|
1
|
Bertinat R, Holyoak T, Gatica R, Jara N, González-Chavarría I, Westermeier F. The neglected PCK1/glucagon (inter)action in nutrient homeostasis beyond gluconeogenesis: Disease pathogenesis and treatment. Mol Metab 2025; 94:102112. [PMID: 39954782 PMCID: PMC11909762 DOI: 10.1016/j.molmet.2025.102112] [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: 11/30/2024] [Revised: 01/30/2025] [Accepted: 02/10/2025] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND Glucagon plays a central role in hepatic adaptation during fasting, with the upregulation of hepatic phosphoenolpyruvate carboxykinase 1 (PCK1) traditionally associated with increased gluconeogenesis. However, recent experimental models and clinical studies have challenged this view, suggesting a more complex interplay between PCK1 and glucagon, which extends beyond gluconeogenesis and has broader implications for metabolic regulation in health and disease. SCOPE OF REVIEW This review provides a comprehensive overview of the current evidence on the multifaceted roles of PCK1 in glucagon-dependent hepatic adaptation during fasting, which is crucial for maintaining systemic homeostasis not only of glucose, but also of lipids and amino acids. We explore the relationship between PCK1 deficiency and glucagon resistance in metabolic disorders, including inherited PCK1 deficiency and metabolic dysfunction-associated steatotic liver disease (MASLD), and compare findings from experimental animal models with whole-body or tissue-specific ablation of PCK1 or the glucagon receptor. We propose new research platforms to advance the therapeutic potential of targeting PCK1 in metabolic diseases. MAJOR CONCLUSIONS We propose that hepatic PCK1 deficiency might be an acquired metabolic disorder linking alterations in lipid metabolism with impaired glucagon signaling. Our findings highlight interesting links between glycerol, PCK1 deficiency, elevated plasma alanine levels and glucagon resistance. We conclude that the roles of PCK1 and glucagon in metabolic regulation are more complex than previously assumed. In this (un)expected scenario, hepatic PCK1 deficiency and glucagon resistance appear to exert limited control over glycemia, but have broader metabolic effects related to lipid and amino acid dysregulation. Given the shift in glucagon research from receptor inhibition to activation, we propose that a similar paradigm shift is needed in the study of hepatic PCK1. Understanding PCK1 expression and activity in the glucagon-dependent hepatic adaptation to fasting might provide new perspectives and therapeutic opportunities for metabolic diseases.
Collapse
Affiliation(s)
- Romina Bertinat
- Centro de Microscopía Avanzada, CMA-BIO BIO, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción, Chile; Laboratorio de Lipoproteínas y Cáncer, Departamento de Fisiopatología, Universidad de Concepción, Concepción, Chile.
| | - Todd Holyoak
- Department of Biology, Faculty of Science, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2L 3G1, Canada
| | - Rodrigo Gatica
- Escuela de Veterinaria, Facultad de Ciencias, Universidad Mayor, Santiago, Chile
| | - Nery Jara
- Departamento de Farmacología, Universidad de Concepción, Concepción, Chile
| | - Iván González-Chavarría
- Laboratorio de Lipoproteínas y Cáncer, Departamento de Fisiopatología, Universidad de Concepción, Concepción, Chile
| | - Francisco Westermeier
- Institute of Biomedical Science, Department of Health Studies, FH JOANNEUM University of Applied Sciences, Graz, Austria; Centro de Biología y Química Aplicada (CIBQA), Universidad Bernardo O'Higgins, Santiago, Chile.
| |
Collapse
|
|
2
|
Sabatini S, Sen P, Carli F, Pezzica S, Rosso C, Lembo E, Verrastro O, Daly A, Govaere O, Cockell S, Hyötyläinen T, Mingrone G, Bugianesi E, Anstee QM, Orešič M, Gastaldelli A. Hepatic glucose production rises with the histological severity of metabolic dysfunction-associated steatohepatitis. Cell Rep Med 2024; 5:101820. [PMID: 39566466 PMCID: PMC11604487 DOI: 10.1016/j.xcrm.2024.101820] [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: 08/25/2023] [Revised: 07/25/2024] [Accepted: 10/16/2024] [Indexed: 11/22/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are associated with a high prevalence of type 2 diabetes (T2D). Individuals with MASLD exhibit insulin resistance (IR) and hyperglycemia, but it is unclear whether hepatic glucose production (HGP) is increased with MASLD severity. We evaluated HGP in a cohort of histologically characterized individuals with MASL/MASH using stable isotope infusion (6,6-2H2-glucose, U-2H5-glycerol) and liver-specific genome-scale metabolic models (GEMs). Tracer-measured HGP is increased with liver fibrosis and inflammation, but not steatosis, and is associated with lipolysis and IR. The GEM-derived gluconeogenesis is elevated due to high glucogenic/energy metabolite uptakes (lactate, glycerol, and free fatty acid [FFA]), and the expression of insulin action genes (IRS1, IRS2, and AKT2) is reduced in MASH with fibrosis F2-F4, with/without T2D, suggesting these as putative mechanisms for increased fasting HGP and hyperglycemia. In conclusion, elevated HGP, lipolysis, and IR help to explain the mechanisms for the increased risk of hyperglycemia and T2D in MASH.
Collapse
Affiliation(s)
- Silvia Sabatini
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy
| | - Partho Sen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
| | - Fabrizia Carli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy
| | - Samantha Pezzica
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy
| | - Chiara Rosso
- Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, 10124 Turin, Italy
| | - Erminia Lembo
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
| | - Ornella Verrastro
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ann Daly
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Olivier Govaere
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Department of Imaging and Pathology, KU Leuven and University Hospitals Leuven, Leuven, Belgium
| | - Simon Cockell
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
| | - Tuulia Hyötyläinen
- School of Science and Technology, Örebro University, 70281 Örebro, Sweden
| | - Geltrude Mingrone
- Department of Medical and Surgical Sciences, Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Division of Diabetes & Nutritional Sciences, School of Cardiovascular and Metabolic Medicine & Sciences, King's College Hospital, London, UK
| | - Elisabetta Bugianesi
- Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, 10124 Turin, Italy
| | - Quentin M Anstee
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne NE7 7DN, UK
| | - Matej Orešič
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; School of Medical Sciences, Örebro University, 70281 Örebro, Sweden.
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, 56121 Pisa, Italy; Diabetes Division, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
| |
Collapse
|
|
3
|
Huang S, Liang H, Chen Y, Liu C, Luo P, Wang H, Du Q. Hypoxanthine ameliorates diet-induced insulin resistance by improving hepatic lipid metabolism and gluconeogenesis via AMPK/mTOR/PPARα pathway. Life Sci 2024; 357:123096. [PMID: 39369847 DOI: 10.1016/j.lfs.2024.123096] [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: 06/11/2024] [Revised: 09/09/2024] [Accepted: 09/28/2024] [Indexed: 10/08/2024]
Abstract
AIM Insulin resistance (IR) is a pivotal metabolic disorder associated with type 2 diabetes and metabolic syndrome. This study investigated the potential of hypoxanthine (Hx), a purine metabolite and uric acid precursor, in ameliorating IR and regulating hepatic glucose and lipid metabolism. METHODS We utilized both in vitro IR-HepG2 cells and in vivo diet-induced IR mice to investigate the impact of Hx. The HepG2 cells were treated with Hx to evaluate its effects on glucose production and lipid deposition. Activity-based protein profiling (ABPP) was applied to identify Hx-target proteins and the underlying pathways. In vivo studies involved administration of Hx to IR mice, followed by assessments of IR-associated indices, with explores on the potential regulating mechanisms on hepatic glucose and lipid metabolism. KEY FINDINGS Hx intervention significantly reduced glucose production and lipid deposition in a dose-dependent manner without affecting cell viability in IR-HepG2 cells. ABPP identified key Hx-target proteins engaged in fatty acid and pyruvate metabolism. In vivo, Hx treatment reduced IR severities, as evidenced by decreased HOMA-IR, fasting blood glucose, and serum lipid profiles. Histological assessments confirmed reduced liver lipid deposition. Mechanistic insights revealed that Hx suppresses hepatic gluconeogenesis and fatty acid synthesis, and promotes fatty acid oxidation via the AMPK/mTOR/PPARα pathway. SIGNIFICANCE This study delineates a novel role of Hx in regulating hepatic metabolism, offering a potential therapeutic strategy for IR and associated metabolic disorders. The findings provide a foundation for further investigation into the role of purine metabolites in metabolic regulation and their clinical implications.
Collapse
Affiliation(s)
- Sizhe Huang
- Centre of General Practice, the Seventh Affiliated Hospital, Southern Medical University, Foshan 528000, Guangdong, PR China
| | - Hengmiao Liang
- Centre of General Practice, the Seventh Affiliated Hospital, Southern Medical University, Foshan 528000, Guangdong, PR China
| | - Yuting Chen
- Department of Laboratory Medicine, the Seventh Affiliated Hospital, Southern Medical University, Foshan 528000, Guangdong, PR China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China
| | - Ce Liu
- Department of Laboratory Medicine, the Seventh Affiliated Hospital, Southern Medical University, Foshan 528000, Guangdong, PR China
| | - Piao Luo
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China.
| | - Huijun Wang
- Centre of General Practice, the Seventh Affiliated Hospital, Southern Medical University, Foshan 528000, Guangdong, PR China; Department of Laboratory Medicine, the Seventh Affiliated Hospital, Southern Medical University, Foshan 528000, Guangdong, PR China.
| | - Qingfeng Du
- Centre of General Practice, the Seventh Affiliated Hospital, Southern Medical University, Foshan 528000, Guangdong, PR China; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, PR China.
| |
Collapse
|
|
4
|
Mutlu B, Sharabi K, Sohn JH, Yuan B, Latorre-Muro P, Qin X, Yook JS, Lin H, Yu D, Camporez JPG, Kajimura S, Shulman GI, Hui S, Kamenecka TM, Griffin PR, Puigserver P. Small molecules targeting selective PCK1 and PGC-1α lysine acetylation cause anti-diabetic action through increased lactate oxidation. Cell Chem Biol 2024; 31:1772-1786.e5. [PMID: 39341205 PMCID: PMC11500315 DOI: 10.1016/j.chembiol.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 06/27/2024] [Accepted: 09/04/2024] [Indexed: 09/30/2024]
Abstract
Small molecules selectively inducing peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α acetylation and inhibiting glucagon-dependent gluconeogenesis causing anti-diabetic effects have been identified. However, how these small molecules selectively suppress the conversion of gluconeogenic metabolites into glucose without interfering with lipogenesis is unknown. Here, we show that a small molecule SR18292 inhibits hepatic glucose production by increasing lactate and glucose oxidation. SR18292 increases phosphoenolpyruvate carboxykinase 1 (PCK1) acetylation, which reverses its gluconeogenic reaction and favors oxaloacetate (OAA) synthesis from phosphoenolpyruvate. PCK1 reverse catalytic reaction induced by SR18292 supplies OAA to tricarboxylic acid (TCA) cycle and is required for increasing glucose and lactate oxidation and suppressing gluconeogenesis. Acetylation mimetic mutant PCK1 K91Q favors anaplerotic reaction and mimics the metabolic effects of SR18292 in hepatocytes. Liver-specific expression of PCK1 K91Q mutant ameliorates hyperglycemia in obese mice. Thus, SR18292 blocks gluconeogenesis by enhancing gluconeogenic substrate oxidation through PCK1 lysine acetylation, supporting the anti-diabetic effects of these small molecules.
Collapse
Affiliation(s)
- Beste Mutlu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Kfir Sharabi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA; Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Jee Hyung Sohn
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Bo Yuan
- Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA
| | - Pedro Latorre-Muro
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Xin Qin
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Jin-Seon Yook
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
| | - Hua Lin
- Department of Molecular Medicine, The Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL 33458, USA
| | - Deyang Yu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA
| | - João Paulo G Camporez
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520-8020, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06520-8020, USA
| | - Shingo Kajimura
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 020815, USA
| | - Gerald I Shulman
- Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06520-8020, USA; Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06520-8020, USA; Howard Hughes Medical Institute, Chevy Chase, MD 020815, USA
| | - Sheng Hui
- Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA
| | - Theodore M Kamenecka
- Department of Molecular Medicine, The Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL 33458, USA
| | - Patrick R Griffin
- Department of Molecular Medicine, The Wertheim UF Scripps Institute for Biomedical Innovation and Technology, University of Florida, Jupiter, FL 33458, USA
| | - Pere Puigserver
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
| |
Collapse
|
|
5
|
Chen M, Pan P, Zhang H, Li R, Ren D, Jiang B. Latilactobacillus sakei QC9 alleviates hyperglycaemia in high-fat diet and streptozotocin-induced type 2 diabetes mellitus mice via the microbiota-gut-liver axis. Food Funct 2024; 15:8008-8029. [PMID: 38984868 DOI: 10.1039/d4fo02316a] [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: 07/11/2024]
Abstract
Probiotics have been considered a promising option for mitigating the progression of type 2 diabetes mellitus (T2DM). Here, Latilactobacillus sakei QC9 (L. sakei QC9) with a hypoglycemic effect was screened out from 30 food-derived strains through α-glucosidase and α-amylase activity inhibition tests in vitro and a 4-week in vivo preliminary animal experiment. To further understand its alleviating effect on long-term hyperglycaemia occurring in T2DM, we conducted an experiment that lasted for 8 weeks. The results showed that taking L. sakei QC9 can regulate glucose and lipid metabolism while improving the antioxidant capacity and alleviating chronic inflammation. In addition, our results demonstrated that L. sakei QC9 may mediate the microbiota-gut-liver axis by regulating the composition of intestinal flora (increasing the abundance of butyrate-producing bacteria) and increasing the content of short-chain fatty acids (especially butyrate), affecting the PI3K/Akt signalling pathway in the liver, thereby achieving the purpose of alleviating the development of T2DM. In summary, our work is the first to prove the long-term hypoglycemic effect of L. sakei in high-fat diet (HFD) and streptozotocin (STZ)-induced T2DM mice and supports the possibility of L. sakei QC9 being used as a new treatment for alleviating T2DM.
Collapse
Affiliation(s)
- Mengling Chen
- College of Food Science and Engineering, Jilin Agricultural University, 130118 Changchun, China.
| | - Pengyuan Pan
- College of Food Science and Engineering, Jilin Agricultural University, 130118 Changchun, China.
| | - Hongyan Zhang
- College of Food Science and Engineering, Jilin Agricultural University, 130118 Changchun, China.
| | - Rao Li
- College of Food Science and Engineering, Jilin Agricultural University, 130118 Changchun, China.
| | - Dayong Ren
- College of Food Science and Engineering, Jilin Agricultural University, 130118 Changchun, China.
| | - Bin Jiang
- College of Food Science and Engineering, Jilin Agricultural University, 130118 Changchun, China.
| |
Collapse
|
|
6
|
Sabbatinelli J, Giuliani A, Kwiatkowska KM, Matacchione G, Belloni A, Ramini D, Prattichizzo F, Pellegrini V, Piacenza F, Tortato E, Bonfigli AR, Gentilini D, Procopio AD, Garagnani P, Olivieri F, Bronte G. DNA Methylation-derived biological age and long-term mortality risk in subjects with type 2 diabetes. Cardiovasc Diabetol 2024; 23:250. [PMID: 39003492 PMCID: PMC11245869 DOI: 10.1186/s12933-024-02351-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 07/06/2024] [Indexed: 07/15/2024] Open
Abstract
BACKGROUND Individuals with type 2 diabetes (T2D) face an increased mortality risk, not fully captured by canonical risk factors. Biological age estimation through DNA methylation (DNAm), i.e. the epigenetic clocks, is emerging as a possible tool to improve risk stratification for multiple outcomes. However, whether these tools predict mortality independently of canonical risk factors in subjects with T2D is unknown. METHODS Among a cohort of 568 T2D patients followed for 16.8 years, we selected a subgroup of 50 subjects, 27 survived and 23 deceased at present, passing the quality check and balanced for all risk factors after propensity score matching. We analyzed DNAm from peripheral blood leukocytes using the Infinium Human MethylationEPIC BeadChip (Illumina) to evaluate biological aging through previously validated epigenetic clocks and assess the DNAm-estimated levels of selected inflammatory proteins and blood cell counts. We tested the associations of these estimates with mortality using two-stage residual-outcome regression analysis, creating a reference model on data from the group of survived patients. RESULTS Deceased subjects had higher median epigenetic age expressed with DNAmPhenoAge algorithm (57.49 [54.72; 60.58] years. vs. 53.40 [49.73; 56.75] years; p = 0.012), and accelerated DunedinPoAm pace of aging (1.05 [1.02; 1.11] vs. 1.02 [0.98; 1.06]; p = 0.012). DNAm PhenoAge (HR 1.16, 95% CI 1.05-1.28; p = 0.004) and DunedinPoAm (HR 3.65, 95% CI 1.43-9.35; p = 0.007) showed an association with mortality independently of canonical risk factors. The epigenetic predictors of 3 chronic inflammation-related proteins, i.e. CXCL10, CXCL11 and enRAGE, C-reactive protein methylation risk score and DNAm-based estimates of exhausted CD8 + T cell counts were higher in deceased subjects when compared to survived. CONCLUSIONS These findings suggest that biological aging, as estimated through existing epigenetic tools, is associated with mortality risk in individuals with T2D, independently of common risk factors and that increased DNAm-surrogates of inflammatory protein levels characterize deceased T2D patients. Replication in larger cohorts is needed to assess the potential of this approach to refine mortality risk in T2D.
Collapse
Affiliation(s)
- Jacopo Sabbatinelli
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
- Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy
| | - Angelica Giuliani
- Istituti Clinici Scientifici Maugeri IRCCS, Cardiac Rehabilitation Unit of Bari Institute, Bari, Italy.
| | | | | | - Alessia Belloni
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
| | - Deborah Ramini
- Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy
| | | | | | - Francesco Piacenza
- Advanced Technology Center for Aging Research, IRCCS INRCA, Ancona, Italy
| | - Elena Tortato
- Department of Metabolic Diseases and Diabetology, IRCCS INRCA, Ancona, Italy
| | | | - Davide Gentilini
- Department of Brain and Behavioral Sciences, Università di Pavia, Pavia, Italy
- Bioinformatics and Statistical Genomics Unit, Istituto Auxologico Italiano IRCCS, Cusano Milanino, Milan, Italy
| | - Antonio Domenico Procopio
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
- Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy
| | - Paolo Garagnani
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.
| | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
- Advanced Technology Center for Aging Research, IRCCS INRCA, Ancona, Italy
| | - Giuseppe Bronte
- Department of Clinical and Molecular Sciences (DISCLIMO), Università Politecnica delle Marche, Ancona, Italy
- Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy
| |
Collapse
|
|
7
|
Westcott F, Dearlove DJ, Hodson L. Hepatic fatty acid and glucose handling in metabolic disease: Potential impact on cardiovascular disease risk. Atherosclerosis 2024; 394:117237. [PMID: 37633797 DOI: 10.1016/j.atherosclerosis.2023.117237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/09/2023] [Accepted: 08/10/2023] [Indexed: 08/28/2023]
Abstract
The prevalence of metabolic diseases, including type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing. Although invariably associated with obesity, the importance of fat deposition in non-adipose tissue organs has yet to be fully explored. Pathological ectopic fat deposition within the liver (known as (MASLD)) has been suggested to underlie the development of T2DM and is now emerging as an independent risk factor for cardiovascular disease (CVD). The process of hepatic de novo lipogenesis (DNL), that is the synthesis of fatty acids from non-lipid precursors (e.g. glucose), has received much attention as it sits at the intersect of hepatic glucose and fatty acid handling. An upregulation of the DNL pathway has been suggested to be central in the development of metabolic diseases (including MASLD, insulin resistance, and T2DM). Here we review the evidence to determine if hepatic DNL may play a role in the development of MASLD and T2DM and therefore underlie an increased risk of CVD.
Collapse
Affiliation(s)
- Felix Westcott
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK
| | - David J Dearlove
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, UK; Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, UK.
| |
Collapse
|
|
8
|
Hatano R, Lee E, Sato H, Kiuchi M, Hirahara K, Nakagawa Y, Shimano H, Nakayama T, Tanaka T, Miki T. Hepatic ketone body regulation of renal gluconeogenesis. Mol Metab 2024; 84:101934. [PMID: 38604598 PMCID: PMC11039402 DOI: 10.1016/j.molmet.2024.101934] [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: 01/08/2024] [Revised: 02/20/2024] [Accepted: 04/02/2024] [Indexed: 04/13/2024] Open
Abstract
OBJECTIVES During fasting, liver pivotally regulates blood glucose levels through glycogenolysis and gluconeogenesis. Kidney also produces glucose through gluconeogenesis. Gluconeogenic genes are transactivated by fasting, but their expression patterns are chronologically different between the two organs. We find that renal gluconeogenic gene expressions are positively correlated with the blood β-hydroxybutyrate concentration. Thus, we herein aim to investigate the regulatory mechanism and its physiological implications. METHODS Gluconeogenic gene expressions in liver and kidney were examined in hyperketogenic mice such as high-fat diet (HFD)-fed and ketogenic diet-fed mice, and in hypoketogenic PPARα knockout (PPARα-/-) mice. Renal gluconeogenesis was evaluated by rise in glycemia after glutamine loading in vivo. Functional roles of β-hydroxybutyrate in the regulation of renal gluconeogenesis were investigated by metabolome analysis and RNA-seq analysis of proximal tubule cells. RESULTS Renal gluconeogenic genes were transactivated concurrently with blood β-hydroxybutyrate uprise under ketogenic states, but the increase was blunted in hypoketogenic PPARα-/- mice. Administration of 1,3-butandiol, a ketone diester, transactivated renal gluconeogenic gene expression in fasted PPARα-/- mice. In addition, HFD-fed mice showed fasting hyperglycemia along with upregulated renal gluconeogenic gene expression, which was blunted in HFD-fed PPARα-/- mice. In vitro experiments and metabolome analysis in renal tubular cells showed that β-hydroxybutyrate directly promotes glucose and NH3 production through transactivating gluconeogenic genes. In addition, RNA-seq analysis revealed that β-hydroxybutyrate-induced transactivation of Pck1 was mediated by C/EBPβ. CONCLUSIONS Our findings demonstrate that β-hydroxybutyrate mediates hepato-renal interaction to maintain homeostatic regulation of blood glucose and systemic acid-base balance through renal gluconeogenesis regulation.
Collapse
Affiliation(s)
- Ryo Hatano
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Eunyoung Lee
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Hiromi Sato
- Laboratory of Clinical Pharmacology and Pharmacometrics, Chiba University, Graduate School of Pharmaceutical Sciences, Chiba 260-8670, Japan
| | - Masahiro Kiuchi
- Department of Immunology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Kiyoshi Hirahara
- Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Department of Immunology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Yoshimi Nakagawa
- Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan
| | - Hitoshi Shimano
- Department of Endocrinology and Metabolism, Institute of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
| | - Toshinori Nakayama
- Department of Immunology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Tomoaki Tanaka
- Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Department of Molecular Diagnosis, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan
| | - Takashi Miki
- Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan; Research Institute of Disaster Medicine (RIDM), Chiba University, Graduate School of Medicine, Chiba 260-8670, Japan.
| |
Collapse
|
|
9
|
Scoditti E, Sabatini S, Carli F, Gastaldelli A. Hepatic glucose metabolism in the steatotic liver. Nat Rev Gastroenterol Hepatol 2024; 21:319-334. [PMID: 38308003 DOI: 10.1038/s41575-023-00888-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2023] [Indexed: 02/04/2024]
Abstract
The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies.
Collapse
Affiliation(s)
- Egeria Scoditti
- Institute of Clinical Physiology, National Research Council, Lecce, Italy
| | - Silvia Sabatini
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Fabrizia Carli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy.
| |
Collapse
|
|
10
|
Abdelrahman Z, Maxwell AP, McKnight AJ. Genetic and Epigenetic Associations with Post-Transplant Diabetes Mellitus. Genes (Basel) 2024; 15:503. [PMID: 38674437 PMCID: PMC11050138 DOI: 10.3390/genes15040503] [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: 04/10/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ transplantation. PTDM prevalence varies due to different diabetes definitions. Consensus guidelines for the diagnosis of PTDM have been published based on random blood glucose levels, glycated hemoglobin (HbA1c), and oral glucose tolerance test (OGTT). The task of diagnosing PTDM continues to pose challenges, given the potential for diabetes to manifest at different time points after transplantation, thus demanding constant clinical vigilance and repeated testing. Interpreting HbA1c levels can be challenging after renal transplantation. Pre-transplant risk factors for PTDM include obesity, sedentary lifestyle, family history of diabetes, ethnicity (e.g., African-Caribbean or South Asian ancestry), and genetic risk factors. Risk factors for PTDM include immunosuppressive drugs, weight gain, hepatitis C, and cytomegalovirus infection. There is also emerging evidence that genetic and epigenetic variation in the organ transplant recipient may influence the risk of developing PTDM. This review outlines many known risk factors for PTDM and details some of the pathways, genetic variants, and epigenetic features associated with PTDM. Improved understanding of established and emerging risk factors may help identify people at risk of developing PTDM and may reduce the risk of developing PTDM or improve the management of this complication of organ transplantation.
Collapse
Affiliation(s)
- Zeinab Abdelrahman
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK; (Z.A.); (A.P.M.)
| | - Alexander Peter Maxwell
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK; (Z.A.); (A.P.M.)
- Regional Nephrology Unit, Belfast City Hospital, Belfast BT9 7AB, UK
| | - Amy Jayne McKnight
- Centre for Public Health, Queen’s University of Belfast, Belfast BT12 6BA, UK; (Z.A.); (A.P.M.)
| |
Collapse
|
|
11
|
Chapple B, Woodfin S, Moore W. The Perfect Cup? Coffee-Derived Polyphenols and Their Roles in Mitigating Factors Affecting Type 2 Diabetes Pathogenesis. Molecules 2024; 29:751. [PMID: 38398503 PMCID: PMC10891742 DOI: 10.3390/molecules29040751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 01/29/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Type 2 diabetes (T2D) is a growing health concern with an estimated 462 million people having been diagnosed worldwide. T2D is characterized by chronically elevated blood glucose and insulin resistance, which culminate in a diminished function of the β-cell mass in its later stages. This can be perpetuated by and result in inflammation, excess reactive oxygen species production, obesity, and the dysregulation of multiple cellular pathways. Many naturally occurring small molecules have been investigated in terms of their roles in modulating glucose homeostasis and β-cell function. Many of these compounds can be found in commonly used sources of food and drink. Interestingly, a correlation has been observed between coffee consumption and T2D incidence. However, the specific compounds responsible for this correlation and their mechanisms are still somewhat undetermined. This paper reviews recent research findings on the effects of several polyphenols that are either found in coffee or are metabolites of compounds found in coffee (enterodiol, enterolactone, matairesinol, secoisolariciresinol, kaempferol, quercetin, and chlorogenic acid) on glucose homeostasis and health complications associated with glucose dysregulation, with a special emphasis on their potential anti-diabetic effects. The factors that affect polyphenol content in coffee are also addressed.
Collapse
Affiliation(s)
| | | | - William Moore
- Department of Biology and Chemistry, School of Health Sciences, Liberty University, Lynchburg, VA 24515, USA; (B.C.); (S.W.)
| |
Collapse
|
|
12
|
Jafari-Rastegar N, Hosseininia HS, Mousavi-Niri N, Khakpai F, Naseroleslami M. Tyrosol-loaded Nano-niosomes Attenuate Diabetic Injury by TargetingGlucose Metabolism, Inflammation, and Glucose Transfer. Pharm Nanotechnol 2024; 12:351-364. [PMID: 37927074 DOI: 10.2174/0122117385251271231018104311] [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: 02/28/2023] [Revised: 08/01/2023] [Accepted: 08/17/2023] [Indexed: 11/07/2023]
Abstract
INTRODUCTION The increasing prevalence of type 2 diabetes, has become a global concern, making it imperative to control. Chemical drugs commonly recommended for diabetes treatment cause many complications and drug resistance over time. METHODS The polyphenol tyrosol has many health benefits, including anti-diabetes properties. Tyrosol's efficacy can be significantly increased when it is used as a niosome in the treatment of diabetes. In this study, Tyrosol and nano-Tyrosol are examined for their effects on genes implicated in type 2 diabetes in streptozotocin-treated rats. Niosome nanoparticles containing 300 mg surfactant (span60: tween60) and 10 mg cholesterol were hydrated in thin films with equal molar ratios. After 72 hours, nano-niosomal formulas were assessed for their physicochemical properties. MTT assays were conducted on HFF cells to assess the cellular toxicity of the nano niosome contacting optimal Tyrosol. Finally, the expression of PEPCK, GCK, TNF-ɑ, IL6, GLUT2 and GLUT9 was measured by real-time PCR. Physiochemical properties of the SEM images of niosomes loaded with Tyrosol revealed the nanoparticles had a vehicular structure. RESULTS In this study, there were two stages of release: initial release (8 hours) and sustainable release (72 hours). Meanwhile, free-form drugs were considerably more toxic than niosomal drugs in terms of their cellular toxicity. An in vivo comparison of oral Tyrosol gavage with nano-Tyrosol showed a significant increase in GCK (P < 0.001), GLUT2 (P < 0.001), and GLUT9 (P < 0.001). Furthermore, nano-Tyrosol decreased the expression of TNF-ɑ (P < 0.05), PEPCK (P < 0.001), and IL-6 (P < 0.05) which had been increased by diabetes mellitus. The results confirmed nano-Tyrosol's anti-diabetes and anti-inflammatory effects. CONCLUSION These findings suggest that nano-Tyrosol has potential applications in diabetes treatment and associated inflammation. Further research is needed to better understand the mechanism of action.
Collapse
Affiliation(s)
- Nima Jafari-Rastegar
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Herbal Pharmacology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Haniyeh Sadat Hosseininia
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Cytotech & Bioinformatics Research Group, Tehran, Iran
| | - Neda Mousavi-Niri
- Department of Biotechnology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Khakpai
- Cognitive and Neuroscience Research Center (CNRC), Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Naseroleslami
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| |
Collapse
|
|
13
|
Gonzalez-Rellan MJ, Fernández U, Parracho T, Novoa E, Fondevila MF, da Silva Lima N, Ramos L, Rodríguez A, Serrano-Maciá M, Perez-Mejias G, Chantada-Vazquez P, Riobello C, Veyrat-Durebex C, Tovar S, Coppari R, Woodhoo A, Schwaninger M, Prevot V, Delgado TC, Lopez M, Diaz-Quintana A, Dieguez C, Guallar D, Frühbeck G, Diaz-Moreno I, Bravo SB, Martinez-Chantar ML, Nogueiras R. Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism. Cell Metab 2023; 35:1630-1645.e5. [PMID: 37541251 PMCID: PMC10487638 DOI: 10.1016/j.cmet.2023.07.003] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 05/08/2023] [Accepted: 07/10/2023] [Indexed: 08/06/2023]
Abstract
Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues-K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.
Collapse
Affiliation(s)
- María J Gonzalez-Rellan
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Uxía Fernández
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Tamara Parracho
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Eva Novoa
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Marcos F Fondevila
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Natalia da Silva Lima
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Lucía Ramos
- Department of Biochemistry, CIMUS, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Amaia Rodríguez
- CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain; Department of Endocrinology & Nutrition, Metabolic Research Laboratory, Clínica Universidad de Navarra, University of Navarra, IdiSNA, Pamplona, Navarra, Spain
| | - Marina Serrano-Maciá
- Liver Disease Lab, BRTA CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain
| | - Gonzalo Perez-Mejias
- Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla-CSIC. Avda. Americo Vespucio 49, 41092 Sevilla, Spain
| | - Pilar Chantada-Vazquez
- Proteomic Unit, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela 15705, A Coruña, Spain
| | - Cristina Riobello
- Gene Regulatory Control in Disease, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Christelle Veyrat-Durebex
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Sulay Tovar
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Roberto Coppari
- Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland; Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Ashwin Woodhoo
- Gene Regulatory Control in Disease, CIMUS, University of Santiago de Compostela, Santiago de Compostela, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain
| | - Markus Schwaninger
- University of Lübeck, Institute for Experimental and Clinical Pharmacology and Toxicology, Lübeck, Germany
| | - Vincent Prevot
- University of Lille, Inserm, CHU Lille, Laboratory of Development and Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition, UMR-S 1172, European Genomic Institute for Diabetes (EGID), 59000 Lille, France
| | - Teresa C Delgado
- Liver Disease Lab, BRTA CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain
| | - Miguel Lopez
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Antonio Diaz-Quintana
- Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla-CSIC. Avda. Americo Vespucio 49, 41092 Sevilla, Spain
| | - Carlos Dieguez
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Diana Guallar
- Department of Biochemistry, CIMUS, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
| | - Gema Frühbeck
- CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain; Department of Endocrinology & Nutrition, Metabolic Research Laboratory, Clínica Universidad de Navarra, University of Navarra, IdiSNA, Pamplona, Navarra, Spain
| | - Irene Diaz-Moreno
- Instituto de Investigaciones Químicas (IIQ), Centro de Investigaciones Científicas Isla de la Cartuja (cicCartuja), Universidad de Sevilla-CSIC. Avda. Americo Vespucio 49, 41092 Sevilla, Spain
| | - Susana B Bravo
- Proteomic Unit, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela 15705, A Coruña, Spain
| | - Maria L Martinez-Chantar
- Liver Disease Lab, BRTA CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Derio, Bizkaia, Spain.
| | - Ruben Nogueiras
- Department of Physiology, CIMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; CIBER Fisiopatologia de la Obesidad y Nutrición (CIBERobn), Madrid, Spain; Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain.
| |
Collapse
|
|
14
|
Ye Q, Liu Y, Zhang G, Deng H, Wang X, Tuo L, Chen C, Pan X, Wu K, Fan J, Pan Q, Wang K, Huang A, Tang N. Deficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice. Nat Commun 2023; 14:1402. [PMID: 36918564 PMCID: PMC10015095 DOI: 10.1038/s41467-023-37142-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 03/03/2023] [Indexed: 03/16/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including steatosis, nonalcoholic steatohepatitis (NASH) and fibrosis. We demonstrated that phosphoenolpyruvate carboxykinase 1 (PCK1) plays a central role in MAFLD progression. Male mice with liver Pck1 deficiency fed a normal diet displayed hepatic lipid disorder and liver injury, whereas fibrosis and inflammation were aggravated in mice fed a high-fat diet with drinking water containing fructose and glucose (HFCD-HF/G). Forced expression of hepatic PCK1 by adeno-associated virus ameliorated MAFLD in male mice. PCK1 deficiency stimulated lipogenic gene expression and lipid synthesis. Moreover, loss of hepatic PCK1 activated the RhoA/PI3K/AKT pathway by increasing intracellular GTP levels, increasing secretion of platelet-derived growth factor-AA (PDGF-AA), and promoting hepatic stellate cell activation. Treatment with RhoA and AKT inhibitors or gene silencing of RhoA or AKT1 alleviated MAFLD progression in vivo. Hepatic PCK1 deficiency may be important in hepatic steatosis and fibrosis development through paracrine secretion of PDGF-AA in male mice, highlighting a potential therapeutic strategy for MAFLD.
Collapse
Affiliation(s)
- Qian Ye
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Yi Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Guiji Zhang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Haijun Deng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiaojun Wang
- Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Lin Tuo
- Department of Infectious Disease, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China
| | - Chang Chen
- Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Xuanming Pan
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Kang Wu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Jiangao Fan
- Department of Gastroenterology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qin Pan
- Department of Gastroenterology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kai Wang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Ailong Huang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| | - Ni Tang
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
| |
Collapse
|
|
15
|
Chen D, Wang YY, Li SP, Zhao HM, Jiang FJ, Wu YX, Tong Y, Pang QF. Maternal propionate supplementation ameliorates glucose and lipid metabolic disturbance in hypoxia-induced fetal growth restriction. Food Funct 2022; 13:10724-10736. [PMID: 36177734 DOI: 10.1039/d2fo01481e] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Intrauterine growth restriction (IUGR), one of the major complications of pregnancy, is characterized by low birth weight and results in higher risks for long-term problems including developing metabolic and cardiovascular diseases. Short-chain fatty acids (SCFAs), especially propionate, have been reported to correct glucose and lipid disorders in metabolic diseases. We hypothesized that maternal propionate supplementation could prevent glucose and lipid metabolic disturbance in hypoxia-induced IUGR. Here, in our study, maternal hypoxia was induced from gestational day (GD) 11 to GD 17.5 to establish an IUGR mouse model. Maternal propionate treatment reversed reduced birth weight in male IUGR offspring. Hepatic transcriptomics demonstrated that SP treatment significantly lowered glucose and lipid metabolism-related genes (Scd1, G6pc, Pck1 and Fasl) in IUGR offspring. KOG enrichment analysis showed that propionate-induced down-regulated differential expressed genes (DEGs) mainly belonged to lipid transport and metabolism. KEGG enrichment results showed that the down-regulated DEGs were mostly enriched in PPAR and FoxO signaling pathways. We also found that maternal oral administration of SP decreased serum lipid content, attenuated hepatic insulin resistance and liver lipid accumulation, reduced hepatic key gene expressions of gluconeogenesis and lipogenesis, increased energy expenditure and improved liver function in 11-week-old male IUGR offspring. These results indicate that maternal propionate supplementation increases birth weight and corrects hepatic glucose and lipid metabolic disturbance and energy expenditure in male mice born with IUGR, which may provide a basis for using propionate to treat IUGR disease.
Collapse
Affiliation(s)
- Dan Chen
- Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Binhu District, Wuxi 214122, Jiangsu Province, China.
| | - Ying-Ying Wang
- Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Binhu District, Wuxi 214122, Jiangsu Province, China.
| | - Sheng-Peng Li
- Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Binhu District, Wuxi 214122, Jiangsu Province, China.
| | - Hui-Min Zhao
- Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Binhu District, Wuxi 214122, Jiangsu Province, China.
| | - Feng-Juan Jiang
- Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Binhu District, Wuxi 214122, Jiangsu Province, China.
| | - Ya-Xian Wu
- Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Binhu District, Wuxi 214122, Jiangsu Province, China.
| | - Ying Tong
- Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Binhu District, Wuxi 214122, Jiangsu Province, China.
| | - Qing-Feng Pang
- Department of Physiopathology, Wuxi School of Medicine, Jiangnan University, 1800 Lihu Avenue, Binhu District, Wuxi 214122, Jiangsu Province, China.
| |
Collapse
|
|
16
|
Kyriakoudi S, Theodoulou A, Potamiti L, Schumacher F, Zachariou M, Papacharalambous R, Kleuser B, Panayiotidis MI, Drousiotou A, Petrou PP. Stbd1-deficient mice display insulin resistance associated with enhanced hepatic ER-mitochondria contact. Biochimie 2022; 200:172-183. [PMID: 35691532 DOI: 10.1016/j.biochi.2022.06.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 05/19/2022] [Accepted: 06/07/2022] [Indexed: 11/25/2022]
Abstract
Starch binding domain-containing protein 1 (STBD1) is an endoplasmic reticulum (ER)-resident, glycogen-binding protein. In addition to glycogen, STBD1 has been shown to interact with several proteins implicated in glycogen synthesis and degradation, yet its function in glycogen metabolism remains largely unknown. In addition to the bulk of the ER, STBD1 has been reported to localize at regions of physical contact between mitochondria and the ER, known as Mitochondria-ER Contact sites (MERCs). Given the emerging correlation between distortions in the integrity of hepatic MERCs and insulin resistance, our study aimed to delineate the role of STBD1 in vivo by addressing potential abnormalities in glucose metabolism and ER-mitochondria communication associated with insulin resistance in mice with targeted inactivation of Stbd1 (Stbd1KO). We show that Stbd1KO mice at the age of 24 weeks displayed reduced hepatic glycogen content and aberrant control of glucose homeostasis, compatible with insulin resistance. In line with the above, Stbd1-deficient mice presented with increased fasting blood glucose and insulin levels, attenuated activation of insulin signaling in the liver and skeletal muscle and elevated liver sphingomyelin content, in the absence of hepatic steatosis. Furthermore, Stbd1KO mice were found to exhibit enhanced ER-mitochondria association and increased mitochondrial fragmentation in the liver. Nevertheless, the enzymatic activity of hepatic respiratory chain complexes and ER stress levels in the liver were not altered. Our findings identify a novel important role for STBD1 in the control of glucose metabolism, associated with the integrity of hepatic MERCs.
Collapse
Affiliation(s)
- Styliana Kyriakoudi
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus
| | - Andria Theodoulou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus
| | - Louiza Potamiti
- Cancer Genetics, Therapeutics & Ultrastructural Pathology Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus
| | - Fabian Schumacher
- Freie Universität Berlin, Institute of Pharmacy, Königin-Luise-Str. 2+4, Berlin, Germany
| | - Margarita Zachariou
- Bioinformatics Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus
| | - Revekka Papacharalambous
- Neuropathology Lab, Center for Neuromuscular Disorders, The Cyprus Institute of Neurology and Generics, P.O. Box 23462, 1683, Nicosia, Cyprus
| | - Burkhard Kleuser
- Freie Universität Berlin, Institute of Pharmacy, Königin-Luise-Str. 2+4, Berlin, Germany
| | - Mihalis I Panayiotidis
- Cancer Genetics, Therapeutics & Ultrastructural Pathology Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus
| | - Anthi Drousiotou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus
| | - Petros P Petrou
- Biochemical Genetics Department, The Cyprus Institute of Neurology and Genetics, P.O. Box 23462, 1683, Nicosia, Cyprus.
| |
Collapse
|
|
17
|
Meng D, Zhang B, Wang Y, Zheng T, Hu R, Wang B, Otsu K, Wang Y, Huang G. p38α Deficiency in T Cells Ameliorates Diet-Induced Obesity, Insulin Resistance, and Adipose Tissue Senescence. Diabetes 2022; 71:1205-1217. [PMID: 35349644 DOI: 10.2337/db21-0653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 03/22/2022] [Indexed: 11/13/2022]
Abstract
Adipose tissue-resident T cells play vital roles in regulating inflammation and metabolism in obesity, but the underlying mechanisms remain unclear. Here, we show that high-fat diet (HFD) feeding enhances p38 activity in adipose-resident T cells. T cell-specific deletion of p38α, an essential subunit of p38 expressed in most immune cells, protected mice from HFD-induced obesity, hepatic steatosis, adipose tissue inflammation, and insulin resistance. Mice with p38α deletion in T cells exhibited higher energy expenditure. Mechanistically, p38α promoted T-cell glycolysis through mechanistic target of rapamycin signaling, leading to enhanced Th1 differentiation. Accordingly, genetic deletion of p38α alleviated ongoing diet-induced obesity. Unexpectedly, p38α signaling in T cells promoted adipose tissue senescence during obesity and aging. Taken together, our results identify p38α in T cells as an essential regulator of obesity, insulin resistance, and adipose tissue senescence, and p38α may be a therapeutic target for obese- or aging-associated diseases.
Collapse
Affiliation(s)
- Deyun Meng
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baohua Zhang
- Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Yanyan Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Tingting Zheng
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Ran Hu
- Basic Department of Cancer Center, Shanghai Tenth People's Hospital of Tongji University, Shanghai, China
| | - Bin Wang
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| | - Kinya Otsu
- Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Osaka, Japan
- School of Cardiovascular Medicine and Sciences, King's College London, London, U.K
| | - Ying Wang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gonghua Huang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
| |
Collapse
|
|
18
|
Xu R, Zhu C, Li Y, Andrade M, Yin DP. Gastric Bypass Regulates Early Inflammatory Responses in High-Fat Diet-Induced Obese Mice. J Surg Res 2022; 273:161-171. [PMID: 35085943 PMCID: PMC8960359 DOI: 10.1016/j.jss.2021.12.027] [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: 05/29/2021] [Revised: 12/17/2021] [Accepted: 12/27/2021] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Obesity and diabetes are characterized by chronic inflammatory responses. Roux-en-Y gastric bypass (RYGB) is increasingly regarded as an effective approach for the improvement of glucose homeostasis. In this study, we examined the effects of RYGB on the regulation of early inflammatory responses in the liver and adipose tissue in high-fat diet (HFD)-induced obese (DIO) mice. MATERIALS AND METHODS RYGB was performed in DIO mice followed by analyses of adiposity, insulin sensitivity, plasma and tissue cytokines and adipokines, tissue NF-κB and JNK/c-Jun activation, and tissue macrophage and T-cell subsets. RESULTS We found that RYGB resulted in sustained improvement of adiposity and insulin sensitivity. Plasma insulin and leptin levels were increased in untreated DIO mice and reduced in RYGB mice. RYGB maintained plasma adiponectin levels and inhibited monocyte chemoattractant protein-1 and interleukin 6 in white adipose tissue (WAT) and liver. RYGB inhibited NF-κB activation in WAT and muscle, but not in the liver. However, RYGB attenuated the JNK/c-Jun signaling pathway in the liver and WAT at 1 wk after surgery, suggesting that RYGB regulates the tissue-specific inflammatory pathway. RYGB reduced M1-like (F4/80+/CD11c+) differentiation and enhanced M2-like population (F4/80+/CD206c+). RYGB also regulated CD4+ and CD8+ T-cell infiltration and increased Treg cells in the liver and WAT at the same time point. CONCLUSIONS Our findings demonstrate that RYGB improves obesity and insulin resistance, which are associated with the regulation of early inflammatory reactions in the liver and WAT.
Collapse
Affiliation(s)
- Rui Xu
- Department of Surgery, The First College of Clinical Medical Science, Yichang Central People's Hospital, CTGU, Yichang, Hubei, China
| | - Chenyu Zhu
- Department of Surgery, The First College of Clinical Medical Science, Yichang Central People's Hospital, CTGU, Yichang, Hubei, China
| | - Yuxin Li
- Department of Surgery, The University of Chicago, Chicago, Illinois
| | - Michael Andrade
- Department of Surgery, The University of Chicago, Chicago, Illinois
| | - Deng Ping Yin
- Department of Surgery, The University of Chicago, Chicago, Illinois.
| |
Collapse
|
|
19
|
Norton L, Shannon C, Gastaldelli A, DeFronzo RA. Insulin: The master regulator of glucose metabolism. Metabolism 2022; 129:155142. [PMID: 35066003 DOI: 10.1016/j.metabol.2022.155142] [Citation(s) in RCA: 143] [Impact Index Per Article: 47.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 01/13/2022] [Accepted: 01/16/2022] [Indexed: 02/07/2023]
Abstract
Insulin is the master regulator of glucose, lipid, and protein metabolism. Following ingestion of an oral glucose load or mixed meal, the plasma glucose concentration rises, insulin secretion by the beta cells is stimulated and the hyperinsulinemia, working in concert with hyperglycemia, causes: (i) suppression of endogenous (primarily reflects hepatic) glucose production, (ii) stimulation of glucose uptake by muscle, liver, and adipocytes, (iii) inhibition of lipolysis leading to a decline in plasma FFA concentration which contributes to the suppression of hepatic glucose production and augmentation of muscle glucose uptake, and (iv) vasodilation in muscle, which contributes to enhanced muscle glucose disposal. Herein, the integrated physiologic impact of insulin to maintain normal glucose homeostasis is reviewed and the molecular basis of insulin's diverse actions in muscle, liver, adipocytes, and vasculature are discussed.
Collapse
Affiliation(s)
- Luke Norton
- Diabetes Division, UT Health, San Antonio, TX, United States of America
| | - Chris Shannon
- Diabetes Division, UT Health, San Antonio, TX, United States of America
| | - Amalia Gastaldelli
- Diabetes Division, UT Health, San Antonio, TX, United States of America; Cardiometabolic Risk Unit Institute of Clinical Physiology, CNR, Pisa, Italy
| | - Ralph A DeFronzo
- Diabetes Division, UT Health, San Antonio, TX, United States of America.
| |
Collapse
|
|
20
|
Uematsu S, Ohno S, Tanaka KY, Hatano A, Kokaji T, Ito Y, Kubota H, Hironaka KI, Suzuki Y, Matsumoto M, Nakayama KI, Hirayama A, Soga T, Kuroda S. Multi-omics-based label-free metabolic flux inference reveals obesity-associated dysregulatory mechanisms in liver glucose metabolism. iScience 2022; 25:103787. [PMID: 35243212 PMCID: PMC8859528 DOI: 10.1016/j.isci.2022.103787] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 12/01/2021] [Accepted: 01/13/2022] [Indexed: 02/07/2023] Open
Abstract
Glucose homeostasis is maintained by modulation of metabolic flux. Enzymes and metabolites regulate the involved metabolic pathways. Dysregulation of glucose homeostasis is a pathological event in obesity. Analyzing metabolic pathways and the mechanisms contributing to obesity-associated dysregulation in vivo is challenging. Here, we introduce OMELET: Omics-Based Metabolic Flux Estimation without Labeling for Extended Trans-omic Analysis. OMELET uses metabolomic, proteomic, and transcriptomic data to identify relative changes in metabolic flux, and to calculate contributions of metabolites, enzymes, and transcripts to the changes in metabolic flux. By evaluating the livers of fasting ob/ob mice, we found that increased metabolic flux through gluconeogenesis resulted primarily from increased transcripts, whereas that through the pyruvate cycle resulted from both increased transcripts and changes in substrates of metabolic enzymes. With OMELET, we identified mechanisms underlying the obesity-associated dysregulation of metabolic flux in the liver.
We developed OMELET to infer metabolic flux from label-free multi-omic data Contributions of metabolites, enzymes, and transcripts for flux were inferred Gluconeogenic flux increased in fasting ob/ob mice by increased transcripts Increased pyruvate cycle fluxes were led by increased transcripts and substrates
Collapse
Affiliation(s)
- Saori Uematsu
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Satoshi Ohno
- Molecular Genetic Research Laboratory, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.,Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Kaori Y Tanaka
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Atsushi Hatano
- Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, 757 Ichibancho, Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Toshiya Kokaji
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yuki Ito
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan.,Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Hiroyuki Kubota
- Division of Integrated Omics, Research Center for Transomics Medicine, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Ken-Ichi Hironaka
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Yutaka Suzuki
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan
| | - Masaki Matsumoto
- Department of Omics and Systems Biology, Graduate School of Medical and Dental Sciences, Niigata University, 757 Ichibancho, Asahimachi-dori, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Keiichi I Nakayama
- Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
| | - Akiyoshi Hirayama
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan
| | - Shinya Kuroda
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8562, Japan.,Molecular Genetic Research Laboratory, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.,Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| |
Collapse
|
|
21
|
TOX4, an insulin receptor-independent regulator of hepatic glucose production, is activated in diabetic liver. Cell Metab 2022; 34:158-170.e5. [PMID: 34914893 PMCID: PMC8732315 DOI: 10.1016/j.cmet.2021.11.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 09/12/2021] [Accepted: 11/18/2021] [Indexed: 01/07/2023]
Abstract
Increased hepatic glucose production (HGP) contributes to hyperglycemia in type 2 diabetes. Hormonal regulation of this process is primarily, but not exclusively, mediated by the AKT-FoxO1 pathway. Here, we show that cAMP and dexamethasone regulate the high-mobility group superfamily member TOX4 to mediate HGP, independent of the insulin receptor/FoxO1 pathway. TOX4 inhibition decreases glucose production in primary hepatocytes and liver and increases glucose tolerance. Combined genetic ablation of TOX4 and FoxO1 in liver has additive effects on glucose tolerance and gluconeogenesis. Moreover, TOX4 ablation fails to reverse the metabolic derangement brought by insulin receptor knockout. TOX4 expression is increased in livers of patients with steatosis and diabetes and in diet-induced obese and db/db mice. In the latter two murine models, knockdown Tox4 decreases glycemia and improves glucose tolerance. We conclude that TOX4 is an insulin receptor-independent regulator of HGP and a candidate contributor to the pathophysiology of diabetes.
Collapse
|
|
22
|
Kitamoto T, Kuo T, Okabe A, Kaneda A, Accili D. An integrative transcriptional logic model of hepatic insulin resistance. Proc Natl Acad Sci U S A 2021; 118:e2102222118. [PMID: 34732569 PMCID: PMC8609333 DOI: 10.1073/pnas.2102222118] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/17/2021] [Indexed: 12/27/2022] Open
Abstract
Abnormalities of lipid/lipoprotein and glucose metabolism are hallmarks of hepatic insulin resistance in type 2 diabetes. The former antedate the latter, but the latter become progressively refractory to treatment and contribute to therapeutic failures. It's unclear whether the two processes share a common pathogenesis and what underlies their progressive nature. In this study, we investigated the hypothesis that genes in the lipid/lipoprotein pathway and those in the glucose metabolic pathway are governed by different transcriptional regulatory logics that affect their response to physiologic (fasting/refeeding) as well as pathophysiologic cues (insulin resistance and hyperglycemia). To this end, we obtained genomic and transcriptomic maps of the key insulin-regulated transcription factor, FoxO1, and integrated them with those of CREB, PPAR-α, and glucocorticoid receptor. We found that glucose metabolic genes are primarily regulated by promoter and intergenic enhancers in a fasting-dependent manner, while lipid genes are regulated through fasting-dependent intron enhancers and fasting-independent enhancerless introns. Glucose genes also showed a remarkable transcriptional resiliency (i.e., the ability to compensate following constitutive FoxO1 ablation through an enrichment of active marks at shared PPAR-α/FoxO1 regulatory elements). Unexpectedly, insulin resistance and hyperglycemia were associated with a "spreading" of FoxO1 binding to enhancers and the emergence of unique target sites. We surmise that this unusual pattern correlates with the progressively intractable nature of hepatic insulin resistance. This transcriptional logic provides an integrated model to interpret the combined lipid and glucose abnormalities of type 2 diabetes.
Collapse
Affiliation(s)
- Takumi Kitamoto
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032;
- Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032
| | - Taiyi Kuo
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032
- Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032
| | - Atsushi Okabe
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba 260-8677, Japan
| | - Domenico Accili
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032
- Naomi Berrie Diabetes Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032
| |
Collapse
|
|
23
|
Ham JR, Lee HI, Lee Y, Lee HJ, Kim HY, Son YJ, Lee MK, Lee MJ. Dual beneficial effects of naked barley “Betaone” extract on high-fat diet/streptozotocin-induced hyperglycemia and hepatosteatosis in mice. J Cereal Sci 2021; 102:103358. [DOI: 10.1016/j.jcs.2021.103358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
|
|
24
|
Espinoza-Hernández F, Andrade-Cetto A, Escandón-Rivera S, Mata-Torres G, Mata R. Contribution of fasting and postprandial glucose-lowering mechanisms to the acute hypoglycemic effect of traditionally used Eryngium cymosum F.Delaroche. JOURNAL OF ETHNOPHARMACOLOGY 2021; 279:114339. [PMID: 34166734 DOI: 10.1016/j.jep.2021.114339] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 06/10/2021] [Accepted: 06/13/2021] [Indexed: 05/28/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Eryngium cymosum F. Delaroche was detected as a traditional remedy against type 2 diabetes consumed by patients of Tlanchinol in the state of Hidalgo, Mexico. AIM OF THE STUDY Assessing the hypoglycemic effect and safety of the traditional extract of E. cymosum and relating it to key glucose-lowering mechanisms both in fasting and postprandial state. MATERIALS AND METHODS The aqueous extract of E. cymosum was subjected to HPLC analysis to identify its main components. Hyperglycaemic STZ-NA Wistar rats were administered with the extract to evaluate its effect on blood glucose levels and a possible dose-dependence. Afterward, it was evaluated in both pyruvate and maltose tolerance tests in STZ-NA rats to characterize its effect on gluconeogenesis and carbohydrate breakdown, two of the main mechanisms responsible for fasting and postprandial hyperglycaemia in type 2 diabetes patients. In addition, the inhibitory capacity of the extract was evaluated on key enzymes involved in gluconeogenesis and a-glucosidases. Moreover, insulin concentrations were measured in normoglycemic rats in both conditions to establish a link between the hypoglycaemic effect of the extract with insulin release and functioning. RESULTS Caffeic acid (1), chlorogenic acid (2), and rosmarinic acid (3) were identified as the main constituents of the aqueous extract of E. cymosum, which exerted a hypoglycaemic effect in hyperglycaemic STZ-NA rats. It has a significant antihyperglycemic effect in the pyruvate tolerance test, and it was able to reduce the postprandial hyperglycaemia in maltose tolerance tests significantly. Moreover, it effectively reduced the activity of both gluconeogenic enzymes reaching almost 100% of inhibition, while it presented a modest 32% inhibition of aglucosidases. On the other hand, the extract decreased insulin levels after its oral administration in healthy rats in both nutritional states, without affecting normoglycemia in normal curves and reducing the postprandial peak in glucose load curves. CONCLUSIONS The traditional consumed form of aerial parts of E. cymosum is safe and regulated glucose levels both in fasting and in postprandial state.
Collapse
Affiliation(s)
- Fernanda Espinoza-Hernández
- Laboratorio de Etnofarmacología, Departamento de Biología Celular, Facultad de Ciencias, Universidad Nacional Autónoma de México, Av. Universidad 3000, Circuito Exterior S/N, Delegación Coyoacán, C.P, 04510, Ciudad Universitaria, Ciudad de México, Mexico.
| | - Adolfo Andrade-Cetto
- Laboratorio de Etnofarmacología, Departamento de Biología Celular, Facultad de Ciencias, Universidad Nacional Autónoma de México, Av. Universidad 3000, Circuito Exterior S/N, Delegación Coyoacán, C.P, 04510, Ciudad Universitaria, Ciudad de México, Mexico.
| | - Sonia Escandón-Rivera
- Laboratorio de Etnofarmacología, Departamento de Biología Celular, Facultad de Ciencias, Universidad Nacional Autónoma de México, Av. Universidad 3000, Circuito Exterior S/N, Delegación Coyoacán, C.P, 04510, Ciudad Universitaria, Ciudad de México, Mexico.
| | - Gerardo Mata-Torres
- Laboratorio de Etnofarmacología, Departamento de Biología Celular, Facultad de Ciencias, Universidad Nacional Autónoma de México, Av. Universidad 3000, Circuito Exterior S/N, Delegación Coyoacán, C.P, 04510, Ciudad Universitaria, Ciudad de México, Mexico.
| | - Rachel Mata
- Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Av. Universidad 3000, Circuito Exterior S/N, Delegación Coyoacán, C.P, 04510, Ciudad Universitaria, Ciudad de México, Mexico.
| |
Collapse
|
|
25
|
Ramos LV, da Costa THM, Arruda SF. The effect of coffee consumption on glucose homeostasis and redox-inflammatory responses in high-fat diet-induced obese rats. J Nutr Biochem 2021; 100:108881. [PMID: 34653600 DOI: 10.1016/j.jnutbio.2021.108881] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 07/28/2021] [Accepted: 09/20/2021] [Indexed: 01/24/2023]
Abstract
Coffee effects on glucose homeostasis in obesity remain controversial. We investigated whether coffee mitigates the negative effects on glucose metabolism induced by a high-fat diet and the interrelationships with redox-inflammatory responses. Rats were treated with: control (CT-); coffee (CT+) 3.9 g of freeze-dried coffee/kg of diet; high-fat (HF-); or high-fat + coffee 3.9 g of freeze-dried coffee/kg of diet (HF+) diet. The high-fat diet increased weight gain, feed efficiency, HOMA β, muscle and hepatic glycogen, intestinal CAT and SOD activity, hepatic protein (CARB) and lipid oxidation (MDA), muscle Prkaa1 mRNA and IL6 levels, and decreased food intake, hepatic GR, GPX and SOD activities, intestinal CARB, intestinal Slc2a2 and Slc5a1 and hepatic Prkaa1 and Prkaa2 mRNA levels, hepatic glucose-6-phosphatase and muscle hexokinase (HK) activities, compared to the control diet. The high-fat diet with coffee increased hepatic GST activity and TNF and decreased IL6 and intestinal glucosidase activity compared with the high-fat diet. The coffee diet increased muscle glycogen, hepatic CARB and PEPCK activity, and decreased hepatic GR and SOD activities and intestinal CARB, compared with the control diet. Coffee increased insulin levels, HOMA IR/β, FRAP, muscle Prkaa1 mRNA levels and hepatic and muscle phosphofructokinase-1, and it decreased intestinal CAT, hepatic Slc2a2 mRNA levels and muscle HK activity, regardless of the diet type. In conclusion, chronic coffee consumption improves antioxidant and anti-inflammatory responses, but does not ameliorate glucose homeostasis in a high-fat diet-induced obesity model. In addition, coffee consumption increases insulin secretion and promotes muscle glycogen synthesis in rats maintained on a control diet.
Collapse
Affiliation(s)
- Larissa Valadares Ramos
- Postgraduate Program in Human Nutrition, Faculty of Health Sciences, Campus Universitário Darcy Ribeiro, Universidade de Brasília, Brasília, Brazil.
| | - Teresa Helena Macedo da Costa
- Postgraduate Program in Human Nutrition, Faculty of Health Sciences, Campus Universitário Darcy Ribeiro, Universidade de Brasília, Brasília, Brazil
| | - Sandra Fernandes Arruda
- Postgraduate Program in Human Nutrition, Faculty of Health Sciences, Campus Universitário Darcy Ribeiro, Universidade de Brasília, Brasília, Brazil
| |
Collapse
|
|
26
|
Porphyromonas gingivalis induces entero-hepatic metabolic derangements with alteration of gut microbiota in a type 2 diabetes mouse model. Sci Rep 2021; 11:18398. [PMID: 34526589 PMCID: PMC8443650 DOI: 10.1038/s41598-021-97868-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 08/25/2021] [Indexed: 11/08/2022] Open
Abstract
Periodontal infection induces systemic inflammation; therefore, aggravating diabetes. Orally administered periodontal pathogens may directly alter the gut microbiota. We orally treated obese db/db diabetes mice using Porphyromonas gingivalis (Pg). We screened for Pg-specific peptides in the intestinal fecal specimens and examined whether Pg localization influenced the intestinal microbiota profile, in turn altering the levels of the gut metabolites. We evaluated whether the deterioration in fasting hyperglycemia was related to the changes in the intrahepatic glucose metabolism, using proteome and metabolome analyses. Oral Pg treatment aggravated both fasting and postprandial hyperglycemia (P < 0.05), with a significant (P < 0.01) increase in dental alveolar bone resorption. Pg-specific peptides were identified in fecal specimens following oral Pg treatment. The intestinal Pg profoundly altered the gut microbiome profiles at the phylum, family, and genus levels; Prevotella exhibited the largest increase in abundance. In addition, Pg-treatment significantly altered intestinal metabolite levels. Fasting hyperglycemia was associated with the increase in the levels of gluconeogenesis-related enzymes and metabolites without changes in the expression of proinflammatory cytokines and insulin resistance. Oral Pg administration induced gut microbiota changes, leading to entero-hepatic metabolic derangements, thus aggravating hyperglycemia in an obese type 2 diabetes mouse model.
Collapse
|
|
27
|
Jeddi S, Gheibi S, Kashfi K, Ghasemi A. Sodium hydrosulfide has no additive effects on nitrite-inhibited renal gluconeogenesis in type 2 diabetic rats. Life Sci 2021; 283:119870. [PMID: 34352258 DOI: 10.1016/j.lfs.2021.119870] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/20/2021] [Accepted: 07/25/2021] [Indexed: 11/19/2022]
Abstract
OBJECTIVE Increased renal and hepatic gluconeogenesis are important sources of fasting hyperglycemia in type 2 diabetes (T2D). The inhibitory effect of co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on hepatic but not renal gluconeogenesis has been reported in rats with T2D. The present study aimed to determine the effects of co-administration of sodium nitrite and NaSH on the expression of genes involved in renal gluconeogenesis in rats with T2D. METHODS T2D was induced by a combination of a high-fat diet and low-dose streptozotocin (30 mg/kg). Male Wistar rats were divided into 5 groups (n = 6/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite and NaSH were administered for nine weeks at a dose of 50 mg/L (in drinking water) and 0.28 mg/kg (daily intraperitoneal injection), respectively. Serum levels of urea and creatinine, and mRNA expressions of PEPCK, G6Pase, FBPase, PC, PI3K, AKT, PGC-1α, and FoxO1 in the renal tissue, were measured at the end of the study. RESULTS Nitrite decreased mRNA expression of PEPCK by 39%, G6Pase by 43%, FBPase by 41%, PC by 63%, PGC-1α by 45%, and FoxO1 by 27% in the renal tissue of rats with T2D; co-administration of nitrite and NaSH further decreases FoxO1, while had no additive effects on the tissue expression of the other genes. In addition, nitrite+NaSH decreased elevated serum urea levels by 58% and creatinine by 37% in rats with T2D. CONCLUSION The inhibitory effect of nitrite on gluconeogenesis in T2D rats is at least in part due to decreased mRNA expressions of renal gluconeogenic genes. Unlike effects on hepatic gluconeogenesis, co-administration of nitrite and NaSH has no additive effects on genes involved in renal gluconeogenesis in rats with T2D.
Collapse
Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sevda Gheibi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Lund University, Malmö, Sweden
| | - Khosrow Kashfi
- Department of Molecular, Cellular, Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
28
|
Abstract
The reactions of the tricarboxylic acid (TCA) cycle allow the controlled combustion of fat and carbohydrate. In principle, TCA cycle intermediates are regenerated on every turn and can facilitate the oxidation of an infinite number of nutrient molecules. However, TCA cycle intermediates can be lost to cataplerotic pathways that provide precursors for biosynthesis, and they must be replaced by anaplerotic pathways that regenerate these intermediates. Together, anaplerosis and cataplerosis help regulate rates of biosynthesis by dictating precursor supply, and they play underappreciated roles in catabolism and cellular energy status. They facilitate recycling pathways and nitrogen trafficking necessary for catabolism, and they influence redox state and oxidative capacity by altering TCA cycle intermediate concentrations. These functions vary widely by tissue and play emerging roles in disease. This article reviews the roles of anaplerosis and cataplerosis in various tissues and discusses how they alter carbon transitions, and highlights their contribution to mechanisms of disease. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Collapse
Affiliation(s)
- Melissa Inigo
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
| | - Stanisław Deja
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; .,Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Shawn C Burgess
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA; .,Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| |
Collapse
|
|
29
|
Aslam M, Syed NIH, Jahan S. Effect of Caralluma tuberculata on regulation of carbohydrate metabolizing genes in alloxan-induced rats. JOURNAL OF ETHNOPHARMACOLOGY 2021; 271:113897. [PMID: 33567306 DOI: 10.1016/j.jep.2021.113897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 01/29/2021] [Accepted: 01/29/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Caralluma tuberculata (C. tuberculata) has traditionally been used in Pakistan and other parts of the world as a folk treatment for diabetes mellitus. A few studies indicated its antihyperglycemic effect, however, the mystery remained unfolded as how did it modify the pathophysiological condition. AIM OF STUDY Hence, this study aimed to explore underlying mechanism(s) for its hypoglycemic activity at biochemical and molecular levels. MATERIALS AND METHODS Methanol extract (ME) of C. tuberculata as well as its hexane (HF) and aqueous (AF) fractions were explored for their effect on total glycogen in liver and skeletal muscle of alloxan-induced rats by spectroscopy. Moreover, the expression of genes related to hepatic carbohydrate metabolizing enzymes was quantified. At molecular level, mRNA expression of glucose transporter 2 (GLUT-2), glycogen synthase (GS), glucokinase (GK), hexokinase 1 (HK-1), pyruvate kinase (PK), glucose 6 phosphate dehydrogenase (G-6-PDH), pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6 phosphatase (G-6-Pase) was determined by using quantitative real time polymerase chain reaction (qRT-PCR) after administration of ME (350 mg), HF(3 mg), AF (10 mg) and metformin (500 mg). The doses were administered twice daily according to per kg of body weight. RESULTS A significant reduction in hepatic and skeletal muscle glycogen content was exhibited. The data of qRT-PCR revealed that gene's expression of GLUT-2 was significantly decreased after treatment with ME and HF, whilst it was unaltered by AF, however, a significant decrease was observed in genes corresponding to GS, GK and HK-1 after treatment with ME. Similarly, there was a significant decrease in expression of genes corresponding to GS, GK and HK-1 following treatment with HF. Surprisingly, post-treatment with AF didn't modify the gene's expression of GS and GK, whilst it caused a profound decrease in expression of HK-1 gene. Contrarily, the expression of gene related to PK was significantly up-regulated post-administration with ME, HF and AF. The expression levels of G-6-PDH, however, remained unaltered after treatment with the experimental extract and fractions of the plant. In addition, HF and AF did not cause any modification in PEPCK, whereas ME caused a significant down-regulation of the gene. Treatment with all the extract and fractions of the plant caused a substantial decrease in the gene's expression of PC, while there was a significant increase in the expression of gene related to G-6-Pase. CONCLUSION The three experimental extract and fractions caused a substantial decrease in glycogen content in liver and skeletal muscle tissues. The analysis by qRT-PCR showed that glucose transport via GLUT-2 was profoundly declined by ME and HF. The expression of genes related to various metabolic pathways involved in metabolism of carbohydrate in hepatocytes revealed explicitly that the ME, HF and AF decreased the phenomena of glycogenesis and gluconeogenesis. Contrarily, all the extract and fractions of the plant activated glycogenolysis and glycolysis but did not modify the pentose phosphate shunt pathway.
Collapse
Affiliation(s)
- Maria Aslam
- Department of Pharmacology, Punjab University College of Pharmacy, University of the Punjab, Old Campus, Lahore, 54000, Pakistan.
| | - Nawazish-I-Husain Syed
- Department of Pharmacology, Punjab University College of Pharmacy, University of the Punjab, Old Campus, Lahore, 54000, Pakistan.
| | - Shah Jahan
- Department of Immunology, University of Health Sciences, Lahore, Pakistan.
| |
Collapse
|
|
30
|
Podhorecka M. Metformin - its anti-cancer effects in hematologic malignancies. Oncol Rev 2021; 15:514. [PMID: 33747367 PMCID: PMC7967492 DOI: 10.4081/oncol.2021.514] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 01/26/2021] [Indexed: 02/08/2023] Open
Abstract
The main anti-diabetic effect of metformin mediated through stimulation of adenosine monophosphate (AMP)-activated protein kinase (AMPK) is the inhibition of hepatic gluconeogenesis and triggering glucose uptake in skeletal muscles. Additionally, some new pathways, besides the AMPK activation, were discovered, that can explain wide-range properties of metformin. All these properties are now attracting the attention of researchers in the fields other than diabetes and the drug has been reported to have anti-cancer, immunoregulatory and anti-aging effects. Among others, the beneficial effects of metformin in hematological disorders like leukemias, lymphomas, and multiple myeloma were reported. Despite a great progress in therapy, these diseases are still incurable in most cases. Thus, there is an urgent need to discover novel, less toxic and more effective drugs especially for older or chemotherapy-resistant patients. In this review article, the current findings on the anti-cancer effect of metformin together with underlying possible mechanisms in blood cancers are discussed. However. to evaluate precisely these promising effects of metformin, more studies are required, because many of the published results are preclinical.
Collapse
Affiliation(s)
- Monika Podhorecka
- Department of Hematooncology and Bone Marrow Transplantation Medical University of Lublin, Poland
| |
Collapse
|
|
31
|
LaMoia TE, Shulman GI. Cellular and Molecular Mechanisms of Metformin Action. Endocr Rev 2021; 42:77-96. [PMID: 32897388 PMCID: PMC7846086 DOI: 10.1210/endrev/bnaa023] [Citation(s) in RCA: 390] [Impact Index Per Article: 97.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/04/2020] [Indexed: 02/07/2023]
Abstract
Metformin is a first-line therapy for the treatment of type 2 diabetes, due to its robust glucose-lowering effects, well-established safety profile, and relatively low cost. While metformin has been shown to have pleotropic effects on glucose metabolism, there is a general consensus that the major glucose-lowering effect in patients with type 2 diabetes is mostly mediated through inhibition of hepatic gluconeogenesis. However, despite decades of research, the mechanism by which metformin inhibits this process is still highly debated. A key reason for these discrepant effects is likely due to the inconsistency in dosage of metformin across studies. Widely studied mechanisms of action, such as complex I inhibition leading to AMPK activation, have only been observed in the context of supra-pharmacological (>1 mM) metformin concentrations, which do not occur in the clinical setting. Thus, these mechanisms have been challenged in recent years and new mechanisms have been proposed. Based on the observation that metformin alters cellular redox balance, a redox-dependent mechanism of action has been described by several groups. Recent studies have shown that clinically relevant (50-100 μM) concentrations of metformin inhibit hepatic gluconeogenesis in a substrate-selective manner both in vitro and in vivo, supporting a redox-dependent mechanism of metformin action. Here, we review the current literature regarding metformin's cellular and molecular mechanisms of action.
Collapse
Affiliation(s)
- Traci E LaMoia
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.,Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| | - Gerald I Shulman
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.,Department of Cellular & Molecular Physiology, Yale School of Medicine, New Haven, Connecticut
| |
Collapse
|
|
32
|
Jeddi S, Gheibi S, Carlström M, Kashfi K, Ghasemi A. Long-term co-administration of sodium nitrite and sodium hydrosulfide inhibits hepatic gluconeogenesis in male type 2 diabetic rats: Role of PI3K-Akt-eNOS pathway. Life Sci 2020; 265:118770. [PMID: 33212150 DOI: 10.1016/j.lfs.2020.118770] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/05/2020] [Accepted: 11/13/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVE A deficiency in hydrogen sulfide (H2S) and nitric oxide (NO) contributes to the development of type 2 diabetes (T2D). An inhibitory effect on liver gluconeogenesis has been reported in rats with T2D with co-administration of sodium nitrite and sodium hydrosulfide (NaSH); the underlying mechanisms have however not yet been elucidated. The aim of this study is to determine the long-term effects of co-administering sodium nitrite and NaSH on expression of genes involved in liver gluconeogenesis in rats with T2D. METHODS T2D was induced using a high fat diet combined with low-dose of streptozotocin (30 mg/kg). Rats were divided into 5 groups (n = 7/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite+NaSH. Nitrite (50 mg/L) and NaSH (0.28 mg/kg) were administered for 9 weeks. Intraperitoneal pyruvate tolerance test (PTT) was performed at the end of the ninth week and mRNA expressions of PI3K, Akt, eNOS, PEPCK, G6Pase, and FBPase were measured in the liver. RESULTS Co-administration of nitrite and NaSH decreased elevated serum glucose concentrations during PTT. Compared to T2D + nitrite, co-administration of nitrite and NaSH resulted in significant increases in mRNA expression of PI3K, Akt, and eNOS and significant decreases in mRNA expression of G6Pase and FBPase but had no effect on PEPCK expression. CONCLUSION Long-term NaSH administration at low-dose, potentiated the inhibitory effects of nitrite on mRNA expression of key liver gluconeogenic enzymes in rats with T2D. This inhibitory effect of nitrite and NaSH co-administration on gluconeogenesis were associated with increased gene expression of PI3K, Akt, and eNOS in the liver.
Collapse
Affiliation(s)
- Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sevda Gheibi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Clinical Sciences in Malmö, Unit of Molecular Metabolism, Lund University Diabetes Centre, Clinical Research Center, Malmö University Hospital, Lund University, Malmö, Sweden
| | - Mattias Carlström
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, USA.
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
33
|
Shah AM, Wondisford FE. Tracking the carbons supplying gluconeogenesis. J Biol Chem 2020; 295:14419-14429. [PMID: 32817317 PMCID: PMC7573258 DOI: 10.1074/jbc.rev120.012758] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 08/12/2020] [Indexed: 11/06/2022] Open
Abstract
As the burden of type 2 diabetes mellitus (T2DM) grows in the 21st century, the need to understand glucose metabolism heightens. Increased gluconeogenesis is a major contributor to the hyperglycemia seen in T2DM. Isotope tracer experiments in humans and animals over several decades have offered insights into gluconeogenesis under euglycemic and diabetic conditions. This review focuses on the current understanding of carbon flux in gluconeogenesis, including substrate contribution of various gluconeogenic precursors to glucose production. Alterations of gluconeogenic metabolites and fluxes in T2DM are discussed. We also highlight ongoing knowledge gaps in the literature that require further investigation. A comprehensive analysis of gluconeogenesis may enable a better understanding of T2DM pathophysiology and identification of novel targets for treating hyperglycemia.
Collapse
Affiliation(s)
- Ankit M Shah
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA
| | - Fredric E Wondisford
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey, USA
| |
Collapse
|
|
34
|
A diterpene derivative enhanced insulin signaling induced by high glucose level in HepG2 cells. J Nat Med 2020; 74:434-440. [PMID: 31960210 DOI: 10.1007/s11418-019-01384-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 12/20/2019] [Indexed: 10/25/2022]
Abstract
The predominant feature of type 2 diabetes is insulin resistance. Identifying a drug able to reduce insulin resistance is an urgent requirement. ent-3α-Formylabieta-8(14),13(15)-dien-16,12β-olide had been identified as a new diterpene derivative which showed anticancer activity. This study explores the hypoglycemic effect of ent-3α-formylabieta-8(14),13(15)-dien-16,12β-olide and studied its mechanism. The insulin response of HepG2 cells following ent-3α-formylabieta-8(14),13(15)-dien-16,12β-olide treatment, as a model for liver cancer cells, was assessed. The results demonstrated that hyperglycemia resulted in a significant increase in the levels of insulin receptor substrate-1 (IRS-1) serine phosphorylation and decrease in Akt phosphorylation. High glucose also inhibited the phosphorylation of insulin-dependent GSK3β. ent-3α-Formylabieta-8(14),13(15)-dien-16,12β-olide treatment improved the effect of insulin on the phosphorylation of IRS-1 Ser307. In addition, this study demonstrated that the effect of ent-3α-formylabieta-8(14),13(15)-dien-16,12β-olide was dependent on the activation of AMP-activated protein kinase. Collectively, experimental data indicated an association between insulin resistance and hyperglycemia in HepG2 cells, and that ent-3α-formylabieta-8(14),13(15)-dien-16,12β-olide reduces IRS-1 Ser307 phosphorylation via activating AMPK, thereby decreasing the insulin signaling blockade.
Collapse
|
|
35
|
Loss of TSC complex enhances gluconeogenesis via upregulation of Dlk1-Dio3 locus miRNAs. Proc Natl Acad Sci U S A 2020; 117:1524-1532. [PMID: 31919282 DOI: 10.1073/pnas.1918931117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Loss of the tumor suppressor tuberous sclerosis complex 1 (Tsc1) in the liver promotes gluconeogenesis and glucose intolerance. We asked whether this could be attributed to aberrant expression of small RNAs. We performed small-RNA sequencing on liver of Tsc1-knockout mice, and found that miRNAs of the delta-like homolog 1 (Dlk1)-deiodinase iodothyronine type III (Dio3) locus are up-regulated in an mTORC1-dependent manner. Sustained mTORC1 signaling during development prevented CpG methylation and silencing of the Dlk1-Dio3 locus, thereby increasing miRNA transcription. Deletion of miRNAs encoded by the Dlk1-Dio3 locus reduced gluconeogenesis, glucose intolerance, and fasting blood glucose levels. Thus, miRNAs contribute to the metabolic effects observed upon loss of TSC1 and hyperactivation of mTORC1 in the liver. Furthermore, we show that miRNA is a downstream effector of hyperactive mTORC1 signaling.
Collapse
|
|
36
|
Ren L. Protective effect of ganoderic acid against the streptozotocin induced diabetes, inflammation, hyperlipidemia and microbiota imbalance in diabetic rats. Saudi J Biol Sci 2019; 26:1961-1972. [PMID: 31889779 PMCID: PMC6923438 DOI: 10.1016/j.sjbs.2019.07.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 06/15/2019] [Accepted: 07/05/2019] [Indexed: 01/03/2023] Open
Abstract
Diabetes mellitus (DM) is a metabolic disorder with numerous symptoms categorized via serves hyperglycemia effect along with altered fat, protein and carbohydrate metabolism mainly resultant from defects in insulin action/secretion or both. The aim of the current experimental study was to comfort the neuroprotective effect of ganoderic acid against the streptozotocin (STZ)-induced type I diabetes mellitus in mice and explore the underlying mechanism. Differentiation of 3T3-L1 preadipocytes effect; hepatic and glucose consumption effect of ganoderic acid was estimated on HepG2 cell lines and peroxisome proliferator-activated receptor (PPAR). FFA content was estimated in adipose and hepatic tissues. Ganoderic acid induced the 3T3-L1 preadipocytes differentiation. The mRNA expression of PPAR was increased in the high glucose-treated group in HepG2 and ganoderic acid treatment down-regulated the mRNA expression of PPAR. Ganoderic acid exhibited the inhibitory effect of α-glucosidase and α-amylase. Ganoderic acid demonstrated the reduced blood glucose and increase insulin level and also reduced the free fatty in hepatic and adipose tissue. Histopathological study showed the enhancement of β-cells in ganoderic acid-treated mice. Finally, their prebiotic effects on gut microbiota were illustrated via enhancing the population of diabetes resistant bacteria and also reducing the quantity of diabetes sensitive bacteria. Ganoderic acid attenuated STZ induced T1DM in mice via inflammatory pathways.
Collapse
|
|
37
|
Kalemba KM, Wang Y, Xu H, Chiles E, McMillin SM, Kwon H, Su X, Wondisford FE. Glycerol induces G6pc in primary mouse hepatocytes and is the preferred substrate for gluconeogenesis both in vitro and in vivo. J Biol Chem 2019; 294:18017-18028. [PMID: 31645433 PMCID: PMC6885632 DOI: 10.1074/jbc.ra119.011033] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/15/2019] [Indexed: 12/27/2022] Open
Abstract
Gluconeogenesis (GNG) is de novo production of glucose from endogenous carbon sources. Although it is a commonly studied pathway, particularly in disease, there is a lack of consensus about substrate preference. Moreover, primary hepatocytes are the current gold standard for in vitro liver studies, but no direct comparison of substrate preference at physiological fasting concentrations has been performed. We show that mouse primary hepatocytes prefer glycerol to pyruvate/lactate in glucose production assays and 13C isotope tracing studies at the high concentrations commonly used in the literature, as well as at more relevant fasting, physiological concentrations. In addition, when glycerol, pyruvate/lactate, and glutamine are all present, glycerol is responsible for over 75% of all glucose carbons labeled. We also found that glycerol can induce a rate-limiting enzyme of GNG, glucose-6-phosphatase. Lastly, we suggest that glycerol is a better substrate than pyruvate to test in vivo production of glucose in fasting mice. In conclusion, glycerol is the major carbon source for GNG in vitro and in vivo and should be compared with other substrates when studying GNG in the context of metabolic disease states.
Collapse
Affiliation(s)
- Katarzyna M Kalemba
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901
| | - Yujue Wang
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901
| | - Huiting Xu
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901
| | - Eric Chiles
- Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08903
| | - Sara M McMillin
- Fred Wilson School of Pharmacy, High Point University, High Point, North Carolina
| | - Hyokjoon Kwon
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901
| | - Xiaoyang Su
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901; Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08903
| | - Fredric E Wondisford
- Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey 08901; Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey 08903.
| |
Collapse
|
|
38
|
Zhang L, Huang Y, Wang M, Guo Y, Liang J, Yang X, Qi W, Wu Y, Si J, Zhu S, Li Z, Li R, Shi C, Wang S, Zhang Q, Tang Z, Wang L, Li K, Fei JF, Lan G. Development and Genome Sequencing of a Laboratory-Inbred Miniature Pig Facilitates Study of Human Diabetic Disease. iScience 2019; 19:162-176. [PMID: 31376679 PMCID: PMC6677790 DOI: 10.1016/j.isci.2019.07.025] [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] [Subscribe] [Scholar Register] [Received: 03/18/2019] [Revised: 06/11/2019] [Accepted: 07/13/2019] [Indexed: 01/10/2023] Open
Abstract
Pig has been proved to be a valuable large animal model used for research on diabetic disease. However, their translational value is limited given their distinct anatomy and physiology. For the last 30 years, we have been developing a laboratory Asian miniature pig inbred line (Bama miniature pig [BM]) from the primitive Bama xiang pig via long-term selective inbreeding. Here, we assembled a BM reference genome at full chromosome-scale resolution with a total length of 2.49 Gb. Comparative and evolutionary genomic analyses identified numerous variations between the BM and commercial pig (Duroc), particularly those in the genetic loci associated with the features advantageous to diabetes studies. Resequencing analyses revealed many differentiated gene loci associated with inbreeding and other selective forces. These together with transcriptome analyses of diabetic pig models provide a comprehensive genetic basis for resistance to diabetogenic environment, especially related to energy metabolism.
Collapse
Affiliation(s)
- Li Zhang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Yuemeng Huang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China; College of Veterinary Medicine, Northwest A&F University, Yangling 712100, China
| | - Meng Wang
- Novogene Bioinformatics Institute, Beijing 100083, China
| | - Yafen Guo
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Jing Liang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China.
| | - Xiurong Yang
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Wenjing Qi
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Yanjun Wu
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Jinglei Si
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Siran Zhu
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China
| | - Zhe Li
- Novogene Bioinformatics Institute, Beijing 100083, China
| | - Ruiqiang Li
- Novogene Bioinformatics Institute, Beijing 100083, China
| | - Chao Shi
- Shandong Provincial Key Laboratory of Biochemical Engineering, College of Marine Science and Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China.
| | - Shuo Wang
- Shandong Provincial Key Laboratory of Biochemical Engineering, College of Marine Science and Biological Engineering, Qingdao University of Science and Technology, Qingdao 266042, China
| | - Qunjie Zhang
- Institution of Genomics and Bioinformatics, South China Agricultural University, Guangzhou 510642, China
| | - Zhonglin Tang
- Research Centre for Animal Genome, Agricultural Genome Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518124, China; Genome Analysis Laboratory of the Ministry of Agriculture, Agricultural Genome Institute at Shenzhen, Chinese Academy of Agricultural Sciences, Shenzhen 518124, China
| | - Lixian Wang
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Kui Li
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Ji-Feng Fei
- Institute for Brain Research and Rehabilitation, South China Normal University, Guangzhou 510631, China
| | - Ganqiu Lan
- College of Animal Science and Technology, Guangxi University, Nanning 530004, China.
| |
Collapse
|
|
39
|
Abstract
PURPOSE OF REVIEW Increased glucose production associated with hepatic insulin resistance contributes to the development of hyperglycemia in T2D. The molecular mechanisms accounting for increased glucose production remain controversial. Our aims were to review recent literature concerning molecular mechanisms regulating glucose production and to discuss these mechanisms in the context of physiological experiments and observations in humans and large animal models. RECENT FINDINGS Genetic intervention studies in rodents demonstrate that insulin can control hepatic glucose production through both direct effects on the liver, and through indirect effects to inhibit adipose tissue lipolysis and limit gluconeogenic substrate delivery. However, recent experiments in canine models indicate that the direct effects of insulin on the liver are dominant over the indirect effects to regulate glucose production. Recent molecular studies have also identified insulin-independent mechanisms by which hepatocytes sense intrahepatic carbohydrate levels to regulate carbohydrate disposal. Dysregulation of hepatic carbohydrate sensing systems may participate in increased glucose production in the development of diabetes.
Collapse
Affiliation(s)
- Ashot Sargsyan
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
| | - Mark A Herman
- Duke Molecular Physiology Institute, Duke University, Durham, NC, USA.
- Division of Diabetes, Endocrinology, and Metabolism, Duke University, Durham, NC, USA.
| |
Collapse
|
|
40
|
Li L, Martin-Levilain J, Jiménez-Sánchez C, Karaca M, Foti M, Martinou JC, Maechler P. In vivo stabilization of OPA1 in hepatocytes potentiates mitochondrial respiration and gluconeogenesis in a prohibitin-dependent way. J Biol Chem 2019; 294:12581-12598. [PMID: 31285263 DOI: 10.1074/jbc.ra119.007601] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 06/14/2019] [Indexed: 12/13/2022] Open
Abstract
Patients with fatty liver diseases present altered mitochondrial morphology and impaired metabolic function. Mitochondrial dynamics and related cell function require the uncleaved form of the dynamin-like GTPase OPA1. Stabilization of OPA1 might then confer a protective mechanism against stress-induced tissue damages. To study the putative role of hepatic mitochondrial morphology in a sick liver, we expressed a cleavage-resistant long form of OPA1 (L-OPA1Δ) in the liver of a mouse model with mitochondrial liver dysfunction (i.e. the hepatocyte-specific prohibitin-2 knockout (Hep-Phb2-/-) mice). Liver prohibitin-2 deficiency caused excessive proteolytic cleavage of L-OPA1, mitochondrial fragmentation, and increased apoptosis. These molecular alterations were associated with lipid accumulation, abolished gluconeogenesis, and extensive liver damage. Such liver dysfunction was associated with severe hypoglycemia. In prohibitin-2 knockout mice, expression of L-OPA1Δ by in vivo adenovirus delivery restored the morphology but not the function of mitochondria in hepatocytes. In prohibitin-competent mice, elongation of liver mitochondria by expression of L-OPA1Δ resulted in excessive glucose production associated with increased mitochondrial respiration. In conclusion, mitochondrial dynamics participates in the control of hepatic glucose production.
Collapse
Affiliation(s)
- Lingzi Li
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, 1206 Geneva, Switzerland.,Faculty Diabetes Centre, University of Geneva Medical Centre, 1206 Geneva, Switzerland
| | - Juliette Martin-Levilain
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, 1206 Geneva, Switzerland.,Faculty Diabetes Centre, University of Geneva Medical Centre, 1206 Geneva, Switzerland
| | - Cecilia Jiménez-Sánchez
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, 1206 Geneva, Switzerland.,Faculty Diabetes Centre, University of Geneva Medical Centre, 1206 Geneva, Switzerland
| | - Melis Karaca
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, 1206 Geneva, Switzerland.,Faculty Diabetes Centre, University of Geneva Medical Centre, 1206 Geneva, Switzerland
| | - Michelangelo Foti
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, 1206 Geneva, Switzerland.,Faculty Diabetes Centre, University of Geneva Medical Centre, 1206 Geneva, Switzerland
| | - Jean-Claude Martinou
- Cell Biology Department, Faculty of Sciences, University of Geneva, 1205 Geneva, Switzerland
| | - Pierre Maechler
- Department of Cell Physiology and Metabolism, University of Geneva Medical Centre, 1206 Geneva, Switzerland .,Faculty Diabetes Centre, University of Geneva Medical Centre, 1206 Geneva, Switzerland
| |
Collapse
|
|
41
|
Abruzzese GA, Heber MF, Ferrer MJ, Ferreira SR, Silva AF, Motta AB. Effects of in utero androgen excess and metformin treatment on hepatic functions. Mol Cell Endocrinol 2019; 491:110416. [PMID: 30880153 DOI: 10.1016/j.mce.2019.03.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Revised: 03/08/2019] [Accepted: 03/08/2019] [Indexed: 12/27/2022]
Abstract
This study aimed to evaluate the role of prenatal hyperandrogenization in liver functions and the extent of metformin as treatment. Pregnant rats were hyperandrogenized with subcutaneous testosterone (1mg/rat) between 16 and 19 of pregnancy. Prenatally hyperandrogenized (PH) female offspring displayed, at the adult life, two phenotypes; a PH irregular ovulatory phenotype (PHiov) and a PH anovulatory (PHanov) phenotype. From day 70 to the moment of sacrifice (90 days of age), 50% of the animals of each group received a daily oral dose of 50 mg/kg of metformin. We found that both PH phenotypes displayed a hepatic disruptions of insulin and glucose pathway and that metformin treatment reversed some of these alterations in a specific-phenotype manner. Our findings show, for the first time, that androgen excess in utero promotes hepatic dysfunctions and that metformin treatment is able to specifically reverse those hepatic alterations and sheds light on the possible mechanisms of metformin action.
Collapse
Affiliation(s)
- Giselle Adriana Abruzzese
- Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Paraguay 2155, CP1121, Ciudad Autónoma de Buenos Aires, Argentina
| | - María Florencia Heber
- Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Paraguay 2155, CP1121, Ciudad Autónoma de Buenos Aires, Argentina
| | - María José Ferrer
- Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Paraguay 2155, CP1121, Ciudad Autónoma de Buenos Aires, Argentina
| | - Silvana Rocío Ferreira
- Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Paraguay 2155, CP1121, Ciudad Autónoma de Buenos Aires, Argentina
| | - Aimé Florencia Silva
- Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Paraguay 2155, CP1121, Ciudad Autónoma de Buenos Aires, Argentina
| | - Alicia Beatriz Motta
- Laboratorio de Fisio-patología Ovárica, Centro de Estudios Farmacológicos y Botánicos (CEFYBO), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Facultad de Medicina, Universidad de Buenos Aires (UBA), Paraguay 2155, CP1121, Ciudad Autónoma de Buenos Aires, Argentina.
| |
Collapse
|
|
42
|
Waise TMZ, Rasti M, Duca FA, Zhang SY, Bauer PV, Rhodes CJ, Lam TKT. Inhibition of upper small intestinal mTOR lowers plasma glucose levels by inhibiting glucose production. Nat Commun 2019; 10:714. [PMID: 30755615 PMCID: PMC6372624 DOI: 10.1038/s41467-019-08582-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Accepted: 01/16/2019] [Indexed: 12/11/2022] Open
Abstract
Glucose homeostasis is partly controlled by the energy sensor mechanistic target of rapamycin (mTOR) in the muscle and liver. However, whether mTOR in the small intestine affects glucose homeostasis in vivo remains unknown. Here, we first report that delivery of rapamycin or an adenovirus encoding the dominant negative acting mTOR-mutated protein into the upper small intestine is sufficient to inhibit small intestinal mTOR signaling and lower glucose production in rodents with high fat diet-induced insulin resistance. Second, we found that molecular activation of small intestinal mTOR blunts the glucose-lowering effect of the oral anti-diabetic agent metformin, while inhibiting small intestinal mTOR alone lowers plasma glucose levels by inhibiting glucose production in rodents with diabetes as well. Thus, these findings illustrate that inhibiting upper small intestinal mTOR is sufficient and necessary to lower glucose production and enhance glucose homeostasis, and thereby unveil a previously unappreciated glucose-lowering effect of small intestinal mTOR. The mechanistic target of rapamycin (TOR) functions as an energy sensor and contributes to the control of glucose homeostasis. Here, the authors show that mTOR in the upper small intestine regulates hepatic glucose production and is required for the glucose lowering effect of metformin.
Collapse
Affiliation(s)
- T M Zaved Waise
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada
| | - Mozhgan Rasti
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada
| | - Frank A Duca
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada.,School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, AZ, 85721, USA
| | - Song-Yang Zhang
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada
| | - Paige V Bauer
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada.,Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada
| | - Christopher J Rhodes
- Kovler Diabetes Center, Department of Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Chicago, Chicago, IL, 60637, USA.,MedImmune LLC, Gaithersburg, MD, 20878, USA
| | - Tony K T Lam
- Toronto General Hospital Research Institute, UHN, Toronto, ON, M5G 1L7, Canada. .,Department of Physiology, University of Toronto, Toronto, ON, M5S 1A8, Canada. .,Department of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. .,Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, M5G 2C4, Canada.
| |
Collapse
|
|
43
|
Beddow SA, Gattu AK, Vatner DF, Paolella L, Alqarzaee A, Tashkandi N, Popov VB, Church CD, Rodeheffer MS, Cline GW, Geisler JG, Bhanot S, Samuel VT. PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats. Endocrinology 2019; 160:205-219. [PMID: 30445425 PMCID: PMC6307100 DOI: 10.1210/en.2018-00630] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 11/06/2018] [Indexed: 11/19/2022]
Abstract
The increased hepatic gluconeogenesis in type 2 diabetes mellitus has often been ascribed to increased transcription of phosphoenolpyruvate carboxykinase 1, cystolic form (PEPCK1), although recent evidence has questioned this attribution. To assess the metabolic role of PEPCK1, we treated regular chow fed and high-fat fed (HFF) male Sprague-Dawley rats with a 2'-O-methoxyethyl chimeric antisense oligonucleotide (ASO) against PEPCK1 and compared them with control ASO-treated rats. PEPCK1 ASO effectively decreased PEPCK1 expression in the liver and white adipose tissue. In chow fed rats, PEPCK1 ASO did not alter adiposity, plasma glucose, or insulin. In contrast, PEPCK1 ASO decreased the white adipose tissue mass in HFF rats but without altering basal rates of lipolysis, de novo lipogenesis, or glyceroneogenesis in vivo. Despite the protection from adiposity, hepatic insulin sensitivity was impaired in HFF PEPCK1 ASO-treated rats. PEPCK1 ASO worsened hepatic steatosis, although without additional impairments in hepatic insulin signaling or activation of inflammatory signals in the liver. Instead, the development of hepatic insulin resistance and the decrease in hepatic glycogen synthesis during a hyperglycemic clamp was attributed to a decrease in hepatic glucokinase (GCK) expression and decreased synthesis of glycogen via the direct pathway. The decrease in GCK expression was associated with increased expression of activating transcription factor 3, a negative regulator of GCK transcription. These studies have demonstrated that PEPCK1 is integral to coordinating cellular metabolism in the liver and adipose tissue, although it does not directly effect hepatic glucose production or adipose glyceroneogenesis.
Collapse
Affiliation(s)
- Sara A Beddow
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
| | - Arijeet K Gattu
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
| | - Daniel F Vatner
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Lauren Paolella
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
| | | | - Nedda Tashkandi
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
| | - Violeta B Popov
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Christopher D Church
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Matthew S Rodeheffer
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut
| | - Gary W Cline
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
| | | | | | - Varman T Samuel
- Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
- West Haven Veterans Affairs Medical Center, West Haven, Connecticut
| |
Collapse
|
|
44
|
Ascorbic acid therapy: A potential strategy against comorbid depression-like behavior in streptozotocin-nicotinamide-induced diabetic rats. Biomed Pharmacother 2018; 109:351-359. [PMID: 30399569 DOI: 10.1016/j.biopha.2018.10.070] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 10/12/2018] [Accepted: 10/12/2018] [Indexed: 01/07/2023] Open
Abstract
This study examined the potency and efficacy of ascorbic acid (AA) in the management of depression-like behavior in diabetic rats. Diabetes mellitus was induced by single intraperitoneal injections of nicotinamide (120 mg/kg) and streptozotocin (65 mg/kg) administered 15 min apart. Diabetic (blood glucose ≥250 mg/dL) rats were subjected to intermittent foot-shocks to induce comorbid depression. Seven groups of diabetes comorbid depressed rats received vehicle (1 mL/kg) or AA (10, 25, 50, 100, 200, or 400 mg/kg) orally for eleven days. Three control groups namely- nondiabetic, diabetic, and depressed rats received the vehicles only. The potency (ED50) and efficacy (Emax) of AA against immobility period, hypercorticosteronemia, adrenal hyperplasia, hyperglycemia, hypoinsulinemia, oxidative stress, and inflammatory response were estimated. AA administration caused a dose-dependent decrease (P < 0.05) in immobility period with maximum inhibition of 69% (efficacy) at 200 mg/kg and ED50 of 14 mg/kg (potency). AA at 200 mg/kg produced the maximal reduction in hypercorticosteronemia (55.1%) and adrenal hyperplasia (52.6%) with ED50 of 9.8 and 14.4 mg/kg, respectively. AA at 400 mg/kg produced the maximal reduction in hyperglycemia (35.5%), hypoinsulinemia (32.7%), and lipid peroxidation (82%) with ED50 of 18.6, 13.7, and 20.7 mg/kg, respectively. Moreover, AA at 400 mg/kg produced the maximal increase in SOD content (83%), CAT activity (77.9%), and IL-10 level (63%) with ED50 of 21.5, 21, and 21 mg/kg, respectively. In conclusion, the present results suggest that AA has therapeutic potential against diabetes comorbid depression but better regulation of hyperglycemia and hypoinsulinemia is required to achieve maximal benefits.
Collapse
|
|
45
|
Zhang Y, Chen J, Zeng Y, Huang D, Xu Q. Involvement of AMPK activation in the inhibition of hepatic gluconeogenesis by Ficus carica leaf extract in diabetic mice and HepG2 cells. Biomed Pharmacother 2018; 109:188-194. [PMID: 30396076 DOI: 10.1016/j.biopha.2018.10.077] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 10/09/2018] [Accepted: 10/14/2018] [Indexed: 12/25/2022] Open
Abstract
The aim of this study was to explore the possible mechanisms of Ficus carica leaf (FCL) extract in suppressing hepatic gluconeogenesis in diabetic mice. Diabetic mice (streptozotocin-induced) received 1 g/kg of FCL extract twice a day for 6 weeks. Fasting blood glucose levels were measured and a 2-h oral glucose tolerance test was conducted. AMP-activated protein kinase (AMPK), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), and peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α) expression was examined. HepG2 hepatocytes were treated with FCL extract and an AMPK inhibitor (compound C) or agonist (AICAR), and PEPCK, G6pase, PGC-1α, AMPK, forkhead transcription factor O1 (FOXO1), and hepatic nuclear factor 4α (HNF4α) expression was determined. The results showed that FCL extract inhibited the expression of PEPCK and G6Pase in the liver of diabetic mice and HepG2 hepatocytes. FCL extract activated AMPK and decreased PGC-1α, HNF4α, and FOXO1 expression. The AMPK inhibitor attenuated those effects through inhibiting gluconeogenesis, while the AMPK agonist partially enhanced gluconeogenesis. In conclusion, FCL extract inhibits hepatic gluconeogenesis via activation of AMPK and down-regulation of gluconeogenic enzymes.
Collapse
Affiliation(s)
- Yin Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China.
| | - Jincheng Chen
- Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Yiming Zeng
- Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Dandan Huang
- Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| | - Qiuxia Xu
- Department of Pharmacy, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, 362000, People's Republic of China
| |
Collapse
|
|
46
|
Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 2018; 98:2133-2223. [PMID: 30067154 PMCID: PMC6170977 DOI: 10.1152/physrev.00063.2017] [Citation(s) in RCA: 1653] [Impact Index Per Article: 236.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/22/2018] [Accepted: 03/24/2018] [Indexed: 12/15/2022] Open
Abstract
The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.
Collapse
Affiliation(s)
- Max C Petersen
- Departments of Internal Medicine and Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine , New Haven, Connecticut
| | - Gerald I Shulman
- Departments of Internal Medicine and Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine , New Haven, Connecticut
| |
Collapse
|
|
47
|
Zhu X, Li H, Wu Y, Zhou J, Yang G, Wang W, Kang D, Ye S. CREB-upregulated lncRNA MEG3 promotes hepatic gluconeogenesis by regulating miR-302a-3p-CRTC2 axis. J Cell Biochem 2018; 120:4192-4202. [PMID: 30260029 DOI: 10.1002/jcb.27706] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 08/27/2018] [Indexed: 12/29/2022]
Abstract
Hepatic gluconeogenesis is the major contributor to hyperglycemia in diabetes. Long noncoding RNA (lncRNA) maternally expressed gene 3 (MEG3) has been shown to promote hepatic insulin resistance; however, the underlying mechanism involving hepatic gluconeogenesis remains unclear. This study aims to investigate the potential role of MEG3 in hepatic gluconeogenesis. Mouse primary hepatocytes were used in this study. Cell transfection was performed for the overexpression or knockdown of specific genes. Expressions of MEG3, miR-302a-3p, CREB-regulated transcriptional coactivator 2 (CRTC2), protein kinase A (PKA), cAMP-response element binding protein (CREB), PPARγ coactivator-1α (PGC-1α), phosphoenolpyruvate carboxykinase (PEPCK), and glucose-6-phosphatase (G6Pc) were determined by quantitative real-time polymerase chain reaction (qRT-qPCR) and Western blot analysis, respectively. The association among MEG3, miR-302a-3p, and CRTC2 was disclosed by dual-luciferase reporter assay. MEG3 was highly expressed in high glucagon-treated mouse primary hepatocytes. CREB-induced MEG3 upregulation increased gluconeogenic gene expression in high glucagon-treated primary hepatocytes, while MEG3 interference led to an opposite effect. MEG3 served as a competing endogenous RNA (ceRNA) to upregulate CRTC2 by targeting miR-302a-3p in primary hepatocytes, thereby increasing PGC-1α-PEPCK/G6Pc. CREB-upregulated MEG3-enhanced hepatic gluconeogenesis via mediating miR-302a-3p-CRTC2 axis, revealing that MEG3 might be a potential target and therapeutic strategy for diabetes.
Collapse
Affiliation(s)
- Xiang Zhu
- School of Medicine, Shandong University, Jinan, Shandong, China.,Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Hongqi Li
- Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yuanbo Wu
- Department of Neurology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Jian Zhou
- Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Guangwei Yang
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Weidong Wang
- Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Dongmei Kang
- Department of Gerontology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Shandong Ye
- Department of Endocrinology, The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| |
Collapse
|
|
48
|
Hunter RW, Hughey CC, Lantier L, Sundelin EI, Peggie M, Zeqiraj E, Sicheri F, Jessen N, Wasserman DH, Sakamoto K. Metformin reduces liver glucose production by inhibition of fructose-1-6-bisphosphatase. Nat Med 2018; 24:1395-1406. [PMID: 30150719 PMCID: PMC6207338 DOI: 10.1038/s41591-018-0159-7] [Citation(s) in RCA: 198] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 07/24/2018] [Indexed: 01/03/2023]
Abstract
Metformin is a first-line drug for the treatment of individuals with type 2 diabetes, yet its precise mechanism of action remains unclear. Metformin exerts its antihyperglycemic action primarily through lowering hepatic glucose production (HGP). This suppression is thought to be mediated through inhibition of mitochondrial respiratory complex I, and thus elevation of 5'-adenosine monophosphate (AMP) levels and the activation of AMP-activated protein kinase (AMPK), though this proposition has been challenged given results in mice lacking hepatic AMPK. Here we report that the AMP-inhibited enzyme fructose-1,6-bisphosphatase-1 (FBP1), a rate-controlling enzyme in gluconeogenesis, functions as a major contributor to the therapeutic action of metformin. We identified a point mutation in FBP1 that renders it insensitive to AMP while sparing regulation by fructose-2,6-bisphosphate (F-2,6-P2), and knock-in (KI) of this mutant in mice significantly reduces their response to metformin treatment. We observe this during a metformin tolerance test and in a metformin-euglycemic clamp that we have developed. The antihyperglycemic effect of metformin in high-fat diet-fed diabetic FBP1-KI mice was also significantly blunted compared to wild-type controls. Collectively, we show a new mechanism of action for metformin and provide further evidence that molecular targeting of FBP1 can have antihyperglycemic effects.
Collapse
Affiliation(s)
- Roger W Hunter
- Nestlé Institute of Health Sciences SA, Lausanne, Switzerland
- School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, UK
| | - Curtis C Hughey
- Department of Molecular Physiology and Biophysics and the Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA
| | - Louise Lantier
- Department of Molecular Physiology and Biophysics and the Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA
| | - Elias I Sundelin
- Departments of Clinical Medicine and Biomedicine, Aarhus University, Aarhus, Denmark
| | - Mark Peggie
- MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, UK
| | - Elton Zeqiraj
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Astbury Centre for Structural Molecular Biology, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK
| | - Frank Sicheri
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Departments of Biochemistry and Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Niels Jessen
- Departments of Clinical Medicine and Biomedicine, Aarhus University, Aarhus, Denmark
| | - David H Wasserman
- Department of Molecular Physiology and Biophysics and the Vanderbilt Mouse Metabolic Phenotyping Center, Vanderbilt University, Nashville, TN, USA
| | - Kei Sakamoto
- Nestlé Institute of Health Sciences SA, Lausanne, Switzerland.
| |
Collapse
|
|
49
|
Wang J, Xu S, Gao J, Zhang L, Zhang Z, Yang W, Li Y, Liao S, Zhou H, Liu P, Liang B. SILAC-based quantitative proteomic analysis of the livers of spontaneous obese and diabetic rhesus monkeys. Am J Physiol Endocrinol Metab 2018; 315:E294-E306. [PMID: 29664677 DOI: 10.1152/ajpendo.00016.2018] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Type 2 diabetes mellitus (T2DM) is a severe metabolic disorder that affects more than 10% of the population worldwide. Obesity is a major cause of insulin resistance and contributes to the development of T2DM. Liver is an essential metabolic organ that plays crucial roles in the pathogenesis of obesity and diabetes. However, the underlying mechanisms of liver in the transition of obesity to diabetes are not fully understood. The nonhuman primate rhesus monkey is an appropriate animal for research of human diseases. Here, we first screened and selected three individuals of spontaneously diabetic rhesus monkeys. Interestingly, the diabetic monkeys were obese with a high body mass index at the beginning, but gradually lost their body weight during one year of observation. Furthermore, we performed stable isotope labeling with amino acids in cell culture-based quantitative proteomics to identify proteins and signaling pathways with altered expression in the liver of obese and diabetic monkeys. In total, 3,509 proteins were identified and quantified, of which 185 proteins displayed an altered expression level. Gene ontology analysis revealed that the expression of proteins involved in fatty acids β-oxidation and galactose metabolism was increased in obese monkeys; while proteins involved in oxidative phosphorylation and branched chain amino acid (BCAA) degradation were upregulated in diabetic monkeys. In addition, we observed mild apoptosis in the liver of diabetic monkeys, suggesting liver injury at the late onset of diabetes. Taken together, our liver proteomics may reveal a distinct metabolic transition from fatty acids β-oxidation in obese monkey to BCAA degradation in diabetic monkeys.
Collapse
Affiliation(s)
- Junlong Wang
- College of Pharmaceutical Sciences, Soochow University , Suzhou , China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming , China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences , Kunming , China
| | - Shimeng Xu
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences , Beijing , China
| | - Jing Gao
- Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
| | - Linqiang Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming , China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences , Kunming , China
| | - Zhiguo Zhang
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming , China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences , Kunming , China
| | - Wenhui Yang
- Key Laboratory of Cardiovascular Disease of Yunnan Province, Department of Geriatrics, Yan'an Affiliated Hospital of Kunming Medical University , Kunming , China
| | - Yunhai Li
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming , China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences , Kunming , China
| | - Shasha Liao
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming , China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences , Kunming , China
| | - Hu Zhou
- Department of Analytical Chemistry and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai , China
| | - Pingsheng Liu
- National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences , Beijing , China
| | - Bin Liang
- College of Pharmaceutical Sciences, Soochow University , Suzhou , China
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences , Kunming , China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences , Kunming , China
| |
Collapse
|
|
50
|
Pérez-García A, Dongil P, Hurtado-Carneiro V, Blazquez E, Sanz C, Alvarez E. PAS Kinase deficiency alters the glucokinase function and hepatic metabolism. Sci Rep 2018; 8:11091. [PMID: 30038292 PMCID: PMC6056484 DOI: 10.1038/s41598-018-29234-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 07/03/2018] [Indexed: 12/15/2022] Open
Abstract
The liver controls metabolic homeostasis in response to fasting and refeeding periods. Glucokinase (GCK) adjusts hepatic glucose phosphorylation to blood glucose levels, acting as a glucose sensor. Our objective was to determine whether PAS kinase (PASK), a nutrient sensor, could be affecting the expression or activity of liver GCK and the response to fasting and refeeding states of key hepatic metabolic pathways. PASK-deficient mice have impaired insulin signaling (AKT overactivation). Furthermore, PASK deficiency modified the expression of several transcription factors involved in the adjustment to fasting and refeeding. Foxo1 decreased under fasting conditions, while Ppara and Pparg were overexpressed in PASK-deficient mice. However, PEPCK protein levels were similar or higher, while the expression of Cpt1a decreased in PASK-deficient mice. By contrast, Lxra and Chrebp were overexpressed after refeeding, while the expression of Acc and Fas decreased in PASK-deficient mice. Likewise, with a decreased expression of Gck and increased nuclear location of the complex GCK-GCKR, GCK activity decreased in PASK-deficient mice. Therefore, PASK regulated some of the genes and proteins responsible for glucose sensing, such as glucokinase, and for insulin signalling, affecting glucose and lipid metabolism and consequently certain critical hepatic functions.
Collapse
Affiliation(s)
- A Pérez-García
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
| | - P Dongil
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain
| | - V Hurtado-Carneiro
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - E Blazquez
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - C Sanz
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain. .,Department of Cell Biology, Faculty of Medicine, Complutense University of Madrid, Madrid, Spain.
| | - E Alvarez
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Complutense University of Madrid, Institute of Medical Research at the Hospital Clínico San Carlos (IdISSC), Ciudad Universitaria, s/n, 28040, Madrid, Spain.,Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| |
Collapse
|