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Delvadia P, Dhote V, Mandloi AS, Soni R, Shah J. Dual GLP-1 and GIP Agonist Tirzepatide Exerted Neuroprotective Action in a Parkinson's Disease Rat Model. ACS Chem Neurosci 2025; 16:818-825. [PMID: 39964252 DOI: 10.1021/acschemneuro.4c00729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025] Open
Abstract
Parkinson's disease (PD) is an age-related progressive disorder that leads to dopaminergic loss and subsequent motor dysfunction. Current therapies mainly deal with symptomatic effects, and hence, therapies targeting progressive neurodegeneration need to developed. In this study, tirzepatide, a coagonist of glucagon like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, exhibited a neuroprotective effect in preliminary studies. This study aims to evaluate the effect of tirzepatide, in comparison with exendin-4, in a rat model of PD. The effect of tirzepatide (50 and 100 nmol/kg, s.c.) and exendin-4 (8 μg/kg, s.c.) on behavioral functions, oxidative markers, inflammatory markers, dopamine level, and alpha-synuclein expression were studied against a rotenone (2 mg/kg)-induced toxicity model in rats. Tirzepatide prevented rotenone-induced motor deficits. Additionally, it significantly inhibited the rotenone-induced increase in proinflammatory cytokines TNF-α and IL-6. Furthermore, it upregulated striatal dopamine levels. It alleviated oxidative stress and alpha-synuclein aggregation. Both doses of tirzepatide exert neuroprotective effects in a PD rat model. Furthermore, the effect is dose-dependent, and a 100 nmol/kg dose of tirzepatide was found to be more effective.
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Affiliation(s)
- Prashant Delvadia
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Vipin Dhote
- VNS Group of Institutions, Faculty of Pharmacy, Bhopal 462044, India
| | | | - Ritu Soni
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
| | - Jigna Shah
- Department of Pharmacology, Institute of Pharmacy, Nirma University, Ahmedabad, Gujarat 382481, India
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2
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Ford BE, Chachra SS, Alshawi A, Oakley F, Fairclough RJ, Smith DM, Tiniakos D, Agius L. Compromised chronic efficacy of a glucokinase activator AZD1656 in mouse models for common human GCKR variants. Biochem Pharmacol 2024; 229:116499. [PMID: 39173844 DOI: 10.1016/j.bcp.2024.116499] [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: 05/15/2024] [Revised: 07/23/2024] [Accepted: 08/19/2024] [Indexed: 08/24/2024]
Abstract
Glucokinase activators (GKAs) have been developed as blood glucose lowering drugs for type 2 diabetes. Despite good short-term efficacy, several GKAs showed a decline in efficacy chronically during clinical trials. The underlying mechanisms remain incompletely understood. We tested the hypothesis that deficiency in the liver glucokinase regulatory protein (GKRP) as occurs with common human GCKR variants affects chronic GKA efficacy. We used a Gckr-P446L mouse model for the GCKR exonic rs1260326 (P446L) variant and the Gckr-del/wt mouse to model transcriptional deficiency to test for chronic efficacy of the GKA, AZD1656 in GKRP-deficient states. In the Gckr-P446L mouse, the blood glucose lowering efficacy of AZD1656 (3 mg/kg body wt) after 2 weeks was independent of genotype. However after 19 weeks, efficacy was maintained in wild-type but declined in the LL genotype, in conjunction with raised hepatic glucokinase activity and without raised liver lipids. Sustained blood glucose lowering efficacy in wild-type mice was associated with qualitatively similar but more modest changes in the liver transcriptome compared with the P446L genotype, consistent with GKA therapy representing a more modest glucokinase excess than the P446L genotype. Chronic treatment with AZD1656 in the Gckr-del/wt mouse was associated with raised liver triglyceride and hepatocyte microvesicular steatosis. The results show that in mouse models of liver GKRP deficiency in conjunction with functional liver glucokinase excess as occurs in association with common human GCKR variants, GKRP-deficiency predisposes to declining efficacy of the GKA in lowering blood glucose and to GKA induced elevation in liver lipids.
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Affiliation(s)
- Brian E Ford
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Shruti S Chachra
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Ahmed Alshawi
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Medical Laboratory Technique Department, Kufa Institute, Al-Furat Al-Awsat Technical University, Kufa, Iraq
| | - Fiona Oakley
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Rebecca J Fairclough
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - David M Smith
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Dina Tiniakos
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Dept of Pathology, Aretaieion Hospital Medical School, National and Kapodistrian University of Athens, Greece
| | - Loranne Agius
- Biosciences Institute, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
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3
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Gurlo T, Prakash TP, Wang Z, Archang M, Pei L, Rosenberger M, Pirie E, Lee RG, Butler PC. Efficacy of IAPP suppression in mouse and human islets by GLP-1 analogue conjugated antisense oligonucleotide. Front Mol Biosci 2023; 10:1096286. [PMID: 36814640 PMCID: PMC9939749 DOI: 10.3389/fmolb.2023.1096286] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 01/20/2023] [Indexed: 02/09/2023] Open
Abstract
Insulin resistance is the major risk factor for Type 2 diabetes (T2D). In vulnerable individuals, insulin resistance induces a progressive loss of insulin secretion with islet pathology revealing a partial deficit of beta cells and islet amyloid derived from islet amyloid polypeptide (IAPP). IAPP is co-expressed and secreted with insulin by beta cells, expression of both proteins being upregulated in response to insulin resistance. If IAPP expression exceeds the threshold for clearance of misfolded proteins, beta cell failure occurs exacerbated by the action of IAPP toxicity to compromise the autophagy lysosomal pathway. We postulated that suppression of IAPP expression by an IAPP antisense oligonucleotide delivered to beta cells by the GLP-1 agonist exenatide (eGLP1-IAPP-ASO) is a potential disease modifying therapy for T2D. While eGLP1-IAPP-ASO suppressed mouse IAPP and transgenic human IAPP expression in mouse islets, it had no discernable effects on IAPP expression in human islets under the conditions studied. Suppression of transgenic human IAPP expression in mouse islets attenuated disruption of the autophagy lysosomal pathway in beta cells, supporting the potential of this strategy.
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Affiliation(s)
- Tatyana Gurlo
- Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States,*Correspondence: Tatyana Gurlo, ; Peter C. Butler,
| | | | - Zhongying Wang
- Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Maani Archang
- Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Lina Pei
- Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Madeline Rosenberger
- Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
| | - Elaine Pirie
- IONIS Pharmaceuticals, Carlsbad, CA, United States
| | | | - Peter C. Butler
- Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States,*Correspondence: Tatyana Gurlo, ; Peter C. Butler,
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4
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Kroon T, Hagstedt T, Alexandersson I, Ferm A, Petersson M, Maurer S, Zarrouki B, Wallenius K, Oakes ND, Boucher J. Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats. Sci Transl Med 2022; 14:eabh1316. [DOI: 10.1126/scitranslmed.abh1316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Circadian rhythms play a critical role in regulating metabolism, including daily cycles of feeding/fasting. Glucokinase (GCK) is central for whole-body glucose homeostasis and oscillates according to a circadian clock. GCK activators (GKAs) effectively reduce hyperglycemia, but their use is also associated with hypoglycemia, hyperlipidemia, and hepatic steatosis. Given the circadian rhythmicity and natural postprandial activation of GCK, we hypothesized that GKA treatment would benefit from being timed specifically during feeding periods. Acute treatment of obese Zucker rats with the GKA AZD1656 robustly increased flux into all major metabolic pathways of glucose disposal, enhancing glucose elimination. Four weeks of continuous AZD1656 treatment of obese Zucker rats improved glycemic control; however, hepatic steatosis and inflammation manifested. In contrast, timing AZD1656 to feeding periods robustly reduced hepatic steatosis and inflammation in addition to improving glycemia, whereas treatment timed to fasting periods caused overall detrimental metabolic effects. Mechanistically, timing AZD1656 to feeding periods diverted newly synthesized lipid toward direct VLDL secretion rather than intrahepatic storage. In line with increased hepatic insulin signaling, timing AZD1656 to feeding resulted in robust activation of AKT, mTOR, and SREBP-1C after glucose loading, pathways known to regulate VLDL secretion and hepatic de novo lipogenesis. In conclusion, intermittent AZD1656 treatment timed to feeding periods promotes glucose disposal when needed the most, restores metabolic flexibility and hepatic insulin sensitivity, and thereby avoids hepatic steatosis. Thus, chronotherapeutic approaches may benefit the development of GKAs and other drugs acting on metabolic targets.
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Affiliation(s)
- Tobias Kroon
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
- Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothernburg 41345, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothernburg 40530 Sweden
| | - Therese Hagstedt
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Ida Alexandersson
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Annett Ferm
- Animal Sciences and Technologies, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Marie Petersson
- Animal Sciences and Technologies, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Stefanie Maurer
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Bader Zarrouki
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Kristina Wallenius
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Nicholas D. Oakes
- Functional and Mechanistic Safety, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg 43183, Sweden
| | - Jeremie Boucher
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg 43183, Sweden
- Lundberg Laboratory for Diabetes Research, University of Gothenburg, Gothernburg 41345, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothernburg 40530 Sweden
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5
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Lupse B, Heise N, Maedler K, Ardestani A. PHLPP1 deletion restores pancreatic β-cell survival and normoglycemia in the db/db mouse model of obesity-associated diabetes. Cell Death Dis 2022; 8:57. [PMID: 35136063 PMCID: PMC8825859 DOI: 10.1038/s41420-022-00853-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 01/11/2022] [Accepted: 01/25/2022] [Indexed: 11/15/2022]
Abstract
The Pleckstrin homology domain leucine-rich repeat protein phosphatases (PHLPPs) are novel therapeutic targets for the restoration of β-cell survival and function in diabetes. Their upregulation and activation in β-cells under conditions of both type 1 and type 2 diabetes directly correlates with β-cell failure; β-cell death and loss of insulin secretory function through disturbance of cell survival control mechanisms. PHLPPs directly dephosphorylate and regulate activities of β-cell survival-dependent kinases AKT and MST1 constituting a regulatory triangle loop to control β-cell apoptosis. PHLPP1 deletion in severely diabetic leptin receptor-deficient db/db mice restored normoglycemia and β-cell area through increased β-cell proliferation and reduced β-cell apoptosis. The beneficial effects of PHLPP1 deficiency in a severe mouse model of obesity and diabetes make PHLPP a new target for β-cell-directed diabetes therapy.
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Affiliation(s)
- Blaz Lupse
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany
| | - Nick Heise
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany
| | - Kathrin Maedler
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
| | - Amin Ardestani
- Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany. .,Department of Molecular Medicine, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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6
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Ford BE, Chachra SS, Alshawi A, Brennan A, Harnor S, Cano C, Baker DJ, Smith DM, Fairclough RJ, Agius L. Chronic glucokinase activator treatment activates liver Carbohydrate response element binding protein and improves hepatocyte ATP homeostasis during substrate challenge. Diabetes Obes Metab 2020; 22:1985-1994. [PMID: 32519798 DOI: 10.1111/dom.14111] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/01/2020] [Accepted: 06/07/2020] [Indexed: 01/16/2023]
Abstract
AIM To test the hypothesis that glucokinase activators (GKAs) induce hepatic adaptations that alter intra-hepatocyte metabolite homeostasis. METHODS C57BL/6 mice on a standard rodent diet were treated with a GKA (AZD1656) acutely or chronically. Hepatocytes were isolated from the mice after 4 or 8 weeks of treatment for analysis of cellular metabolites and gene expression in response to substrate challenge. RESULTS Acute exposure of mice to AZD1656 or a liver-selective GKA (PF-04991532), before a glucose tolerance test, or challenge of mouse hepatocytes with GKAs ex vivo induced various Carbohydrate response element binding protein (ChREBP) target genes, including Carbohydrate response element binding protein beta isoform (ChREBP-β), Gckr and G6pc. Both glucokinase activation and ChREBP target gene induction by PF-04991532 were dependent on the chirality of the molecule, confirming a mechanism linked to glucokinase activation. Hepatocytes from mice treated with AZD1656 for 4 or 8 weeks had lower basal glucose 6-phosphate levels and improved ATP homeostasis during high substrate challenge. They also had raised basal ChREBP-β mRNA and AMPK-α mRNA (Prkaa1, Prkaa2) and progressively attenuated substrate induction of some ChREBP target genes and Prkaa1 and Prkaa2. CONCLUSIONS Chronic GKA treatment of C57BL/6 mice for 8 weeks activates liver ChREBP and improves the resilience of hepatocytes to compromised ATP homeostasis during high-substrate challenge. These changes are associated with raised mRNA levels of ChREBP-β and both catalytic subunits of AMP-activated protein kinase.
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Affiliation(s)
- Brian E Ford
- Biosciences Institute, Newcastle University, Medical School, Newcastle upon Tyne, UK
| | - Shruti S Chachra
- Biosciences Institute, Newcastle University, Medical School, Newcastle upon Tyne, UK
| | - Ahmed Alshawi
- Biosciences Institute, Newcastle University, Medical School, Newcastle upon Tyne, UK
| | - Alfie Brennan
- Newcastle Drug Discovery, Newcastle Centre for Cancer, School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Suzannah Harnor
- Newcastle Drug Discovery, Newcastle Centre for Cancer, School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - Celine Cano
- Newcastle Drug Discovery, Newcastle Centre for Cancer, School of Natural and Environmental Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | - David J Baker
- Bioscience, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - David M Smith
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Rebecca J Fairclough
- Emerging Innovations Unit, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Loranne Agius
- Biosciences Institute, Newcastle University, Medical School, Newcastle upon Tyne, UK
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7
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Sofogianni A, Filippidis A, Chrysavgis L, Tziomalos K, Cholongitas E. Glucagon-like peptide-1 receptor agonists in non-alcoholic fatty liver disease: An update. World J Hepatol 2020; 12:493-505. [PMID: 32952876 PMCID: PMC7475780 DOI: 10.4254/wjh.v12.i8.493] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/02/2020] [Accepted: 06/20/2020] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the predominant cause of chronic liver disease worldwide. NAFLD progresses in some cases to non-alcoholic steatohepatitis (NASH), which is characterized, in addition to liver fat deposition, by hepatocyte ballooning, inflammation and liver fibrosis, and in some cases may lead to hepatocellular carcinoma. NAFLD prevalence increases along with the rising incidence of type 2 diabetes mellitus (T2DM). Currently, lifestyle interventions and weight loss are used as the major therapeutic strategy in the vast majority of patients with NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used in the management of T2DM and do not have major side effects like hypoglycemia. In patients with NAFLD, the GLP-1 receptor production is down-regulated. Recently, several animal and human studies have emphasized the role of GLP-1RAs in ameliorating liver fat accumulation, alleviating the inflammatory environment and preventing NAFLD progression to NASH. In this review, we summarize the updated literature data on the beneficial effects of GLP-1RAs in NAFLD/NASH. Finally, as GLP-1RAs seem to be an attractive therapeutic option for T2DM patients with concomitant NAFLD, we discuss whether GLP-1RAs should represent the first line pharmacotherapy for these patients.
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Affiliation(s)
- Areti Sofogianni
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
| | - Athanasios Filippidis
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
| | - Lampros Chrysavgis
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki 54636, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece.
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Liu J, Yang K, Yang J, Xiao W, Le Y, Yu F, Gu L, Lang S, Tian Q, Jin T, Wei R, Hong T. Liver-derived fibroblast growth factor 21 mediates effects of glucagon-like peptide-1 in attenuating hepatic glucose output. EBioMedicine 2019; 41:73-84. [PMID: 30827929 PMCID: PMC6443026 DOI: 10.1016/j.ebiom.2019.02.037] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 01/30/2019] [Accepted: 02/18/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Glucagon-like peptide-1 (GLP-1) and its based agents improve glycemic control. Although their attenuating effect on hepatic glucose output has drawn our attention for decades, the potential mechanisms remain unclear. METHODS Cytokine array kit was used to assess cytokine profiles in db/db mice and mouse primary hepatocytes treated with exenatide (exendin-4). Two diabetic mouse models (db/db and Pax6m/+) were treated with a GLP-1 analog exenatide or liraglutide. The expression and secretion of fibroblast growth factor 21 (FGF21) in the livers of diabetic mice, primary mouse and human hepatocytes, and the human hepatic cell line HepG2 treated with or without GLP-1 analog were measured. Blockage of FGF21 with neutralizing antibody or siRNA, or hepatocytes isolated from Fgf21 knockout mice were used, and the expression and activity of key enzymes in gluconeogenesis were analyzed. Serum FGF21 level was evaluated in patients with type 2 diabetes (T2D) receiving exenatide treatment. FINDINGS Utilizing the cytokine array, we identified that FGF21 secretion was upregulated by exenatide (exendin-4). Similarly, FGF21 production in hepatocytes was stimulated by exenatide or liraglutide. FGF21 blockage attenuated the inhibitory effects of the GLP-1 analogs on hepatic glucose output. Similar results were also observed in primary hepatocytes from Fgf21 knockout mice. Furthermore, exenatide treatment increased serum FGF21 level in patients with T2D, particularly in those with better glucose control. INTERPRETATION We identify that function of GLP-1 in inhibiting hepatic glucose output is mediated via the liver hormone FGF21. Thus, we provide a new extra-pancreatic mechanism by which GLP-1 regulates glucose homeostasis. FUND: National Key Research and Development Program of China, the National Natural Science Foundation of China, the Natural Science Foundation of Beijing and Peking University Medicine Seed Fund for Interdisciplinary Research.
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Affiliation(s)
- Junling Liu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Kun Yang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Jin Yang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Wenhua Xiao
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Yunyi Le
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Fei Yu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Liangbiao Gu
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Shan Lang
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China
| | - Qing Tian
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China
| | - Tianru Jin
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Banting and Best Diabetes Center, University of Toronto, Toronto, Ontario, Canada
| | - Rui Wei
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China.
| | - Tianpei Hong
- Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China; Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China.
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9
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Vella A, Freeman JLR, Dunn I, Keller K, Buse JB, Valcarce C. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Sci Transl Med 2019; 11:11/475/eaau3441. [DOI: 10.1126/scitranslmed.aau3441] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 06/07/2018] [Accepted: 12/10/2018] [Indexed: 12/19/2022]
Abstract
The therapeutic success of interventions targeting glucokinase (GK) activation for the treatment of type 2 diabetes has been limited by hypoglycemia, steatohepatitis, and loss of efficacy over time. The clinical characteristics of patients with GK-activating mutations or GK regulatory protein (GKRP) loss-of-function mutations suggest that a hepatoselective GK activator (GKA) that does not activate GK in β cells or affect the GK-GKRP interaction may reduce hyperglycemia in patients with type 2 diabetes while limiting hypoglycemia and liver-associated adverse effects. Here, we review the rationale for TTP399, an oral hepatoselective GKA, and its progression from preclinical to clinical development, with an emphasis on the results of a randomized, double-blind, placebo- and active-controlled phase 2 study of TTP399 in patients with type 2 diabetes. In this 6-month study, TTP399 (800 mg/day) was associated with a clinically significant and sustained reduction in glycated hemoglobin, with a placebo-subtracted least squares mean HbA1c change from baseline of −0.9% (P < 0.01). Compared to placebo, TTP399 (800 mg/day) also increased high-density lipoprotein cholesterol (3.2 mg/dl; P < 0.05), decreased fasting plasma glucagon (−20 pg/ml; P < 0.05), and decreased weight in patients weighing ≥100 kg (−3.4 kg; P < 0.05). TTP399 did not cause hypoglycemia, had no detrimental effect on plasma lipids or liver enzymes, and did not increase blood pressure, highlighting the importance of tissue selectivity and preservation of physiological regulation when targeting key metabolic regulators such as GK.
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10
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Faita F, Di Lascio N, Rossi C, Kusmic C, Solini A. Ultrasonographic Characterization of the db/db Mouse: An Animal Model of Metabolic Abnormalities. J Diabetes Res 2018; 2018:4561309. [PMID: 29707583 PMCID: PMC5863337 DOI: 10.1155/2018/4561309] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 12/13/2017] [Accepted: 01/04/2018] [Indexed: 12/18/2022] Open
Abstract
The availability of an animal model able to reliably mirror organ damage occurring in metabolic diseases is an urgent need. These models, mostly rodents, have not been fully characterized in terms of cardiovascular, renal, and hepatic ultrasound parameters, and only sparse values can be found in literature. Aim of this paper is to provide a detailed, noninvasive description of the heart, vessels, liver, and kidneys of the db/db mouse by ultrasound imaging. Sixteen wild type and thirty-four db/db male mice (11-week-old) were studied. State-of-the-art ultrasound technology was used to acquire images of cardiovascular, renal, and hepatic districts. A set of parameters describing function of the selected organs was evaluated. db/db mice are characterized by systolic and diastolic dysfunction, confirmed by strain analysis. Abdominal aortic and carotid stiffness do not seem to be increased in diabetic rodents; furthermore, they are characterized by a smaller mean diameter for both vessels. Renal microcirculation is significantly compromised, while liver steatosis is only slightly higher in db/db mice than in controls. We offer here for the first time an in vivo detailed ultrasonographic characterization of the db/db mouse, providing a useful tool for a thoughtful choice of the right rodent model for any experimental design.
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MESH Headings
- Animals
- Aorta, Abdominal/diagnostic imaging
- Aorta, Abdominal/physiopathology
- Blood Glucose/metabolism
- Carotid Artery, Common/diagnostic imaging
- Carotid Artery, Common/physiopathology
- Diabetes Mellitus/blood
- Diabetes Mellitus/diagnostic imaging
- Diabetes Mellitus/genetics
- Diabetes Mellitus/physiopathology
- Disease Models, Animal
- Echocardiography, Doppler, Pulsed
- Genetic Predisposition to Disease
- Heart/diagnostic imaging
- Heart/physiopathology
- Lipids/blood
- Liver/diagnostic imaging
- Liver/physiopathology
- Male
- Mice, Inbred C57BL
- Microcirculation
- Perfusion Imaging/methods
- Phenotype
- Predictive Value of Tests
- Renal Artery/diagnostic imaging
- Renal Artery/physiopathology
- Renal Circulation
- Ultrasonography, Doppler, Pulsed
- Vascular Stiffness
- Ventricular Function, Left
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Affiliation(s)
- Francesco Faita
- Institute of Clinical Physiology, Italian National Research Council, Pisa, Italy
| | - Nicole Di Lascio
- Institute of Clinical Physiology, Italian National Research Council, Pisa, Italy
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Chiara Rossi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Claudia Kusmic
- Institute of Clinical Physiology, Italian National Research Council, Pisa, Italy
| | - Anna Solini
- Department of Surgical, Medical, Molecular, and Critical Area Pathology, University of Pisa, Pisa, Italy
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11
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Ahangarpour A, Oroojan AA, Badavi M. Exendin-4 protects mice from D-galactose-induced hepatic and pancreatic dysfunction. PATHOBIOLOGY OF AGING & AGE RELATED DISEASES 2017; 8:1418593. [PMID: 29321828 PMCID: PMC5757233 DOI: 10.1080/20010001.2017.1418593] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 12/14/2017] [Indexed: 01/08/2023]
Abstract
Investigations into pharmaceutical intervention of pancreatic and hepatic dysfunction associated with metabolic disturbances have received relatively little attention. The aim of this study was to investigate the protective effects of exendin-4 in mice receiving D-galactose, a reducing sugar that triggers ROS production and inflammatory mediators affecting the pancreas and liver. Exendin-4 is an United States Food and Drug Administration (FDA) approved glucagon-like peptide that increases insulin dependent glycogen synthesis and glucose uptake. Male NMRI mice (20–25 g), 3 months of age, were randomly divided into 6 groups of 12 mice each: control, exendin-4 (1 nmol/kg), exendin-4 (10 nmol/kg), D-galactose, D-galactose + exendin-4 (1 nmol/kg) and D-galactose + exendin-4 (10 nmol/kg). D-galactose (500 mg/kg) was given daily by oral gavage for 6 weeks. During the last 10 days, exendin-4 (1 and 10 nmol/kg) was injected intraperitoneally daily. Glucose, insulin, insulin resistance, lipid profiles, and hepatic enzyme levels significantly increased in the D-galactose group (p < 0.05), along with a significant decrease in superoxide dismutase activity and pancreatic islet insulin secretion (p < 0.05). Exendin-4 decreased D-galactose-induced increases in serum glucose and insulin, insulin resistance, lipid profiles, and hepatic enzymes, and improved pancreatic islet insulin secretion and antioxidant defense status. The results show that exendin-4 can prevent complications in mice with compromised pancreatic and hepatic function. Long term administration of D-galactose in mice may be a useful model to study insulin resistance, metabolic syndrome, and aging.
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Affiliation(s)
- Akram Ahangarpour
- Diabetes Research Center, Department of Physiology, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Ali Akbar Oroojan
- Department of Physiology, Student Research Committee of Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran
| | - Mohammad Badavi
- Physiology Research Center, Department of Physiology, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
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12
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Exenatide reverses dysregulated microRNAs in high-fat diet-induced obese mice. Obes Res Clin Pract 2016; 10:315-26. [DOI: 10.1016/j.orcp.2015.07.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Revised: 06/28/2015] [Accepted: 07/20/2015] [Indexed: 12/24/2022]
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13
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Roma LP, Duprez J, Jonas JC. Glucokinase activation is beneficial or toxic to cultured rat pancreatic islets depending on the prevailing glucose concentration. Am J Physiol Endocrinol Metab 2015; 309:E632-9. [PMID: 26264555 DOI: 10.1152/ajpendo.00154.2015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 08/10/2015] [Indexed: 11/22/2022]
Abstract
In rat pancreatic islets, β-cell gene expression, survival, and subsequent acute glucose stimulation of insulin secretion (GSIS) are optimally preserved by prolonged culture at 10 mM glucose (G10) and markedly altered by culture at G5 or G30. Here, we tested whether pharmacological glucokinase (GK) activation prevents these alterations during culture or improves GSIS after culture. Rat pancreatic islets were cultured 1-7 days at G5, G10, or G30 with or without 3 μM of the GK activator Ro 28-0450 (Ro). After culture, β-cell apoptosis and islet gene mRNA levels were measured, and the acute glucose-induced increase in NAD(P)H autofluorescence, intracellular calcium concentration, and insulin secretion were tested in the absence or presence of Ro. Prolonged culture of rat islets at G5 or G30 instead of G10 triggered β-cell apoptosis and reduced their glucose responsiveness. Addition of Ro during culture differently affected β-cell survival and glucose responsiveness depending on the glucose concentration during culture: it was beneficial to β-cell survival and function at G5, detrimental at G10, and ineffective at G30. In contrast, acute GK activation with Ro increased the glucose sensitivity of islets cultured at G10 but failed at restoring β-cell glucose responsiveness after culture at G5 or G30. We conclude that pharmacological GK activation prevents the alteration of β-cell survival and function by long-term culture at G5 but mimics glucotoxicity when added to G10. The complex effects of glucose on the β-cell phenotype result from changes in glucose metabolism and not from an effect of glucose per se.
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Affiliation(s)
- Leticia P Roma
- Université catholique de Louvain, Institut de recherche expérimentale et clinique, Pôle d'endocrinologie, diabète et nutrition, Brussels, Belgium; and
| | - Jessica Duprez
- Université catholique de Louvain, Institut de recherche expérimentale et clinique, Pôle d'endocrinologie, diabète et nutrition, Brussels, Belgium; and
| | - Jean-Christophe Jonas
- Université catholique de Louvain, Institut de recherche expérimentale et clinique, Pôle d'endocrinologie, diabète et nutrition, Brussels, Belgium; and Fonds de la recherche scientifique-FNRS, Brussels, Belgium
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14
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Eiden M, Koulman A, Hatunic M, West JA, Murfitt S, Osei M, Adams C, Wang X, Chu Y, Marney L, Roberts LD, O'Rahilly S, Semple RK, Savage DB, Griffin JL. Mechanistic insights revealed by lipid profiling in monogenic insulin resistance syndromes. Genome Med 2015; 7:63. [PMID: 26273324 PMCID: PMC4535665 DOI: 10.1186/s13073-015-0179-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 06/02/2015] [Indexed: 01/21/2023] Open
Abstract
Background Evidence from several recent metabolomic studies suggests that increased concentrations of triacylglycerols with shorter (14–16 carbon atoms), saturated fatty acids are associated with insulin resistance and the risk of type 2 diabetes. Although causality cannot be inferred from association studies, patients in whom the primary cause of insulin resistance can be genetically defined offer unique opportunities to address this challenge. Methods We compared metabolite profiles in patients with congenital lipodystrophy or loss-of-function insulin resistance (INSR gene) mutations with healthy controls. Results The absence of significant differences in triacylglycerol species in the INSR group suggest that changes previously observed in epidemiological studies are not purely a consequence of insulin resistance. The presence of triacylglycerols with lower carbon numbers and high saturation in patients with lipodystrophy suggests that these metabolite changes may be associated with primary adipose tissue dysfunction. The observed pattern of triacylglycerol species is indicative of increased de novo lipogenesis in the liver. To test this we investigated the distribution of these triacylglycerols in lipoprotein fractions using size exclusion chromatography prior to mass spectrometry. This associated these triacylglycerols with very low-density lipoprotein particles, and hence release of triacylglycerols into the blood from the liver. To test further the hepatic origin of these triacylglycerols we induced de novo lipogenesis in the mouse, comparing ob/ob and wild-type mice on a chow or high fat diet, confirming that de novo lipogenesis induced an increase in relatively shorter, more saturated fatty acids. Conclusions Overall, these studies highlight hepatic de novo lipogenesis in the pathogenesis of metabolic dyslipidaemia in states where energy intake exceeds the capacity of adipose tissue. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0179-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Michael Eiden
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK
| | - Albert Koulman
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK
| | - Mensud Hatunic
- Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - James A West
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK ; Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK
| | - Steven Murfitt
- Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK
| | - Michael Osei
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK
| | - Claire Adams
- Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Xinzhu Wang
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK ; Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK
| | - Yajing Chu
- Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK
| | - Luke Marney
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK
| | - Lee D Roberts
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK ; Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK
| | - Stephen O'Rahilly
- Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Robert K Semple
- Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - David B Savage
- Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - Julian L Griffin
- MRC Human Nutrition Research, Elsie Widdowson Laboratory, 120 Fulbourn Road, Cambridge, CB1 9NL UK ; Department of Biochemistry and the Cambridge Systems Biology Centre, University of Cambridge, Tennis Court Road, Cambridge, UK
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15
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Li CL, Zhao LJ, Zhou XL, Wu HX, Zhao JJ. Review on the effect of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors for the treatment of non-alcoholic fatty liver disease. ACTA ACUST UNITED AC 2015; 35:333-336. [PMID: 26072069 DOI: 10.1007/s11596-015-1433-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Revised: 03/20/2015] [Indexed: 01/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease and it represents the hepatic manifestation of metabolic syndrome, which includes type 2 diabetes mellitus (T2DM), dyslipidemia, central obesity and hypertension. Glucagon-like peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4 (DPP-4) inhibitors were widely used to treat T2DM. These agents improve glycemic control, promote weight loss and improve lipid metabolism. Recent studies have demonstrated that the GLP-1 receptor (GLP-1R) is present and functional in human and rat hepatocytes. In this review, we present data from animal researches and human clinical studies that showed GLP-1 analogues and DPP-4 inhibitors can decrease hepatic triglyceride (TG) content and improve hepatic steatosis, although some effects could be a result of improvements in metabolic parameters. Multiple hepatocyte signal transduction pathways and mRNA from key enzymes in fatty acid metabolism appear to be activated by GLP-1 and its analogues. Thus, the data support the need for more rigorous prospective clinical trials to further investigate the potential of incretin therapies to treat patients with NAFLD.
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Affiliation(s)
- Chao-Lin Li
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
- Department of Endocrinology, Jinan, China
| | - Lu-Jie Zhao
- Hemodialysis Center, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, 264000, China
| | - Xin-Li Zhou
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
| | - Hui-Xiao Wu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China
| | - Jia-Jun Zhao
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021, China.
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16
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Nakamura A, Terauchi Y. Present status of clinical deployment of glucokinase activators. J Diabetes Investig 2014; 6:124-32. [PMID: 25802718 PMCID: PMC4364845 DOI: 10.1111/jdi.12294] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 09/24/2014] [Accepted: 09/25/2014] [Indexed: 12/14/2022] Open
Abstract
Glucokinase is one of four members of the hexokinase family of enzymes. Its expression is limited to the major organs (such as the pancreas, liver, brain and the gastrointestinal tract) that are thought to have an integrated role in glucose sensing. In the liver, phosphorylation of glucose by glucokinase promotes glycogen synthesis, whereas in the β-cells, it results in insulin release. Studies of glucokinase-linked genetically-modified mice and mutations in humans have illustrated the important roles played by glucokinase in whole-body glucose homeostasis, and suggest that the use of pharmacological agents that augment glucokinase activity could represent a viable treatment strategy in patients with type 2 diabetes. Since 2003, many glucokinase activators (GKAs) have been developed, and their ability to lower the blood glucose has been shown in several animal models of type 2 diabetes. Also, we and others have shown in mouse models that GKAs also have the effect of stimulating the proliferation of β-cells. However, the results of recent phase II trials have shown that GKAs lose their efficacy within several months of use, and that their use is associated with a high incidence of hypoglycemia; furthermore, patients treated with GKAs frequently developed dyslipidemia. A better understanding of the role of glucokinase in metabolic effects is required to resolve several issues identified in clinical trials.
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Affiliation(s)
- Akinobu Nakamura
- Division of Immunology and Metabolism, Hokkaido University Graduate School of Medicine Sapporo, Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University Yokohama, Japan
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17
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Kawaguchi T, Itou M, Taniguchi E, Sata M. Exendin‑4, a glucagon‑like peptide‑1 receptor agonist, modulates hepatic fatty acid composition and Δ‑5‑desaturase index in a murine model of non‑alcoholic steatohepatitis. Int J Mol Med 2014; 34:782-7. [PMID: 24993337 DOI: 10.3892/ijmm.2014.1826] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 05/28/2014] [Indexed: 12/12/2022] Open
Abstract
Glucagon‑like peptide‑1 (GLP‑1) is involved in the development of non‑alcoholic steatohepatitis (NASH), which is characterized by fatty acid imbalance. The aim of this study was to investigate the effects of the GLP‑1 receptor (GLP‑1R) agonist, exendin‑4 (Ex‑4), on hepatic fatty acid metabolism and its key enzyme, Δ‑5‑desaturase, in a murine model of NASH. NASH was induced in db/db mice fed a methionine‑choline deficient (MCD) diet. Ex‑4 (n=4) or saline [control (CON); n=4] was administered intraperitoneally for 8 weeks. Steatohepatitis activity was evaluated by non‑alcoholic fatty liver disease (NAFLD) activity score. Hepatic fatty acid composition and Δ‑5‑desaturase index were analyzed by gas chromatography. Ex‑4 treatment significantly reduced body weight and the NAFLD activity score. Hepatic concentrations of long‑chain saturated fatty acids (SFAs) were significantly higher in the Ex‑4 group compared to the CON group (23240±955 vs. 31710±8436 µg/g•liver, P<0.05).Ex‑4 significantly reduced hepatic n‑3 polyunsaturated fatty acid (PUFA)/n‑6 PUFA ratio compared to the CON group (13.83±3.15 vs. 8.73±1.95, P<0.05). In addition, the hepatic Δ‑5‑desaturase index was significantly reduced in the Ex‑4 group compared to the CON group (31.1±12.4 vs. 10.5±3.1, P<0.05). In conclusion, the results showed that Ex‑4 improved steatohepatitis in a murine model of NASH. Furthermore, Ex‑4 altered hepatic long‑chain saturated and PUFA composition and reduced the Δ‑5‑desaturase index. Thus, Ex‑4 may improve NASH by regulating hepatic fatty acid metabolism.
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Affiliation(s)
- Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830‑0011, Japan
| | - Minoru Itou
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830‑0011, Japan
| | - Eitaro Taniguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830‑0011, Japan
| | - Michio Sata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume 830‑0011, Japan
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