC and AG.
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Affiliation(s)
- Zhuo Chen
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Yawei Sun
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Lijing Chen
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Yang Zhang
- Institute of Animal Science, Xinjiang Academy of Animal Sciences, Urumqi, China
| | - Jinquan Wang
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China
| | - Hongbo Li
- Institute of Animal Science, Xinjiang Academy of Animal Sciences, Urumqi, China
| | - Xiangming Yan
- Institute of Animal Science, Xinjiang Academy of Animal Sciences, Urumqi, China
| | - Lining Xia
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China,Xinjiang Key Laboratory of New Drug Study and Creation for Herbivorous Animals (XJKLNDSCHA), Xinjiang Agricultural University, Urumqi, China,*Correspondence: Lining Xia,
| | - Gang Yao
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi, China,Xinjiang Key Laboratory of New Drug Study and Creation for Herbivorous Animals (XJKLNDSCHA), Xinjiang Agricultural University, Urumqi, China,Gang Yao,
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16
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Hagan DW, Ferreira SM, Santos GJ, Phelps EA. The role of GABA in islet function. Front Endocrinol (Lausanne) 2022; 13:972115. [PMID: 36246925 PMCID: PMC9558271 DOI: 10.3389/fendo.2022.972115] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 08/29/2022] [Indexed: 11/13/2022] Open
Abstract
Gamma aminobutyric acid (GABA) is a non-proteinogenic amino acid and neurotransmitter that is produced in the islet at levels as high as in the brain. GABA is synthesized by the enzyme glutamic acid decarboxylase (GAD), of which the 65 kDa isoform (GAD65) is a major autoantigen in type 1 diabetes. Originally described to be released via synaptic-like microvesicles or from insulin secretory vesicles, beta cells are now understood to release substantial quantities of GABA directly from the cytosol via volume-regulated anion channels (VRAC). Once released, GABA influences the activity of multiple islet cell types through ionotropic GABAA receptors and metabotropic GABAB receptors. GABA also interfaces with cellular metabolism and ATP production via the GABA shunt pathway. Beta cells become depleted of GABA in type 1 diabetes (in remaining beta cells) and type 2 diabetes, suggesting that loss or reduction of islet GABA correlates with diabetes pathogenesis and may contribute to dysfunction of alpha, beta, and delta cells in diabetic individuals. While the function of GABA in the nervous system is well-understood, the description of the islet GABA system is clouded by differing reports describing multiple secretion pathways and effector functions. This review will discuss and attempt to unify the major experimental results from over 40 years of literature characterizing the role of GABA in the islet.
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Affiliation(s)
- D. Walker Hagan
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Sandra M. Ferreira
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
| | - Gustavo J. Santos
- Islet Biology and Metabolism Lab – I.B.M. Lab, Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina - UFSC, Florianópolis, Brazil
| | - Edward A. Phelps
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, United States
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17
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de Bie TH, Balvers MGJ, de Vos RCH, Witkamp RF, Jongsma MA. The influence of a tomato food matrix on the bioavailability and plasma kinetics of oral gamma-aminobutyric acid (GABA) and its precursor glutamate in healthy men. Food Funct 2022; 13:8399-8410. [PMID: 35852458 DOI: 10.1039/d2fo01358d] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gamma-aminobutyric acid (GABA) and its precursor glutamate play signaling roles in a range of tissues. Both function as neurotransmitters in the central nervous system, but they also modulate pancreatic and immune functioning, for example. Besides endogenous production, both compounds are found in food products, reaching relatively high levels in tomatoes. Recent studies in rodents suggest beneficial effects of oral GABA on glucose homeostasis and blood pressure. However, the bioavailability from food remains unknown. We studied the bioavailability of GABA and glutamate from tomatoes relative to a solution in water. After a fasting blood sample was taken, eleven healthy men randomly received 1 liter of 4 different drinks in a cross-over design with a one-week interval. The drinks were a solution of 888 mg L-1 GABA, a solution of 3673 mg L-1 glutamate, pureed fresh tomatoes and plain water as the control. Following intake, 18 blood samples were taken at intervals for 24 hours. Plasma GABA and glutamate concentrations were determined by ultra-pressure liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS). Fasting plasma GABA and glutamate concentrations were found to be 16.71 (SD 2.18) ng mL-1 and 4626 (SD 1666) ng mL-1, respectively. Fasting GABA levels were constant (5.8 CV%) between individuals, while fasting glutamate levels varied considerably (23.5 CV%). GABA from pureed tomatoes showed similar bioavailability to that of a solution in water. For glutamate, the absorption from pureed tomatoes occurred more slowly as seen from a longer tmax (0.98 ± 0.14 h vs. 0.41 ± 0.04 h, P = 0.003) and lower Cmax (7815 ± 627 ng mL-1vs. 16 420 ± 2778 ng mL-1, P = 0.006). These data suggest that GABA is bioavailable from tomatoes, and that food products containing GABA could potentially induce health effects similar to those claimed for GABA supplements. The results merit further studies on the bioavailability of GABA from other food products and the health effects of GABA-rich diets. The clinical trial registry number is NCT04086108 (https://clinicaltrials.gov/ct2/show/NCT04303468).
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Affiliation(s)
- Tessa H de Bie
- Division of Human Nutrition and Health, Wageningen University & Research, P.O. Box 17, 6700 AA Wageningen, The Netherlands. .,Wageningen Plant Research, Wageningen University & Research, P.O. Box 16, 6700 AA Wageningen, The Netherlands
| | - Michiel G J Balvers
- Division of Human Nutrition and Health, Wageningen University & Research, P.O. Box 17, 6700 AA Wageningen, The Netherlands.
| | - Ric C H de Vos
- Wageningen Plant Research, Wageningen University & Research, P.O. Box 16, 6700 AA Wageningen, The Netherlands
| | - Renger F Witkamp
- Division of Human Nutrition and Health, Wageningen University & Research, P.O. Box 17, 6700 AA Wageningen, The Netherlands.
| | - Maarten A Jongsma
- Wageningen Plant Research, Wageningen University & Research, P.O. Box 16, 6700 AA Wageningen, The Netherlands
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18
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Prud’homme GJ, Kurt M, Wang Q. Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations. FRONTIERS IN AGING 2022; 3:931331. [PMID: 35903083 PMCID: PMC9314780 DOI: 10.3389/fragi.2022.931331] [Citation(s) in RCA: 90] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 06/06/2022] [Indexed: 12/06/2022]
Abstract
The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.
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Affiliation(s)
- Gérald J. Prud’homme
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, ON, Canada
- *Correspondence: Gérald J. Prud’homme,
| | - Mervé Kurt
- Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, ON, Canada
| | - Qinghua Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China
- Shanghai Yinuo Pharmaceutical Co., Ltd., Shanghai, China
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19
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Fahmy AM, William S, Hegab A, Tm D. Schistosomicidal and hepatoprotective activity of gamma-aminobutyric acid (GABA) alone or combined with praziquantel against Schistosoma mansoni infection in murine model. Exp Parasitol 2022; 238:108260. [PMID: 35447136 DOI: 10.1016/j.exppara.2022.108260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 04/03/2022] [Accepted: 04/10/2022] [Indexed: 01/22/2023]
Abstract
OBJECTIVE This study aimed to evaluate the efficacy of gamma-aminobutyric acid (GABA) alone or combined with praziquantel (PZQ) against Schistosoma (S) mansoni infection in a murine model. METHODS Five groups, 8 mice each, were studied; GI served as normal controls; GII: S. mansoni-infected control group and the other three S. mansoni-infected groups received drug regimens for 5 consecutive days as follows GIII: Infected-PZQ treated group (200 mg/kg/day); GIV: Infected-GABA treated group (300 mg/kg/day) and GV: Infected-PZQ-GABA treated group (100 mg/kg/day for each drug). All animal groups were sacrificed two weeks later and different parasitological, histopathological and biochemical parameters were assessed. RESULTS Combined GABA-PZQ treated group recorded the highest significant reduction in all parasitological, histopathological and biochemical parameters followed by PZQ and finally GABA groups. Combined GABA-PZQ treatment led to the complete disappearance of immature eggs and marked reduction of deposited eggs in liver tissues and improved liver pathology. Significant improvement in hepatic oxidative stress levels, serum albumin and total protein in response to GABA treatment alone or combined with PZQ. CONCLUSION GABA had schistosomicidal, hepatoprotective and antioxidant activities against S. mansoni infection, GABA disrupted parasite pairing and activity, reduced the total number of worms recovered and the number of ova in the tissues. GABA may be considered an adjuvant therapy to potentiate PZQ antiparasitic activity and eradicate infection-induced liver damage and oxidative stress.
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Affiliation(s)
- Azza Moustafa Fahmy
- Department of Immunology and Drug Evaluation, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt.
| | - Samia William
- Department of Immunology and Drug Evaluation, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
| | - Amany Hegab
- Department of Developmental Pharmacology, National Organization for Drug Control and Research, Egypt
| | - Diab Tm
- Department of Immunology and Drug Evaluation, Theodor Bilharz Research Institute, Imbaba, Giza, Egypt
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20
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Designing Personalized Antigen-Specific Immunotherapies for Autoimmune Diseases-The Case for Using Ignored Target Cell Antigen Determinants. Cells 2022; 11:cells11071081. [PMID: 35406645 PMCID: PMC8997884 DOI: 10.3390/cells11071081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 12/15/2022] Open
Abstract
We have proposed that antigen-specific immunotherapies (ASIs) for autoimmune diseases could be enhanced by administering target cell antigen epitopes (determinants) that are immunogenic but ignored by autoreactive T cells because these determinants may have large pools of naïve cognate T cells available for priming towards regulatory responses. Here, we identified an immunogenic preproinsulin determinant (PPIL4-20) that was ignored by autoimmune responses in type 1 diabetes (T1D)-prone NOD mice. The size of the PPIL4-20-specific splenic naive T cell pool gradually increased from 2–12 weeks in age and remained stable thereafter, while that of the major target determinant insulin B-chain9-23 decreased greatly after 12 weeks in age, presumably due to recruitment into the autoimmune response. In 15–16 week old mice, insulin B-chain9-23/alum immunization induced modest-low level of splenic T cell IL-10 and IL-4 responses, little or no spreading of these responses, and boosted IFNγ responses to itself and other autoantigens. In contrast, PPIL4-20/alum treatment induced robust IL-10 and IL-4 responses, which spread to other autoantigens and increased the frequency of splenic IL-10-secreting Treg and Tr-1-like cells, without boosting IFNγ responses to ß-cell autoantigens. In newly diabetic NOD mice, PPIL4-20, but not insulin B-chain9-23 administered intraperitoneally (with alum) or intradermally (as soluble antigen) supplemented with oral GABA induced long-term disease remission. We discuss the potential of personalized ASIs that are based on an individual’s naïve autoantigen-reactive T cell pools and the use of HLA-appropriate ignored autoantigen determinants to safely enhance the efficacy of ASIs.
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Shimizu-Okabe C, Okada S, Okamoto S, Masuzaki H, Takayama C. Specific Expression of KCC2 in the α Cells of Normal and Type 1 Diabetes Model Mouse Pancreatic Islets. Acta Histochem Cytochem 2022; 55:47-56. [PMID: 35444351 PMCID: PMC8913275 DOI: 10.1267/ahc.21-00078] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/22/2021] [Indexed: 01/14/2023] Open
Abstract
Gamma-aminobutyric acid (GABA) is an inhibitory neurotransmitter in the mature brain; however, it acts excitatory during development. This difference in action depends on the intracellular chloride ion concentration, primarily regulated by potassium chloride co-transporter2 (KCC2). Sufficient KCC2 expression results in its inhibitory action. GABA is also abundant in pancreatic islets, where it acts differentially on the islet cells, and is involved in carbohydrate metabolism. However, the mechanisms underlying the differential action remain unknown. We performed immunohistochemistry for glutamic acid decarboxylase (GAD), a synthetic enzyme for GABA, and KCC2 in normal adult islets. GAD was co-localized with insulin in β cells, whereas KCC2 was expressed in glucagon-positive α cells. These results are in line with previous observations that GABA decreases glucagon release but increases insulin release, and suggest that GABA and insulin may work together in reducing blood glucose levels under hyperglycemia. Next, we examined the streptozotocin-induced type1 diabetes mellitus mouse model. GAD and insulin expression levels were markedly decreased. KCC2 was expressed in glucagon-positive cells, whereas insulin- and somatostatin-positive cells were KCC2-negative. These findings suggest that in diabetes model, reduced GABA release may cause disinhibition of glucagon release, resulting in increased blood sugar levels and the maintenance of hyperglycemic state.
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Affiliation(s)
| | - Shigeki Okada
- Department of Molecular Anatomy, School of Medicine, University of the Ryukyus
| | - Shiki Okamoto
- Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology School of Medicine, University of the Ryukyus
| | - Hiroaki Masuzaki
- Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology School of Medicine, University of the Ryukyus
| | - Chitoshi Takayama
- Department of Molecular Anatomy, School of Medicine, University of the Ryukyus
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Eguchi N, Toribio AJ, Alexander M, Xu I, Whaley DL, Hernandez LF, Dafoe D, Ichii H. Dysregulation of β-Cell Proliferation in Diabetes: Possibilities of Combination Therapy in the Development of a Comprehensive Treatment. Biomedicines 2022; 10:biomedicines10020472. [PMID: 35203680 PMCID: PMC8962301 DOI: 10.3390/biomedicines10020472] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/12/2022] [Accepted: 02/15/2022] [Indexed: 02/01/2023] Open
Abstract
Diabetes mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia as a result of insufficient insulin levels and/or impaired function as a result of autoimmune destruction or insulin resistance. While Type 1 DM (T1DM) and Type 2 DM (T2DM) occur through different pathological processes, both result in β-cell destruction and/or dysfunction, which ultimately lead to insufficient β-cell mass to maintain normoglycemia. Therefore, therapeutic agents capable of inducing β-cell proliferation is crucial in treating and reversing diabetes; unfortunately, adult human β-cell proliferation has been shown to be very limited (~0.2% of β-cells/24 h) and poorly responsive to many mitogens. Furthermore, diabetogenic insults result in damage to β cells, making it ever more difficult to induce proliferation. In this review, we discuss β-cell mass/proliferation pathways dysregulated in diabetes and current therapeutic agents studied to induce β-cell proliferation. Furthermore, we discuss possible combination therapies of proliferation agents with immunosuppressants and antioxidative therapy to improve overall long-term outcomes of diabetes.
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Moullé VS. Autonomic control of pancreatic beta cells: What is known on the regulation of insulin secretion and beta-cell proliferation in rodents and humans. Peptides 2022; 148:170709. [PMID: 34896576 DOI: 10.1016/j.peptides.2021.170709] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Revised: 11/17/2021] [Accepted: 12/07/2021] [Indexed: 11/21/2022]
Abstract
Insulin secretion and pancreatic beta-cell proliferation are tightly regulated by several signals such as hormones, nutrients, and neurotransmitters. However, the autonomic control of beta cells is not fully understood. In this review, we describe mechanisms involved in insulin secretion as well as metabolic and mitogenic actions on its target tissues. Since pancreatic islets are physically connected to the brain by nerves, parasympathetic and sympathetic neurotransmitters can directly potentiate or repress insulin secretion and beta-cell proliferation. Finally, we highlight the role of the autonomic nervous system in metabolic diseases such as diabetes and obesity.
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Endogenous Levels of Gamma Amino-Butyric Acid Are Correlated to Glutamic-Acid Decarboxylase Antibody Levels in Type 1 Diabetes. Biomedicines 2021; 10:biomedicines10010091. [PMID: 35052771 PMCID: PMC8773285 DOI: 10.3390/biomedicines10010091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/16/2021] [Accepted: 12/28/2021] [Indexed: 11/29/2022] Open
Abstract
Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. GABA is gaining increasing interest in diabetes research due to its immune-modulatory and beta-cell stimulatory effects and is a highly interesting drug candidate for the treatment of type 1 diabetes (T1D). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), one of the targets for autoantibodies linked to T1D. Using mass spectrometry, we have quantified the endogenous circulating levels of GABA in patients with new-onset and long-standing T1D and found that the levels are unaltered when compared to healthy controls, i.e., T1D patients do not have a deficit of systemic GABA levels. In T1D, GABA levels were negatively correlated with IL-1 beta, IL-12, and IL-15 15 and positively correlated to levels of IL-36 beta and IL-37. Interestingly, GABA levels were also correlated to the levels of GAD-autoantibodies. The unaltered levels of GABA in T1D patients suggest that the GABA secretion from beta-cells only has a minor impact on the circulating systemic levels. However, the local levels of GABA could be altered within pancreatic islets in the presence of GAD-autoantibodies.
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Espes D, Liljebäck H, Hill H, Elksnis A, Caballero-Corbalan J, Carlsson PO. GABA induces a hormonal counter-regulatory response in subjects with long-standing type 1 diabetes. BMJ Open Diabetes Res Care 2021; 9:9/1/e002442. [PMID: 34635547 PMCID: PMC8506884 DOI: 10.1136/bmjdrc-2021-002442] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Accepted: 09/29/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION Experimentally, gamma-aminobutyric acid (GABA) has been found to exert immune-modulatory effects and induce beta-cell regeneration, which make it a highly interesting substance candidate for the treatment of type 1 diabetes (T1D). In many countries, including those in the European Union, GABA is considered a pharmaceutical drug. We have therefore conducted a safety and dose escalation trial with the first controlled-release formulation of GABA, Remygen (Diamyd Medical). RESEARCH DESIGN AND METHODS Six adult male subjects with long-standing T1D (age 24.8±1.5 years, disease duration 14.7±2.2 years) were enrolled in an 11-day dose escalation trial with a controlled-release formulation of GABA, Remygen. Pharmacokinetics, glucose control and hormonal counter-regulatory response during hypoglycemic clamps were evaluated at every dose increase (200 mg, 600 mg and 1200 mg). RESULTS During the trial there were no serious and only a few, transient, adverse events reported. Without treatment, the counter-regulatory hormone response to hypoglycemia was severely blunted. Intake of 600 mg GABA more than doubled the glucagon, epinephrine, growth hormone and cortisol responses to hypoglycemia. CONCLUSIONS We find that the GABA treatment was well tolerated and established a counter-regulatory response to hypoglycemia in long-standing T1D. Further studies regarding not only the clinical potential of Remygen for beta-cell regeneration but also its potential use as hypoglycemic prophylaxis are warranted. TRAIL REGISTRATION NUMBER NCT03635437 and EudraCT2018-001115-73.
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Affiliation(s)
- Daniel Espes
- Department of Medical Cell Biology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Department of Medical Sciences, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Hanna Liljebäck
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Henrik Hill
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Andris Elksnis
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | | | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
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Fugaban JII, Vazquez Bucheli JE, Kim B, Holzapfel WH, Todorov SD. Safety and beneficial properties of bacteriocinogenic Pediococcus acidilactici and Pediococcus pentosaceus isolated from silage. Lett Appl Microbiol 2021; 73:725-734. [PMID: 34549812 DOI: 10.1111/lam.13562] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/28/2021] [Accepted: 09/15/2021] [Indexed: 10/20/2022]
Abstract
The control of Listeria monocytogenes is a relevant goal for dairy products, a process that begins from the supply of feed and management of animals' health. In the present study, we evaluated the safety of two bacteriocinogenic Pediococcus strains and show that both can be considered as safe, based on their haemolytic activity, biogenic amine production and antibiotic resistance, all evaluated through phenotypical and biomolecular approaches. Both strains have shown potential as a producer of γ-aminobutiric acid (GABA) and carry an incomplete set of genes related to folate biosynthesis; both strains were able to adhere to Caco-2 cell lines with adhesion rates of 6·59% ± 3·73 and 0·84% ± 0·48. Laboratory prepared clover silage, inoculated with each bacteriocinogenic Pediococcus strain and contaminated with L. monocytogenes, proved the hypothesis for bioprotective effect of the tested strains, with the tested pathogen eliminated in the first 24 h of the experiment. These results indicate that evaluated strains can be potential beneficial candidates for application in silage production.
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Affiliation(s)
- J I I Fugaban
- ProBacLab, Department of Advanced Convergence, Handong Global University, Pohang, Gyeongbuk, Republic of Korea
| | - J E Vazquez Bucheli
- ProBacLab, Department of Advanced Convergence, Handong Global University, Pohang, Gyeongbuk, Republic of Korea
| | - B Kim
- HEM Inc., Pohang, Gyungbuk, Republic of Korea
| | - W H Holzapfel
- ProBacLab, Department of Advanced Convergence, Handong Global University, Pohang, Gyeongbuk, Republic of Korea
| | - S D Todorov
- ProBacLab, Department of Advanced Convergence, Handong Global University, Pohang, Gyeongbuk, Republic of Korea
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Rezazadeh H, Sharifi MR, Soltani N. Insulin resistance and the role of gamma-aminobutyric acid. JOURNAL OF RESEARCH IN MEDICAL SCIENCES 2021; 26:39. [PMID: 34484371 PMCID: PMC8384006 DOI: 10.4103/jrms.jrms_374_20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 12/09/2020] [Accepted: 02/02/2021] [Indexed: 12/17/2022]
Abstract
Insulin resistance (IR) is mentioned to be a disorder in insulin ability in insulin-target tissues. Skeletal muscle (SkM) and liver function are more affected by IR than other insulin target cells. SkM is the main site for the consumption of ingested glucose. An effective treatment for IR has two properties: An inhibition of β-cell death and a promotion of β-cell replication. Gamma-aminobutyric acid (GABA) can improve beta-cell mass and function. Multiple studies have shown that GABA decreases IR probably via increase in glucose transporter 4 (GLUT4) gene expression and prevention of gluconeogenesis pathway in the liver. This review focused on the general aspects of IR in skeletal muscle (SkM), liver; the cellular mechanism(s) lead to the development of IR in these organs, and the role of GABA to reduce insulin resistance.
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Affiliation(s)
- Hossein Rezazadeh
- Department of Physiology, School of Medicine, Isfahan University of Medical Science, Isfahan Iran
| | - Mohammad Reza Sharifi
- Department of Physiology, School of Medicine, Isfahan University of Medical Science, Isfahan Iran
| | - Nepton Soltani
- Department of Physiology, School of Medicine, Isfahan University of Medical Science, Isfahan Iran
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Martínez MS, Manzano A, Olivar LC, Nava M, Salazar J, D’Marco L, Ortiz R, Chacín M, Guerrero-Wyss M, Cabrera de Bravo M, Cano C, Bermúdez V, Angarita L. The Role of the α Cell in the Pathogenesis of Diabetes: A World beyond the Mirror. Int J Mol Sci 2021; 22:9504. [PMID: 34502413 PMCID: PMC8431704 DOI: 10.3390/ijms22179504] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 08/26/2021] [Accepted: 08/26/2021] [Indexed: 12/11/2022] Open
Abstract
Type 2 Diabetes Mellitus (T2DM) is one of the most prevalent chronic metabolic disorders, and insulin has been placed at the epicentre of its pathophysiological basis. However, the involvement of impaired alpha (α) cell function has been recognized as playing an essential role in several diseases, since hyperglucagonemia has been evidenced in both Type 1 and T2DM. This phenomenon has been attributed to intra-islet defects, like modifications in pancreatic α cell mass or dysfunction in glucagon's secretion. Emerging evidence has shown that chronic hyperglycaemia provokes changes in the Langerhans' islets cytoarchitecture, including α cell hyperplasia, pancreatic beta (β) cell dedifferentiation into glucagon-positive producing cells, and loss of paracrine and endocrine regulation due to β cell mass loss. Other abnormalities like α cell insulin resistance, sensor machinery dysfunction, or paradoxical ATP-sensitive potassium channels (KATP) opening have also been linked to glucagon hypersecretion. Recent clinical trials in phases 1 or 2 have shown new molecules with glucagon-antagonist properties with considerable effectiveness and acceptable safety profiles. Glucagon-like peptide-1 (GLP-1) agonists and Dipeptidyl Peptidase-4 inhibitors (DPP-4 inhibitors) have been shown to decrease glucagon secretion in T2DM, and their possible therapeutic role in T1DM means they are attractive as an insulin-adjuvant therapy.
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Affiliation(s)
- María Sofía Martínez
- MedStar Health Internal Medicine, Georgetown University Affiliated, Baltimore, MD 21218-2829, USA;
| | - Alexander Manzano
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (A.M.); (L.C.O.); (M.N.); (J.S.); (C.C.)
| | - Luis Carlos Olivar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (A.M.); (L.C.O.); (M.N.); (J.S.); (C.C.)
| | - Manuel Nava
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (A.M.); (L.C.O.); (M.N.); (J.S.); (C.C.)
| | - Juan Salazar
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (A.M.); (L.C.O.); (M.N.); (J.S.); (C.C.)
| | - Luis D’Marco
- Department of Nephrology, Hospital Clinico Universitario de Valencia, INCLIVA, University of Valencia, 46010 Valencia, Spain;
| | - Rina Ortiz
- Facultad de Medicina, Universidad Católica de Cuenca, Ciudad de Cuenca, Azuay 010105, Ecuador;
| | - Maricarmen Chacín
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080022, Colombia; (M.C.); (V.B.)
| | - Marion Guerrero-Wyss
- Escuela de Nutrición y Dietética, Facultad de Ciencias Para el Cuidado de la Salud, Universidad San Sebastián, Valdivia 5090000, Chile;
| | | | - Clímaco Cano
- Endocrine and Metabolic Diseases Research Center, School of Medicine, Universidad del Zulia, Maracaibo 4002, Venezuela; (A.M.); (L.C.O.); (M.N.); (J.S.); (C.C.)
| | - Valmore Bermúdez
- Facultad de Ciencias de la Salud, Universidad Simón Bolívar, Barranquilla 080022, Colombia; (M.C.); (V.B.)
| | - Lisse Angarita
- Escuela de Nutrición y Dietética, Facultad de Medicina, Universidad Andres Bello, Sede Concepción 4260000, Chile
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Ghit A, Assal D, Al-Shami AS, Hussein DEE. GABA A receptors: structure, function, pharmacology, and related disorders. J Genet Eng Biotechnol 2021; 19:123. [PMID: 34417930 PMCID: PMC8380214 DOI: 10.1186/s43141-021-00224-0] [Citation(s) in RCA: 190] [Impact Index Per Article: 47.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/08/2021] [Indexed: 02/03/2023]
Abstract
Background γ-Aminobutyric acid sub-type A receptors (GABAARs) are the most prominent inhibitory neurotransmitter receptors in the CNS. They are a family of ligand-gated ion channel with significant physiological and therapeutic implications. Main body GABAARs are heteropentamers formed from a selection of 19 subunits: six α (alpha1-6), three β (beta1-3), three γ (gamma1-3), three ρ (rho1-3), and one each of the δ (delta), ε (epsilon), π (pi), and θ (theta) which result in the production of a considerable number of receptor isoforms. Each isoform exhibits distinct pharmacological and physiological properties. However, the majority of GABAARs are composed of two α subunits, two β subunits, and one γ subunit arranged as γ2β2α1β2α1 counterclockwise around the center. The mature receptor has a central chloride ion channel gated by GABA neurotransmitter and modulated by a variety of different drugs. Changes in GABA synthesis or release may have a significant effect on normal brain function. Furthermore, The molecular interactions and pharmacological effects caused by drugs are extremely complex. This is due to the structural heterogeneity of the receptors, and the existence of multiple allosteric binding sites as well as a wide range of ligands that can bind to them. Notably, dysfunction of the GABAergic system contributes to the development of several diseases. Therefore, understanding the relationship between GABAA receptor deficits and CNS disorders thus has a significant impact on the discovery of disease pathogenesis and drug development. Conclusion To date, few reviews have discussed GABAA receptors in detail. Accordingly, this review aims to summarize the current understanding of the structural, physiological, and pharmacological properties of GABAARs, as well as shedding light on the most common associated disorders.
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Affiliation(s)
- Amr Ghit
- Department of Biology and Biotechnology, University of Pavia, Pavia, Italy. .,Department of Biotechnology, Institute of Graduate Studies and Research (IGSR), Alexandria University, Alexandria, Egypt.
| | - Dina Assal
- Department of Biotechnology, American University in Cairo (AUC), Cairo, Egypt
| | - Ahmed S Al-Shami
- Department of Biotechnology, Institute of Graduate Studies and Research (IGSR), Alexandria University, Alexandria, Egypt.,Department of Zoology, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Diaa Eldin E Hussein
- Animal Health Research Institute (AHRI), Agricultural Research Center (ARC), Port of Alexandria, Alexandria, Egypt
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Szlapinski SK, Hill DJ. Metabolic Adaptations to Pregnancy in Healthy and Gestational Diabetic Pregnancies: The Pancreas - Placenta Axis. Curr Vasc Pharmacol 2021; 19:141-153. [PMID: 32196450 DOI: 10.2174/1570161118666200320111209] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 02/20/2020] [Accepted: 03/01/2020] [Indexed: 12/16/2022]
Abstract
Normal pregnancy is associated with increased insulin resistance as a metabolic adaptation to the nutritional demands of the placenta and fetus, and this is amplified in obese mothers. Insulin resistance is normally compensated for by an adaptive increase in pancreatic β-cell mass together with enhanced glucose-stimulated insulin release. Placentally-derived hormones and growth factors are central to the altered pancreatic morphology and function. A failure of β-cells to undergo adaptive change after the first trimester has been linked with gestational diabetes. In the pregnant mouse, an increase in β-cell replication contributes to a 2-3-fold increase in mass peaking in late gestation, depending on the proliferation of existing β-cells, the differentiation of resident progenitor β-cells, or islet cell transdifferentiation. Using mouse models and human studies placenta- and islet of Langerhans-derived molecules have been identified that are likely to contribute to the metabolic adaptations to pregnancy and whose physiology is altered in the obese, glucose-intolerant mother. Maternal obesity during pregnancy can create a pro-inflammatory environment that can disrupt the response of the β-cells to the endocrine signals of pregnancy and limit the adaptive changes in β-cell mass and function, resulting in an increased risk of gestational diabetes.
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Affiliation(s)
- Sandra K Szlapinski
- Lawson Health Research Institute, St. Joseph's Health Care, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada
| | - David J Hill
- Lawson Health Research Institute, St. Joseph's Health Care, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada
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31
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Tang C, Kong L, Shan M, Lu Z, Lu Y. Protective and ameliorating effects of probiotics against diet-induced obesity: A review. Food Res Int 2021; 147:110490. [PMID: 34399486 DOI: 10.1016/j.foodres.2021.110490] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 05/05/2021] [Accepted: 05/23/2021] [Indexed: 02/07/2023]
Abstract
Diet-induced obesity is one of the major public health concerns all over the world, and obesity also contributes to the development of other chronic diseases such as non-alcoholic fatty acid liver disease, type 2 diabetes mellitus and cardiovascular diseases. Evidence shows that the pathogenesis of obesity and obesity-associated chronic diseases are closely related to dysregulation of lipid metabolism, glucose metabolism and cholesterol metabolism, and oxidative stress, endoplasmic reticulum stress, abnormal gut microbiome and chronic low-grade inflammation. Recently, in view of potential effects on lipid metabolism, glucose metabolism, cholesterol metabolism and intestinal microbiome, as well as anti-oxidative and anti-inflammatory activities, natural probiotics, including live and dead probiotics, and probiotic components and metabolites, have attracted increasing attention and are considered as novel strategies for preventing and ameliorating obesity and obesity-related chronic diseases. Specifically, this review is presented on the anti-obesity effects of probiotics and underlying molecular mechanisms, which will provide a theoretical basis of anti-obesity probiotics for the development of functional foods.
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Affiliation(s)
- Chao Tang
- College of Food Science & Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Liangyu Kong
- College of Food Science & Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Mengyuan Shan
- College of Food Science & Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhaoxin Lu
- College of Food Science & Technology, Nanjing Agricultural University, Nanjing 210095, China.
| | - Yingjian Lu
- College of Food Science & Engineering, Nanjing University of Finance and Economics, Nanjing 210023, China.
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Bui TPN, de Vos WM. Next-generation therapeutic bacteria for treatment of obesity, diabetes, and other endocrine diseases. Best Pract Res Clin Endocrinol Metab 2021; 35:101504. [PMID: 33785319 DOI: 10.1016/j.beem.2021.101504] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The human gut microbiota has appeared as an important factor affecting host health and intestinal bacteria have recently emerged as potential therapeutics to treat diabetes and other endocrine diseases. These mainly anaerobic bacteria have been identified either via comparative "omics" analysis of the intestinal microbiota in healthy and diseased subjects or of data collected by fecal microbiota transplantation studies. Both approaches require advanced and in-depth sequencing technologies to perform massive genomic screening to select bacteria with potential benefits. It has been shown that these potentially therapeutic bacteria can either produce bioactive products that directly influence the host patho-physiology and endocrine systems or produce specific signaling molecules that may do so. These bioactive compounds can be formed via degradation of dietary or host-derived components or the conversion of intermediate compounds produced by fermentation of intestinal bacteria. Several of these bacteria have shown causality in preclinical models and entered clinical phase studies, while their mode of action is being analyzed. In this review, we summarize the research on the most promising bacterial candidates with therapeutic properties with a specific focus on diabetes.
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Affiliation(s)
- Thi Phuong Nam Bui
- Laboratory of Microbiology, Wageningen University, Stippeneng 4, 6708, WE, Wageningen, the Netherlands; Caelus Pharmaceuticals BV, 3474, KG, Zegveld, the Netherlands
| | - Willem M de Vos
- Laboratory of Microbiology, Wageningen University, Stippeneng 4, 6708, WE, Wageningen, the Netherlands; Human Microbiome Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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Jeong AH, Hwang J, Jo K, Kim S, Ahn Y, Suh HJ, Choi HS. Fermented Gamma Aminobutyric Acid Improves Sleep Behaviors in Fruit Flies and Rodent Models. Int J Mol Sci 2021; 22:3537. [PMID: 33805468 PMCID: PMC8036604 DOI: 10.3390/ijms22073537] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 03/20/2021] [Accepted: 03/25/2021] [Indexed: 01/05/2023] Open
Abstract
The aim of this study was to investigate the effect of Lactobacillus brevis-fermented γ-aminobutyric acid (LB-GABA) on sleep behaviors in invertebrate and vertebrate models. In Drosophila melanogaster, LB-GABA-treated group showed an 8-9%-longer sleep duration than normal group did. LB-GABA-treated group also showed a 46.7% lower level of nighttime activity with a longer (11%) sleep duration under caffeine-induced arousal conditions. The LB-GABA-mediated inhibition of activity was confirmed as a reduction of total movement of flies using a video tracking system. In the pentobarbital-induced sleep test in mice, LB-GABA (100 mg/kg) shortened the time of onset of sleep by 32.2% and extended sleeping time by 59%. In addition, mRNA and protein level of GABAergic/Serotonergic neurotransmitters were upregulated following treatment with LB-GABA (2.0%). In particular, intestine- and brain-derived GABAA protein levels were increased by sevenfold and fivefold, respectively. The electroencephalography (EEG) analysis in rats showed that LB-GABA significantly increased non-rapid eye movement (NREM) (53%) with the increase in theta (θ, 59%) and delta (δ, 63%) waves, leading to longer sleep time (35%), under caffeine-induced insomnia conditions. LB-GABA showed a dose-dependent agonist activity on human GABAA receptor with a half-maximal effective concentration (EC50) of 3.44 µg/mL in human embryonic kidney 293 (HEK293) cells.
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Affiliation(s)
- A-Hyun Jeong
- Department of Public Health Science, Korea University, Seoul 02841, Korea; (A.-H.J.); (J.H.); (K.J.); (S.K.); (Y.A.); (H.J.S.)
- Interdisciplinary Program in Precision Public Health, Korea University, Seoul 02841, Korea
| | - Jisu Hwang
- Department of Public Health Science, Korea University, Seoul 02841, Korea; (A.-H.J.); (J.H.); (K.J.); (S.K.); (Y.A.); (H.J.S.)
| | - Kyungae Jo
- Department of Public Health Science, Korea University, Seoul 02841, Korea; (A.-H.J.); (J.H.); (K.J.); (S.K.); (Y.A.); (H.J.S.)
| | - Singeun Kim
- Department of Public Health Science, Korea University, Seoul 02841, Korea; (A.-H.J.); (J.H.); (K.J.); (S.K.); (Y.A.); (H.J.S.)
| | - Yejin Ahn
- Department of Public Health Science, Korea University, Seoul 02841, Korea; (A.-H.J.); (J.H.); (K.J.); (S.K.); (Y.A.); (H.J.S.)
| | - Hyung Joo Suh
- Department of Public Health Science, Korea University, Seoul 02841, Korea; (A.-H.J.); (J.H.); (K.J.); (S.K.); (Y.A.); (H.J.S.)
| | - Hyeon-Son Choi
- Department of Food Nutrition, Sangmyung University, Seoul 03016, Korea
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GABA B-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice. Biomedicines 2021; 9:biomedicines9010043. [PMID: 33418884 PMCID: PMC7825043 DOI: 10.3390/biomedicines9010043] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/26/2020] [Accepted: 12/30/2020] [Indexed: 12/17/2022] Open
Abstract
Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABAA-Rs and/or GABAB-Rs). Treatment with GABA, which activates both GABAA-Rs and GABAB-Rs), and/or a GABAA-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABAB-Rs. Here, we tested lesogaberan, a peripherally restricted GABAB-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin+ cells, suggesting that lesogaberan helped to rapidly inhibit β-cell destruction. Hence, GABAB-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABAB-Rs and GABAA-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.
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Pöllänen PM, Ryhänen SJ, Toppari J, Ilonen J, Vähäsalo P, Veijola R, Siljander H, Knip M. Dynamics of Islet Autoantibodies During Prospective Follow-Up From Birth to Age 15 Years. J Clin Endocrinol Metab 2020; 105:5901133. [PMID: 32882033 PMCID: PMC7686032 DOI: 10.1210/clinem/dgaa624] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/31/2020] [Indexed: 01/23/2023]
Abstract
CONTEXT We set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). We also assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context. DESIGN HLA-predisposed children (N = 1006, 53.0% boys) recruited from the general population during 1994 to 1997 were observed from birth over a median time of 14.9 years (range, 1.9-15.5 years) for ZnT8A, islet cell (ICA), insulin (IAA), glutamate decarboxylase (GADA), and islet antigen-2 (IA-2A) antibodies, and for T1D. RESULTS By age 15.5 years, 35 (3.5%) children had progressed to T1D. Islet autoimmunity developed in 275 (27.3%) children at a median age of 7.4 years (range, 0.3-15.1 years). The ICA seroconversion rate increased toward puberty, but the biochemically defined autoantibodies peaked at a young age. Before age 2 years, ZnT8A and IAA appeared commonly as the first autoantibody, but in the preschool years IA-2A- and especially GADA-initiated autoimmunity increased. Thereafter, GADA-positive seroconversions continued to appear steadily until ages 10 to 15 years. Inverse IAA seroconversions occurred frequently (49.3% turned negative) and marked a prolonged delay from seroconversion to diagnosis compared to persistent IAA (8.2 vs 3.4 years; P = .01). CONCLUSIONS In HLA-predisposed children, the primary autoantibody is characteristic of age and might reflect the events driving the disease process toward clinical T1D. Autoantibody persistence affects the risk of T1D. These findings provide a framework for identifying disease subpopulations and for personalizing the efforts to predict and prevent T1D.
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Affiliation(s)
- Petra M Pöllänen
- Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Samppa J Ryhänen
- Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jorma Toppari
- Department of Pediatrics, Turku University Hospital, and Institute of Biomedicine and Centre for Population Health Research, University of Turku, Turku, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku and Clinical Microbiology, Turku University Hospital, Turku, Finland
| | - Paula Vähäsalo
- Department of Pediatrics, PEDEGO Research Group, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Riitta Veijola
- Department of Pediatrics, PEDEGO Research Group, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Heli Siljander
- Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Mikael Knip
- Pediatric Research Center, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
- Folkhälsan Research Center, Helsinki, Finland
- Correspondence and Reprint Requests: Mikael Knip, MD, PhD, Children’s Hospital, University of Helsinki, P.O. Box 22 (Stenbäckinkatu 11), FI-00014 Helsinki, Finland. E-mail:
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Herrema H, Niess JH. Intestinal microbial metabolites in human metabolism and type 2 diabetes. Diabetologia 2020; 63:2533-2547. [PMID: 32880688 PMCID: PMC7641949 DOI: 10.1007/s00125-020-05268-4] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 07/13/2020] [Indexed: 12/12/2022]
Abstract
Humans with the metabolic syndrome and type 2 diabetes have an altered gut microbiome. Emerging evidence indicates that it is not only the microorganisms and their structural components, but also their metabolites that influences the host and contributes to the development of the metabolic syndrome and type 2 diabetes. Here, we discuss some of the mechanisms underlying how microbial metabolites are recognised by the host or are further processed endogenously in the context of type 2 diabetes. We discuss the possibility that gut-derived microbial metabolites fuel the development of the metabolic syndrome and type 2 diabetes. Graphical abstract.
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Affiliation(s)
- Hilde Herrema
- Department of Experimental Vascular Medicine, Amsterdam University Medical Centers, Location AMC, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.
| | - Jan Hendrik Niess
- Department of Biomedicine, University of Basel, Hebelstrasse 20, CH-4031, Basel, Switzerland.
- University Center for Gastrointestinal and Liver Diseases, St Clara Hospital and University Hospital of Basel, Basel, Switzerland.
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Untereiner A, Xu J, Bhattacharjee A, Cabrera O, Hu C, Dai FF, Wheeler MB. γ-aminobutyric acid stimulates β-cell proliferation through the mTORC1/p70S6K pathway, an effect amplified by Ly49, a novel γ-aminobutyric acid type A receptor positive allosteric modulator. Diabetes Obes Metab 2020; 22:2021-2031. [PMID: 32558194 DOI: 10.1111/dom.14118] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/11/2020] [Accepted: 06/14/2020] [Indexed: 12/15/2022]
Abstract
AIM To examine the mechanism of action of γ-aminobutyric acid (GABA) on β-cell proliferation and investigate if co-treatment with Ly49, a novel GABA type A receptor positive allosteric modulator (GABAA -R PAM), amplifies this effect. METHODS Human or mouse islets were co-treated for 4-5 days with GABA and selected receptor or cell signalling pathway modulators. Immunofluorescence was used to determine protein co-localization, cell number or proliferation, and islet size. Osmotic minipumps were surgically implanted in mice to assess Ly49 effects on pancreatic β-cells. RESULTS Amplification of GABAA -R signalling enhanced GABA-stimulated β-cell proliferation in cultured mouse islets. Co-treatment of GABA with an inhibitor specific for PI3K, mTORC1/2, or p70S6K, abolished GABA-stimulated β-cell proliferation in mouse and human islets. Nuclear p-AktSer473 and p-p70S6KThr421/Ser424 expression in pancreatic β-cells was increased in GABA-treated mice compared with vehicle-treated mice, an effect augmented with GABA and Ly49 co-treatment. Mice co-treated with GABA and Ly49 exhibited enhanced β-cell area and proliferation compared with GABA-treated mice. Furthermore, S961 injection (an insulin receptor antagonist) resulted in enhanced plasma insulin in GABA and Ly49 co-treated mice compared with GABA-treated mice. Importantly, GABA co-treated with Ly49 increased β-cell proliferation in human islets providing a potential application for human subjects. CONCLUSIONS We show that GABA stimulates β-cell proliferation via the PI3K/mTORC1/p70S6K pathway in both mouse and human islets. Furthermore, we show that Ly49 enhances the β-cell regenerative effects of GABA, showing potential in the intervention of diabetes.
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Affiliation(s)
- Ashley Untereiner
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Jie Xu
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Alpana Bhattacharjee
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Over Cabrera
- Diabetes and Complications Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Key Clinical Center for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
- Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China
| | - Feihan F Dai
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Michael B Wheeler
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
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Regulated expression and function of the GABA B receptor in human pancreatic beta cell line and islets. Sci Rep 2020; 10:13469. [PMID: 32778664 PMCID: PMC7417582 DOI: 10.1038/s41598-020-69758-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 06/26/2020] [Indexed: 02/06/2023] Open
Abstract
G protein-coupled receptors are seven transmembrane signaling molecules that are involved in a wide variety of physiological processes. They constitute a large protein family of receptors with almost 300 members detected in human pancreatic islet preparations. However, the functional role of these receptors in pancreatic islets is unknown in most cases. We generated a new stable human beta cell line from neonatal pancreas. This cell line, named ECN90 expresses both subunits (GABBR1 and GABBR2) of the metabotropic GABAB receptor compared to human islet. In ECN90 cells, baclofen, a specific GABAB receptor agonist, inhibits cAMP signaling causing decreased expression of beta cell-specific genes such as MAFA and PCSK1, and reduced insulin secretion. We next demonstrated that in primary human islets, GABBR2 mRNA expression is strongly induced under cAMP signaling, while GABBR1 mRNA is constitutively expressed. We also found that induction and activation of the GABAB receptor in human islets modulates insulin secretion.
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Marquina-Sanchez B, Fortelny N, Farlik M, Vieira A, Collombat P, Bock C, Kubicek S. Single-cell RNA-seq with spike-in cells enables accurate quantification of cell-specific drug effects in pancreatic islets. Genome Biol 2020; 21:106. [PMID: 32375897 PMCID: PMC7201533 DOI: 10.1186/s13059-020-02006-2] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 03/27/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Single-cell RNA-seq (scRNA-seq) is emerging as a powerful tool to dissect cell-specific effects of drug treatment in complex tissues. This application requires high levels of precision, robustness, and quantitative accuracy-beyond those achievable with existing methods for mainly qualitative single-cell analysis. Here, we establish the use of standardized reference cells as spike-in controls for accurate and robust dissection of single-cell drug responses. RESULTS We find that contamination by cell-free RNA can constitute up to 20% of reads in human primary tissue samples, and we show that the ensuing biases can be removed effectively using a novel bioinformatics algorithm. Applying our method to both human and mouse pancreatic islets treated ex vivo, we obtain an accurate and quantitative assessment of cell-specific drug effects on the transcriptome. We observe that FOXO inhibition induces dedifferentiation of both alpha and beta cells, while artemether treatment upregulates insulin and other beta cell marker genes in a subset of alpha cells. In beta cells, dedifferentiation and insulin repression upon artemether treatment occurs predominantly in mouse but not in human samples. CONCLUSIONS This new method for quantitative, error-correcting, scRNA-seq data normalization using spike-in reference cells helps clarify complex cell-specific effects of pharmacological perturbations with single-cell resolution and high quantitative accuracy.
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Affiliation(s)
- Brenda Marquina-Sanchez
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria
| | - Nikolaus Fortelny
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria
| | - Matthias Farlik
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, 1090, Vienna, Austria
| | | | | | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria.
- Department of Laboratory Medicine, Medical University of Vienna, 1090, Vienna, Austria.
| | - Stefan Kubicek
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria.
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Korol SV, Jin Z, Birnir B. GABA A Receptor-Mediated Currents and Hormone mRNAs in Cells Expressing More Than One Hormone Transcript in Intact Human Pancreatic Islets. Int J Mol Sci 2020; 21:E600. [PMID: 31963438 PMCID: PMC7013858 DOI: 10.3390/ijms21020600] [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: 12/11/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 11/16/2022] Open
Abstract
In pancreatic islets, the major cell-types are α, β and δ cells. The γ-aminobutyric acid (GABA) signalling system is expressed in human pancreatic islets. In single hormone transcript-expressing cells, we have previously characterized the functional properties of islet GABAA receptors (iGABAARs). Here, we extended these studies to islet cells expressing mRNAs for more than one hormone and sought for correlation between iGABAAR activity level and relative mRNA expression ratio. The single-cell RT-PCR in combination with the patch-clamp current recordings was used to examine functional properties of iGABAARs in the multiple hormone mRNA-expressing cells. We detected cells expressing double (α/β, α/δ, β/δ cell-types) and triple (α/β/δ cell-type) hormone transcripts. The most common mixed-identity cell-type was the α/β group where the cells could be grouped into β- and α-like subgroups. The β-like cells had low GCG/INS expression ratio (<0.6) and significantly higher frequency of iGABAAR single-channel openings than the α-like cells where the GCG/INS expression ratio was high (>1.2). The hormone expression levels and iGABAAR single-channel characteristics varied in the α/β/δ cell-type. Clearly, multiple hormone transcripts can be expressed in islet cells whereas iGABAAR single-channel functional properties appear to be α or β cell specific.
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Affiliation(s)
- Sergiy V. Korol
- Department of Medical Cell Biology, Uppsala University, BMC, Box 593, 75124 Uppsala, Sweden; (Z.J.); (B.B.)
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Yi Z, Waseem Ghani M, Ghani H, Jiang W, Waseem Birmani M, Ye L, Bin L, Cun LG, Lilong A, Mei X. Gimmicks of gamma-aminobutyric acid (GABA) in pancreatic β-cell regeneration through transdifferentiation of pancreatic α- to β-cells. Cell Biol Int 2020; 44:926-936. [PMID: 31903671 DOI: 10.1002/cbin.11302] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 01/04/2020] [Indexed: 02/06/2023]
Abstract
In vivo regeneration of lost or dysfunctional islet β cells can fulfill the promise of improved therapy for diabetic patients. To achieve this, many mitogenic factors have been attempted, including gamma-aminobutyric acid (GABA). GABA remarkably affects pancreatic islet cells' (α cells and β cells) function through paracrine and/or autocrine binding to its membrane receptors on these cells. GABA has also been studied for promoting the transformation of α cells to β cells. Nonetheless, the gimmickry of GABA-induced α-cell transformation to β cells has two different perspectives. On the one hand, GABA was found to induce α-cell transformation to β cells in vivo and insulin-secreting β-like cells in vitro. On the other hand, GABA treatment showed that it has no α- to β-cell transformation response. Here, we will summarize the physiological effects of GABA on pancreatic islet β cells with an emphasis on its regenerative effects for transdifferentiation of islet α cells to β cells. We will also critically discuss the controversial results about GABA-mediated transdifferentiation of α cells to β cells.
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Affiliation(s)
- Zhao Yi
- Department of Animal Science and Medicine, Agricultural College, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China.,Department of Animal Breeding, Genetics and Reproduction, Agricultural Collage, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Muhammad Waseem Ghani
- Department of Animal Science and Medicine, Agricultural College, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China.,Department of Animal Breeding, Genetics and Reproduction, Agricultural Collage, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Hammad Ghani
- Nawaz Sharif Medical College, University of Gujrat, Punjab, 50180, Pakistan
| | - Wu Jiang
- Department of Animal Science and Medicine, Agricultural College, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China.,Department of Animal Breeding, Genetics and Reproduction, Agricultural Collage, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Muhammad Waseem Birmani
- Department of Animal Science and Medicine, Agricultural College, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Li Ye
- Department of Animal Science and Medicine, Agricultural College, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China.,Department of Animal Breeding, Genetics and Reproduction, Agricultural Collage, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Liu Bin
- Department of Animal Science and Medicine, Agricultural College, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China.,Department of Animal Breeding, Genetics and Reproduction, Agricultural Collage, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Lang Guan Cun
- Department of Animal Science and Medicine, Agricultural College, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China.,Department of Animal Breeding, Genetics and Reproduction, Agricultural Collage, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - An Lilong
- Department of Animal Science and Medicine, Agricultural College, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
| | - Xiao Mei
- Department of Animal Science and Medicine, Agricultural College, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China.,Department of Animal Breeding, Genetics and Reproduction, Agricultural Collage, Guangdong Ocean University, Zhanjiang, Guangdong, 524088, China
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Patterson E, Ryan PM, Wiley N, Carafa I, Sherwin E, Moloney G, Franciosi E, Mandal R, Wishart DS, Tuohy K, Ross RP, Cryan JF, Dinan TG, Stanton C. Gamma-aminobutyric acid-producing lactobacilli positively affect metabolism and depressive-like behaviour in a mouse model of metabolic syndrome. Sci Rep 2019; 9:16323. [PMID: 31704943 PMCID: PMC6841999 DOI: 10.1038/s41598-019-51781-x] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 09/20/2019] [Indexed: 12/22/2022] Open
Abstract
Metabolic and neuroactive metabolite production represents one of the mechanisms through which the gut microbiota can impact health. One such metabolite, gamma-aminobutyric acid (GABA), can modulate glucose homeostasis and alter behavioural patterns in the host. We previously demonstrated that oral administration of GABA-producing Lactobacillus brevis DPC6108 has the potential to increase levels of circulating insulin in healthy rats. Therefore, the objective of this study was to assess the efficacy of endogenous microbial GABA production in improving metabolic and behavioural outcomes in a mouse model of metabolic dysfunction. Diet-induced obese and metabolically dysfunctional mice received one of two GABA-producing strains, L. brevis DPC6108 or L. brevis DSM32386, daily for 12 weeks. After 8 and 10 weeks of intervention, the behavioural and metabolic profiles of the mice were respectively assessed. Intervention with both L. brevis strains attenuated several abnormalities associated with metabolic dysfunction, causing a reduction in the accumulation of mesenteric adipose tissue, increased insulin secretion following glucose challenge, improved plasma cholesterol clearance and reduced despair-like behaviour and basal corticosterone production during the forced swim test. Taken together, this exploratory dataset indicates that intervention with GABA-producing lactobacilli has the potential to improve metabolic and depressive- like behavioural abnormalities associated with metabolic syndrome in mice.
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Affiliation(s)
- E Patterson
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland
| | - P M Ryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland
| | - N Wiley
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland
| | - I Carafa
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland.,Department of Food Quality and Nutrition, Research and Innovation Centre-Fondazione Edmund Mach, San Michele all'Adige, Trento, Italy
| | - E Sherwin
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - G Moloney
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - E Franciosi
- Department of Food Quality and Nutrition, Research and Innovation Centre-Fondazione Edmund Mach, San Michele all'Adige, Trento, Italy
| | - R Mandal
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada
| | - D S Wishart
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.,Department of Computing Science, University of Alberta, Edmonton, Alberta, Canada.,National Institute for Nanotechnology, Edmonton, Alberta, Canada
| | - K Tuohy
- Department of Food Quality and Nutrition, Research and Innovation Centre-Fondazione Edmund Mach, San Michele all'Adige, Trento, Italy
| | - R P Ross
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - J F Cryan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - T G Dinan
- APC Microbiome Ireland, University College Cork, Cork, Ireland.,Department of Psychiatry and Neurobehavioural Science, University College Cork, Cork, Ireland
| | - C Stanton
- APC Microbiome Ireland, University College Cork, Cork, Ireland. .,Teagasc Food Research Centre, Moorepark, Fermoy, Cork, Ireland.
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Menegaz D, Hagan DW, Almaça J, Cianciaruso C, Rodriguez-Diaz R, Molina J, Dolan RM, Becker MW, Schwalie PC, Nano R, Lebreton F, Kang C, Sah R, Gaisano HY, Berggren PO, Baekkeskov S, Caicedo A, Phelps EA. Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell. Nat Metab 2019; 1:1110-1126. [PMID: 32432213 PMCID: PMC7236889 DOI: 10.1038/s42255-019-0135-7] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Accepted: 10/04/2019] [Indexed: 12/13/2022]
Abstract
Pancreatic beta cells synthesize and secrete the neurotransmitter γ-aminobutyric acid (GABA) as a paracrine and autocrine signal to help regulate hormone secretion and islet homeostasis. Islet GABA release has classically been described as a secretory vesicle-mediated event. Yet, a limitation of the hypothesized vesicular GABA release from islets is the lack of expression of a vesicular GABA transporter in beta cells. Consequentially, GABA accumulates in the cytosol. Here we provide evidence that the human beta cell effluxes GABA from a cytosolic pool in a pulsatile manner, imposing a synchronizing rhythm on pulsatile insulin secretion. The volume regulatory anion channel (VRAC), functionally encoded by LRRC8A or Swell1, is critical for pulsatile GABA secretion. GABA content in beta cells is depleted and secretion is disrupted in islets from type 1 and type 2 diabetic patients, suggesting that loss of GABA as a synchronizing signal for hormone output may correlate with diabetes pathogenesis.
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Affiliation(s)
- Danusa Menegaz
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - D Walker Hagan
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Joana Almaça
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Chiara Cianciaruso
- Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Rayner Rodriguez-Diaz
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Judith Molina
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Robert M Dolan
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Matthew W Becker
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA
| | - Petra C Schwalie
- Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
- Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Rita Nano
- Pancreatic Islet Processing Facility, Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fanny Lebreton
- Cell Isolation and Transplantation Center, Faculty of Medicine, Department of Surgery, Geneva University Hospitals and University of Geneva, Geneva, Switzerland
| | - Chen Kang
- Center for Cardiovascular Research and Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
| | - Rajan Sah
- Center for Cardiovascular Research and Division of Cardiology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, USA
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA
| | - Herbert Y Gaisano
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Per-Olof Berggren
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA
- The Rolf Luft Research Center for Diabetes & Endocrinology, Karolinska Institutet, Stockholm, Sweden
- Division of Integrative Biosciences and Biotechnology, WCU Program, University of Science and Technology, Pohang, Korea
| | - Steinunn Baekkeskov
- Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
- Departments of Medicine and Microbiology/Immunology, Diabetes Center, University of California San Francisco, San Francisco, CA, USA.
| | - Alejandro Caicedo
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
- Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
- Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, FL, USA.
- Program in Neuroscience, Miller School of Medicine, University of Miami, Miami, FL, USA.
| | - Edward A Phelps
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL, USA.
- Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
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Tian J, Dang H, O'Laco KA, Song M, Tiu BC, Gilles S, Zakarian C, Kaufman DL. Homotaurine Treatment Enhances CD4 + and CD8 + Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice. Immunohorizons 2019; 3:498-510. [PMID: 31636084 PMCID: PMC6823932 DOI: 10.4049/immunohorizons.1900019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 10/02/2019] [Indexed: 12/16/2022] Open
Abstract
Immune cells express γ-aminobutyric acid receptors (GABA-R), and GABA administration can inhibit effector T cell responses in models of autoimmune disease. The pharmacokinetic properties of GABA, however, may be suboptimal for clinical applications. The amino acid homotaurine is a type A GABA-R (GABAA-R) agonist with good pharmacokinetics and appears safe for human consumption. In this study, we show that homotaurine inhibits in vitro T cell proliferation to a similar degree as GABA but at lower concentrations. In vivo, oral homotaurine treatment had a modest ability to reverse hyperglycemia in newly hyperglycemic NOD mice but was ineffective after the onset of severe hyperglycemia. In severely diabetic NOD mice, the combination of homotaurine and low-dose anti-CD3 treatment significantly increased 1) disease remission, 2) the percentages of splenic CD4+and CD8+ regulatory T cells compared with anti-CD3 alone, and 3) the frequencies of CD4+ and CD8+ regulatory T cells in the pancreatic lymph nodes compared with homotaurine monotherapy. Histological examination of their pancreata provided no evidence of the large-scale GABAA-R agonist-mediated replenishment of islet β-cells that has been reported by others. However, we did observe a few functional islets in mice that received combined therapy. Thus, GABAA-R activation enhanced CD4+and CD8+ regulatory T cell responses following the depletion of effector T cells, which was associated with the preservation of some functional islets. Finally, we observed that homotaurine treatment enhanced β-cell replication and survival in a human islet xenograft model. Hence, GABAA-R agonists, such as homotaurine, are attractive candidates for testing in combination with other therapeutic agents in type 1 diabetes clinical trials.
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Affiliation(s)
- Jide Tian
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095
| | - Hoa Dang
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095
| | - Karen Anne O'Laco
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095
| | - Min Song
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095
| | - Bryan-Clement Tiu
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095
| | - Spencer Gilles
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095
| | - Christina Zakarian
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095
| | - Daniel L Kaufman
- Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095
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45
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Wang Q, Ren L, Wan Y, Prud'homme GJ. GABAergic regulation of pancreatic islet cells: Physiology and antidiabetic effects. J Cell Physiol 2019; 234:14432-14444. [PMID: 30693506 DOI: 10.1002/jcp.28214] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 01/15/2019] [Indexed: 01/24/2023]
Abstract
Diabetes occurs when pancreatic β-cell death exceeds β-cell growth, which leads to loss of β-cell mass. An effective therapy must have two actions: promotion of β-cell replication and suppression of β-cell death. Previous studies have established an important role for γ-aminobutyric acid (GABA) in islet-cell hormone homeostasis, as well as the maintenance of the β-cell mass. GABA exerts paracrine actions on α cells in suppressing glucagon secretion, and it has autocrine actions on β cells that increase insulin secretion. Multiple studies have shown that GABA increases the mitotic rate of β cells. In mice, following β-cell depletion with streptozotocin, GABA therapy can restore the β-cell mass. Enhanced β-cell replication appears to depend on growth and survival pathways involving Akt activation. Some studies have also suggested that it induces transdifferentiation of α cells into β cells, but this has been disputed and requires further investigation. In addition to proliferative effects, GABA protects β cells against injury and markedly reduces their apoptosis under a variety of conditions. The antiapoptotic effects depend at least in part on the enhancement of sirtuin-1 and Klotho activity, which both inhibit activation of the NF-κB inflammatory pathway. Importantly, in xenotransplanted human islets, GABA therapy stimulates β-cell replication and insulin secretion. Thus, the intraislet GABAergic system is a target for the amelioration of diabetes therapy, including β-cell survival and regeneration. GABA (or GABAergic drugs) can be combined with other antidiabetic drugs for greater effect.
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Affiliation(s)
- Qinghua Wang
- Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China.,Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Liwei Ren
- Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China
| | - Yun Wan
- Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China
| | - Gerald J Prud'homme
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.,Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
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46
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Son DO, Liu W, Li X, Prud'homme GJ, Wang Q. Combined effect of GABA and glucagon-like peptide-1 receptor agonist on cytokine-induced apoptosis in pancreatic β-cell line and isolated human islets. J Diabetes 2019; 11:563-572. [PMID: 30520247 DOI: 10.1111/1753-0407.12881] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 11/19/2018] [Accepted: 11/23/2018] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Treatment with GABA or glucagon-like peptide-1 (GLP-1) can preserve pancreatic β-cell mass and prevent diabetes. Recently, we reported that the combination of GABA and sitagliptin (a dipeptidyl peptidase-4 inhibitor that increases endogenous GLP-1) was more effective than either agent alone in reducing drug-induced β-cell damage and promoting β-cell regeneration in mice. However, in human islets, it remains unclear whether GABA and GLP-1 exert similar effects. METHODS To investigate GABA and GLP-1 interactions, human islets or INS-1 cells were treated with GABA and/or exendin-4, a GLP-1 receptor agonist (GLP-1RA) in clinical use, and incubated with a cytokine mixture for 24 hours. Cleaved caspase-3 and annexin V binding were measured by western blot and flow cytometry analysis, respectively, to investigate effects on cytokine-induced apoptosis. RESULTS Cytokine-induced apoptosis was reduced by either GABA or exendin-4 alone. This was markedly improved by combining GABA and exendin-4, resulting in a reversal of apoptosis. The combination notably increased Akt pathway signaling. Furthermore, sirtuin-1 (SIRT1) and α-Klotho, both reported to have protective effects on β-cells, were increased. Importantly, the combination ameliorated insulin secretion by human β-cells. CONCLUSIONS The combination of GABA and a GLP-1RA exerted additive effects on β-cell survival and function, suggesting that this combination may be superior to either drug alone in the treatment of diabetes.
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Affiliation(s)
- Dong Ok Son
- Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
- Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Canada
| | - Wenjuan Liu
- Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
- Department of Endocrinology, Huashan Hospital, Medical School, Fudan University, Shanghai, China
| | - Xiaoming Li
- Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
| | - Gerald J Prud'homme
- Department of Laboratory Medicine, St. Michael's Hospital, Toronto
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
| | - Qinghua Wang
- Division of Endocrinology and Metabolism, Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Canada
- Department of Endocrinology, Huashan Hospital, Medical School, Fudan University, Shanghai, China
- Department of Physiology, University of Toronto, Toronto, Canada
- Department of Medicine, University of Toronto, Toronto, Canada
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47
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Hata T, Rehman F, Hori T, Nguyen JH. GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury. J Surg Res 2019; 236:172-183. [PMID: 30694753 PMCID: PMC6420924 DOI: 10.1016/j.jss.2018.11.047] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 11/01/2018] [Accepted: 11/21/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND Acute liver failure (ALF) from severe acute liver injury is a critical condition associated with high mortality. The purpose of this study was to investigate the impact of preemptive administration of γ-aminobutyric acid (GABA) on hepatic injury and survival outcomes in mice with experimentally induced ALF. MATERIALS AND METHODS To induce ALF, C57BL/6NHsd mice were administered GABA, saline, or nothing for 7 d, followed by intraperitoneal administration of 500 μg of tumor necrosis factor α and 20 mg of D-galactosamine. The study mice were humanely euthanized 4-5 h after ALF was induced or observed for survival. Proteins present in the blood samples and liver tissue from the euthanized mice were analyzed using Western blot and immunohistochemical and histopathologic analyses. For inhibition studies, we administered the STAT3-specific inhibitor, NSC74859, 90 min before ALF induction. RESULTS We found that GABA-treated mice had substantial attenuation of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive hepatocytes and hepatocellular necrosis, decreased caspase-3, H2AX, and p38 MAPK protein levels and increased expressions of Jak2, STAT3, Bcl-2, and Mn-SOD, with improved mitochondrial integrity. The reduced apoptotic proteins led to a significantly prolonged survival after ALF induction in GABA-treated mice. The STAT3-specific inhibitor NSC74859 eliminated the survival advantage in GABA-treated mice with ALF, indicating the involvement of the STAT3 pathway in GABA-induced reduction in apoptosis. CONCLUSIONS Our results showed that preemptive treatment with GABA protected against severe acute liver injury in mice via GABA-mediated STAT3 signaling. Preemptive administration of GABA may be a useful approach to optimize marginal donor livers before transplantation.
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Affiliation(s)
- Toshiyuki Hata
- Department of Hepatobiliary-pancreatic and Transplant Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Fatima Rehman
- Department of Biology, University of North Florida, Jacksonville, Florida
| | - Tomohide Hori
- Department of Hepatobiliary-pancreatic and Transplant Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Justin H Nguyen
- Division of Transplant Surgery, Mayo Clinic, Jacksonville, Florida.
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Tian J, Dang H, Karashchuk N, Xu I, Kaufman DL. A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA's Ability to Inhibit Inflammatory T Cells. J Diabetes Res 2019; 2019:5783545. [PMID: 30937314 PMCID: PMC6413367 DOI: 10.1155/2019/5783545] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/04/2019] [Accepted: 01/09/2019] [Indexed: 12/19/2022] Open
Abstract
A major goal of T1D research is to develop new approaches to increase β-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote β-cell replication and survival, as well as inhibit autoreactive T cell responses. We previously showed that positive allosteric modulators (PAMs) of GABAA-Rs could promote rat β-cell line INS-1 and human islet cell replication in vitro. Here, we assessed whether treatment with alprazolam, a widely prescribed GABAA-R PAM, could promote β-cell survival and replication in human islets after implantation into NOD/scid mice. We observed that alprazolam treatment significantly reduced human islet cell apoptosis following transplantation and increased β-cell replication in the xenografts. Evidently, the GABAA-R PAM works in conjunction with GABA secreted from β-cells to increase β-cell survival and replication. Treatment with both the PAM and GABA further enhanced human β-cell replication. Alprazolam also augmented the ability of suboptimal doses of GABA to inhibit antigen-specific T cell responses in vitro. Thus, combined GABAA-R agonist and PAM treatment may help control inflammatory immune responses using reduced drug dosages. Together, these findings suggest that GABAA-R PAMs represent a promising drug class for safely modulating islet cells toward beneficial outcomes to help prevent or reverse T1D and, together with a GABAA-R agonist, may have broader applications for ameliorating other disorders in which inflammation contributes to the disease process.
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Affiliation(s)
- Jide Tian
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Hoa Dang
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Nataliya Karashchuk
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Irvin Xu
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
| | - Daniel L. Kaufman
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USA
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Zhong F, Jiang Y. Endogenous Pancreatic β Cell Regeneration: A Potential Strategy for the Recovery of β Cell Deficiency in Diabetes. Front Endocrinol (Lausanne) 2019; 10:101. [PMID: 30842756 PMCID: PMC6391341 DOI: 10.3389/fendo.2019.00101] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 02/04/2019] [Indexed: 12/11/2022] Open
Abstract
Endogenous pancreatic β cell regeneration is a potential strategy for β cell expansion or neogenesis to treat diabetes. Regeneration can occur through stimulation of existing β cell replication or conversion of other pancreatic cells into β cells. Recently, various strategies and approaches for stimulation of endogenous β cell regeneration have been evaluated, but they were not suitable for clinical application. In this paper, we comprehensively review these strategies, and further discuss various factors involved in regulation of β cell regeneration under physiological or pathological conditions, such as mediators, transcription factors, signaling pathways, and potential pharmaceutical drugs. Furthermore, we discuss possible reasons for the failure of regenerative medicines in clinical trials, and possible strategies for improving β cell regeneration. As β cell heterogeneity and plasticity determines their function and environmental adaptability, we focus on β cell subtype markers and discuss the importance of research evaluating the characteristics of new β cells. In addition, based on the autoimmunologic features of type 1 diabetes, NOD/Lt-SCID-IL2rg null (NSG) mice grafted with human immune cells and β cells are recommended for use in evaluation of antidiabetic regenerative medicines. This review will further understand current advances in endogenous β cell regeneration, and provide potential new strategies for the treatment of diabetes focused on cell therapy.
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Affiliation(s)
- Fan Zhong
- Department of Gastroenterology, Songjiang Hospital Affiliated First People's Hospital, Shanghai Jiao Tong University, Shanghai, China
- Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China
| | - Yan Jiang
- Institutes of Biomedical Sciences of Shanghai Medical College, Fudan University, Shanghai, China
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50
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Untereiner A, Abdo S, Bhattacharjee A, Gohil H, Pourasgari F, Ibeh N, Lai M, Batchuluun B, Wong A, Khuu N, Liu Y, Al Rijjal D, Winegarden N, Virtanen C, Orser BA, Cabrera O, Varga G, Rocheleau J, Dai FF, Wheeler MB. GABA promotes β-cell proliferation, but does not overcome impaired glucose homeostasis associated with diet-induced obesity. FASEB J 2018; 33:3968-3984. [PMID: 30509117 DOI: 10.1096/fj.201801397r] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
γ-Aminobutyric acid (GABA) administration has been shown to increase β-cell mass, leading to a reversal of type 1 diabetes in mice. Whether GABA has any effect on β cells of healthy and prediabetic/glucose-intolerant obese mice remains unknown. In the present study, we show that oral GABA administration ( ad libitum) to mice indeed increased pancreatic β-cell mass, which led to a modest enhancement in insulin secretion and glucose tolerance. However, GABA treatment did not further increase insulin-positive islet area in high fat diet-fed mice and was unable to prevent or reverse glucose intolerance and insulin resistance. Mechanistically, whether in vivo or in vitro, GABA treatment increased β-cell proliferation. In vitro, the effect was shown to be mediated via the GABAA receptor. Single-cell RNA sequencing analysis revealed that GABA preferentially up-regulated pathways linked to β-cell proliferation and simultaneously down-regulated those networks required for other processes, including insulin biosynthesis and metabolism. Interestingly, single-cell differential expression analysis revealed GABA treatment gave rise to a distinct subpopulation of β cells with a unique transcriptional signature, including urocortin 3 ( ucn3), wnt4, and hepacam2. Taken together, this study provides new mechanistic insight into the proliferative nature of GABA but suggests that β-cell compensation associated with prediabetes overlaps with, and negates, its proliferative effects.-Untereiner, A., Abdo, S., Bhattacharjee, A., Gohil, H., Pourasgari, F., Ibeh, N., Lai, M., Batchuluun, B., Wong, A., Khuu, N., Liu, Y., Al Rijjal, D., Winegarden, N., Virtanen, C., Orser, B. A., Cabrera, O., Varga, G., Rocheleau, J., Dai, F. F., Wheeler, M. B. GABA promotes β-cell proliferation, but does not overcome impaired glucose homeostasis associated with diet-induced obesity.
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Affiliation(s)
- Ashley Untereiner
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Shaaban Abdo
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Alpana Bhattacharjee
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Himaben Gohil
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | | | - Neke Ibeh
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Mi Lai
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | | | - Anthony Wong
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Nicholas Khuu
- Princess Margaret Genomics Centre, University Health Network, Toronto, Ontario, Canada
| | - Ying Liu
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Dana Al Rijjal
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Neil Winegarden
- Princess Margaret Genomics Centre, University Health Network, Toronto, Ontario, Canada
| | - Carl Virtanen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Beverley A Orser
- Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada
| | - Over Cabrera
- Diabetes and Complications Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
| | - Gabor Varga
- Diabetes and Complications Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA
| | - Jonathan Rocheleau
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Feihan F Dai
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Michael B Wheeler
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
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