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Henriksen K, Jørgensen A, Kaur S, Gerwig R, Brøgger Svane CA, Knop FK, Størling J. Exploring the functional, protective, and transcriptomic effects of GIP on cytokine-exposed human pancreatic islets and EndoC-βH5 cells. Mol Cell Endocrinol 2025; 602:112522. [PMID: 40122442 DOI: 10.1016/j.mce.2025.112522] [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: 10/24/2024] [Revised: 02/03/2025] [Accepted: 03/14/2025] [Indexed: 03/25/2025]
Abstract
Immune-mediated beta-cell destruction and lack of alpha-cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects, as well as its cytoprotective effects shown in rodent beta cells. To further increase our understanding of GIP's effects on human beta cells, we here examined the functional, protective, and transcriptomic effects of GIP in human EndoC-βH5 beta cells and isolated human islets in the presence or absence of proinflammatory cytokines (interferon (IFN)-γ ± interleukin (IL)-1β) as a mimic of type 1 diabetes. GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-βH5 cells and increased insulin and glucagon secretion from human islets at high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-βH5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis in EndoC-βH5 cells or human islets, and GIP did not protect against cytokine-induced functional impairment in EndoC-βH5 cells. GIP treatment of human islets for 24 h had no effects on the transcriptome and did not modulate cytokine-induced transcriptional changes. However, GIP augmented IL-1β + IFNγ-induced secretion of interleukin (IL)-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-βH5 cells, GIP reduced IFN-γ-induced secretion of tumor necrosis factor (TNF)-α, IL-2, IL-6, and IL-10 but increased the secretion of CXCL8, CCL2, CCL4, and CCL11. In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our findings indicate that GIP neither exerts cytoprotective effects against cytokines nor modulate the transcriptome of human islets. GIP may, however, exert selective modulatory effects on secreted inflammatory factors from cytokine-exposed beta cells and islets.
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Affiliation(s)
- Kristine Henriksen
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Anne Jørgensen
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Simranjeet Kaur
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Rebekka Gerwig
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Cecilie Amalie Brøgger Svane
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Joachim Størling
- Translational Type 1 Diabetes Research, Department of Clinical and Translational Research, Steno Diabetes Center Copenhagen, Herlev, Denmark; Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Moo EV, Møller TC, Sørensen FA, Inoue A, Bräuner‐Osborne H. Arrestin-independent internalization of the GLP-1 receptor is facilitated by a GRK, clathrin, and caveolae-dependent mechanism. FEBS J 2025; 292:1675-1695. [PMID: 39756024 PMCID: PMC11970717 DOI: 10.1111/febs.17338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 07/04/2024] [Accepted: 11/19/2024] [Indexed: 01/07/2025]
Abstract
The glucagon-like peptide-1 receptor (GLP-1R) plays an important role in regulating insulin secretion and reducing body weight, making it a prominent target in the treatment of type 2 diabetes and obesity. Extensive research on GLP-1R signaling has provided insights into the connection between receptor function and physiological outcomes, such as the correlation between Gs signaling and insulin secretion, yet the exact mechanisms regulating signaling remain unclear. Here, we explore the internalization pathway of GLP-1R, which is crucial for controlling insulin release and maintaining pancreatic beta-cell function. Utilizing a reliable and sensitive time-resolved fluorescence resonance energy transfer (TR-FRET) internalization assay, combined with HEK293-derived knockout cell lines, we were able to directly compare the involvement of different endocytic machinery in GLP-1R internalization. Our findings indicate that the receptor internalizes independently of arrestin and is dependent on Gs and Gi/o activation and G protein-coupled receptor kinase phosphorylation. Mechanistically, we observed that the receptor undergoes distinct clathrin- and caveolae-mediated internalization in HEK293 cells. This study also investigated the role of arrestins in GLP-1R function and regulation. These insights into key endocytic components that are involved in the GLP-1R internalization pathway could enhance the rational design of GLP-1R therapeutics for type 2 diabetes and other GLP-1R-related diseases.
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Affiliation(s)
- Ee Von Moo
- Department of Drug Design and PharmacologyUniversity of CopenhagenDenmark
| | | | | | - Asuka Inoue
- Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
- Graduate School of Pharmaceutical SciencesKyoto UniversityJapan
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Kashio M. Thermosensitive TRPM2: The regulatory mechanisms of its temperature sensitivity and physiological functions. J Physiol Sci 2025; 75:100008. [PMID: 39919606 PMCID: PMC11979660 DOI: 10.1016/j.jphyss.2025.100008] [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: 08/30/2024] [Accepted: 01/25/2025] [Indexed: 02/09/2025]
Abstract
Transient receptor potential melastatin 2 (TRPM2) is a non-selective cation channel with high Ca2+ permeability. TRPM2 exhibits temperature sensitivity, detecting warm to noxious high temperatures. This temperature sensitivity is regulated by several endogenous factors, including reactive oxygen species, adenosine diphosphate ribose, Ca2+ ions, and TRPM2 phosphorylation by protein kinase C, which alter TRPM2 activity at body temperature. Consequently, at core body temperature, TRPM2 regulates the physiological functions of TRPM2-expressing cells and tissues, such as immunocytes, pancreatic β cells, and the brain. In contrast, TRPM2 in sensory neurons detects warm temperatures. The current review summarizes the regulatory mechanisms of TRPM2 and its roles in physiological processes, focusing on temperature-dependent phenomena.
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Affiliation(s)
- Makiko Kashio
- Department of Cell Physiology, Faculty of Life Sciences, Kumamoto University, Japan.
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4
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Ma Y, Zhang H, Yan Q, Wang P, Guo W, Yu L. The antidiabetic effect of safflower yellow by regulating the GOAT/ghrelin/GHS-R1a/cAMP/TRPM2 pathway. Sci Rep 2025; 15:5037. [PMID: 39934157 PMCID: PMC11814266 DOI: 10.1038/s41598-025-87201-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 01/16/2025] [Indexed: 02/13/2025] Open
Abstract
Safflower yellow (SY), derived from Carthamus tinctorius L., is a valuable natural edible pigment that exhibits anti-type 2 diabetes mellitus (T2DM) efficacy; however, its mechanism of action is unclear, which hinders its effective use. In this study, we examined the impact of SY on glucose metabolism and insulin secretion both in vivo and in vitro and elucidated the possible underlying mechanism. First, molecular docking demonstrated a strong binding affinity between SY and ghrelin O-acyltransferase (GOAT) protein, which was validated by a cell heat transfer assay (CETSA) and drug affinity response target stability (DARTS) in MIN6 cells. In MIN6 cells, SY increased insulin secretion and showed time- and dose-dependent inhibition of GOAT expression and acyl ghrelin (AG) secretion without affecting the overall levels of ghrelin. Furthermore, ELISA revealed that SY enhanced high glucose (HG)-induced insulin secretion, and immunofluorescence revealed the co-localization of GOAT and ghrelin in MIN6 cells, which was suppressed by SY treatment. The mechanism analysis by Western blot demonstrated that SY downregulated the protein levels of GOAT and GHS-R1a in MIN6 cells while increasing HG-stimulated cAMP and activation of transient receptor potential melastatin 2 (TRPM2). In in vivo experiments, the intraperitoneal injection of SY significantly improved pathological damage to the pancreas, glucose tolerance, and insulin resistance in a mouse model of high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM in a dose-dependent manner. SY enhanced insulin secretion by inhibiting the GOAT/ghrelin system in vivo. In conclusion, we demonstrated that SY exhibits an observable protective effect on diabetes through the GOAT/ghrelin/GHS-R1a/cAMP/TRPM2 pathway. Our findings provide a basis for further investigation of the hypoglycemic mechanism of SY and its potential for further development and utilization.
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Affiliation(s)
- Yunxiao Ma
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China
| | - Haifeng Zhang
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China
| | - Qihui Yan
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China
| | - Ping Wang
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China
| | - Weiying Guo
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China.
| | - Lu Yu
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China.
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Wu Y, Wang H, Xu H. Autophagy-lysosome pathway in insulin & glucagon homeostasis. Front Endocrinol (Lausanne) 2025; 16:1541794. [PMID: 39996055 PMCID: PMC11847700 DOI: 10.3389/fendo.2025.1541794] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 01/22/2025] [Indexed: 02/26/2025] Open
Abstract
Lysosome, a highly dynamic organelle, is an important nutrient sensing center. They utilize different ion channels and transporters to complete the mission in degradation, trafficking, nutrient sensing and integration of various metabolic pathways to maintain cellular homeostasis. Glucose homeostasis relies on tightly regulated insulin secretion by pancreatic β cells, and their dysfunction is a hallmark of type 2 diabetes. Glucagon also plays an important role in hyperglycemia in diabetic patients. Currently, lysosome has been recognized as a nutrient hub to regulate the homeostasis of insulin and other hormones. In this review, we will discuss recent advances in understanding lysosome-mediated autophagy and lysosomal proteins involved in maintaining insulin and glucagon homeostasis, as well as their contributions to the etiology of diabetes.
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Affiliation(s)
- Yi Wu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
- Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, China
- Shanghai Key Laboratory of Molecular Imaging, School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Hui Wang
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
| | - Huoyan Xu
- School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai, China
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Jabůrek M, Klöppel E, Průchová P, Mozheitova O, Tauber J, Engstová H, Ježek P. Mitochondria to plasma membrane redox signaling is essential for fatty acid β-oxidation-driven insulin secretion. Redox Biol 2024; 75:103283. [PMID: 39067330 PMCID: PMC11332078 DOI: 10.1016/j.redox.2024.103283] [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: 07/17/2024] [Revised: 07/22/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024] Open
Abstract
We asked whether acute redox signaling from mitochondria exists concomitantly to fatty acid- (FA-) stimulated insulin secretion (FASIS) at low glucose by pancreatic β-cells. We show that FA β-oxidation produces superoxide/H2O2, providing: i) mitochondria-to-plasma-membrane redox signaling, closing KATP-channels synergically with elevated ATP (substituting NADPH-oxidase-4-mediated H2O2-signaling upon glucose-stimulated insulin secretion); ii) activation of redox-sensitive phospholipase iPLA2γ/PNPLA8, cleaving mitochondrial FAs, enabling metabotropic GPR40 receptors to amplify insulin secretion (IS). At fasting glucose, palmitic acid stimulated IS in wt mice; palmitic, stearic, lauric, oleic, linoleic, and hexanoic acids also in perifused pancreatic islets (PIs), with suppressed 1st phases in iPLA2γ/PNPLA8-knockout mice/PIs. Extracellular/cytosolic H2O2-monitoring indicated knockout-independent redox signals, blocked by mitochondrial antioxidant SkQ1, etomoxir, CPT1 silencing, and catalase overexpression, all inhibiting FASIS, keeping ATP-sensitive K+-channels open, and diminishing cytosolic [Ca2+]-oscillations. FASIS in mice was a postprandially delayed physiological event. Redox signals of FA β-oxidation are thus documented, reaching the plasma membrane, essentially co-stimulating IS.
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Affiliation(s)
- Martin Jabůrek
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic
| | - Eduardo Klöppel
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic
| | - Pavla Průchová
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic
| | - Oleksandra Mozheitova
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic
| | - Jan Tauber
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic
| | - Hana Engstová
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic
| | - Petr Ježek
- Department of Mitochondrial Physiology, No.75, Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, Prague, 14220, Czech Republic.
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7
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Ježek P, Dlasková A, Engstová H, Špačková J, Tauber J, Průchová P, Kloppel E, Mozheitova O, Jabůrek M. Mitochondrial Physiology of Cellular Redox Regulations. Physiol Res 2024; 73:S217-S242. [PMID: 38647168 PMCID: PMC11412358 DOI: 10.33549/physiolres.935269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024] Open
Abstract
Mitochondria (mt) represent the vital hub of the molecular physiology of the cell, being decision-makers in cell life/death and information signaling, including major redox regulations and redox signaling. Now we review recent advances in understanding mitochondrial redox homeostasis, including superoxide sources and H2O2 consumers, i.e., antioxidant mechanisms, as well as exemplar situations of physiological redox signaling, including the intramitochondrial one and mt-to-cytosol redox signals, which may be classified as acute and long-term signals. This review exemplifies the acute redox signals in hypoxic cell adaptation and upon insulin secretion in pancreatic beta-cells. We also show how metabolic changes under these circumstances are linked to mitochondrial cristae narrowing at higher intensity of ATP synthesis. Also, we will discuss major redox buffers, namely the peroxiredoxin system, which may also promote redox signaling. We will point out that pathological thresholds exist, specific for each cell type, above which the superoxide sources exceed regular antioxidant capacity and the concomitant harmful processes of oxidative stress subsequently initiate etiology of numerous diseases. The redox signaling may be impaired when sunk in such excessive pro-oxidative state.
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Affiliation(s)
- P Ježek
- Laboratory of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
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8
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Dave BP, Chorawala MR, Shah IV, Shah NN, Bhagat SU, Prajapati BG, Thakkar PC. From diabetes to diverse domains: the multifaceted roles of GLP-1 receptor agonists. Mol Biol Rep 2024; 51:835. [PMID: 39042283 DOI: 10.1007/s11033-024-09793-y] [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: 04/14/2024] [Accepted: 07/09/2024] [Indexed: 07/24/2024]
Abstract
Glucagon-like Peptide-1 (GLP-1) receptor agonists (GLP-1RAs) emerged as a primary treatment for type-2 diabetes mellitus (T2DM), however, their multifaceted effects on various target organs beyond glycemic control opened a new era of treatment. We conducted a comprehensive literature search using databases including Scopus, Google Scholar, PubMed, and the Cochrane Library to identify clinical, in-vivo, and in-vitro studies focusing on the diverse effects of GLP-1 receptor agonists. Eligible studies were selected based on their relevance to the varied roles of GLP-1RAs in T2DM management and their impact on other physiological functions. Numerous studies have reported the efficacy of GLP-1RAs in improving outcomes in T2DM, with demonstrated benefits including glucose-dependent insulinotropic actions, modulation of insulin signaling pathways, and reductions in glycemic excursions. Additionally, GLP-1 receptors are expressed in various tissues and organs, suggesting their widespread physiological functions beyond glycemic control potentially include neuroprotective, anti-inflammatory, cardioprotective, and metabolic benefits. However, further scientific studies are still underway to maximize the benefits of GLP-1RAs and to discover additional roles in improving health benefits. This article sought to review not only the actions of GLP1RAs in the treatment of T2DM but also explore its effects on potential targets in other disorders.
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Affiliation(s)
- Bhavarth P Dave
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Ishika V Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Nidhi N Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Shivam U Bhagat
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, Gujarat, 380009, India
| | - Bhupendra G Prajapati
- Department of Pharmaceutics and Pharmaceutical Technology, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Mehsana, Gujarat, India.
- Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 73000, Thailand.
| | - Pratik C Thakkar
- Department of Physiology, Faculty of Medical & Health Sciences, Manaaki Mānawa - The Centre for Heart Research, University of Auckland, 85 Park Road, Auckland, 1142, New Zealand.
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Benzi A, Heine M, Spinelli S, Salis A, Worthmann A, Diercks B, Astigiano C, Pérez Mato R, Memushaj A, Sturla L, Vellone V, Damonte G, Jaeckstein MY, Koch-Nolte F, Mittrücker HW, Guse AH, De Flora A, Heeren J, Bruzzone S. The TRPM2 ion channel regulates metabolic and thermogenic adaptations in adipose tissue of cold-exposed mice. Front Endocrinol (Lausanne) 2024; 14:1251351. [PMID: 38390373 PMCID: PMC10882718 DOI: 10.3389/fendo.2023.1251351] [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: 07/01/2023] [Accepted: 11/16/2023] [Indexed: 02/24/2024] Open
Abstract
Introduction During thermogenesis, adipose tissue (AT) becomes more active and enhances oxidative metabolism. The promotion of this process in white AT (WAT) is called "browning" and, together with the brown AT (BAT) activation, is considered as a promising approach to counteract obesity and metabolic diseases. Transient receptor potential cation channel, subfamily M, member 2 (TRPM2), is an ion channel that allows extracellular Ca2+ influx into the cytosol, and is gated by adenosine diphosphate ribose (ADPR), produced from NAD+ degradation. The aim of this study was to investigate the relevance of TRPM2 in the regulation of energy metabolism in BAT, WAT, and liver during thermogenesis. Methods Wild type (WT) and Trpm2-/- mice were exposed to 6°C and BAT, WAT and liver were collected to evaluate mRNA, protein levels and ADPR content. Furthermore, O2 consumption, CO2 production and energy expenditure were measured in these mice upon thermogenic stimulation. Finally, the effect of the pharmacological inhibition of TRPM2 was assessed in primary adipocytes, evaluating the response upon stimulation with the β-adrenergic receptor agonist CL316,243. Results Trpm2-/- mice displayed lower expression of browning markers in AT and lower energy expenditure in response to thermogenic stimulus, compared to WT animals. Trpm2 gene overexpression was observed in WAT, BAT and liver upon cold exposure. In addition, ADPR levels and mono/poly-ADPR hydrolases expression were higher in mice exposed to cold, compared to control mice, likely mediating ADPR generation. Discussion Our data indicate TRPM2 as a fundamental player in BAT activation and WAT browning. TRPM2 agonists may represent new pharmacological strategies to fight obesity.
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Affiliation(s)
- Andrea Benzi
- Department of Experimental Medicine-Section of Biochemistry, University of Genova, Genova, Italy
| | - Markus Heine
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sonia Spinelli
- Laboratory of Molecular Nephrology, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Annalisa Salis
- Department of Experimental Medicine-Section of Biochemistry, University of Genova, Genova, Italy
| | - Anna Worthmann
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Björn Diercks
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Cecilia Astigiano
- Department of Experimental Medicine-Section of Biochemistry, University of Genova, Genova, Italy
| | - Raúl Pérez Mato
- Department of Experimental Medicine-Section of Biochemistry, University of Genova, Genova, Italy
| | - Adela Memushaj
- Department of Experimental Medicine-Section of Biochemistry, University of Genova, Genova, Italy
| | - Laura Sturla
- Department of Experimental Medicine-Section of Biochemistry, University of Genova, Genova, Italy
| | - Valerio Vellone
- Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genoa, Genova, Italy
- Pathology Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Gianluca Damonte
- Department of Experimental Medicine-Section of Biochemistry, University of Genova, Genova, Italy
| | - Michelle Y Jaeckstein
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Friedrich Koch-Nolte
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hans-Willi Mittrücker
- Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Guse
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Antonio De Flora
- Department of Experimental Medicine-Section of Biochemistry, University of Genova, Genova, Italy
| | - Joerg Heeren
- Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Santina Bruzzone
- Department of Experimental Medicine-Section of Biochemistry, University of Genova, Genova, Italy
- IRCCS Ospedale Policlinico San Martino, Genova, Italy
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Paradiž Leitgeb E, Kerčmar J, Križančić Bombek L, Pohorec V, Skelin Klemen M, Slak Rupnik M, Gosak M, Dolenšek J, Stožer A. Exendin-4 affects calcium signalling predominantly during activation and activity of beta cell networks in acute mouse pancreas tissue slices. Front Endocrinol (Lausanne) 2024; 14:1315520. [PMID: 38292770 PMCID: PMC10826511 DOI: 10.3389/fendo.2023.1315520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 12/22/2023] [Indexed: 02/01/2024] Open
Abstract
Tight control of beta cell stimulus-secretion coupling is crucial for maintaining homeostasis of energy-rich nutrients. While glucose serves as a primary regulator of this process, incretins augment beta cell function, partly by enhancing cytosolic [Ca2+] dynamics. However, the details of how precisely they affect beta cell recruitment during activation, their active time, and functional connectivity during plateau activity, and how they influence beta cell deactivation remain to be described. Performing functional multicellular Ca2+ imaging in acute mouse pancreas tissue slices enabled us to systematically assess the effects of the GLP-1 receptor agonist exendin-4 (Ex-4) simultaneously in many coupled beta cells with high resolution. In otherwise substimulatory glucose, Ex-4 was able to recruit approximately a quarter of beta cells into an active state. Costimulation with Ex-4 and stimulatory glucose shortened the activation delays and accelerated beta cell activation dynamics. More specifically, active time increased faster, and the time required to reach half-maximal activation was effectively halved in the presence of Ex-4. Moreover, the active time and regularity of [Ca2+]IC oscillations increased, especially during the first part of beta cell response. In contrast, subsequent addition of Ex-4 to already active cells did not significantly enhance beta cell activity. Network analyses further confirmed increased connectivity during activation and activity in the presence of Ex-4, with hub cell roles remaining rather stable in both control experiments and experiments with Ex-4. Interestingly, Ex-4 demonstrated a biphasic effect on deactivation, slightly prolonging beta cell activity at physiological concentrations and shortening deactivation delays at supraphysiological concentrations. In sum, costimulation by Ex-4 and glucose increases [Ca2+]IC during beta cell activation and activity, indicating that the effect of incretins may, to an important extent, be explained by enhanced [Ca2+]IC signals. During deactivation, previous incretin stimulation does not critically prolong cellular activity, which corroborates their low risk of hypoglycemia.
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Affiliation(s)
- Eva Paradiž Leitgeb
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Jasmina Kerčmar
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | | | - Vilijem Pohorec
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Maša Skelin Klemen
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Marjan Slak Rupnik
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
- Alma Mater Europaea-European Center Maribor, Maribor, Slovenia
| | - Marko Gosak
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Alma Mater Europaea-European Center Maribor, Maribor, Slovenia
- Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
| | - Jurij Dolenšek
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
- Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia
| | - Andraž Stožer
- Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia
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11
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Folli F, Finzi G, Manfrini R, Galli A, Casiraghi F, Centofanti L, Berra C, Fiorina P, Davalli A, La Rosa S, Perego C, Higgins PB. Mechanisms of action of incretin receptor based dual- and tri-agonists in pancreatic islets. Am J Physiol Endocrinol Metab 2023; 325:E595-E609. [PMID: 37729025 PMCID: PMC10874655 DOI: 10.1152/ajpendo.00236.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/15/2023] [Accepted: 09/16/2023] [Indexed: 09/22/2023]
Abstract
Simultaneous activation of the incretin G-protein-coupled receptors (GPCRs) via unimolecular dual-receptor agonists (UDRA) has emerged as a new therapeutic approach for type 2 diabetes. Recent studies also advocate triple agonism with molecules also capable of binding the glucagon receptor. In this scoping review, we discuss the cellular mechanisms of action (MOA) underlying the actions of these novel and therapeutically important classes of peptide receptor agonists. Clinical efficacy studies of several UDRAs have demonstrated favorable results both as monotherapies and when combined with approved hypoglycemics. Although the additive insulinotropic effects of dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic peptide receptor (GIPR) agonism were anticipated based on the known actions of either glucagon-like peptide-1 (GLP-1) or glucose-dependent insulinotropic peptide (GIP) alone, the additional benefits from GCGR were largely unexpected. Whether additional synergistic or antagonistic interactions among these G-protein receptor signaling pathways arise from simultaneous stimulation is not known. The signaling pathways affected by dual- and tri-agonism require more trenchant investigation before a comprehensive understanding of the cellular MOA. This knowledge will be essential for understanding the chronic efficacy and safety of these treatments.
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Affiliation(s)
- Franco Folli
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
- Unit of Diabetes, Endocrinology and Metabolism, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Giovanna Finzi
- Unit of Pathology, Department of Oncology, ASST Sette Laghi, Varese, Italy
| | - Roberto Manfrini
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
- Unit of Diabetes, Endocrinology and Metabolism, San Paolo Hospital, ASST Santi Paolo e Carlo, Milan, Italy
| | - Alessandra Galli
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Francesca Casiraghi
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
| | - Lucia Centofanti
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, Milan, Italy
| | - Cesare Berra
- IRCCS MultiMedica, Sesto San Giovanni, Milan, Italy
| | - Paolo Fiorina
- International Center for T1D, Pediatric Clinical Research Center Romeo ed Enrica Invernizzi, DIBIC, Università di Milano, Milan, Italy
- Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
- Division of Endocrinology, ASST Fatebenefratelli-Sacco, Milan, Italy
| | - Alberto Davalli
- Diabetes and Endocrinology Unit, Department of Internal Medicine, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano La Rosa
- Unit of Pathology, Department of Medicine and Technological Innovation, University of Insubria, Varese, Italy
| | - Carla Perego
- Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy
| | - Paul B Higgins
- Department of Life & Physical Sciences, Atlantic Technological University, Letterkenny, Ireland
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12
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Ježek P. Pitfalls of Mitochondrial Redox Signaling Research. Antioxidants (Basel) 2023; 12:1696. [PMID: 37759999 PMCID: PMC10525995 DOI: 10.3390/antiox12091696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 08/27/2023] [Accepted: 08/29/2023] [Indexed: 09/29/2023] Open
Abstract
Redox signaling from mitochondria (mt) to the cytosol and plasma membrane (PM) has been scarcely reported, such as in the case of hypoxic cell adaptation or (2-oxo-) 2-keto-isocaproate (KIC) β-like-oxidation stimulating insulin secretion in pancreatic β-cells. Mutual redox state influence between mitochondrial major compartments, the matrix and the intracristal space, and the cytosol is therefore derived theoretically in this article to predict possible conditions, when mt-to-cytosol and mt-to-PM signals may occur, as well as conditions in which the cytosolic redox signaling is not overwhelmed by the mitochondrial antioxidant capacity. Possible peroxiredoxin 3 participation in mt-to-cytosol redox signaling is discussed, as well as another specific case, whereby mitochondrial superoxide release is diminished, whereas the matrix MnSOD is activated. As a result, the enhanced conversion to H2O2 allows H2O2 diffusion into the cytosol, where it could be a predominant component of the H2O2 release. In both of these ways, mt-to-cytosol and mt-to-PM signals may be realized. Finally, the use of redox-sensitive probes is discussed, which disturb redox equilibria, and hence add a surplus redox-buffering to the compartment, where they are localized. Specifically, when attempts to quantify net H2O2 fluxes are to be made, this should be taken into account.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, No. 75, Institute of Physiology of the Czech Academy of Sciences, Vídeňská 1083, 14220 Prague, Czech Republic
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13
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Yamada H, Yoshida M, Funazaki S, Morimoto J, Tonezawa S, Takahashi A, Nagashima S, Masahiko K, Kiyoshi O, Hara K. Retrospective Analysis of the Effectiveness of Oral Semaglutide in Type 2 Diabetes Mellitus and Its Effect on Cardiometabolic Parameters in Japanese Clinical Settings. J Cardiovasc Dev Dis 2023; 10:jcdd10040176. [PMID: 37103055 PMCID: PMC10141082 DOI: 10.3390/jcdd10040176] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/09/2023] [Accepted: 04/16/2023] [Indexed: 04/28/2023] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RA) have a more potent glycated hemoglobin (HbA1c)-lowering effect than existing therapies and are widely used for treating type 2 diabetes mellitus (T2DM). Once-daily oral semaglutide is the world's first oral GLP-1RA. This study aimed to provide real-world data on oral semaglutide in Japanese patients with T2DM and its effects on cardiometabolic parameters. This was a single-center retrospective observational study. We examined changes in HbA1c and body weight (BW) and the rate of achieving HbA1c < 7% after 6 months of oral semaglutide treatment in Japanese patients with T2DM. Furthermore, we examined differences in the efficacy of oral semaglutide with multiple patient backgrounds. A total of 88 patients were included in this study. Overall, the mean (standard error of the mean) HbA1c at 6 months decreased by -1.24% (0.20%) from baseline, and BW at 6 months (n = 85) also decreased by -1.44 kg (0.26 kg) from baseline. The percentage of patients who achieved HbA1c < 7% changed significantly from 14% at baseline to 48%. HbA1c decreased from baseline regardless of age, sex, body mass index, chronic kidney disease, or diabetes duration. Additionally, alanine aminotransferase, total cholesterol, triglyceride, and non-high-density lipoprotein cholesterol were significantly reduced from baseline. Oral semaglutide may be an effective option for the intensification of therapy in Japanese patients with T2DM who have inadequate glycemic control with existing therapy. It may also reduce BW and improve cardiometabolic parameters.
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Affiliation(s)
- Hodaka Yamada
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Masashi Yoshida
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Shunsuke Funazaki
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Jun Morimoto
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Shiori Tonezawa
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Asuka Takahashi
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Shuichi Nagashima
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Kimura Masahiko
- Department of Pharmacy, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Otsuka Kiyoshi
- Department of Pharmacy, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
| | - Kazuo Hara
- Department of Medicine, Division of Endocrinology and Metabolism, Jichi Medical University Saitama Medical Center, 1-847 Amanuma-cho, Omiya-ku, Saitama 330-8503, Japan
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14
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Zhang XM, Song Y, Zhu XY, Wang WJ, Fan XL, El-Aziz TMA. MITOCHONDRIA: The dual function of the transient receptor potential melastatin 2 channels from cytomembrane to mitochondria. Int J Biochem Cell Biol 2023; 157:106374. [PMID: 36708986 DOI: 10.1016/j.biocel.2023.106374] [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: 09/16/2022] [Revised: 12/20/2022] [Accepted: 01/24/2023] [Indexed: 01/26/2023]
Abstract
Mitochondria are closely related to oxidative stress and play an important role in maintaining cell functional homeostasis and meeting cell energy demand. The transient receptor potential melastatin 2 (TRPM2) channel affects the occurrence and progression of diseases by regulating mitochondrial function. TRPM2 channel promotes Ca2+ influx to affect 18 kDa translocator protein (TSPO), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), adenosine triphosphate (ATP) production, and mitochondrial autophagy. The mechanism of Ca2+ influx into the mitochondria by TRPM2 is abundant. Interestingly, the TRPM2 channel inhibits the production of mitochondrial ROS in cancer cells and promotes the production of mitochondrial ROS in normal cells, which induces cell death in normal cells but proliferation in cancer cells. TRPM2 can be a potential target for the treatment of various diseases due to its role as a molecular link between mitochondria and Ca2+ signals.
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Affiliation(s)
- Xiao-Min Zhang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Ying Song
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China.
| | - Xin-Yi Zhu
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Wen-Jun Wang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Xu-Li Fan
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang 310014, China
| | - Tarek Mohamed Abd El-Aziz
- Department of Cellular and Integrative Physiology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, USA; Zoology Department, Faculty of Science, Minia University, El-Minia 61519, Egypt.
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15
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Pan Y, Liu J, Ren J, Luo Y, Sun X. Epac: A Promising Therapeutic Target for Vascular Diseases: A Review. Front Pharmacol 2022; 13:929152. [PMID: 35910387 PMCID: PMC9330031 DOI: 10.3389/fphar.2022.929152] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 06/14/2022] [Indexed: 11/13/2022] Open
Abstract
Vascular diseases affect the circulatory system and comprise most human diseases. They cause severe symptoms and affect the quality of life of patients. Recently, since their identification, exchange proteins directly activated by cAMP (Epac) have attracted increasing scientific interest, because of their role in cyclic adenosine monophosphate (cAMP) signaling, a well-known signal transduction pathway. The role of Epac in cardiovascular disease and cancer is extensively studied, whereas their role in kidney disease has not been comprehensively explored yet. In this study, we aimed to review recent studies on the regulatory effects of Epac on various vascular diseases, such as cardiovascular disease, cerebrovascular disease, and cancer. Accumulating evidence has shown that both Epac1 and Epac2 play important roles in vascular diseases under both physiological and pathological conditions. Additionally, there has been an increasing focus on Epac pharmacological modulators. Therefore, we speculated that Epac could serve as a novel therapeutic target for the treatment of vascular diseases.
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Affiliation(s)
- Yunfeng Pan
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Jia Liu
- Guizhou University of Traditional Chinese Medicine, Guiyang, China
| | - Jiahui Ren
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Yun Luo
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing, China
| | - Xiaobo Sun
- Key Laboratory of Bioactive Substances and Resources Utilization of Chinese Herbal Medicine, Ministry of Education, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Beijing, China
- Key Laboratory of Efficacy Evaluation of Chinese Medicine Against Glycolipid Metabolic Disorders, State Administration of Traditional Chinese Medicine, Beijing, China
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16
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Carvacrol protects the ARPE19 retinal pigment epithelial cells against high glucose-induced oxidative stress, apoptosis, and inflammation by suppressing the TRPM2 channel signaling pathways. Graefes Arch Clin Exp Ophthalmol 2022; 260:2567-2583. [PMID: 35704089 DOI: 10.1007/s00417-022-05731-5] [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: 02/05/2022] [Revised: 05/20/2022] [Accepted: 06/07/2022] [Indexed: 11/04/2022] Open
Abstract
PURPOSE The concentration of plasma high glucose (HGu) in diabetes mellitus (DM) induces the retinal pigment epithelial cell (ARPE19) death via the increase of inflammation, cytosolic (cytROS), and mitochondrial (mitROS) free oxygen radical generations. Transient potential melastatin 2 (TRPM2) cation channel is stimulated by cytROS and mitROS. Hence, the cytROS and mitROS-mediated excessive Ca2+ influxes via the stimulation of TRPM2 channel cause to the induction of DM-mediated retina oxidative cytotoxicity. Because of the antioxidant role of carvacrol (CRV), it may modulate oxidative cytotoxicity via the attenuation of TRPM2 in the ARPE19. We aimed to investigate the modulator action of CRV treatment on the HGu-mediated TRPM2 stimulation, oxidative stress, and apoptosis in the ARPE19 cell model. MATERIAL AND METHODS The ARPE19 cells were divided into four groups as normal glucose (NGu), NGu + Carv, HGu, and HGu + CRV. RESULTS The levels of cell death (propidium iodide/Hoechst rate) and apoptosis markers (caspases 3, 8, and 9), cytokine generations (IL-1β and TNF-α), ROS productions (cytROS, mitROS, and lipid peroxidation), TRPM2 currents, and intracellular free Ca2+ (Fluo/3) were increased in the HGu group after the stimulations of hydrogen peroxide and ADP-ribose, although their levels were diminished via upregulation of glutathione and glutathione peroxidase by the treatments of CRV and TRPM2 blockers. CONCLUSION Current results confirmed that the HGu-induced overload Ca2+ influx and oxidative retinal toxicity in the ARPE19 cells were induced by the stimulation of TRPM2, although they were modulated via the inhibition of TRPM2 by CRV. CRV may be noted as a potential therapeutic antioxidant to the TRPM2 activation-mediated retinal oxidative injury.
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17
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Ježek P, Holendová B, Jabůrek M, Dlasková A, Plecitá-Hlavatá L. Contribution of Mitochondria to Insulin Secretion by Various Secretagogues. Antioxid Redox Signal 2022; 36:920-952. [PMID: 34180254 PMCID: PMC9125579 DOI: 10.1089/ars.2021.0113] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Significance: Mitochondria determine glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells by elevating ATP synthesis. As the metabolic and redox hub, mitochondria provide numerous links to the plasma membrane channels, insulin granule vesicles (IGVs), cell redox, NADH, NADPH, and Ca2+ homeostasis, all affecting insulin secretion. Recent Advances: Mitochondrial redox signaling was implicated in several modes of insulin secretion (branched-chain ketoacid [BCKA]-, fatty acid [FA]-stimulated). Mitochondrial Ca2+ influx was found to enhance GSIS, reflecting cytosolic Ca2+ oscillations induced by action potential spikes (intermittent opening of voltage-dependent Ca2+ and K+ channels) or the superimposed Ca2+ release from the endoplasmic reticulum (ER). The ATPase inhibitory factor 1 (IF1) was reported to tune the glucose sensitivity range for GSIS. Mitochondrial protein kinase A was implicated in preventing the IF1-mediated inhibition of the ATP synthase. Critical Issues: It is unknown how the redox signal spreads up to the plasma membrane and what its targets are, what the differences in metabolic, redox, NADH/NADPH, and Ca2+ signaling, and homeostasis are between the first and second GSIS phase, and whether mitochondria can replace ER in the amplification of IGV exocytosis. Future Directions: Metabolomics studies performed to distinguish between the mitochondrial matrix and cytosolic metabolites will elucidate further details. Identifying the targets of cell signaling into mitochondria and of mitochondrial retrograde metabolic and redox signals to the cell will uncover further molecular mechanisms for insulin secretion stimulated by glucose, BCKAs, and FAs, and the amplification of secretion by glucagon-like peptide (GLP-1) and metabotropic receptors. They will identify the distinction between the hub β-cells and their followers in intact and diabetic states. Antioxid. Redox Signal. 36, 920-952.
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Affiliation(s)
- Petr Ježek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Blanka Holendová
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Martin Jabůrek
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Andrea Dlasková
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Lydie Plecitá-Hlavatá
- Department of Mitochondrial Physiology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
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18
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Liu Y, Lyu Y, Wang H. TRP Channels as Molecular Targets to Relieve Endocrine-Related Diseases. Front Mol Biosci 2022; 9:895814. [PMID: 35573736 PMCID: PMC9095829 DOI: 10.3389/fmolb.2022.895814] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 03/28/2022] [Indexed: 12/03/2022] Open
Abstract
Transient receptor potential (TRP) channels are polymodal channels capable of sensing environmental stimuli, which are widely expressed on the plasma membrane of cells and play an essential role in the physiological or pathological processes of cells as sensors. TRPs often form functional homo- or heterotetramers that act as cation channels to flow Na+ and Ca2+, change membrane potential and [Ca2+]i (cytosolic [Ca2+]), and change protein expression levels, channel attributes, and regulatory factors. Under normal circumstances, various TRP channels respond to intracellular and extracellular stimuli such as temperature, pH, osmotic pressure, chemicals, cytokines, and cell damage and depletion of Ca2+ reserves. As cation transport channels and physical and chemical stimulation receptors, TRPs play an important role in regulating secretion, interfering with cell proliferation, and affecting neural activity in these glands and their adenocarcinoma cells. Many studies have proved that TRPs are widely distributed in the pancreas, adrenal gland, and other glands. This article reviews the specific regulatory mechanisms of various TRP channels in some common glands (pancreas, salivary gland, lacrimal gland, adrenal gland, mammary gland, gallbladder, and sweat gland).
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19
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Oba-Yamamoto C, Takeuchi J, Nakamura A, Nomoto H, Kameda H, Cho KY, Atsumi T, Miyoshi H. Impact of low-starch high-fiber pasta on postprandial blood glucose. Nutr Metab Cardiovasc Dis 2022; 32:487-493. [PMID: 34893415 DOI: 10.1016/j.numecd.2021.10.019] [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: 04/01/2021] [Revised: 10/21/2021] [Accepted: 10/24/2021] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND AIMS Almost all of the energy in noodle dishes is derived from carbohydrates, particularly starch. Recently, we invented a pasta with reduced starch content to about 50% and increased dietary fiber content, designated low-starch high-fiber pasta (LSHFP). In this study, we investigated the ingestion of LSHFP on the postprandial glucose response as a breakfast meal. METHODS AND RESULT This was a randomized, single-blinded, crossover study. The postprandial glucose area under the curve for 4 h (4h-gluAUC), as the primary outcome, and the extent of postprandial glucose elevation (maxΔBG) were evaluated using a continuous glucose monitoring system in healthy volunteers and patients with type 2 diabetes (T2DM) after intake of LSHFP, standard pasta (SP), and rice. The amount of total carbohydrate was matched between LSHFP and SP. Ten individuals with T2DM and 10 individuals who did not have T2DM and were otherwise healthy were enrolled in this crossover study. The 4h-gluAUC for LSHFP (137.6 ± 42.2 mg/dL・h) was significantly smaller than the 4h-gluAUC for rice (201.7 ± 38.7 mg/dL・h) (p = 0.001) and SP (178.5 ± 59.2 mg/dL・h) (p = 0.020). The maxΔBG for rice (118.6 ± 24.2 mg/dL) was significantly higher than those for SP (87.5 ± 19.9 mg/dL) (p < 0.001) and LSHFP (72.7 ± 26.2 mg/dL) (p = 0.001), while the maxΔBG for LSHFP (p = 0.047) was significantly lower than that for SP, in T2DM patients as well as in healthy participants. CONCLUSIONS This study demonstrated that LSHFP can reduce postprandial glucose elevation compared with SP in both healthy participants and patients with T2DM.
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Affiliation(s)
| | - Jun Takeuchi
- Sapporo Diabetes and Thyroid Clinic, Sapporo, Japan
| | - Akinobu Nakamura
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiroshi Nomoto
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hiraku Kameda
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Kyu Y Cho
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Tatsuya Atsumi
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Hideaki Miyoshi
- Department of Rheumatology, Endocrinology, and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan; Division of Diabetes and Obesity, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
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20
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Funazaki S, Yoshida M, Yamada H, Kakei M, Kawakami M, Nagashima S, Hara K, Dezaki K. A novel mechanism of imeglimin-mediated insulin secretion via the cADPR-TRP channel pathway. J Diabetes Investig 2022; 13:34-41. [PMID: 34523242 PMCID: PMC8756313 DOI: 10.1111/jdi.13669] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 09/02/2021] [Accepted: 09/12/2021] [Indexed: 01/20/2023] Open
Abstract
AIMS/INTRODUCTION Imeglimin is a novel oral hypoglycemic agent that improves blood glucose levels through multiple mechanisms of action including the enhancement of glucose-stimulated insulin secretion (GSIS), however, the details of this mechanism have not been clarified. In the process of GSIS, activation of the transient receptor potential melastatin 2 (TRPM2) channel, a type of non-selective cation channel (NSCCs) in β-cells, promotes plasma membrane depolarization. The present study aimed to examine whether imeglimin potentiates GSIS via the TRPM2 channel in β-cells. MATERIALS AND METHODS Pancreatic islets were isolated by collagenase digestion from male wild-type and TRPM2-knockout (KO) mice. Insulin release and nicotinamide adenine dinucleotide (NAD+ ) production in islets were measured under static incubation. NSCC currents in mouse single β-cells were measured by patch-clamp experiments. RESULTS Batch-incubation studies showed that imeglimin enhanced GSIS at stimulatory 16.6 mM glucose, whereas it did not affect basal insulin levels at 2.8 mM glucose. Imeglimin increased the glucose-induced production of NAD+ , a precursor of cADPR, in islets and the insulinotropic effects of imeglimin were attenuated by a cADPR inhibitor 8-Br-cADPR. Furthermore, imeglimin increased NSCC current in β-cells, and abolished this current in TRPM2-KO mice. Imeglimin did not potentiate GSIS in the TRPM2-KO islets, suggesting that imeglimin's increase of NSCC currents through the TRPM2 channel is causally implicated in its insulin releasing effects. CONCLUSIONS Imeglimin may activate TRPM2 channels in β-cells via the production of NAD+ /cADPR, leading to the potentiation of GSIS. Developing approaches to stimulate cADPR-TRPM2 signaling provides a potential therapeutic tool to treat type 2 diabetes.
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Affiliation(s)
- Shunsuke Funazaki
- Department of MedicineDivision of Endocrinology and MetabolismJichi Medical University Saitama Medical CenterSaitamaJapan
| | - Masashi Yoshida
- Department of MedicineDivision of Endocrinology and MetabolismJichi Medical University Saitama Medical CenterSaitamaJapan
| | - Hodaka Yamada
- Department of MedicineDivision of Endocrinology and MetabolismJichi Medical University Saitama Medical CenterSaitamaJapan
| | - Masafumi Kakei
- Department of MedicineDivision of Endocrinology and MetabolismJichi Medical University Saitama Medical CenterSaitamaJapan
| | - Masanobu Kawakami
- Department of MedicineDivision of Endocrinology and MetabolismJichi Medical University Saitama Medical CenterSaitamaJapan
| | - Shuichi Nagashima
- Department of MedicineDivision of Endocrinology and MetabolismJichi Medical University Saitama Medical CenterSaitamaJapan
| | - Kazuo Hara
- Department of MedicineDivision of Endocrinology and MetabolismJichi Medical University Saitama Medical CenterSaitamaJapan
| | - Katsuya Dezaki
- Department of PhysiologyDivision of Integrative PhysiologyJichi Medical UniversityShimotsuke‐shiJapan
- Faculty of PharmacyIryo Sosei UniversityIwakiJapan
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21
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Sanni O, Terre'Blanche G. Therapeutic potentials of agonist and antagonist of adenosine receptors in type 2 diabetes. Rev Endocr Metab Disord 2021; 22:1073-1090. [PMID: 34165671 DOI: 10.1007/s11154-021-09668-8] [Citation(s) in RCA: 5] [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] [Accepted: 06/21/2021] [Indexed: 10/21/2022]
Abstract
Type 2 diabetes has been a global health challenge over the decades and is among the leading causes of death. Several treatment approaches have been developed, but more effective and new therapies are still needed. The role of adenosine in glucose and lipid homeostasis has offered a different therapeutic approach. Adenosine mediates its physiological role through the activation of adenosine receptors. These adenosine receptors have been implicated in glucose and lipid homeostasis. The ability of agonists and antagonists of adenosine receptors to activate or inhibit the adenosine signalling cascade and thereby affecting the balance of glucose and lipid homeostasis has challenged the studies of agonists and antagonists of adenosine receptors, both preclinical and clinical, as potential anti-diabetic drugs. This review provides a background on different anti-diabetic therapeutic approaches, outlining the role of adenosine receptors in glucose and lipid homeostasis, and mechanisms underlying the action of agonists/antagonists of adenosine receptors as a therapeutic potential towards type 2 diabetes.
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Affiliation(s)
- Olakunle Sanni
- Centre of Excellence for Pharmaceutical Sciences (Pharmacen), School of Health Sciences. North-West University (NWU), Potchefstroom, 2357, South Africa.
| | - G Terre'Blanche
- Centre of Excellence for Pharmaceutical Sciences (Pharmacen), School of Health Sciences. North-West University (NWU), Potchefstroom, 2357, South Africa
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22
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Jøns C, Porta-Sánchez A, Lai PFH, Wauchop M, Massé S, Azam MA, Asta J, Rose RA, Nanthakumar K. Mechanism of and strategy to mitigate liraglutide-mediated positive chronotropy. Life Sci 2021; 282:119815. [PMID: 34256040 DOI: 10.1016/j.lfs.2021.119815] [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: 04/14/2021] [Revised: 06/25/2021] [Accepted: 07/05/2021] [Indexed: 11/18/2022]
Abstract
AIM An adverse side-effect of Liraglutide (LG), a Glucagon-Like Peptide 1 (GLP1)-analog commonly used in treatments for diabetes, is positive chronotropy. The goal of this study is to investigate on the mechanism of this drug-induced chronotropy and explore potential means to mitigate this side-effect so as to maximize the therapeutic benefits from LG. MAIN METHODS Experiments were conducted with: 1) Isolated rabbit hearts in a Langendorff set-up to assess for direct effects of drug actions and 2) Murine cardiomyocytes isolated from the sino-atrial node (SAN) to assess the effects of LG on spontaneous action potential (AP) firing and the hyperpolarization-activated current If. KEY FINDINGS LG induced a dose-dependent increase in heart rate. Its effects on sinus node automaticity, which were not suppressed during β-blockade with Propranolol, were abolished by If blockade with Ivabradine. In isolated murine SAN myocytes, LG increased spontaneous AP firing frequency by an increase in diastolic depolarization slope without changing other electrophysiological parameters. SIGNIFICANCE LG-induced positive chronotropy is partly due to a direct effect on the SAN and is independent of the adrenergic cascade and extrinsic autonomic reflex mechanisms. The direct LG-associated increase in heart rate should be mitigated with If blockers rather than β-blockade.
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Affiliation(s)
- Christian Jøns
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, Ontario, Canada; Department of Cardiology, The Heart Centre, Rigshospitalet, Copenhagen, Denmark
| | - Andreu Porta-Sánchez
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, Ontario, Canada; Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain and Hospital Universitario Quirónsalud, Madrid, Spain
| | - Patrick F H Lai
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, Ontario, Canada
| | | | - Stéphane Massé
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, Ontario, Canada
| | - Mohammed Ali Azam
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, Ontario, Canada
| | - John Asta
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, Ontario, Canada
| | - Robert A Rose
- Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
| | - Kumaraswamy Nanthakumar
- The Hull Family Cardiac Fibrillation Management Laboratory, Toronto General Hospital, Toronto, Ontario, Canada; University of Toronto, Toronto, Ontario, Canada.
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23
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Stožer A, Paradiž Leitgeb E, Pohorec V, Dolenšek J, Križančić Bombek L, Gosak M, Skelin Klemen M. The Role of cAMP in Beta Cell Stimulus-Secretion and Intercellular Coupling. Cells 2021; 10:1658. [PMID: 34359828 PMCID: PMC8304079 DOI: 10.3390/cells10071658] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/18/2021] [Accepted: 06/28/2021] [Indexed: 12/22/2022] Open
Abstract
Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The molecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus-secretion coupling cascade, ranging from the proximal regulation of ion channel activity to the central Ca2+ signal and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the relevance for the whole organism and translation to humans.
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Affiliation(s)
- Andraž Stožer
- Institute of Physiology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia; (A.S.); (E.P.L.); (V.P.); (J.D.); (L.K.B.); (M.G.)
| | - Eva Paradiž Leitgeb
- Institute of Physiology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia; (A.S.); (E.P.L.); (V.P.); (J.D.); (L.K.B.); (M.G.)
| | - Viljem Pohorec
- Institute of Physiology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia; (A.S.); (E.P.L.); (V.P.); (J.D.); (L.K.B.); (M.G.)
| | - Jurij Dolenšek
- Institute of Physiology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia; (A.S.); (E.P.L.); (V.P.); (J.D.); (L.K.B.); (M.G.)
- Faculty of Natural Sciences and Mathematics, University of Maribor, SI-2000 Maribor, Slovenia
| | - Lidija Križančić Bombek
- Institute of Physiology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia; (A.S.); (E.P.L.); (V.P.); (J.D.); (L.K.B.); (M.G.)
| | - Marko Gosak
- Institute of Physiology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia; (A.S.); (E.P.L.); (V.P.); (J.D.); (L.K.B.); (M.G.)
- Faculty of Natural Sciences and Mathematics, University of Maribor, SI-2000 Maribor, Slovenia
| | - Maša Skelin Klemen
- Institute of Physiology, Faculty of Medicine, University of Maribor, SI-2000 Maribor, Slovenia; (A.S.); (E.P.L.); (V.P.); (J.D.); (L.K.B.); (M.G.)
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24
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Marzook A, Tomas A, Jones B. The Interplay of Glucagon-Like Peptide-1 Receptor Trafficking and Signalling in Pancreatic Beta Cells. Front Endocrinol (Lausanne) 2021; 12:678055. [PMID: 34040588 PMCID: PMC8143046 DOI: 10.3389/fendo.2021.678055] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Accepted: 04/15/2021] [Indexed: 12/30/2022] Open
Abstract
The glucagon-like peptide 1 receptor (GLP-1R) is a class B G protein-coupled receptor (GPCR) which mediates the effects of GLP-1, an incretin hormone secreted primarily from L-cells in the intestine and within the central nervous system. The GLP-1R, upon activation, exerts several metabolic effects including the release of insulin and suppression of appetite, and has, accordingly, become an important target for the treatment for type 2 diabetes (T2D). Recently, there has been heightened interest in how the activated GLP-1R is trafficked between different endomembrane compartments, controlling the spatial origin and duration of intracellular signals. The discovery of "biased" GLP-1R agonists that show altered trafficking profiles and selective engagement with different intracellular effectors has added to the tools available to study the mechanisms and physiological importance of these processes. In this review we survey early and recent work that has shed light on the interplay between GLP-1R signalling and trafficking, and how it might be therapeutically tractable for T2D and related diseases.
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Affiliation(s)
- Amaara Marzook
- Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
| | - Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Imperial College London, London, United Kingdom
| | - Ben Jones
- Section of Endocrinology and Investigative Medicine, Imperial College London, London, United Kingdom
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25
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Ježek P, Holendová B, Jabůrek M, Tauber J, Dlasková A, Plecitá-Hlavatá L. The Pancreatic β-Cell: The Perfect Redox System. Antioxidants (Basel) 2021; 10:antiox10020197. [PMID: 33572903 PMCID: PMC7912581 DOI: 10.3390/antiox10020197] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/20/2021] [Accepted: 01/25/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic β-cell insulin secretion, which responds to various secretagogues and hormonal regulations, is reviewed here, emphasizing the fundamental redox signaling by NADPH oxidase 4- (NOX4-) mediated H2O2 production for glucose-stimulated insulin secretion (GSIS). There is a logical summation that integrates both metabolic plus redox homeostasis because the ATP-sensitive K+ channel (KATP) can only be closed when both ATP and H2O2 are elevated. Otherwise ATP would block KATP, while H2O2 would activate any of the redox-sensitive nonspecific calcium channels (NSCCs), such as TRPM2. Notably, a 100%-closed KATP ensemble is insufficient to reach the -50 mV threshold plasma membrane depolarization required for the activation of voltage-dependent Ca2+ channels. Open synergic NSCCs or Cl- channels have to act simultaneously to reach this threshold. The resulting intermittent cytosolic Ca2+-increases lead to the pulsatile exocytosis of insulin granule vesicles (IGVs). The incretin (e.g., GLP-1) amplification of GSIS stems from receptor signaling leading to activating the phosphorylation of TRPM channels and effects on other channels to intensify integral Ca2+-influx (fortified by endoplasmic reticulum Ca2+). ATP plus H2O2 are also required for branched-chain ketoacids (BCKAs); and partly for fatty acids (FAs) to secrete insulin, while BCKA or FA β-oxidation provide redox signaling from mitochondria, which proceeds by H2O2 diffusion or hypothetical SH relay via peroxiredoxin "redox kiss" to target proteins.
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26
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Kashio M. Thermosensation involving thermo-TRPs. Mol Cell Endocrinol 2021; 520:111089. [PMID: 33227348 DOI: 10.1016/j.mce.2020.111089] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 02/02/2020] [Accepted: 11/17/2020] [Indexed: 12/13/2022]
Abstract
The transient receptor potential (TRP) channels constitute a superfamily of large ion channels that are activated by a wide range of chemical, mechanical and thermal stimuli. TRP channels with temperature sensitivity are called thermo-TRPs. They are involved in diverse physiological functions through their detection of external environmental temperature and internal body temperature. Each thermo-TRP has its own characteristic temperature threshold for activation. As a group, they cover temperatures ranging from cold to nociceptive high temperatures. Recently, many studies have identified the functions of thermo-TRPs residing in deep organs where they are exposed to body temperature. Importantly, temperature thresholds of thermo-TRPs can be regulated by physiological factors enabling their function at relatively constant body temperature. Moreover, several thermo-TRPs are reportedly engaged in body temperature regulation. This review will summarize the current understanding of thermo-TRPs, including their roles in thermosensation and functional regulation of physiological responses at body temperature and the regulation of body temperature.
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Affiliation(s)
- Makiko Kashio
- Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
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27
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Grespan E, Giorgino T, Natali A, Ferrannini E, Mari A. Different mechanisms of GIP and GLP-1 action explain their different therapeutic efficacy in type 2 diabetes. Metabolism 2021; 114:154415. [PMID: 33137379 DOI: 10.1016/j.metabol.2020.154415] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 06/08/2020] [Accepted: 10/28/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The reduced action of incretin hormones in type 2 diabetes (T2D) is mainly attributed to GIP insensitivity, but efficacy estimates of GIP and GLP-1 differ among studies, and the negligible effects of pharmacological GIP doses remain unexplained. We aimed to characterize incretin action in vivo in subjects with normal glucose tolerance (NGT) or T2D and provide an explanation for the different insulinotropic activity of GIP and GLP-1 in T2D subjects. METHODS We used in vivo data from ten studies employing hormone infusion or an oral glucose test (OGTT). To homogeneously interpret and compare the results of the studies we performed the analysis using a mathematical model of the β-cell incorporating the effects of incretins on the triggering and amplifying pathways. The effect on the amplifying pathway was quantified by a time-dependent factor that is greater than one when insulin secretion (ISR) is amplified by incretins. To validate the model results for GIP in NGT subjects, we performed an extensive literature search of the available data. RESULTS a) the stimulatory effects of GIP and GLP-1 differ markedly: ISR potentiation increases linearly with GLP-1 over the whole dose range, while with GIP infusion it reaches a plateau at ~100 pmol/L GIP, with ISR potentiation of ~2 fold; b) ISR potentiation in T2D is reduced by ~50% for GIP and by ~40% for GLP-1; c) the literature search of GIP in NGT subjects confirmed the saturative effect on insulin secretion. CONCLUSION We show that incretin potentiation of ISR is reduced in T2D, but not abolished, and that the lack of effects of pharmacological GIP doses is due to saturation of the GIP effect more than insensitivity to GIP in T2D.
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Affiliation(s)
- Eleonora Grespan
- Institute of Neuroscience, National Research Council, Padua 35127, Italy
| | - Toni Giorgino
- Biophysics Institute, National Research Council, Milan 20133, Italy; Department of Biosciences, University of Milan, Milan 20133, Italy
| | - Andrea Natali
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa 56126, Italy
| | - Ele Ferrannini
- Institute of Clinical Physiology, National Research Council, Pisa 56124, Italy
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padua 35127, Italy.
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28
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Zhang Q, Dou H, Rorsman P. 'Resistance is futile?' - paradoxical inhibitory effects of K ATP channel closure in glucagon-secreting α-cells. J Physiol 2020; 598:4765-4780. [PMID: 32716554 PMCID: PMC7689873 DOI: 10.1113/jp279775] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Accepted: 07/24/2020] [Indexed: 12/12/2022] Open
Abstract
By secreting insulin and glucagon, the β- and α-cells of the pancreatic islets play a central role in the regulation of systemic metabolism. Both cells are equipped with ATP-regulated potassium (KATP ) channels that are regulated by the intracellular ATP/ADP ratio. In β-cells, KATP channels are active at low (non-insulin-releasing) glucose concentrations. An increase in glucose leads to KATP channel closure, membrane depolarization and electrical activity that culminates in elevation of [Ca2+ ]i and initiation of exocytosis of the insulin-containing secretory granules. The α-cells are also equipped with KATP channels but they are under strong tonic inhibition at low glucose, explaining why α-cells are electrically active under hypoglycaemic conditions and generate large Na+ - and Ca2+ -dependent action potentials. Closure of residual KATP channel activity leads to membrane depolarization and an increase in action potential firing but this stimulation of electrical activity is associated with inhibition rather than acceleration of glucagon secretion. This paradox arises because membrane depolarization reduces the amplitude of the action potentials by voltage-dependent inactivation of the Na+ channels involved in action potential generation. Exocytosis in α-cells is tightly linked to the opening of voltage-gated P/Q-type Ca2+ channels, the activation of which is steeply voltage-dependent. Accordingly, the inhibitory effect of the reduced action potential amplitude exceeds the stimulatory effect resulting from the increased action potential frequency. These observations highlight a previously unrecognised role of the action potential amplitude as a key regulator of pancreatic islet hormone secretion.
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Affiliation(s)
- Quan Zhang
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK
| | - Haiqiang Dou
- Metabolic Physiology Unit, Institute of Neuroscience and Physiology, University of Göteborg, PO Box 430, Göteborg, SE-405 30, Sweden
| | - Patrik Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.,Metabolic Physiology Unit, Institute of Neuroscience and Physiology, University of Göteborg, PO Box 430, Göteborg, SE-405 30, Sweden
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29
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Islam MS. Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells. Cells 2020; 9:cells9030685. [PMID: 32168890 PMCID: PMC7140661 DOI: 10.3390/cells9030685] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2020] [Revised: 03/06/2020] [Accepted: 03/08/2020] [Indexed: 12/17/2022] Open
Abstract
Insulin secretion from the β-cells of the islets of Langerhans is triggered mainly by nutrients such as glucose, and incretin hormones such as glucagon-like peptide-1 (GLP-1). The mechanisms of the stimulus-secretion coupling involve the participation of the key enzymes that metabolize the nutrients, and numerous ion channels that mediate the electrical activity. Several members of the transient receptor potential (TRP) channels participate in the processes that mediate the electrical activities and Ca2+ oscillations in these cells. Human β-cells express TRPC1, TRPM2, TRPM3, TRPM4, TRPM7, TRPP1, TRPML1, and TRPML3 channels. Some of these channels have been reported to mediate background depolarizing currents, store-operated Ca2+ entry (SOCE), electrical activity, Ca2+ oscillations, gene transcription, cell-death, and insulin secretion in response to stimulation by glucose and GLP1. Different channels of the TRP family are regulated by one or more of the following mechanisms: activation of G protein-coupled receptors, the filling state of the endoplasmic reticulum Ca2+ store, heat, oxidative stress, or some second messengers. This review briefly compiles our current knowledge about the molecular mechanisms of regulations, and functions of the TRP channels in the β-cells, the α-cells, and some insulinoma cell lines.
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Affiliation(s)
- Md. Shahidul Islam
- Karolinska Institutet, Department of Clinical Science and Education, Södersjukhuset, Research Center, 5th floor, SE-118 83 Stockholm, Sweden;
- Department of Emergency Care and Internal Medicine, Uppsala University Hospital, Uppsala University, SE-751 85 Uppsala, Sweden
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30
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Idevall-Hagren O, Tengholm A. Metabolic regulation of calcium signaling in beta cells. Semin Cell Dev Biol 2020; 103:20-30. [PMID: 32085965 DOI: 10.1016/j.semcdb.2020.01.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Revised: 01/10/2020] [Accepted: 01/28/2020] [Indexed: 12/22/2022]
Abstract
The cytoplasmic Ca2+ concentration ([Ca2+]cyt) regulates a vast number of cellular functions, including insulin secretion from beta cells. The major physiological insulin secretagogue, glucose, triggers [Ca2+]cyt oscillations in beta cells. Synchronization of the oscillations among the beta cells within an islet underlies the generation of pulsatile insulin secretion. This review describes the mechanisms generating [Ca2+]cyt oscillations, the interactions between [Ca2+]cyt and cell metabolism, as well as the contribution of various organelles to the shaping of [Ca2+]cyt signals and insulin secretion. It also discusses how Ca2+ signals are coordinated and spread throughout the islets and data indicating that altered Ca2+ signaling is associated with beta cell dysfunction and development of type 2 diabetes.
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Affiliation(s)
- Olof Idevall-Hagren
- Department of Medical Cell Biology, Uppsala University, Biomedical Centre, Box 571, SE-751 23 Uppsala, Sweden
| | - Anders Tengholm
- Department of Medical Cell Biology, Uppsala University, Biomedical Centre, Box 571, SE-751 23 Uppsala, Sweden.
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31
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Tomas A, Jones B, Leech C. New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling. J Mol Biol 2019; 432:1347-1366. [PMID: 31446075 DOI: 10.1016/j.jmb.2019.08.009] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 08/06/2019] [Accepted: 08/13/2019] [Indexed: 12/14/2022]
Abstract
Harnessing the translational potential of the GLP-1/GLP-1R system in pancreatic beta cells has led to the development of established GLP-1R-based therapies for the long-term preservation of beta cell function. In this review, we discuss recent advances in the current research on the GLP-1/GLP-1R system in beta cells, including the regulation of signaling by endocytic trafficking as well as the application of concepts such as signal bias, allosteric modulation, dual agonism, polymorphic receptor variants, spatial compartmentalization of cAMP signaling and new downstream signaling targets involved in the control of beta cell function.
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Affiliation(s)
- Alejandra Tomas
- Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, W12 0NN, UK.
| | - Ben Jones
- Section of Investigative Medicine, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, W12 0NN, UK
| | - Colin Leech
- Department of Surgery, State University of New York, Upstate Medical University, Syracuse, NY, 13210, USA
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Kong X, Tu Y, Li B, Zhang L, Feng L, Wang L, Zhang L, Zhou H, Hua X, Ma X. Roux-en-Y gastric bypass enhances insulin secretion in type 2 diabetes via FXR-mediated TRPA1 expression. Mol Metab 2019; 29:1-11. [PMID: 31668381 PMCID: PMC6728758 DOI: 10.1016/j.molmet.2019.08.009] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 08/12/2019] [Accepted: 08/12/2019] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVE Roux-en-Y gastric bypass surgery (RYGB) improves the first phase of glucose-stimulated insulin secretion (GSIS) in patients with type 2 diabetes. How it does so remains unclear. Farnesoid X receptor (FXR), the nuclear receptor of bile acids (BAs), is implicated in bariatric surgery. Moreover, the transient receptor potential ankyrin 1 (TRPA1) channel is expressed in pancreatic β-cells and involved in insulin secretion. We aimed to explore the role of BAs/FXR and TRPA1 in improved GSIS in diabetic rats after RYGB. METHODS RYGB or sham surgery was conducted in spontaneous diabetic Goto-Kakizaki (GK) rats, or FXR or TRPA1 transgenic mice. Gene and protein expression of islets were assessed by qPCR and western blotting. Electrophysiological properties of single β-cells were studied using patch-clamp technique. Binding of FXR and histone acetyltransferase steroid receptor coactivator-1 (SRC1) to the TRPA1 promoter, acetylated histone H3 (ACH3) levels at the TRPA1 promoter were determined using ChIP assays. GSIS was measured using enzyme-linked immunosorbent assays or intravenous glucose tolerance test (IVGTT). RESULTS RYGB increases GSIS, particularly the first-phase of GSIS in both intact islets and GK rats in vivo, and ameliorates hyperglycemia of GK rats. Importantly, the effects of RYGB were attenuated in TRPA1-deficient mice. Moreover, GK β-cells displayed significantly decreased TRPA1 expression and current. Patch-clamp recording revealed that TRPA1-/- β-cells displayed a marked hyperpolarization and decreased glucose-evoked action potential firing, which was associated with impaired GSIS. RYGB restored TRPA1 expression and current in GK β-cells. This was accompanied by improved glucose-evoked electrical activity and insulin secretion. Additionally, RYGB-induced TRPA1 expression involved BAs/FXR-mediated recruitment of SRC1, promoting ACH3 at the promoter of TRPA1. CONCLUSIONS The BAs/FXR/SRC1 axis-mediated restoration of TRPA1 expression plays a critical role in the enhanced GSIS and remission of diabetes in GK rats after RYGB.
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Affiliation(s)
- Xiangchen Kong
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Yifan Tu
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Bingfeng Li
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Longmei Zhang
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Linxian Feng
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Lixiang Wang
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Lin Zhang
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China
| | - Huarong Zhou
- Key laboratory of System Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China
| | - Xianxin Hua
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China; University of Pennsylvania Perelman School of Medicine, 421 Curie Blvd, Philadelphia, PA 19104, USA
| | - Xiaosong Ma
- Shenzhen University Diabetes Institute, School of Medicine, Shenzhen University, Shenzhen 518060, PR China.
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DiNicolantonio JJ, McCarty M. Autophagy-induced degradation of Notch1, achieved through intermittent fasting, may promote beta cell neogenesis: implications for reversal of type 2 diabetes. Open Heart 2019; 6:e001028. [PMID: 31218007 PMCID: PMC6546199 DOI: 10.1136/openhrt-2019-001028] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/06/2019] [Indexed: 02/06/2023] Open
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Sarmiento BE, Santos Menezes LF, Schwartz EF. Insulin Release Mechanism Modulated by Toxins Isolated from Animal Venoms: From Basic Research to Drug Development Prospects. Molecules 2019; 24:E1846. [PMID: 31091684 PMCID: PMC6571724 DOI: 10.3390/molecules24101846] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 04/23/2019] [Accepted: 05/09/2019] [Indexed: 12/12/2022] Open
Abstract
Venom from mammals, amphibians, snakes, arachnids, sea anemones and insects provides diverse sources of peptides with different potential medical applications. Several of these peptides have already been converted into drugs and some are still in the clinical phase. Diabetes type 2 is one of the diseases with the highest mortality rate worldwide, requiring specific attention. Diverse drugs are available (e.g., Sulfonylureas) for effective treatment, but with several adverse secondary effects, most of them related to the low specificity of these compounds to the target. In this context, the search for specific and high-affinity compounds for the management of this metabolic disease is growing. Toxins isolated from animal venom have high specificity and affinity for different molecular targets, of which the most important are ion channels. This review will present an overview about the electrical activity of the ion channels present in pancreatic β cells that are involved in the insulin secretion process, in addition to the diversity of peptides that can interact and modulate the electrical activity of pancreatic β cells. The importance of prospecting bioactive peptides for therapeutic use is also reinforced.
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Affiliation(s)
- Beatriz Elena Sarmiento
- Departamento de Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade de Brasília, Brasília, DF 70910-900, Brazil.
| | - Luis Felipe Santos Menezes
- Departamento de Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade de Brasília, Brasília, DF 70910-900, Brazil.
| | - Elisabeth F Schwartz
- Departamento de Ciências Fisiológicas, Instituto de Ciências Biológicas, Universidade de Brasília, Brasília, DF 70910-900, Brazil.
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Redox TRPs in diabetes and diabetic complications: Mechanisms and pharmacological modulation. Pharmacol Res 2019; 146:104271. [PMID: 31096011 DOI: 10.1016/j.phrs.2019.104271] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 04/04/2019] [Accepted: 05/08/2019] [Indexed: 12/12/2022]
Abstract
Transient receptor potential (TRP) channels have shown to be involved in a wide variety of physiological functions and pathophysiological conditions. Modulation of TRP channels reported to play a major role in number of disorders starting from central nervous system related disorders to cardiovascular, inflammatory, cancer, gastrointestinal and metabolic diseases. Recently, a subset of TRP ion channels called redox TRPs gained importance on account of their ability to sense the cellular redox environment and respond accordingly to such redox stimuli. Diabetes, the silent epidemic of the world is increasing at an alarming rate in spite of novel therapeutic interventions. Moreover, diabetes and its associated complications are reported to arise due to a change in oxidative status of cell induced by hyperglycemia. Such a change in cellular oxidative status can modulate the activities of various redox TRP channels (TRPA1, TRPC5, TRPMs and TRPV1). Targeting redox TRPs have potential in diabetes and diabetic complications like neuropathy, cardiomyopathy, retinopathy, cystopathy, and encephalopathy. Thus in this review, we have discussed the activities of different redox sensing TRPs in diabetes and diabetic complications and how they can be modulated pharmacologically, so as to consider them a potential novel therapeutic target in treating diabetes and its comorbidity.
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An incretin-based tri-agonist promotes superior insulin secretion from murine pancreatic islets via PLC activation. Cell Signal 2018; 51:13-22. [DOI: 10.1016/j.cellsig.2018.07.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 07/24/2018] [Accepted: 07/24/2018] [Indexed: 01/22/2023]
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Gao M, Du Y, Xie JW, Xue J, Wang YT, Qin L, Ma MM, Tang YB, Li XY. Redox signal-mediated TRPM2 promotes Ang II-induced adipocyte insulin resistance via Ca 2+-dependent CaMKII/JNK cascade. Metabolism 2018; 85:313-324. [PMID: 29775644 DOI: 10.1016/j.metabol.2018.05.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 04/21/2018] [Accepted: 05/11/2018] [Indexed: 10/16/2022]
Abstract
BACKGROUND AND OBJECTIVE Redox-sensitive transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable, nonselective cation channel which plays a crucial role in various physiological processes. However, little is known whether TRPM2 is involved in adipocyte dysfunction during hypertension. In the present study, we determined the role of TRPM2 in angiotensin II (Ang II)-induced insulin resistance in adipocytes and the underlying mechanisms. METHODS Ang II-induced adipocyte insulin resistant model was conducted. Data from Ang II-induced hypertensive mice were used to measure the effects of TRPM2 inhibitor on insulin resistance in vivo. Whole-cell patch clamp technique, intracellular Ca2+ concentration measurement, glucose uptake assay, western blot, cDNA and siRNA transfection were employed to investigate the TRPM2/Ca2+/CaMKII/JNK signaling. RESULTS Ang II rose a cation current similar to that activated by hydrogen peroxide (H2O2) or ADP-ribose (ADPR), which was blocked by TRPM2 inhibitor or TRPM2 siRNA in adipocytes. Knockdown of TRPM2 significantly improved the lowered insulin sensitivity induced by Ang II, including insulin stimulated glucose uptake, phosphorylation of IRS1 and Akt, interaction between IR and IRS1 and the membrane translocation of GLUT4, whereas overexpression of TRPM2 resulted in the opposite effects. These results were related to the potentiated effects of TRPM2 on Ca2+ influx and CaMKII/JNK cascade activation upon Ang II-induced challenge. Notably, the pharmacological TRPM2 inhibitor, N-(p-amylcinnamoyl)anthranilic acid (ACA), was proved to improve insulin sensitivity in adipose tissue during Ang II-induced hypertension progress. CONCLUSIONS These data suggested that TRPM2 is a positive regulator of Ang II-induced adipocyte insulin resistance via Ca2+/CaMKII/JNK-dependent signaling pathway. Targeting TRPM2 may be a novel therapeutic strategy to treat hypertension-associated insulin resistance.
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Affiliation(s)
- Min Gao
- Department of Pharmacy, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China.
| | - Yu Du
- Guangdong Provincial Key Laboratory of Liver Disease Research, Cell-gene Therapy Translational Medicine Research Center, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, China
| | - Jing-Wen Xie
- Department of Pharmacy, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Jing Xue
- Department of Pharmacy, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Yi-Ting Wang
- Department of Pharmacy, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Li Qin
- Department of Pharmacy, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China
| | - Ming-Ming Ma
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Yong-Bo Tang
- Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Xiao-Yan Li
- Department of Pharmacy, the Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510655, China.
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Luo Y, Yu X, Ma C, Luo J, Yang W. Identification of a Novel EF-Loop in the N-terminus of TRPM2 Channel Involved in Calcium Sensitivity. Front Pharmacol 2018; 9:581. [PMID: 29915540 PMCID: PMC5994415 DOI: 10.3389/fphar.2018.00581] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 05/15/2018] [Indexed: 01/10/2023] Open
Abstract
As an oxidative stress sensor, transient receptor potential melastatin 2 (TRPM2) channel is involved in many physiological and pathological processes including warmth sensing, ischemia injury, inflammatory diseases and diabetes. Intracellular calcium is critical for TRPM2 channel activation and the IQ-like motif in the N-terminus has been shown to be important by mediating calmodulin binding. Sequence analysis predicted two potential EF-loops in the N-terminus of TRPM2. Site-directed mutagenesis combining with functional assay showed that substitution with alanine of several residues, most of which are conserved in the typical EF-loop, including D267, D278, D288, and E298 dramatically reduced TRPM2 channel currents. By further changing the charges or side chain length of these conserved residues, our results indicate that the negative charge of D267 and the side chain length of D278 are critical for calcium-induced TRPM2 channel activation. G272I mutation also dramatically reduced the channel currents, suggesting that this site is critical for calcium-induced TRPM2 channel activation. Furthermore, D267A mutant dramatically reduced the currents induced by calcium alone compared with that by ADPR, indicating that D267 residue in D267–D278 motif is the most important site for calcium sensitivity of TRPM2. In addition, inside-out recordings showed that mutations at D267, G272, D278, and E298 had no effect on single-channel conductance. Taken together, our data indicate that D267–D278 motif in the N-terminus as a novel EF-loop is critical for calcium-induced TRPM2 channel activation.
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Affiliation(s)
- Yuhuan Luo
- Department of Neurobiology, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiafei Yu
- Department of Neurobiology, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Cheng Ma
- Co-facility Center, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianhong Luo
- Department of Neurobiology, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
| | - Wei Yang
- Department of Neurobiology, Institute of Neuroscience, NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University School of Medicine, Hangzhou, China
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Almasi S, Kennedy BE, El-Aghil M, Sterea AM, Gujar S, Partida-Sánchez S, El Hiani Y. TRPM2 channel-mediated regulation of autophagy maintains mitochondrial function and promotes gastric cancer cell survival via the JNK-signaling pathway. J Biol Chem 2018; 293:3637-3650. [PMID: 29343514 DOI: 10.1074/jbc.m117.817635] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 12/22/2017] [Indexed: 12/16/2022] Open
Abstract
A lack of effective treatment is one of the main factors contributing to gastric cancer-related death. Discovering effective targets and understanding their underlying anti-cancer mechanism are key to achieving the best response to treatment and to limiting side effects. Although recent studies have shown that the cation channel transient receptor potential melastatin-2 (TRPM2) is crucial for cancer cell survival, the exact mechanism remains unclear, limiting its therapeutic potential. Here, using molecular and functional assays, we investigated the role of TRPM2 in survival of gastric cancer cells. Our results indicated that TRPM2 knockdown in AGS and MKN-45 cells decreases cell proliferation and enhances apoptosis. We also observed that the TRPM2 knockdown impairs mitochondrial metabolism, indicated by a decrease in basal and maximal mitochondrial oxygen consumption rates and ATP production. These mitochondrial defects coincided with a decrease in autophagy and mitophagy, indicated by reduced levels of autophagy- and mitophagy-associated proteins (i.e. ATGs, LC3A/B II, and BNIP3). Moreover, we found that TRPM2 modulates autophagy through a c-Jun N-terminal kinase (JNK)-dependent and mechanistic target of rapamycin-independent pathway. We conclude that in the absence of TRPM2, down-regulation of the JNK-signaling pathway impairs autophagy, ultimately causing the accumulation of damaged mitochondria and death of gastric cancer cells. Of note, by inhibiting cell proliferation and promoting apoptosis, the TRPM2 down-regulation enhanced the efficacy of paclitaxel and doxorubicin in gastric cancer cells. Collectively, we provide compelling evidence that TRPM2 inhibition may benefit therapeutic approaches for managing gastric cancer.
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Affiliation(s)
| | | | | | - Andra M Sterea
- Physiology, Biophysics Faculty of Life Science, Dalhousie University, Halifax and
| | - Shashi Gujar
- Pathology.,Microbiology and Immunology, and.,the Centre for Innovative and Collaborative Health Services Research, Quality and System Performance, IWK Health Centre, Halifax, Nova Scotia B3H 4R2, Canada
| | - Santiago Partida-Sánchez
- Center for Microbial Pathogenesis, Research Institute at Nationwide Children's Hospital and.,the Department of Pediatrics, College of Medicine, Ohio State University, Columbus, Ohio 43205
| | - Yassine El Hiani
- Physiology, Biophysics Faculty of Life Science, Dalhousie University, Halifax and
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Rorsman P, Ashcroft FM. Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men. Physiol Rev 2018; 98:117-214. [PMID: 29212789 PMCID: PMC5866358 DOI: 10.1152/physrev.00008.2017] [Citation(s) in RCA: 517] [Impact Index Per Article: 73.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 05/30/2017] [Accepted: 06/18/2017] [Indexed: 12/14/2022] Open
Abstract
The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration. Impaired insulin secretion results in the chronic hyperglycemia that characterizes type 2 diabetes (T2DM), which currently afflicts >450 million people worldwide. The healthy β-cell acts as a glucose sensor matching its output to the circulating glucose concentration. It does so via metabolically induced changes in electrical activity, which culminate in an increase in the cytoplasmic Ca2+ concentration and initiation of Ca2+-dependent exocytosis of insulin-containing secretory granules. Here, we review recent advances in our understanding of the β-cell transcriptome, electrical activity, and insulin exocytosis. We highlight salient differences between mouse and human β-cells, provide models of how the different ion channels contribute to their electrical activity and insulin secretion, and conclude by discussing how these processes become perturbed in T2DM.
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Affiliation(s)
- Patrik Rorsman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom; Department of Neuroscience and Physiology, Metabolic Research Unit, Göteborg, Sweden; and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
| | - Frances M Ashcroft
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, United Kingdom; Department of Neuroscience and Physiology, Metabolic Research Unit, Göteborg, Sweden; and Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom
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Tengholm A, Gylfe E. cAMP signalling in insulin and glucagon secretion. Diabetes Obes Metab 2017; 19 Suppl 1:42-53. [PMID: 28466587 DOI: 10.1111/dom.12993] [Citation(s) in RCA: 155] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 04/24/2017] [Accepted: 04/26/2017] [Indexed: 01/24/2023]
Abstract
The "second messenger" archetype cAMP is one of the most important cellular signalling molecules with central functions including the regulation of insulin and glucagon secretion from the pancreatic β- and α-cells, respectively. cAMP is generally considered as an amplifier of insulin secretion triggered by Ca2+ elevation in the β-cells. Both messengers are also positive modulators of glucagon release from α-cells, but in this case cAMP may be the important regulator and Ca2+ have a more permissive role. The actions of cAMP are mediated by protein kinase A (PKA) and the guanine nucleotide exchange factor Epac. The present review focuses on how cAMP is regulated by nutrients, hormones and neural factors in β- and α-cells via adenylyl cyclase-catalysed generation and phosphodiesterase-mediated degradation. We will also discuss how PKA and Epac affect ion fluxes and the secretory machinery to transduce the stimulatory effects on insulin and glucagon secretion. Finally, we will briefly describe disturbances of the cAMP system associated with diabetes and how cAMP signalling can be targeted to normalize hypo- and hypersecretion of insulin and glucagon, respectively, in diabetic patients.
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Affiliation(s)
- Anders Tengholm
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
| | - Erik Gylfe
- Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden
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Uchida K, Dezaki K, Yoneshiro T, Watanabe T, Yamazaki J, Saito M, Yada T, Tominaga M, Iwasaki Y. Involvement of thermosensitive TRP channels in energy metabolism. J Physiol Sci 2017; 67:549-560. [PMID: 28656459 PMCID: PMC10717017 DOI: 10.1007/s12576-017-0552-x] [Citation(s) in RCA: 65] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 06/12/2017] [Indexed: 12/22/2022]
Abstract
To date, 11 thermosensitive transient receptor potential (thermo-TRP) channels have been identified. Recent studies have characterized the mechanism of thermosensing by thermo-TRPs and the physiological role of thermo-TRPs in energy metabolism. In this review, we highlight the role of various thermo-TRPs in energy metabolism and hormone secretion. In the pancreas, TRPM2 and other TRPs regulate insulin secretion. TRPV2 expressed in brown adipocytes contributes to differentiation and/or thermogenesis. Sensory nerves that express TRPV1 promote increased energy expenditure by activating sympathetic nerves and adrenaline secretion. Here, we first show that capsaicin-induced adrenaline secretion is completely impaired in TRPV1 knockout mice. The thermogenic effects of TRPV1 agonists are attributable to brown adipose tissue (BAT) activation in mice and humans. Moreover, TRPA1- and TRPM8-expressing sensory nerves also contribute to potentiation of BAT thermogenesis and energy expenditure in mice. Together, thermo-TRPs are promising targets for combating obesity and metabolic disorders.
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Affiliation(s)
- Kunitoshi Uchida
- Division of Cell Signaling, Okazaki Institute for Integrative Biosciences (National Institute for Physiological Sciences), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan.
- Department of Physiological Sciences, SOKENDAI (The University of Advanced Studies), 38 Nishigounaka, Myodaiji, Okazaki, Aichi, 444-8585, Japan.
- Department of Physiological Science and Molecular Biology, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka, Fukuoka, 814-0193, Japan.
| | - Katsuya Dezaki
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 320-0498, Japan
| | - Takeshi Yoneshiro
- Diabetes Center, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA, 94143-0669, USA
| | - Tatsuo Watanabe
- Faculty of Future Industry, Happy Science University, 4427-1 Hitotsumatsu-hei, Chosei-mura, Chiba, 299-4325, Japan
| | - Jun Yamazaki
- Department of Physiological Science and Molecular Biology, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka, Fukuoka, 814-0193, Japan
| | - Masayuki Saito
- Hokkaido University, Kita18-Nishi9, Kita-ku, Sapporo, Hokkaido, 060-0818, Japan
| | - Toshihiko Yada
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 320-0498, Japan
| | - Makoto Tominaga
- Division of Cell Signaling, Okazaki Institute for Integrative Biosciences (National Institute for Physiological Sciences), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi, 444-8787, Japan
- Department of Physiological Sciences, SOKENDAI (The University of Advanced Studies), 38 Nishigounaka, Myodaiji, Okazaki, Aichi, 444-8585, Japan
| | - Yusaku Iwasaki
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 320-0498, Japan.
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Ito K, Ookawara S, Ishibashi K, Morishita Y. Transgene and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus. NANO REVIEWS & EXPERIMENTS 2017; 8:1341758. [PMID: 30410709 PMCID: PMC6167029 DOI: 10.1080/20022727.2017.1341758] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 06/05/2017] [Indexed: 11/09/2022]
Abstract
Gene therapy that targets the pancreas and intestines with delivery systems using nano-sized carriers such as viral and non-viral vectors could improve the control of blood glucose levels, resulting in an improved prognosis for patients with diabetes mellitus. Allogenic pancreatic islet cell transplantations using such delivery systems have been developed as therapeutic options for diabetes mellitus. This review focuses on transgenes and islet cell delivery systems using nano-sized carriers for the treatment of diabetes mellitus.
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Affiliation(s)
- Kiyonori Ito
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Susumu Ookawara
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Kenichi Ishibashi
- Department of Medical Physiology, Meiji Pharmaceutical University, Tokyo, Japan
| | - Yoshiyuki Morishita
- Division of Nephrology, First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
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Abstract
Living organisms continually experience changes in ambient temperature. To detect such temperature changes for adaptive behavioral responses, we evolved the ability to sense temperature. Thermosensitive transient receptor potential (TRP) channels, so-called thermo-TRPs, are involved in many physiologic functions in diverse organisms and constitute important temperature sensors. One of the important roles of thermo-TRPs is detecting ambient temperature in sensory neurons. Importantly, the functional expression of thermo-TRPs is observed not only in sensory neurons but also in tissues and cells that are not exposed to drastic temperature changes, indicating that thermo-TRPs are involved in many physiologic functions within the body's normal temperature range. Among such thermo-TRPs, this review focuses on one thermo-sensitive metabolic sensor in particular, TRPM2, and summarizes recent progress to clarify the regulatory mechanisms and physiologic functions of TRPM2 at body temperature under various metabolic states.
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Affiliation(s)
- Makiko Kashio
- a Department of Physiology , Aichi Medical University , Nagakute , Aichi , Japan
| | - Makoto Tominaga
- b Division of Cell Signaling , Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences) , Okazaki , Aichi , Japan.,c Department of Physiological Sciences , SOKENDAI , Okazaki , Aichi , Japan.,d Institute for Environmental and Gender-Specific Medicine, Juntendo University , Bunkyo-ku, Tokyo , Japan
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45
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Molecular regulation of insulin granule biogenesis and exocytosis. Biochem J 2017; 473:2737-56. [PMID: 27621482 DOI: 10.1042/bcj20160291] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 04/19/2016] [Indexed: 12/15/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia, insulin resistance and hyperinsulinemia in early disease stages but a relative insulin insufficiency in later stages. Insulin, a peptide hormone, is produced in and secreted from pancreatic β-cells following elevated blood glucose levels. Upon its release, insulin induces the removal of excessive exogenous glucose from the bloodstream primarily by stimulating glucose uptake into insulin-dependent tissues as well as promoting hepatic glycogenesis. Given the increasing prevalence of T2DM worldwide, elucidating the underlying mechanisms and identifying the various players involved in the synthesis and exocytosis of insulin from β-cells is of utmost importance. This review summarizes our current understanding of the route insulin takes through the cell after its synthesis in the endoplasmic reticulum as well as our knowledge of the highly elaborate network that controls insulin release from the β-cell. This network harbors potential targets for anti-diabetic drugs and is regulated by signaling cascades from several endocrine systems.
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Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function. EBioMedicine 2017; 18:146-156. [PMID: 28389215 PMCID: PMC5405175 DOI: 10.1016/j.ebiom.2017.03.040] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 03/09/2017] [Accepted: 03/27/2017] [Indexed: 12/26/2022] Open
Abstract
In Wfs1-/-Ay/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in β-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2+ response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in β-cell priming for insulin release by regulating β-cell metabolism and gene expressions. Because ER stress is also involved in the β-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes.
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Ito K, Dezaki K, Yoshida M, Yamada H, Miura R, Rita RS, Ookawara S, Tabei K, Kawakami M, Hara K, Morishita Y, Yada T, Kakei M. Endogenous α2A-Adrenoceptor-Operated Sympathoadrenergic Tones Attenuate Insulin Secretion via cAMP/TRPM2 Signaling. Diabetes 2017; 66:699-709. [PMID: 28028077 DOI: 10.2337/db16-1166] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2016] [Accepted: 12/21/2016] [Indexed: 11/13/2022]
Abstract
In pancreatic β-cells, pharmacological concentrations of catecholamines, including adrenaline, have been used to inhibit insulin release and explore the multiple mechanisms involved. However, the significance of these signaling pathways for physiological adrenergic functions in β-cells is largely unknown. In the process of glucose-induced insulin secretion, opening of background current through nonselective cation channels (NSCCs) might facilitate membrane depolarization by closure of the ATP-sensitive K+ channels. Here, we examined whether physiological insulinostatic adrenaline action is mediated via the transient receptor potential melastatin 2 (TRPM2) channel, a type of NSCC, in β-cells. Results showed that physiological concentrations of adrenaline strongly suppressed glucose-induced and incretin-potentiated cAMP production and insulin secretion and inhibited NSCCs current and membrane excitability via the α2A-adrenoceptor in wild-type mice; however, insulin secretion was not attenuated in TRPM2-knockout (KO) mice. Administration of yohimbine, an α2-adrenoceptor antagonist, failed to affect glucose tolerance in TRPM2-KO mice, in contrast to an improved glucose tolerance in wild-type mice receiving the antagonist. The current study demonstrated that a physiological concentration of adrenaline attenuates insulin release via coupling of α2A-adrenoceptor to cAMP/TRPM2 signaling, thereby providing a potential therapeutic tool to treat patients with type 2 diabetes.
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Affiliation(s)
- Kiyonori Ito
- First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Katsuya Dezaki
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan
| | - Masashi Yoshida
- First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Hodaka Yamada
- First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Rina Miura
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan
| | - Rauza Sukma Rita
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan
| | - Susumu Ookawara
- First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Kaoru Tabei
- First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
- Minamiuonuma City Hospital, Niigata, Japan
| | - Masanobu Kawakami
- First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
- Nerima Hikarigaoka Hospital, Tokyo, Japan
| | - Kazuo Hara
- First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Yoshiyuki Morishita
- First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Toshihiko Yada
- Division of Integrative Physiology, Department of Physiology, Jichi Medical University, Tochigi, Japan
| | - Masafumi Kakei
- First Department of Integrated Medicine, Saitama Medical Center, Jichi Medical University, Saitama, Japan
- Saitama Citizens Medical Center, Saitama, Japan
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Gupta P, Bala M, Gupta S, Dua A, Dabur R, Injeti E, Mittal A. Efficacy and risk profile of anti-diabetic therapies: Conventional vs traditional drugs—A mechanistic revisit to understand their mode of action. Pharmacol Res 2016; 113:636-674. [DOI: 10.1016/j.phrs.2016.09.029] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 09/23/2016] [Accepted: 09/23/2016] [Indexed: 12/17/2022]
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Kakei M, Yoshida M, Dezaki K, Ito K, Yamada H, Funazaki S, Kawakami M, Sugawara H, Yada T. Glucose and GTP-binding protein-coupled receptor cooperatively regulate transient receptor potential-channels to stimulate insulin secretion [Review]. Endocr J 2016; 63:867-876. [PMID: 27321586 DOI: 10.1507/endocrj.ej16-0262] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
In pancreatic β-cells, glucose-induced closure of the ATP-sensitive K+ (KATP) channel is an initial process triggering glucose-stimulated insulin secretion (GSIS). This KATP-channel dependent pathway has been believed to be a central mechanism for GSIS. However, since the resting membrane potential of cells is determined by the balance of the net result of current amplitudes in outward and inward directions, it must be taken into consideration that not only KATP channel inhibition but also inward current via the basal opening of non-selective cation channels (NSCCs) plays a crucial role in membrane potential regulation. The basal activity of NSCCs is essential to effectively evoke depolarization in concert with KATP channel closure that is dependent on glucose metabolism. The present study summarizes recent findings regarding the roles of NSCCs in GSIS and GTP-binding protein coupled receptor-(GPCR) operated potentiation of GSIS.
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Affiliation(s)
- Masafumi Kakei
- Internal Medicine, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan
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Ravnskjaer K, Madiraju A, Montminy M. Role of the cAMP Pathway in Glucose and Lipid Metabolism. Handb Exp Pharmacol 2016; 233:29-49. [PMID: 26721678 DOI: 10.1007/164_2015_32] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
3'-5'-Cyclic adenosine monophosphate (cyclic AMP or cAMP) was first described in 1957 as an intracellular second messenger mediating the effects of glucagon and epinephrine on hepatic glycogenolysis (Berthet et al., J Biol Chem 224(1):463-475, 1957). Since this initial characterization, cAMP has been firmly established as a versatile molecular signal involved in both central and peripheral regulation of energy homeostasis and nutrient partitioning. Many of these effects appear to be mediated at the transcriptional level, in part through the activation of the transcription factor CREB and its coactivators. Here we review current understanding of the mechanisms by which the cAMP signaling pathway triggers metabolic programs in insulin-responsive tissues.
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