|
1
|
Alhusayen R, Dienes S, Lam M, Alavi A, Alikhan A, Aleshin M, Bahashwan E, Daveluy S, Goldfarb N, Garg A, Gulliver W, Jaleel T, Kimball AB, Kirchhof MG, Kirby J, Lenczowski J, Lev-Tov H, Lowes MA, Lara-Corrales I, Micheletti R, Okun M, Orenstein L, Poelman S, Piguet V, Porter M, Resnik B, Sibbald C, Shi V, Sayed C, Wong SM, Zaenglein A, Veillette H, Hsiao JL, Naik HB. North American clinical practice guidelines for the medical management of hidradenitis suppurativa in special patient populations. J Am Acad Dermatol 2025; 92:825-852. [PMID: 39725212 DOI: 10.1016/j.jaad.2024.11.071] [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: 06/20/2024] [Revised: 11/16/2024] [Accepted: 11/23/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND Hidradenitis suppurativa (HS) affects different patient populations that require unique considerations in their management. However, no HS guidelines for these populations exist. OBJECTIVE To provide evidence-based consensus recommendations for patients with HS in 7 special patient populations: (i) pregnancy, (ii) breastfeeding, (iii) pediatrics, (iv) malignancy, (v) tuberculosis infection, (vi) hepatitis B or C infection, and (vii) HIV disease. METHODS Recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation system to ascertain level of evidence and selected through a modified Delphi consensus process. RESULTS One hundred eighteen expert consensus statements are provided for the management of patients with HS across these 7 special patient populations.
Collapse
Affiliation(s)
- Raed Alhusayen
- Sunnybrook Research Institute, Toronto, Ontario, Canada; Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
| | - Serena Dienes
- Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Megan Lam
- Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Afsaneh Alavi
- Department of Dermatology, Mayo Clinic, Rochester, Minnesota
| | - Ali Alikhan
- Sutter Medical Foundation, Sacramento, California
| | - Maria Aleshin
- Department of Dermatology, Stanford University School of Medicine, Stanford, California
| | - Emad Bahashwan
- Division of Dermatology, Faculty of Medicine, University of Bisha, Bisha, Saudi Arabia
| | - Steve Daveluy
- Department of Dermatology, Wayne State University School of Medicine, Detroit, Michigan
| | - Noah Goldfarb
- Department of Dermatology, University of Minnesota, Minneapolis, Minnesota
| | - Amit Garg
- Department of Dermatology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, New Hyde Park, New York
| | - Wayne Gulliver
- Department of Dermatology, Memorial University of Newfoundland, St. John's, Canada
| | - Tarannum Jaleel
- Department of Dermatology, Duke University School of Medicine, Durham, North Carolina
| | - Alexa B Kimball
- Clinical Laboratory for Epidemiology and Applied Research in Skin (CLEARS), Department of Dermatology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Department of Dermatology, Harvard Medical School, Boston, Massachusetts
| | - Mark G Kirchhof
- Division of Dermatology, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Division of Dermatology, Department of Medicine, Ottawa Hospital, Ottawa, Ontario, Canada
| | - Joslyn Kirby
- Incyte Corporation, Wilmington, Delaware; Department of Dermatology, Penn State Health, Hershey, Pennsylvania
| | | | - Hadar Lev-Tov
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, Florida
| | - Michelle A Lowes
- Laboratory for Investigative Dermatology, The Rockefeller University, New York, New York
| | - Irene Lara-Corrales
- Division of Dermatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Robert Micheletti
- Departments of Dermatology and Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Lauren Orenstein
- Department of Dermatology, Emory University School of Medicine, Atlanta, Georgia
| | - Susan Poelman
- Division of Dermatology, University of Calgary and Beacon Dermatology, Calgary, Alberta, Canada
| | - Vincent Piguet
- Division of Dermatology, Department of Medicine, University of Toronto and Women's College Hospital, Toronto, Ontario, Canada
| | - Martina Porter
- Department of Dermatology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Barry Resnik
- Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, Florida; Resnik Skin Institute, Miami, Florida
| | - Cathryn Sibbald
- Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Dermatology, Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Vivian Shi
- Department of Dermatology, University of Washington, Seattle, Washington
| | - Christopher Sayed
- Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Se Mang Wong
- Department of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Andrea Zaenglein
- Department of Dermatology, Penn State Health, Hershey, Pennsylvania; Penn State Children's Hospital, Hershey, Pennsylvania
| | - Helene Veillette
- Division of Dermatology, Department of Medicine, CHU de Québec-Université Laval, Québec, Canada
| | - Jennifer L Hsiao
- Department of Dermatology, University of Southern California, Los Angeles, California
| | - Haley B Naik
- Department of Dermatology, University of California, San Francisco, California
| |
Collapse
|
|
2
|
Li Z, He Y, Chen J, Ran D, Yue J, Fu Q, Shi H. Transcriptomic Analysis of Metformin's Effect on Bovine Viral Diarrhea Virus Infection. Vet Sci 2024; 11:376. [PMID: 39195830 PMCID: PMC11358930 DOI: 10.3390/vetsci11080376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 08/10/2024] [Accepted: 08/13/2024] [Indexed: 08/29/2024] Open
Abstract
(1) Background: Bovine viral diarrhea virus (BVDV) causes calf diarrhea, bovine respiratory syndrome, and cow abortion, resulting in substantial economic losses in the cattle industry. Owing to its persistent infection mechanism, BVDV is a major challenge in the treatment of cattle. (2) Methods: To determine how metformin (Met) inhibits the interaction between BVDV and host cells, we treated BVDV-infected cells with Met. We then performed an RNA sequencing (RNA-seq) analysis of Met-treated cells infected with BVDV to identify differentially expressed genes (DEGs). Consequently, the RNA-seq results were validated through real-time quantitative PCR (qPCR). (3) Results: Our analysis revealed 3169 DEGs in the Met-treated cells (Met group) vs. the negative controls (NC group) and 2510 DEGs in the BVDV-infected cells after pretreatment with Met (MetBVDV group) vs. the BVDV-infected cells (BVDV group). The DEGs were involved in MDBK interactions during BVDV infection, as indicated by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The potential interactions of the DEGs were confirmed via a protein-protein interaction (PPI) network. Met treatment induced autophagy signaling activity and the expression of the autophagy-related genes ATG2A, ATG4B, ATG10, and ATG12 in BVDV-infected Met-pretreated cells. (4) Conclusions: We found that the host transcriptomic profile was affected by BVDV infection and Met pretreatment. These findings offer valuable new insights and provide support for future studies on the inhibition of BVDV replication by Met.
Collapse
Affiliation(s)
- Zeyu Li
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China; (Z.L.); (Y.H.); (J.C.); (D.R.)
- Xinjiajng Key Laboratory of New Drug Study and Creation for Herbivorous Animals, Urumqi 830052, China
| | - Yuanxiu He
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China; (Z.L.); (Y.H.); (J.C.); (D.R.)
- Xinjiajng Key Laboratory of New Drug Study and Creation for Herbivorous Animals, Urumqi 830052, China
| | - Junzhen Chen
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China; (Z.L.); (Y.H.); (J.C.); (D.R.)
- Xinjiajng Key Laboratory of New Drug Study and Creation for Herbivorous Animals, Urumqi 830052, China
| | - Duoliang Ran
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China; (Z.L.); (Y.H.); (J.C.); (D.R.)
- Xinjiajng Key Laboratory of New Drug Study and Creation for Herbivorous Animals, Urumqi 830052, China
| | - Jianbo Yue
- Division of Natural and Applied Science, Duke Kunshan University, Kunshan 215316, China;
| | - Qiang Fu
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China; (Z.L.); (Y.H.); (J.C.); (D.R.)
- Xinjiajng Key Laboratory of New Drug Study and Creation for Herbivorous Animals, Urumqi 830052, China
| | - Huijun Shi
- College of Veterinary Medicine, Xinjiang Agricultural University, Urumqi 830052, China; (Z.L.); (Y.H.); (J.C.); (D.R.)
- Xinjiajng Key Laboratory of New Drug Study and Creation for Herbivorous Animals, Urumqi 830052, China
| |
Collapse
|
|
3
|
Landis D, Sutter A, Khemka S, Songtanin B, Nichols J, Nugent K. Metformin as adjuvant treatment in hepatitis C virus infections and associated complications. Am J Med Sci 2024; 368:90-98. [PMID: 38701970 DOI: 10.1016/j.amjms.2024.04.019] [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: 06/11/2023] [Revised: 03/27/2024] [Accepted: 04/29/2024] [Indexed: 05/06/2024]
Abstract
Hepatitis C virus is an important global cause of hepatitis and subsequently cirrhosis and hepatocellular carcinoma. These infections may also cause extrahepatic manifestations, including insulin resistance and type 2 diabetes mellitus. These two complications can potentially reduce sustained virologic responses (SVR) in some drug regimens for this infection. Metformin has important biochemical effects that can limit viral replication in cellular cultures and can improve the response to antiviral drug therapy based on ribavirin and interferon. Clinical studies comparing treatment regimens with interferon, ribavirin, metformin with these regimens without metformin have demonstrated that metformin increases viral clearance, establishes higher rates of SVRs, and increases insulin sensitivity. Metformin also reduces the frequency of hepatocellular carcinoma in patients who have had SVRs. Larger treatment trials are needed to determine metformin's short-term and long-term treatment effects in patients with diabetes using newer antiviral drugs. In particular, if metformin reduces the frequency of cirrhosis and hepatocellular carcinoma, this would significantly reduce the morbidity and mortality associated with this infection.
Collapse
Affiliation(s)
- Dylan Landis
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Alex Sutter
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Sachi Khemka
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Busara Songtanin
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Jacob Nichols
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States
| | - Kenneth Nugent
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States.
| |
Collapse
|
|
4
|
Jitobaom K, Boonarkart C, Thongon S, Sirihongthong T, Sornwong A, Auewarakul P, Suptawiwat O. In vitro synergistic antiviral activity of repurposed drugs against enterovirus 71. Arch Virol 2024; 169:169. [PMID: 39078431 DOI: 10.1007/s00705-024-06097-1] [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: 01/10/2024] [Accepted: 06/13/2024] [Indexed: 07/31/2024]
Abstract
Enteroviruses cause viral diseases that are harmful to children. Hand, foot, and mouth disease (HFMD) with neurological complications is mainly caused by enterovirus 71 (EV71). Despite its clinical importance, there is no effective antiviral drug against EV71. However, several repurposed drugs have been shown to have antiviral activity against related viruses. Treatments with single drugs and two-drug combinations were performed in vitro to assess anti-EV71 activity. Three repurposed drug candidates with broad-spectrum antiviral activity were found to demonstrate potent anti-EV71 activity: prochlorperazine, niclosamide, and itraconazole. To improve antiviral activity, combinations of two drugs were tested. Niclosamide and itraconazole showed synergistic antiviral activity in Vero cells, whereas combinations of niclosamide-prochlorperazine and itraconazole-prochlorperazine showed only additive effects. Furthermore, the combination of itraconazole and prochlorperazine showed an additive effect in neuroblastoma cells. Itraconazole and prochlorperazine exert their antiviral activities by inhibiting Akt phosphorylation. Repurposing of drugs can provide a treatment solution for HFMD, and our data suggest that combining these drugs can enhance that efficacy.
Collapse
Affiliation(s)
- Kunlakanya Jitobaom
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Chompunuch Boonarkart
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Songkran Thongon
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Thanyaporn Sirihongthong
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Arpakorn Sornwong
- Department of Central instrument and Research Laboratory, Virology and Immunology Laboratory, Chulabhorn Royal Academy, Bangkok, 10210, Thailand
| | - Prasert Auewarakul
- Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Ornpreya Suptawiwat
- Department of Central instrument and Research Laboratory, Virology and Immunology Laboratory, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
- Princess Srisavangavadhana College of Medicine, Chulabhorn Royal Academy, Bangkok, 10210, Thailand.
| |
Collapse
|
|
5
|
Peppas S, Doumas S, Suvarnakar A, Chou J, Arafat A, Ahmad AI, Lewis JH. Clinical outcomes with metformin use in diabetic patients with compensated cirrhosis: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2024; 36:674-682. [PMID: 38477839 DOI: 10.1097/meg.0000000000002754] [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] [Indexed: 03/14/2024]
Abstract
BACKGROUND Previous studies have demonstrated a beneficial effect of metformin in patients with cirrhosis, but no improvement in liver histology. AIM To investigate the impact of metformin on mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. METHODS Medline, Embase and Cochrane databases were searched from inception to February 2023 for studies reporting results regarding the impact of metformin on all-cause mortality and hepatic decompensation in people with diabetes with compensated cirrhosis. The risk of bias was assessed by ROBINS-I Cochrane tool. R software 4.3.1 was used for all analyses. RESULTS Six observational studies were included in the final analysis. Metformin use was associated with reduced all-cause mortality or liver transplantation [hazard ratio (HR): 0.55; 95% confidence interval (CI) 0.37-0.82], while no benefit was shown in the prevention of hepatic decompensation (HR: 0.97; 95% CI: 0.77-1.22). In the subgroup analysis, metformin use was associated with reduced all-cause mortality or liver transplantation (HR: 0.50; 95% CI 0.38-0.65) in patients with metabolic-associated steatohepatitis cirrhosis, while two studies reported no survival benefit in patients with cirrhosis due to hepatitis C (HR: 0.39; 95% CI 0.12-1.20). CONCLUSION Metformin use is associated with reduced all-cause mortality, but not with the prevention of hepatic decompensation in people with diabetes with compensated cirrhosis. The mortality benefit is most likely driven by better diabetes and cardiovascular health control.
Collapse
Affiliation(s)
- Spyros Peppas
- Department of Medicine, MedStar Washington Hospital Center
| | - Stavros Doumas
- Department of Internal Medicine, MedStar Georgetown University Medical Center
| | | | - Jiling Chou
- MedStar Research Health Institute, Hyattsville, Maryland
| | - Ayah Arafat
- MedStar Research Health Institute, Hyattsville, Maryland
| | - Akram I Ahmad
- Divsion of Gastroenterology & Hepatology, Cleveland Clinic Florida, Weston, Florida
| | - James H Lewis
- Division of Gastroenterology & Hepatology, MedStar Georgetown University Medical Center, Washington, DC, USA
| |
Collapse
|
|
6
|
Rezaei S, Timani KA, He JJ. Metformin Treatment Leads to Increased HIV Transcription and Gene Expression through Increased CREB Phosphorylation and Recruitment to the HIV LTR Promoter. Aging Dis 2024; 15:831-850. [PMID: 37450926 PMCID: PMC10917544 DOI: 10.14336/ad.2023.0705] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/05/2023] [Indexed: 07/18/2023] Open
Abstract
Antiretroviral therapy has effectively suppressed HIV infection and replication and prolonged the lifespan of HIV-infected individuals. In the meantime, various complications including type 2 diabetes associated with the long-term antiviral therapy have shown steady increases. Metformin has been the front-line anti-hyperglycemic drug of choice and the most widely prescribed medication for the treatment of type 2 diabetes. However, little is known about the effects of Metformin on HIV infection and replication. In this study, we showed that Metformin treatment enhanced HIV gene expression and transcription in HIV-transfected 293T and HIV-infected Jurkat and human PBMC. Moreover, we demonstrated that Metformin treatment resulted in increased CREB expression and phosphorylation, and TBP expression. Furthermore, we showed that Metformin treatment increased the recruitment of phosphorylated CREB and TBP to the HIV LTR promoter. Lastly, we showed that inhibition of CREB phosphorylation/activation significantly abrogated Metformin-enhanced HIV gene expression. Taken together, these results demonstrated that Metformin treatment increased HIV transcription, gene expression, and production through increased CREB phosphorylation and recruitment to the HIV LTR promoter. These findings may help design the clinical management plan and HIV cure strategy of using Metformin to treat type 2 diabetes, a comorbidity with an increasing prevalence, in people living with HIV.
Collapse
Affiliation(s)
- Sahar Rezaei
- Department of Microbiology and Immunology, Rosalind Franklin University, Chicago Medical School, North Chicago, IL 60064, USA.
- Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL 60064, USA.
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL 60064, USA.
| | - Khalid A Timani
- Department of Microbiology and Immunology, Rosalind Franklin University, Chicago Medical School, North Chicago, IL 60064, USA.
- Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL 60064, USA.
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL 60064, USA.
| | - Johnny J He
- Department of Microbiology and Immunology, Rosalind Franklin University, Chicago Medical School, North Chicago, IL 60064, USA.
- Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL 60064, USA.
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL 60064, USA.
| |
Collapse
|
|
7
|
Wang X, Wang H, Yi P, Baker C, Casey G, Xie X, Luo H, Cai J, Fan X, Soong L, Hu H, Shi PY, Liang Y, Sun J. Metformin restrains ZIKV replication and alleviates virus-induced inflammatory responses in microglia. Int Immunopharmacol 2023; 121:110512. [PMID: 37343373 DOI: 10.1016/j.intimp.2023.110512] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/05/2023] [Accepted: 06/12/2023] [Indexed: 06/23/2023]
Abstract
The re-emergence of Zika virus (ZIKV) remains a major public health threat that has raised worldwide attention. Accumulating evidence suggests that ZIKV can cause serious pathological changes to the human nervous system, including microcephaly in newborns. Recent studies suggest that metformin, an established treatment for diabetes may play a role in viral infection; however, little is known about the interactions between ZIKV infection and metformin administration. Using fluorescent ZIKV by flow cytometry and immunofluorescence imaging, we found that ZIKV can infect microglia in a dose-dependent manner. Metformin diminished ZIKV replication without the alteration of viral entry and phagocytosis. Our study demonstrated that metformin downregulated ZIKV-induced inflammatory response in microglia in a time- and dose-dependent manner. Our RNA-Seq and qRT-PCR analysis found that type I and III interferons (IFN), such as IFNα2, IFNβ1 and IFNλ3 were upregulated in ZIKV-infected cells by metformin treatment, accompanied with the downregulation of GBP4, OAS1, MX1 and ISG15. Together, our results suggest that metformin-mediated modulation in multiple pathways may attribute to restraining ZIKV infection in microglia, which may provide a potential tool to consider for use in unique clinical circumstances.
Collapse
Affiliation(s)
- Xiaofang Wang
- Department of Infectious Disease, Hunan Provincial People's Hospital (The First Affiliated Hospital of Hunan Normal University), Changsha, Hunan 410005, China; Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Hui Wang
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Panpan Yi
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Coleman Baker
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Gonzales Casey
- Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Xuping Xie
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Huanle Luo
- School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou 510275, China
| | - Jiyang Cai
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Xuegong Fan
- Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Lynn Soong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Haitao Hu
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Pei-Yong Shi
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Center for Structural Biology and Molecular Biophysics, University of Texas Medical Branch, Galveston, TX 77555, USA; Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA; Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Translational Sciences, University of Texas Medical Branch, Galveston, TX 77555, USA
| | - Yuejin Liang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
| | - Jiaren Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
| |
Collapse
|
|
8
|
El-Kassas M, El-Folly R, Aboromia M, Aly H, Bahgat M, Hamed M. Effect of achieving sustained virological response with direct-acting antiviral agents on glycemic control in diabetic patients with chronic hepatitis C infection. EGYPTIAN LIVER JOURNAL 2022; 12:25. [DOI: 10.1186/s43066-022-00190-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/26/2022] [Indexed: 12/07/2022] Open
Abstract
Abstract
Background
Hepatitis C virus (HCV) is a significant cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma worldwide. Liver disease is not the only problem caused by chronic HCV infection; many extrahepatic complications, such as insulin resistance, can be associated with HCV infection. The aim of this study was to assess the effect of achieving a sustained virological response after treatment with directly acting antiviral drugs on insulin resistance in patients with chronic HCV infection.
Results
This prospective study was conducted on 46 HCV patients with type 2 diabetes mellitus who received directly acting antiviral drugs for HCV infections. Fasting insulin, fasting blood glucose, and lipid profiles were assessed in all patients at three time points: before treatment, at the end of treatment, and 12 weeks after the end of treatment. Despite using three different directly acting antiviral drug regimens, all patients achieved a sustained viral response, regardless of the regimen used. the Homeostatic Model Assessment for Insulin Resistance decreased significantly at the end of treatment; however, when recalculated at week 12 after end of treatment, the reduction of the Homeostatic Model Assessment for Insulin Resistance was not significant compared to the baseline levels. Total cholesterol and low-density lipoproteins increased at the end of treatment and continued to increase for 12 weeks after the end of treatment.
Conclusions
Improvements in insulin resistance and glycemic control were noted in HCV patients at the end of treatment with directly acting antiviral drugs; this effect was also apparent after 12 weeks. An increase in the levels of total cholesterol and low-density lipoprotein can be expected after treatment with directly acting antiviral drugs.
Collapse
|
|
9
|
Molecular mechanisms of metabolic associated fatty liver disease (MAFLD): functional analysis of lipid metabolism pathways. Clin Sci (Lond) 2022; 136:1347-1366. [PMID: 36148775 PMCID: PMC9508552 DOI: 10.1042/cs20220572] [Citation(s) in RCA: 154] [Impact Index Per Article: 51.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 09/12/2022] [Accepted: 09/14/2022] [Indexed: 01/30/2023]
Abstract
The metabolic-associated fatty liver disease (MAFLD) is a condition of fat accumulation in the liver in combination with metabolic dysfunction in the form of overweight or obesity and insulin resistance. It is also associated with an increased cardiovascular disease risk, including hypertension and atherosclerosis. Hepatic lipid metabolism is regulated by a combination of the uptake and export of fatty acids, de novo lipogenesis, and fat utilization by β-oxidation. When the balance between these pathways is altered, hepatic lipid accumulation commences, and long-term activation of inflammatory and fibrotic pathways can progress to worsen the liver disease. This review discusses the details of the molecular mechanisms regulating hepatic lipids and the emerging therapies targeting these pathways as potential future treatments for MAFLD.
Collapse
|
|
10
|
Ali A, Unnikannan H, Shafarin J, Bajbouj K, Taneera J, Muhammad JS, Hasan H, Salehi A, Awadallah S, Hamad M. Metformin enhances LDL-cholesterol uptake by suppressing the expression of the pro-protein convertase subtilisin/kexin type 9 (PCSK9) in liver cells. Endocrine 2022; 76:543-557. [PMID: 35237909 DOI: 10.1007/s12020-022-03022-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 02/16/2022] [Indexed: 12/11/2022]
Abstract
PURPOSE Metformin (MF) intake associates with reduced levels of circulating low-density lipoprotein-cholesterol (LDL-C). This has been attributed to the activation of AMPK, which differentially regulates the expression of multiple genes involved in cholesterol synthesis and trafficking. However, the exact mechanism underlying the LDL-C lowering effect of MF remains ambiguous. METHODS MF-treated Hep-G2 and HuH7 cells were evaluated for cell viability and the expression status of key lipid metabolism-related genes along with LDL-C uptake efficiency. RESULTS MF treatment resulted in decreased expression and secretion of PCSK9, increased expression of LDLR and enhanced LDL-C uptake in hepatocytes. It also resulted in increased expression of activated AMPK (p-AMPK) and decreased expression of SREBP2 and HNF-1α proteins. Transcriptomic analysis of MF-treated Hep-G2 cells confirmed these findings and showed that other key lipid metabolism-related genes including those that encode apolipoproteins (APOB, APOC2, APOC3 and APOE), MTTP and LIPC are downregulated. Lastly, MF treatment associated with reduced HMG-CoA reductase expression and activity. CONCLUSIONS These findings suggest that MF treatment reduces circulating LDL-C levels by suppressing PCSK9 expression and enhancing LDLR expression; hence the potential therapeutic utility of MF in hypercholesterolemia.
Collapse
Affiliation(s)
- Amjad Ali
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Hema Unnikannan
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Jasmin Shafarin
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
| | - Khuloud Bajbouj
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jalal Taneera
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Jibran Sualeh Muhammad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates
- Department of Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
| | - Haydar Hasan
- Department of Clinical Nutrition and Dietetics, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Albert Salehi
- Department of Clinical science, UMAS, Clinical Research Center, Lund University, Malmö, Sweden
- Department of Neuroscience and Physiology, Metabolic Research Unit, University of Gothenburg, Gothenburg, Sweden
| | - Samir Awadallah
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
| | - Mawieh Hamad
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah, United Arab Emirates.
| |
Collapse
|
|
11
|
Surendran A, Bhalla A, Whyte MB. Improved diabetes control, allowing insulin cessation, after direct acting antiviral treatment (DAAT) of hepatitis C. BMJ Case Rep 2022; 15:e243491. [PMID: 35450872 PMCID: PMC9024205 DOI: 10.1136/bcr-2021-243491] [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] [Accepted: 04/02/2022] [Indexed: 12/15/2022] Open
Abstract
There is a bidirectional relationship between hepatitis C and type 2 diabetes. The risk for developing type 2 diabetes is increased in patients with chronic hepatitis C virus (HCV) infection-with the prevalence of diabetes ranging from 13% to 33%. This is likely underpinned by insulin resistance. Type 2 diabetes may also be a predisposing factor for HCV infection. The new non-interferon-based therapeutic regimens for hepatitis C have transformed care and can eradicate disease. In this report, we show how such a regimen eradicated viral load, improved hepatocellular blood markers and significantly improved dysglycaemia, such that all glucose-lowering medication could be stopped.
Collapse
Affiliation(s)
- Aarthi Surendran
- Department of Diabetes and Endocrinology, Lewisham and Greenwich NHS Trust, University Hospital Lewisham, London, UK
| | - Aditya Bhalla
- Department of Cardiology, Darent Valley Hospital, Dartford and Gravesham NHS Foundation Trust, Dartford, UK
| | | |
Collapse
|
|
12
|
The Hormetic Effect of Metformin: "Less Is More"? Int J Mol Sci 2021; 22:ijms22126297. [PMID: 34208371 PMCID: PMC8231127 DOI: 10.3390/ijms22126297] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/06/2021] [Accepted: 06/10/2021] [Indexed: 02/06/2023] Open
Abstract
Metformin (MTF) is the first-line therapy for type 2 diabetes (T2DM). The euglycemic effect of MTF is due to the inhibition of hepatic glucose production. Literature reports that the principal molecular mechanism of MTF is the activation of 5′-AMP-activated protein kinase (AMPK) due to the decrement of ATP intracellular content consequent to the inhibition of Complex I, although this effect is obtained only at millimolar concentrations. Conversely, micromolar MTF seems to activate the mitochondrial electron transport chain, increasing ATP production and limiting oxidative stress. This evidence sustains the idea that MTF exerts a hormetic effect based on its concentration in the target tissue. Therefore, in this review we describe the effects of MTF on T2DM on the principal target organs, such as liver, gut, adipose tissue, endothelium, heart, and skeletal muscle. In particular, data indicate that all organs, except the gut, accumulate MTF in the micromolar range when administered in therapeutic doses, unmasking molecular mechanisms that do not depend on Complex I inhibition.
Collapse
|
|
13
|
Justice JN, Gubbi S, Kulkarni AS, Bartley JM, Kuchel GA, Barzilai N. A geroscience perspective on immune resilience and infectious diseases: a potential case for metformin. GeroScience 2021; 43:1093-1112. [PMID: 32902818 PMCID: PMC7479299 DOI: 10.1007/s11357-020-00261-6] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 08/27/2020] [Indexed: 12/18/2022] Open
Abstract
We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.
Collapse
Affiliation(s)
- Jamie N Justice
- Sticht Center for Healthy Aging and Alzheimer's Prevention, Internal Medicine - Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
| | - Sriram Gubbi
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20814, USA
| | - Ameya S Kulkarni
- Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| | - Jenna M Bartley
- Center on Aging, University of Connecticut School of Medicine, Farmington, CT, 06030, USA
- Department of Immunology, University of Connecticut School of Medicine, Farmington, CT, 06030, USA
| | - George A Kuchel
- Center on Aging, University of Connecticut School of Medicine, Farmington, CT, 06030, USA
| | - Nir Barzilai
- Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
- Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, 10461, USA
| |
Collapse
|
|
14
|
Xu L, Wang X, Chen Y, Soong L, Chen Y, Cai J, Liang Y, Sun J. Metformin Modulates T Cell Function and Alleviates Liver Injury Through Bioenergetic Regulation in Viral Hepatitis. Front Immunol 2021; 12:638575. [PMID: 33968030 PMCID: PMC8097169 DOI: 10.3389/fimmu.2021.638575] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/23/2021] [Indexed: 12/11/2022] Open
Abstract
Metformin is not only the first-line medication for the treatment of type 2 diabetes, but it is also effective as an anti-inflammatory, anti-oxidative and anti-tumor agent. However, the effect of metformin during viral hepatitis remains elusive. Using an adenovirus (Ad)-induced viral hepatitis mouse model, we found that metformin treatment significantly attenuated liver injury, with reduced serum aspartate transaminase (AST) and alanine transaminase (ALT) levels and liver histological changes, presumably via decreased effector T cell responses. We then demonstrated that metformin reduced mTORC1 activity in T cells from infected mice, as evidenced by decreased phosphorylation of ribosome protein S6 (p-S6). The inhibitory effects on the mTORC1 signaling by metformin was dependent on the tuberous sclerosis complex 1 (TSC1). Mechanistically, metformin treatment modulated the phosphorylation of dynamin-related protein 1 (Drp-1) and mitochondrial fission 1 protein (FIS1), resulting in increased mass in effector T cells. Moreover, metformin treatment promoted mitochondrial superoxide production, which can inhibit excessive T cell activation in viral hepatitis. Together, our results revealed a protective role and therapeutic potential of metformin against liver injury in acute viral hepatitis via modulating effector T cell activation via regulating the mTORC1 pathway and mitochondrial functions.
Collapse
Affiliation(s)
- Lanman Xu
- Department of Infectious Diseases and Liver Diseases, Ningbo Medical Center Lihuili Hospital, Affiliated Lihuili Hospital of Ningbo University, Ningbo Institute of Innovation for Combined Medicine and Engineering, Ningbo, China.,Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States
| | - Xiaofang Wang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.,Department of Infectious Diseases, Key Laboratory of Viral Hepatitis of Hunan, Xiangya Hospital, Central South University, Changsha, China
| | - Yan Chen
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX, United States
| | - Lynn Soong
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.,Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States.,Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States
| | - Yongping Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Provincial Key Laboratory for Accurate Diagnosis and Treatment of Chronic Liver Diseases, Wenzhou, China
| | - Jiyang Cai
- Department of Ophthalmology, University of Texas Medical Branch, Galveston, TX, United States
| | - Yuejin Liang
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.,Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States
| | - Jiaren Sun
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States.,Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States.,Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, United States
| |
Collapse
|
|
15
|
Singh AK, Singh R, Saboo B, Misra A. Non-insulin anti-diabetic agents in patients with type 2 diabetes and COVID-19: A Critical Appraisal of Literature. Diabetes Metab Syndr 2021; 15:159-167. [PMID: 33352455 PMCID: PMC7832723 DOI: 10.1016/j.dsx.2020.12.026] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 12/13/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND & AIMS Several observational studies have recently reported the outcomes of non-insulin anti-diabetic agents (ADA) in patients with T2DM and coronavirus disease 2019 (COVID-19). We sought to review the literature to appraise the clinicians on these outcomes. METHODS A literature search using the specific keywords was carried out in the database of PubMed, MedRxiv and Google Scholar up till December 11, 2020 applying Boolean method. Full text of all the relevant articles that reported the outcomes of ADA in patients with T2DM and COVID-19 were retrieved. Subsequently, an appraisal of literature report was narratively presented. RESULTS Available studies that reported the outcomes of ADA are either case series or retrospective cohorts or prospective observational studies, in absence of the randomized controlled trials (RCTs). Results from these observational studies suggest that amongst all the non-insulin ADA, metformin users prior to the hospitalization had improved outcomes compared to the non-users. Data for dipeptidyl-peptidase-4 inhibitors (DPP-4i) are encouraging although inconsistent. No documentation of any harm or benefit has been observed for sulfonylureas (SUs), sodium glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide receptor agonists (GLP-1RAs). No data is yet available for pioglitazone. CONCLUSION Metformin and DPP-4i should be continued in patients with T2DM until hospitalization or unless contraindicated. No evidence of harm suggests that SUs, SGLT-2i or GLP-1RAs may not be stopped unless very sick, hospitalized or contraindicated. The results from RCTs are needed to claim any meaningful benefit with either metformin or DPP-4i in patients with T2DM and COVID-19.
Collapse
Affiliation(s)
| | - Ritu Singh
- G.D Hospital & Diabetes Institute, Kolkata, India
| | | | - Anoop Misra
- Fortis CDOC Hospital for Diabetes and Allied Science, Chirag Enclave, New Delhi, India; National Diabetes, Obesity and Cholesterol Foundation, New Delhi, India; Diabetes Foundation (India), New Delhi, India
| |
Collapse
|
|
16
|
Smith FC, Stocker SL, Danta M, Carland JE, Kumar SS, Liu Z, Greenfield JR, Braithwaite HE, Cheng TS, Graham GG, Williams KM, Day RO. The safety and pharmacokinetics of metformin in patients with chronic liver disease. Aliment Pharmacol Ther 2020; 51:565-575. [PMID: 31960986 DOI: 10.1111/apt.15635] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/16/2019] [Accepted: 12/23/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND The FDA approved 'label' for metformin lists hepatic insufficiency as a risk for lactic acidosis. Little evidence supports this warning. AIMS To investigate the safety and pharmacokinetics of metformin in patients with chronic liver disease (CLD). METHODS Chronic liver disease patients with and without type 2 diabetes mellitus (T2DM) were studied by a cross-sectional survey of patients already prescribed metformin (n = 34), and by a prospective study where metformin (500 mg, immediate release, twice daily) for up to 6 weeks was prescribed (n = 24). Plasma metformin and lactate concentrations were monitored. Individual pharmacokinetics were obtained and compared to previously published values from healthy and T2DM populations without CLD. RESULTS All plasma metformin and lactate concentrations remained below the putative safety thresholds (metformin, 5 mg/L; lactate, 5 mmol/L). Lactate concentrations were unrelated to average steady-state metformin concentrations. In patients with CLD, T2DM was associated with higher plasma lactate concentrations (48% higher than those without T2DM, P < 0.0001). CLD patients with cirrhosis had 23% higher lactate concentrations than those without cirrhosis (P = 0.01). The pharmacokinetics of metformin in CLD patients were similar to patients with T2DM and no liver disease. The ratio of apparent metformin clearance (CLMet /F) to creatinine clearance was marginally lower in CLD patients compared to healthy subjects (median, interquartile range; 12.6, 9.5-15.9 vs 14.9, 13.4-16.4; P = 0.03). CONCLUSIONS The pharmacokinetics of metformin are not altered sufficiently in CLD patients to raise concerns regarding unsafe concentrations of metformin. There were no unsafe plasma lactate concentrations observed in CLD patients receiving metformin (ACTRN12619001292167; ACTRN12619001348145).
Collapse
Affiliation(s)
- Felicity C Smith
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,School of Medical Science, University of New South Wales, Kensington, NSW, Australia
| | - Sophie L Stocker
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia
| | - Mark Danta
- St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia.,Gastroenterology and Hepatology Department, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Jane E Carland
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia
| | - Shaun S Kumar
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Zhixin Liu
- Stats Central, University of New South Wales, Kensington, NSW, Australia
| | - Jerry R Greenfield
- St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia.,Department of Diabetes and Endocrinology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,Diabetes and Metabolism, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Hannah E Braithwaite
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Tim S Cheng
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia
| | - Garry G Graham
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,School of Medical Science, University of New South Wales, Kensington, NSW, Australia
| | - Kenneth M Williams
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,School of Medical Science, University of New South Wales, Kensington, NSW, Australia
| | - Richard O Day
- Department of Clinical Pharmacology & Toxicology, St Vincent's Hospital, Darlinghurst, NSW, Australia.,School of Medical Science, University of New South Wales, Kensington, NSW, Australia.,St Vincent's Clinical School, University of New South Wales, Kensington, NSW, Australia
| |
Collapse
|
|
17
|
Alezzi ZMM, Abd El Rehim AY, Fathallah WF, Alamrani MA, Othman FH. Factors Affecting the Virological Response Among Chronic Hepatitis C Virus Patients in Yemen. J Interferon Cytokine Res 2019; 38:38-44. [PMID: 29328881 DOI: 10.1089/jir.2017.0098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Hepatitis C virus (HCV) infection is increasingly seen as a major public health problem, threat, and concern worldwide. In Yemen about 1.7% of the population is infected with chronic hepatitis C. This study aimed to detect the predictors for response to pegylated interferon and ribavirin (Peg-IFN/RBV) in chronic HCV Yemeni patients. The study was conducted on 100 patients with chronic HCV who received Peg-IFN/RBV in the 48th Military Hospital in Sana'a Yemen, from 2011 to 2013. All patients were subjected to complete history taking, thorough clinical examinations, routine laboratory investigation, and abdominal ultrasonography. The HCV RNA was assessed at week 72 of treatment to detect whether the patient achieved sustained virological response (SVR). The SVR was achieved in 64% of the samples. Age above 40, Khat chewing, and obesity were the sociodemographic factors that predict good response for Peg-IFN/RBV combined therapy. Platelet count, alpha feto-protein (AFP), aspartate transaminase (AST), and alanine transaminase (ALT) levels were the basic laboratory investigations that gave favorable response. Significant predictors of sustained response included: older than 40 years (OR = 0.136, P = 0.042), Khat chewer (OR = 0.016, P = 0.008), body mass index (BMI) (OR = 0.055, P = 0.029) and increase in fasting blood glucose (OR = 0.925, P = 0.004), alkaline phosphatase (OR = 0.969, P = 0.001), total and bilirubin (OR = 0.058, P = 0.017), AST (OR = 1.033, P = 0.002), and albumin (OR = 6.490, P = 0.021). Studying the independent variables of response, we revealed that male gender, BMI, ALT >40, AFP >10, viremia >600, and hemoglobin and thyroid stimulating hormone (TSH) levels are variables associated with failure of end of treatment response (ETR) and SVR.
Collapse
Affiliation(s)
| | - Ayman Yosry Abd El Rehim
- 2 Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University , Cairo, Egypt
| | - Waleed Fouad Fathallah
- 2 Endemic Medicine Department and Hepatology Unit, Faculty of Medicine, Cairo University , Cairo, Egypt
| | | | - Fouad Hezam Othman
- 3 Department of Community Medicine, Faculty of Medicine & Health Sciences, Taiz University , Taiz, Yemen
| |
Collapse
|
|
18
|
Titov AA, Baker HV, Brusko TM, Sobel ES, Morel L. Metformin Inhibits the Type 1 IFN Response in Human CD4 + T Cells. THE JOURNAL OF IMMUNOLOGY 2019; 203:338-348. [PMID: 31160534 DOI: 10.4049/jimmunol.1801651] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 05/03/2019] [Indexed: 02/07/2023]
Abstract
In systemic lupus erythematosus, defective clearance of apoptotic debris and activation of innate cells result in a chronically activated type 1 IFN response, which can be measured in PBMCs of most patients. Metformin, a widely used prescription drug for Type 2 diabetes, has a therapeutic effect in several mouse models of lupus through mechanisms involving inhibition of oxidative phosphorylation and a decrease in CD4+ T cell activation. In this study, we report that in CD4+ T cells from human healthy controls and human systemic lupus erythematosus patients, metformin inhibits the transcription of IFN-stimulated genes (ISGs) after IFN-α treatment. Accordingly, metformin inhibited the phosphorylation of pSTAT1 (Y701) and its binding to IFN-stimulated response elements that control ISG expression. These effects were independent of AMPK activation or mTORC1 inhibition but were replicated using inhibitors of the electron transport chain respiratory complexes I, III, and IV. This indicates that mitochondrial respiration is required for ISG expression in CD4+ T cells and provides a novel mechanism by which metformin may exert a therapeutic effect in autoimmune diseases.
Collapse
Affiliation(s)
- Anton A Titov
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Henry V Baker
- Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610; and
| | - Todd M Brusko
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Eric S Sobel
- Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610
| | - Laurence Morel
- Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
| |
Collapse
|
|
19
|
Hepatoprotective activity of metformin: A new mission for an old drug? Eur J Pharmacol 2019; 850:1-7. [PMID: 30753869 DOI: 10.1016/j.ejphar.2019.02.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 02/02/2019] [Accepted: 02/08/2019] [Indexed: 02/06/2023]
Abstract
Metformin, as a dimethyl biguanide prescribed as the first-line medication for treatment of type 2 diabetes mellitus, is one of the most frequently used drugs, worldwide. However, the beneficial effects of metformin are not limited to insulin sensitizing and blood glucose lowering effects as recent clinical trials deciphered lower cancer risk in metformin users. In addition, metformin protected the liver against chemical or viral hepatotoxicants through various mechanisms including activation of AMPK via inhibition of mitochondrial complex I, inhibition of mitogen activated protein kinase (MAPK) and inhibition of Smads phosphorylation. Clinical trials are under way to assess possible additive effects of metformin when co-administered along with the standard regimen for hepatocellular carcinoma (HCC) treatment. This review outlines the molecular mechanisms behind protective activity of metformin against different liver diseases.
Collapse
|
|
20
|
Elhelbawy M, Abdel-Razek W, Alsebaey A, Hashim M, Elshenawy H, Waked I. Insulin resistance does not impair response of chronic hepatitis C virus to direct-acting antivirals, and improves with the treatment. Eur J Gastroenterol Hepatol 2019; 31:16-23. [PMID: 30024489 DOI: 10.1097/meg.0000000000001215] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Insulin resistance (IR) is a common complication in chronic hepatitis C virus (HCV) patients. The impact of IR on outcome of therapy with direct antivirals has not been studied. AIM The aim was to assess the impact of direct-acting antiviral (DAA) therapy on IR status in chronic HCV patients. PATIENTS AND METHODS A total of 511 patients [mean age: 50.7±10.4 years, 29.7% pegylated interferon and ribavirin (RBV) experienced] were enrolled. Patients with uncontrolled diabetes, decompensated liver disease, or previous nonresponse to DAAs were excluded. Homeostatic model assessment (HOMA) was calculated before and 12 weeks after treatment, and IR was defined as HOMA greater than 1.9. Patients were treated according to the treating physician's choice, and received 12 weeks of either ombitasvir/ritonavir/paritaprevir/RBV (n=28); sofosbuvir (SOF)/simeprevir (n=36); SOF/ravidasvir (n=101); SOF/pegylated interferon/RBV (n=192); or 24 weeks of SOF/RBV (n=154). RESULTS Most patients received IR pretreatment (80.6%); 51.3% had fibrosis stage F4 and 24.7% had diabetes. A sustained virological response (SVR) at 12 weeks after treatment (SVR12) was achieved in 465 (91%) patients. SVR12 was achieved in 90.5% of patients with IR and in 92.9% of patients without IR (P=0.560), and pretreatment HOMA was not different in responders and nonresponders (P=0.098). The number of patients with IR decreased significantly in patients who achieved an SVR much more than in nonresponders (P<0.0001) and HOMA improved significantly more in patients with SVR than in nonresponders (P=0.001). All treatment protocols were associated with a comparable improvement in HOMA (P=0.101). Predictors of SVR12 included age, platelets, and liver stiffness, but not pretreatment IR. CONCLUSION IR does not impair the response of patients with HCV treated with DAAs, and improves significantly in patients who achieve an SVR.
Collapse
Affiliation(s)
- Mostafa Elhelbawy
- Department of Hepatology and Gastroenterology, National Liver Institute, Menoufia University, Shebeen El-Koom, Egypt
| | | | | | | | | | | |
Collapse
|
|
21
|
Chen Y, Gu F, Guan JL. Metformin Might Inhibit Virus through Increasing Insulin Sensitivity. Chin Med J (Engl) 2018; 131:376-377. [PMID: 29363663 PMCID: PMC5798069 DOI: 10.4103/0366-6999.223856] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Yong Chen
- Department of Rheumatology and Immunology, Huadong Hospital Affiliated with Fudan University, Shanghai 200040, China
| | - Feng Gu
- MOE and MOH Key Laboratory of Medical Molecular Virology, School of Basic Medicine, Shanghai Medical College, Fudan University, Shanghai 325444, China
| | - Jian-Long Guan
- Department of Rheumatology and Immunology, Huadong Hospital Affiliated with Fudan University, Shanghai 200040, China
| |
Collapse
|
|
22
|
Malik F, Mehdi SF, Ali H, Patel P, Basharat A, Kumar A, Ashok F, Stein J, Brima W, Malhotra P, Roth J. Is metformin poised for a second career as an antimicrobial? Diabetes Metab Res Rev 2018; 34:e2975. [PMID: 29271563 DOI: 10.1002/dmrr.2975] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 12/11/2017] [Accepted: 12/13/2017] [Indexed: 12/24/2022]
Abstract
Metformin, a widely used antihyperglycaemic, has a good safety profile, reasonably manageable side-effects, is inexpensive, and causes a desirable amount of weight loss. In 4 studies of patients with tuberculosis (1 prospective and 3 retrospective), metformin administration resulted in better outcomes. In mice with several models of endotoxemia, metformin diminished levels of proinflammatory cytokines and improved survival. Laboratory studies showed effectiveness of the drug on multiple pathogens, including Trichinella spiralis, Staphylococcus aureus, Pseudomonas aeruginosa, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus. Metformin administration in humans and mice produced major changes in the composition of the gut microbiota. These recently discovered microbe-modulating properties of the drug have led investigators to predict wide therapeutic utility for metformin. The recent easing in United States Food and Drug Administration (FDA) guidelines regarding administration of metformin to patients with kidney disease, and reduced anxiety about patient safety in terms of lactic acidosis, increase the probability of broadening of metformin's usage as a treatment of infectious agents. In this text we review articles pertinent to metformin's effects on microorganisms, both pathogens and commensals. We highlight the possible role of metformin in a wide range of infectious diseases and a possible expansion of its therapeutic profile in this field. A systematic review was done of PubMed indexed articles that examined the effects of metformin on a wide range of pathogens. Metformin was found to have efficacy as an antimicrobial agent in patients with tuberculosis. Mice infected with Trypanosomiasis cruzi had higher survival when also treated with metformin. The drug in vitro was active against T. spiralis, S. aureus, P. aeruginosa, and hepatitis B virus. In addition there is emerging literature on its role in sepsis. We conclude that metformin may have a potential role in the therapy for multiple infectious diseases. Metformin, in addition to its traditional effects on glucose metabolism, provides anti-microbial benefits in patients with tuberculosis and in a very wide range of other infections encounters in vitro and in vivo.
Collapse
Affiliation(s)
- Faiza Malik
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Syed Faizan Mehdi
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Haroon Ali
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Priya Patel
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Anam Basharat
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Amrat Kumar
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Fnu Ashok
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Joanna Stein
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| | - Wunnie Brima
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
| | - Prashant Malhotra
- Division of Infectious Diseases, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| | - Jesse Roth
- Laboratory of Diabetes and Diabetes-Related Research, Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Manhasset, NY, USA
| |
Collapse
|
|
23
|
Bui TL, Silva-Hirschberg C, Torres J, Armstrong AW. Hidradenitis suppurativa and diabetes mellitus: A systematic review and meta-analysis. J Am Acad Dermatol 2018; 78:395-402. [DOI: 10.1016/j.jaad.2017.08.042] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 08/16/2017] [Accepted: 08/24/2017] [Indexed: 10/18/2022]
|
|
24
|
Tsai WL, Chang TH, Sun WC, Chan HH, Wu CC, Hsu PI, Cheng JS, Yu ML. Metformin activates type I interferon signaling against HCV via activation of adenosine monophosphate-activated protein kinase. Oncotarget 2017; 8:91928-91937. [PMID: 29190886 PMCID: PMC5696152 DOI: 10.18632/oncotarget.20248] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 07/12/2017] [Indexed: 12/25/2022] Open
Abstract
Activation of the type I interferon (IFN) signaling pathway is essential for the eradication of hepatitis C virus (HCV). Metformin can activate adenosine monophosphate-activated protein kinase (AMPK) to reduce insulin resistance. Cross talks between AMPK and IFN signaling remain unclear. To understand the influence of metformin on the type I IFN signaling pathway and HCV infection, the full-length HCV replicon OR6 cells and the infectious HCV clones JFH1 were used to assess the anti-HCV effect of the insulin sensitizers, metformin and pioglitazone. Immunofluorescence staining and the immunoblotting of HCV viral protein demonstrated that metformin, but not pioglitazone, inhibited HCV replication in OR-6 and JFH-1-infected Huh 7.5.1 cells. Immunoblotting data showed that metformin activated the phosphorylation of STAT-1 and STAT-2 in OR-6 and JFH-1 infected Huh 7.5.1 cells. Metformin enhanced the phosphorylation of AMPK, and the metformin-activated IFN signaling was down-regulated by AMPK inhibitor. After treatment of AMPK inhibitor, the level of HCV core protein decreased by metformin can be rescued. In conclusion, metformin activates type I interferon signaling and inhibits the replication of HCV via activation of AMPK.
Collapse
Affiliation(s)
- Wei-Lun Tsai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Tsung-Hsien Chang
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- Department of Medical Laboratory Science and Biotechnology, Chung Hwa University of Medical Technology, Tainan, Taiwan
| | - Wei-Chi Sun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Hoi-Hung Chan
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Chun-Ching Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Ping-I Hsu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Jin-Shiung Cheng
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
- School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
- Faculty of Internal Medicine, College of Medicine, and Graduate Institute of Clinical Medicine, and Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
| |
Collapse
|
|
25
|
Li X, Gao Y, Xu H, Hou J, Gao P. Diabetes mellitus is a significant risk factor for the development of liver cirrhosis in chronic hepatitis C patients. Sci Rep 2017; 7:9087. [PMID: 28831144 PMCID: PMC5567219 DOI: 10.1038/s41598-017-09825-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 07/31/2017] [Indexed: 12/21/2022] Open
Abstract
We explored the association between diabetes mellitus (DM) and the risk of hepatitis C virus (HCV)-related liver cirrhosis in Chinese patients with chronic hepatitis C (CHC). To examine the link between DM and liver cirrhosis, we conducted a case-control study of 210 Chinese CHC patients diagnosed with liver cirrhosis, comparing them to an age- and sex-matched control group of 431 CHC patients without liver cirrhosis. We conducted logistic regression analyses adjusting for demographic features and liver cirrhosis risk factors, and found that DM increased the risk of developing liver cirrhosis 2-fold [adjusted odds ratio (AOR), 2.132; 95% confidence interval (CI), 1.344–3.382]. Furthermore, the proportion of liver cirrhosis patients and CHC-only patients with elevated serum triglycerides (>1.8 mmol/L) were 5.2% and 17.4%, respectively, yielding an AOR of 0.264 (95% CI, 0.135–0.517). Multivariate analyses that stratified the risk of developing HCV-related liver cirrhosis in DM patients by gender revealed that the estimated AOR (95% CI) for males was 0.415 (0.178–0.969). In conclusion, DM was associated with an increased risk of developing liver cirrhosis in CHC patients in China. Furthermore, among patients diagnosed with both CHC and DM, females had an increased risk of liver cirrhosis development.
Collapse
Affiliation(s)
- Xu Li
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, No. 71 Xinmin Street, Changchun, 130021, China
| | - Yang Gao
- Department of Neurology, The First Hospital of Jilin University, Jilin University, No. 71 Xinmin Street, Changchun, 130021, China
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, No. 71 Xinmin Street, Changchun, 130021, China.,Jilin Province Key Laboratory of Infectious Disease, Laboratory of Molecular Virology, Changchun, 130021, China
| | - Jie Hou
- Department of Nephrology, The First Hospital of Jilin University, Jilin University, No. 71 Xinmin Street, Changchun, 130021, China
| | - Pujun Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University, No. 71 Xinmin Street, Changchun, 130021, China.
| |
Collapse
|
|
26
|
Li X, Xu H, Gao Y, Pan M, Wang L, Gao P. Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis C patients in China. Medicine (Baltimore) 2017; 96:e6508. [PMID: 28353605 PMCID: PMC5380289 DOI: 10.1097/md.0000000000006508] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We investigated the link between diabetes mellitus (DM) and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) risk in treatment-naïve chronic hepatitis C (CHC) patients in China.To examine the association between DM and HCC, we conducted a case-control study of 300 Chinese CHC patients with HCC, compared to an age- and sex-matched control group of 517 CHC patients not diagnosed with HCC.We found that DM was more prevalent in the HCC patient group (18.7%) than in the CHC-only patient group (10.8%). We conducted logistic regression analyses adjusting for demographics features and other HCC risk factors and found that DM increased the risk of HCC development nearly 2-fold [adjusted odds ratio (AOR), 95% confidence interval (95% CI), 1.80 (1.17-2.75)]. Meanwhile, the proportion of HCC patients and CHC-only patients with liver cirrhosis were 79.3% and 46.2%, respectively, yielding an AOR of 4.62 (95% CI, 3.31-6.46). Multivariate analyses comparing the risk of HCV-related HCC development in DM patients with and without liver cirrhosis revealed that the estimated AOR (95% CI) for those with liver cirrhosis was 5.60 (2.25-13.96). However, the HCC risk decreased significantly with a later age of diabetes onset (AOR [95% CI], 0.94 [0.89-0.99]).DM was associated with an increased risk for HCC development in treatment-naïve CHC patients in China. Furthermore, liver cirrhosis and an early DM diagnoses further increased the risks of HCC development in patients diagnosed with both CHC and DM.
Collapse
Affiliation(s)
- Xu Li
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
| | - Hongqin Xu
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
- Jilin Province Key Laboratory of Infectious Disease, Laboratory of Molecular Virology
| | - Yang Gao
- Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Meng Pan
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
| | - Le Wang
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
| | - Pujun Gao
- Department of Hepatology, The First Hospital of Jilin University, Jilin University
| |
Collapse
|
|
27
|
Gastaldi G, Goossens N, Clément S, Negro F. Current level of evidence on causal association between hepatitis C virus and type 2 diabetes: A review. J Adv Res 2017; 8:149-159. [PMID: 28149650 PMCID: PMC5272937 DOI: 10.1016/j.jare.2016.11.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Revised: 11/16/2016] [Accepted: 11/23/2016] [Indexed: 12/15/2022] Open
Abstract
The association between hepatitis C virus (HCV) infection and type 2 diabetes (T2D) has been known for over 20 years. Cross-sectional and longitudinal studies have shown a higher prevalence and incidence, respectively, of T2D in patients with chronic HCV infection. HCV induces glucose metabolism alterations mostly interfering with the insulin signaling chain in hepatocytes, although extrahepatic mechanisms seem to contribute. Both IR and T2D accelerate the histological and clinical progression of chronic hepatitis C as well as the risk of extra-hepatic complications such as nephropathy, acute coronary events and ischemic stroke. Before the availability of direct-acting antivirals (DAAs), the therapeutic choice was limited to interferon (IFN)-based therapy, which reduced the incidence of the extra-hepatic manifestations but was burdened with several contraindications and poor tolerability. A better understanding of HCV-associated glucose metabolism derangements and their reversibility is expected with the use of DAAs.
Collapse
Affiliation(s)
- Giacomo Gastaldi
- Divisions of Endocrinology, Diabetology, Hypertension and Nutrition, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
| | - Nicolas Goossens
- Gastroenterology and Hepatology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
| | - Sophie Clément
- Clinical Pathology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
| | - Francesco Negro
- Gastroenterology and Hepatology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
- Clinical Pathology, Geneva University Hospitals, Rue Gabrielle Perret-Gentil, 1211 Genève 14, Switzerland
| |
Collapse
|
|
28
|
Dongiovanni P, Rametta R, Meroni M, Valenti L. The role of insulin resistance in nonalcoholic steatohepatitis and liver disease development--a potential therapeutic target? Expert Rev Gastroenterol Hepatol 2016; 10:229-42. [PMID: 26641143 DOI: 10.1586/17474124.2016.1110018] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Insulin resistance (IR) is defined by the inability of insulin to exert its metabolic actions, due to impaired activation of intracellular insulin signaling. This condition is caused by genetic defects or by environmental conditions, among which the most common is obesity. Systemic IR determines the development of hepatic fat accumulation, which can progress to nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma, and is a major determinant of liver disease independently of coexisting factors. Therefore, insulin-sensitizing drugs are currently under evaluation to improve steatohepatitis. Indeed, manipulation of nuclear hormone receptors is already under scrutiny for liver disease prevention by amelioration of IR, whereas NOTCH signaling inhibition represents a novel approach. Nevertheless, further research is warranted to better understand the mechanism linking IR to progressive fibrogenesis in the absence of inflammation and to identify novel drug targets.
Collapse
Affiliation(s)
- Paola Dongiovanni
- a Department of Pathophysiology and Transplantation , Università degli Studi di Milano, and Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano , Milano , Italy
| | - Raffaela Rametta
- a Department of Pathophysiology and Transplantation , Università degli Studi di Milano, and Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano , Milano , Italy
| | - Marica Meroni
- a Department of Pathophysiology and Transplantation , Università degli Studi di Milano, and Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano , Milano , Italy
| | - Luca Valenti
- a Department of Pathophysiology and Transplantation , Università degli Studi di Milano, and Internal Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Policlinico Milano , Milano , Italy
| |
Collapse
|
|
29
|
Affiliation(s)
- Gautam Das
- Prince Charles Hospital, Cwm Taf University Health Board; Merthyr Tydfil UK
| | - Hemanth Bolusani
- University Hospital of Wales, Cardiff and Vale University Health Board; Cardiff UK
| |
Collapse
|
|
30
|
García-Compeán D, González-González JA, Lavalle-González FJ, González-Moreno EI, Villarreal-Pérez JZ, Maldonado-Garza HJ. Current Concepts in Diabetes Mellitus and Chronic Liver Disease: Clinical Outcomes, Hepatitis C Virus Association, and Therapy. Dig Dis Sci 2016; 61:371-380. [PMID: 26462490 DOI: 10.1007/s10620-015-3907-2] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 09/27/2015] [Indexed: 02/07/2023]
Abstract
Hereditary type 2 diabetes mellitus is a risk factor for chronic liver disease, and ~30 % of patients with liver cirrhosis develop diabetes. Diabetes mellitus has been associated with cirrhotic and non-cirrhotic hepatitis C virus liver infection, can aggravate the course the liver infection, and can induce a lower sustained response to antiviral treatment. Evidences that HCV may induce metabolic and autoimmune disturbances leading to hypobetalipoproteinemia, steatosis, insulin resistance, impaired glucose tolerance, thyroid disease, and gonadal dysfunction have been found. Prospective studies have demonstrated that diabetes increases the risk of liver complications and death in patients with cirrhosis. However, treatment of diabetes in these patients is complex, as antidiabetic drugs can promote hypoglycemia and lactic acidosis. There have been few therapeutic studies evaluating antidiabetic treatments in patients with liver cirrhosis published to date; thus, the optimal treatment for diabetes and the impact of treatment on morbidity and mortality are not clearly known. As numbers of patients with chronic liver disease and diabetes mellitus are increasing, largely because of the global epidemics of obesity and nonalcoholic fatty liver disease, evaluation of treatment options is becoming more important. This review discusses new concepts on hepatogenous diabetes, the diabetes mellitus–hepatitis C virus association, and clinical implications of diabetes mellitus in patients with chronic liver disease. In addition, the effectiveness and safety of old and new antidiabetic drugs, including incretin-based therapies, will be described.
Collapse
|
|
31
|
Knobler H, Malnick S. Hepatitis C and insulin action: An intimate relationship. World J Hepatol 2016; 8:131-138. [PMID: 26807209 PMCID: PMC4716529 DOI: 10.4254/wjh.v8.i2.131] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 12/10/2015] [Accepted: 12/29/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis C virus (HCV) infection has been shown to be linked to a higher prevalence of type 2 diabetes compared with the general population or with patients with chronic hepatitis B infection and diabetes is the most common extra-hepatic manifestation of HCV. The HCV-diabetes association is due to insulin resistance (IR) that occurs early in the course of the disease even in patients without or with minimal fibrosis. The mechanisms for HCV-induced IR are only partly understood and include a direct inhibitory effect of HCV on insulin signaling pathway. IR in chronic HCV results in an increased progression rate of hepatic fibrosis, cirrhosis and hepatocellular carcinoma. Some but not all studies found that IR reduces the response rate to interferon/ribavirin therapy. Whether IR affects the response to the new direct-acting antiviral treatments is still unknown.
Collapse
Affiliation(s)
- Hilla Knobler
- Hilla Knobler, Diabetes and Metabolic Disease Unit, Kaplan Medical Center, Rehovot 76100, Israel
| | - Stephen Malnick
- Hilla Knobler, Diabetes and Metabolic Disease Unit, Kaplan Medical Center, Rehovot 76100, Israel
| |
Collapse
|
|
32
|
Mesquita I, Moreira D, Sampaio-Marques B, Laforge M, Cordeiro-da-Silva A, Ludovico P, Estaquier J, Silvestre R. AMPK in Pathogens. EXPERIENTIA SUPPLEMENTUM (2012) 2016; 107:287-323. [PMID: 27812985 DOI: 10.1007/978-3-319-43589-3_12] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
During host-pathogen interactions, a complex web of events is crucial for the outcome of infection. Pathogen recognition triggers powerful cellular signaling events that is translated into the induction and maintenance of innate and adaptive host immunity against infection. In opposition, pathogens employ active mechanisms to manipulate host cell regulatory pathways toward their proliferation and survival. Among these, subversion of host cell energy metabolism by pathogens is currently recognized to play an important role in microbial growth and persistence. Extensive studies have documented the role of AMP-activated protein kinase (AMPK) signaling, a central cellular hub involved in the regulation of energy homeostasis, in host-pathogen interactions. Here, we highlight the most recent advances detailing how pathogens hijack cellular metabolism by suppressing or increasing the activity of the host energy sensor AMPK. We also address the role of lower eukaryote AMPK orthologues in the adaptive process to the host microenvironment and their contribution for pathogen survival, differentiation, and growth. Finally, we review the effects of pharmacological or genetic AMPK modulation on pathogen growth and persistence.
Collapse
Affiliation(s)
- Inês Mesquita
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3Bs-PT Government Associate Laboratory, Guimarães, Braga, Portugal
| | - Diana Moreira
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.,Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Belém Sampaio-Marques
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3Bs-PT Government Associate Laboratory, Guimarães, Braga, Portugal
| | | | - Anabela Cordeiro-da-Silva
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,IBMC-Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal.,Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Paula Ludovico
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.,ICVS/3Bs-PT Government Associate Laboratory, Guimarães, Braga, Portugal
| | - Jérôme Estaquier
- CNRS FR 3636, Université Paris Descartes, Paris, France.,Centre de Recherche du CHU de Québec, Université Laval, Québec, QC, Canada
| | - Ricardo Silvestre
- Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal. .,ICVS/3Bs-PT Government Associate Laboratory, Guimarães, Braga, Portugal.
| |
Collapse
|
|
33
|
Bhat A, Sebastiani G, Bhat M. Systematic review: Preventive and therapeutic applications of metformin in liver disease. World J Hepatol 2015; 7:1652-1659. [PMID: 26140084 PMCID: PMC4483546 DOI: 10.4254/wjh.v7.i12.1652] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Revised: 05/05/2015] [Accepted: 06/08/2015] [Indexed: 02/06/2023] Open
Abstract
Metformin, a biguanide derivative, is the most commonly prescribed medication in the treatment of type 2 diabetes mellitus. More recently, the use of metformin has shown potential as a preventive and therapeutic agent for a broad spectrum of conditions, including liver disease and hepatic malignancies. In this systematic review, we critically analyze the literature behind the potential use of metformin across the spectrum of liver disease and malignancies. The PubMed and Ovid MEDLINE databases were searched from 2000 to March 2015, using a combination of relevant text words and MeSH terms: metformin and mammalian target of rapamycin, hepatitis B virus (HBV), hepatitis B virus (HCV), non-alcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC) or cholangiocarcinoma. The search results were evaluated for pertinence to the issue of metformin in liver disease as well as for quality of study design. Metformin has a number of biochemical effects that would suggest a benefit in treating chronic liver diseases, particularly in the context of insulin resistance and inflammation. However, the literature thus far does not support any independent therapeutic role in NAFLD or HCV. Nonetheless, there is Level III evidence for a chemopreventive role in patients with diabetes and chronic liver disease, with decreased incidence of HCC and cholangiocarcinoma. The use of metformin seems to be safe in patients with cirrhosis, and provides a survival benefit. Once hepatic malignancies are already established, metformin does not offer any therapeutic potential. In conclusion, there is insufficient evidence to recommend use of metformin in the adjunctive treatment of chronic liver diseases, including NAFLD and HCV. However, there is good evidence for a chemopreventive role against HCC among patients with diabetes and chronic liver disease, and metformin should be continued in patients even with cirrhosis to provide this benefit.
Collapse
|
|
34
|
Hsu CS. Infectious causes of stroke. THE LANCET. INFECTIOUS DISEASES 2015; 15:631-632. [PMID: 26008833 DOI: 10.1016/s1473-3099(15)00019-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Ching-Sheng Hsu
- Division of Gastroenterology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, No. 289, Jianguo Road, Sindian City, Taipei County 231, Hualien, Taiwan; School of Medicine, Tzu Chi University, Hualien, Taiwan.
| |
Collapse
|
|
35
|
Kukla M, Piotrowski D, Waluga M, Hartleb M. Insulin resistance and its consequences in chronic hepatitis C. Clin Exp Hepatol 2015; 1:17-29. [PMID: 28856251 PMCID: PMC5421163 DOI: 10.5114/ceh.2015.51375] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2015] [Accepted: 03/10/2015] [Indexed: 02/07/2023] Open
Abstract
Chronic hepatitis C (CHC) is generally a slowly progressive disease, but some factors associated with rapid progression have been identified. Hepatitis C virus (HCV) may contribute to a broad spectrum of metabolic disturbances - namely, steatosis, insulin resistance (IR), increased prevalence of impaired glucose tolerance, type 2 diabetes mellitus (T2DM), lipid metabolism abnormalities and atherosclerosis. HCV can directly or indirectly cause both IR and steatosis, but it is still not resolved whether this viral impact bears the same prognostic value as the metabolic counterparts. As the population exposed to HCV ages, the morbidity due to this disease is increasing. The rising epidemic of obesity contributes to higher prevalence of IR and T2DM. Our understanding of the mutual association between both disease states continues to grow, but is still far from complete. This review briefly discusses the most probable mechanisms involved in IR development in the course of CHC. Molecular mechanisms for the direct and indirect influence of HCV on intracellular insulin signaling are described. Subsequently, the consequences of IR/T2DM for disease progression and management are summarized.
Collapse
Affiliation(s)
- Michał Kukla
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Damian Piotrowski
- Department of Infectious Diseases in Bytom, Medical University of Silesia in Katowice, Poland
| | - Marek Waluga
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| | - Marek Hartleb
- Department of Gastroenterology and Hepatology, Medical University of Silesia in Katowice, Poland
| |
Collapse
|
|
36
|
Grasso A, Malfatti F, Andraghetti G, Marenco S, Mazzucchelli C, Labanca S, Cordera R, Testa R, Picciotto A. HOMA, BMI, and Serum Leptin Levels Variations during Antiviral Treatment Suggest Virus-Related Insulin Resistance in Noncirrhotic, Nonobese, and Nondiabetic Chronic Hepatitis C Genotype 1 Patients. Gastroenterol Res Pract 2015; 2015:975695. [PMID: 25821463 PMCID: PMC4363607 DOI: 10.1155/2015/975695] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2014] [Accepted: 02/04/2015] [Indexed: 12/31/2022] Open
Abstract
Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders. Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment. Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P = 0.033 and 0.048, resp.) in patients who achieved an early viral load decay (EVR), a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR. Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype.
Collapse
Affiliation(s)
- Alessandro Grasso
- Gastroenterology Unit, San Paolo Hospital, Via Genova 38, 17100 Savona, Italy
| | - Federica Malfatti
- Gastroenterology Unit, San Paolo Hospital, Via Genova 38, 17100 Savona, Italy
| | - Gabriella Andraghetti
- Department of Endocrinology, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
| | - Simona Marenco
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
| | - Chiara Mazzucchelli
- Department of Endocrinology, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
| | - Sara Labanca
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
| | - Renzo Cordera
- Department of Endocrinology, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
| | - Roberto Testa
- Gastroenterology Unit, San Paolo Hospital, Via Genova 38, 17100 Savona, Italy
| | - Antonino Picciotto
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Viale Benedetto XV 6, 16132 Genoa, Italy
| |
Collapse
|
|
37
|
Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y. Diabetes and Hepatitis C: A Two-Way Association. Front Endocrinol (Lausanne) 2015; 6:134. [PMID: 26441826 PMCID: PMC4568414 DOI: 10.3389/fendo.2015.00134] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2015] [Accepted: 08/17/2015] [Indexed: 12/15/2022] Open
Abstract
Diabetes and hepatitis C infection are both prevalent diseases worldwide, and are associated with increased morbidity and mortality. Most studies, but not all, have shown that patients with chronic hepatitis C are more prone to develop type 2 diabetes (T2D) compared to healthy controls, as well as when compared to patients with other liver diseases, including hepatitis B. Furthermore, epidemiological studies have revealed that patients with T2D may also be at higher risk for worse outcomes of their hepatitis C infection, including reduced rate of sustained virological response, progression to fibrosis and cirrhosis, and higher risk for development of hepatocellular carcinoma. Moreover, hepatitis C infection and mainly its treatment, interferon α, can trigger the development of type 1 diabetes. In this review, we discuss the existing data on this two-way association between diabetes and hepatitis C infection with emphasis on possible mechanisms. It remains to be determined whether the new curative therapies for chronic hepatitis C will improve outcomes in diabetic hepatitis C patients, and conversely whether treatment with Metformin will reduce complications from hepatitis C virus infection. We propose an algorithm for diabetes screening and follow-up in hepatitis C patients.
Collapse
Affiliation(s)
- Sara Salehi Hammerstad
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pediatrics, Oslo University Hospital Ullevål, Oslo, Norway
| | - Shira Frankel Grock
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Hanna J. Lee
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Alia Hasham
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nina Sundaram
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Yaron Tomer
- Department of Medicine, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- James J. Peters VA Medical Center, Bronx, NY, USA
- *Correspondence: Yaron Tomer, Division of Endocrinology, Icahn School of Medicine at Mount Sinai, Box 1055, One Gustave L. Levy Place, New York, NY 10029, USA,
| |
Collapse
|
|
38
|
Vercauteren K, Mesalam AA, Leroux-Roels G, Meuleman P. Impact of lipids and lipoproteins on hepatitis C virus infection and virus neutralization. World J Gastroenterol 2014; 20:15975-91. [PMID: 25473151 PMCID: PMC4239485 DOI: 10.3748/wjg.v20.i43.15975] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 07/09/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infections represent a major global health problem. End-stage liver disease caused by chronic HCV infection is a major indication for liver transplantation. However, after transplantation the engrafted liver inevitably becomes infected by the circulating virus. Direct acting antivirals are not yet approved for use in liver transplant patients, and limited efficacy and severe side effects hamper the use of pegylated interferon combined with ribavirin in a post-transplant setting. Therefore, alternative therapeutic options need to be explored. Viral entry represents an attractive target for such therapeutic intervention. Understanding the mechanisms of viral entry is essential to define the viral and cellular factors involved. The HCV life cycle is dependent of and associated with lipoprotein physiology and the presence of lipoproteins has been correlated with altered antiviral efficacy of entry inhibitors. In this review, we summarise the current knowledge on how lipoprotein physiology influences the HCV life cycle. We focus especially on the influence of lipoproteins on antibodies that target HCV envelope proteins or antibodies that target the cellular receptors of the virus. This information can be particularly relevant for the prevention of HCV re-infection after liver transplantation.
Collapse
|
|
39
|
Negro F. Facts and fictions of HCV and comorbidities: steatosis, diabetes mellitus, and cardiovascular diseases. J Hepatol 2014; 61:S69-78. [PMID: 25443347 DOI: 10.1016/j.jhep.2014.08.003] [Citation(s) in RCA: 121] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Revised: 07/16/2014] [Accepted: 08/01/2014] [Indexed: 12/16/2022]
Abstract
The hepatitis C virus (HCV) is a major cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma worldwide. A significant portion of the morbidity and mortality associated with HCV is a consequence of numerous HCV-associated comorbidities. Type 2 diabetes and atherosclerosis, two known complications of the metabolic syndrome, are noteworthy, because HCV has been suggested to play a role in their pathogenesis. In addition, HCV also causes steatosis, which may increase the risk of cardiovascular events. This review summarizes the evidence supporting the association between HCV and steatosis, insulin resistance/type 2 diabetes and cardiovascular morbidity and mortality. Their diagnostic, prognostic and management aspects are discussed.
Collapse
Affiliation(s)
- Francesco Negro
- Divisions of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, University Hospitals, Geneva, Switzerland.
| |
Collapse
|
|
40
|
Hamed AE. The association between diabetes and liver disease: The need for a consensus. Arab J Gastroenterol 2014; 15:166-8. [DOI: 10.1016/j.ajg.2014.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Accepted: 09/19/2014] [Indexed: 02/08/2023]
|
|
41
|
Xun YH, Zhang YJ, Pan QC, Mao RC, Qin YL, Liu HY, Zhang YM, Yu YS, Tang ZH, Lu MJ, Zang GQ, Zhang JM. Metformin inhibits hepatitis B virus protein production and replication in human hepatoma cells. J Viral Hepat 2014; 21:597-603. [PMID: 24164660 DOI: 10.1111/jvh.12187] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2013] [Accepted: 08/05/2013] [Indexed: 12/12/2022]
Abstract
Hepatitis B virus surface antigen (HBsAg) plays an important role in maintaining the tolerance and may interfere with host innate and adaptive immune responses; therefore, novel therapeutic strategies to reduce HBsAg loads in patients infected with hepatitis B virus (HBV) are emerging as an attractive but challenging issue. Metformin could regulate hepatic metabolism while the latter interacts with HBV infection. We hypothesized that metformin could affect HBsAg expression and HBV replication and may work synergistically when combined with current antivirals. In our study, a notably inhibitory effect on HBsAg production, as well as a moderate inhibition in HBV replication and HBeAg expression was observed following metformin treatment. The 50% effective concentration (EC50) for extracellular HBsAg and intracellular HBsAg in HBV-producing HepG2.2.15 cells was 2.85 mm and 2.75 mm, respectively, with a similarly selective index of about 18. When administered in combination, metformin enhanced the inhibitory effects of interferon-α2b on HBsAg expression and HBV replication and provided a complimentary role in HBsAg expression for lamivudine (LMV). This novel action of metformin derives partially from its inhibition on multiple HBV cis-acting elements. By the virtues of preferably hepatocyte distribution and safety profile, collectively, our results suggest that metformin would be potentially clinically helpful as an HBsAg production inhibitor.
Collapse
Affiliation(s)
- Y-H Xun
- Department of Infectious Diseases, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China; Key Laboratory of Medical Molecular Virology of the Ministries of Education and Health, Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China; Department of Liver Diseases, The Sixth People's Hospital affiliated to Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, China
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Harris K, Smith L. Safety and efficacy of metformin in patients with type 2 diabetes mellitus and chronic hepatitis C. Ann Pharmacother 2014; 47:1348-52. [PMID: 24259699 DOI: 10.1177/1060028013503108] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVE To evaluate the safety and efficacy of metformin in patients with type 2 diabetes mellitus (T2DM) and chronic hepatitis C virus (HCV) with or without cirrhosis and hepatocellular carcinoma (HCC). DATA SOURCES A PubMed (1946-August 2013) search using the keywords type 2 diabetes mellitus, metformin, hepatitis C virus, cirrhosis, and hepatocellular carcinoma was conducted. The references in published articles were reviewed to identify additional references for inclusion. STUDY SELECTION AND DATA EXTRACTION Studies written in English, evaluating metformin use in human patients with T2DM and chronic HCV were included. DATA SYNTHESIS Eight studies met criteria for inclusion. Two prospective, randomized controlled trials showed increased benefit with metformin on virological response in patients with insulin resistance receiving HCV treatment. A prospective observational study evaluated metformin exclusively in patients with T2DM and HCV and showed significant reductions in the occurrence of HCC, liver-related death, and liver transplant. Four retrospective case control studies showed a decreased risk of HCC with metformin treatment in patients with T2DM and chronic liver disease. Finally, a retrospective cohort study indicated an increased survival rate in patients with diabetes and HCC undergoing radiofrequency ablation. Although diarrhea was increased in patients receiving metformin, no serious adverse effects, including lactic acidosis, were reported. CONCLUSIONS Metformin may provide benefit in the treatment of HCV and in reducing the risk of HCC in patients with T2DM and HCV. Further long-term, randomized controlled trials are needed to adequately assess the safety and efficacy of metformin therapy in patients with comorbid diabetes and chronic HCV.
Collapse
Affiliation(s)
- Kira Harris
- Wingate University School of Pharmacy, Wingate, NC, USA
| | | |
Collapse
|
|
43
|
Tallón de Lara P, Himschoot T, Frossard JL, Negro F. Does telaprevir possess a direct antidiabetic effect? Liver Int 2014; 34:967-9. [PMID: 24329983 DOI: 10.1111/liv.12440] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 12/07/2013] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) induces insulin resistance, which improves upon viral clearance. Telaprevir is a protease inhibitor effective against HCV genotype 1. We reported a case, whose history suggests that telaprevir may induce some antidiabetic effect independently of its suppression of HCV. A 56-year-old woman with obesity, type 2 diabetes treated with sitagliptin and metformin, and HCV-related cirrhosis was given triple therapy with pegylated interferon-alpha, ribavirin and telaprevir. After 2 weeks of treatment, HCV RNA was no longer detectable but the patient described a pronounced drop in the capillary glucose levels and episodes of hypoglycaemia that compelled her to stop all antidiabetic treatment. One month after stopping telaprevir, she had to resume her antidiabetic treatment, despite a persisting virological response. Despite reaching a sustained virological response, her diabetes progressed. Although the suppression of HCV replication may have played a role in reducing glucose intolerance, the fact that this patient resumed her prior antidiabetic treatment upon completing the telaprevir treatment, while still aviremic, suggests that telaprevir may have an additional antidiabetic effect. Further evidence about the possible role and mechanisms of telaprevir as antidiabetic agent is warranted.
Collapse
Affiliation(s)
- Paulino Tallón de Lara
- Division of Gastroenterology and Hepatology, University Hospitals, Geneva 4, Switzerland
| | | | | | | |
Collapse
|
|
44
|
A pilot study of add-on oral hypoglycemic agents in treatment-naïve genotype-1 chronic hepatitis C patients receiving peginterferon alfa-2b plus ribavirin. J Formos Med Assoc 2014; 113:716-21. [PMID: 24974131 DOI: 10.1016/j.jfma.2014.05.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Revised: 05/26/2014] [Accepted: 05/27/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND/PURPOSE Insulin resistance (IR) affects sustained virological response (SVR) to peginterferon alfa plus ribavirin (PR) in patients with chronic hepatitis C (CHC). Whether add-on oral hypoglycemic agents (OHAs) to PR improve SVR remains unclear; therefore, we conducted a prospective, randomized pilot trial on 23 consecutive patients with genotype 1 CHC and IR in Taiwan. METHODS Patients were randomized to receive acarbose (Arm A; n = 7) or metformin (Arm B; n = 6) or pioglitazone (Arm C; n = 5) in addition to peginterferon alfa-2b (1.5 μg/kg/week) plus ribavirin (1000-1200 mg/day) or just PR (Arm D; n = 5). The primary end point was SVR, and secondary end points were viral clearance at Weeks 17, 29, and 53. There were no differences among all arms at baseline. RESULTS Using intent-to-treat analysis, SVR was observed in 66.7% (4/6), 83.3% (5/6), 66.7% (4/6), and 60% (3/5) in Arms A, B, C, and D, respectively. SVR was higher in female patients receiving OHA [90% (9/10)] than in male patients [50% (4/8)]. Results of per protocol analysis showed that SVR was 80.0% (4/5) in Arm A, 100% (5/5) in Arm B, 66.7% (4/6) in Arm C, and 60% (3/5) in Arm D. Patients receiving OHA had a higher rapid virologic response: 11/18 (61%) versus 2/5 (40%). Complete early virologic response was comparable between patients receiving OHA and PR [15/18 (83%) vs. 4/5 (80%)]. CONCLUSION Our preliminary data show add-on OHAs to PR might achieve better early viral kinetics and SVR. However, further larger studies are needed to confirm these findings.
Collapse
|
|
45
|
Puri P, Anand AC, Saraswat VA, Acharya SK, Sarin SK, Dhiman RK, Aggarwal R, Singh SP, Amarapurkar D, Arora A, Chhabra M, Chetri K, Choudhuri G, Dixit VK, Duseja A, Jain AK, Kapoor D, Kar P, Koshy A, Kumar A, Madan K, Misra SP, Prasad MV, Nagral A, Puri AS, Jeyamani R, Saigal S, Shah S, Sharma PK, Sood A, Thareja S, Wadhawan M. Consensus Statement of HCV Task Force of the Indian National Association for Study of the Liver (INASL). Part II: INASL Recommendations for Management of HCV in India. J Clin Exp Hepatol 2014; 4:117-40. [PMID: 25755549 PMCID: PMC4116713 DOI: 10.1016/j.jceh.2014.06.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Accepted: 06/04/2014] [Indexed: 12/12/2022] Open
Abstract
The estimated prevalence of hepatitis C virus (HCV) infection in India is between 0.5 and 1.5% with hotspots showing much higher prevalence in some areas of northeast India, in some tribal populations and in certain parts of Punjab. Genotype 3 is the most prevalent type of infection. Recent years have seen development of a large number of new molecules that are revolutionizing the treatment of hepatitis C. Some of the new directly acting agents (DAAs) like sofosbuvir have been called game-changers because they offer the prospect of interferon-free regimens for the treatment of HCV infection. These new drugs have not yet been approved in India and their cost and availability is uncertain at present. Till these drugs become available at an affordable cost, the treatment that was standard of care for the whole world before these newer drugs were approved should continue to be recommended. For India, cheaper options, which are as effective as the standard-of-care (SOC) in carefully selected patients, are also explored to bring treatment within reach of poorer patients. It may be prudent to withhold treatment at present for selected patients with genotype 1 or 4 infection and low levels of fibrosis (F1 or F2), and for patients who are non-responders to initial therapy, interferon intolerant, those with decompensated liver disease, and patients in special populations such as stable patients after liver and kidney transplantation, HIV co-infected patients and those with cirrhosis of liver.
Collapse
Key Words
- ALT, alanine amintraonsferase
- ANC, absolute neutrophil count
- AST, aspartate aminotransferase
- CH–C, Chronic Hepatitis C
- CKD, chronic kidney disease
- CTP, Child-Turcotte-Pugh
- EIA, enzyme immunoassay
- ETR, end-of-treatment response
- EVR, early virological response
- GRADE, Grading of Recommendations Assessment, Development and Evaluation
- HCV, hepatitis C virus
- HIV, Human immunodeficiency virus
- IFNa, interferon alfa
- INASL, Indian National Association for Study of the Liver
- PCR, polymerase chain reaction
- Peg-IFNa, pegylated interferon alfa
- RBV, Ribavirin
- RVR, rapid virological response
- SOC, standard of care
- SVR, sustained virological response
- ULN, upper limit of normal
- anti-HCV, antibody to HCV
- antiviral therapy
- chronic hepatitis
- hepatitis C virus
Collapse
Affiliation(s)
- Pankaj Puri
- Department of Gastroenterology, Army Hospital (R & R), New Delhi 110010, India
| | - Anil C. Anand
- Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospital, New Delhi 110076, India
| | - Vivek A. Saraswat
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical, Sciences, Lucknow, Uttar Pradesh 221016, India
| | - Subrat K. Acharya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Shiv K. Sarin
- Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi 110070, India
| | - Radha K. Dhiman
- Department of Hepatology, Postgraduate Institute of Medical Education and, Research, Chandigarh 160012, India
| | - Rakesh Aggarwal
- Department of Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical, Sciences, Lucknow, Uttar Pradesh 221016, India
| | - Shivaram P. Singh
- Department of Gastroenterology, SCB Medical College, Cuttack, Odisha 753007, India
| | - Deepak Amarapurkar
- Department of Gastroenterology, Bombay Hospital, Mumbai, Maharashtra 400020, India
| | - Anil Arora
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Mohinish Chhabra
- Department of Gastroenterology, Fortis Hospital, Mohali, Punjab 160047, India
| | - Kamal Chetri
- Department of Gastroenterology, International Hospital, Guwahati, Assam 781005, India
| | - Gourdas Choudhuri
- Department of Gastroenterology, Fortis Hospital, Gurgaon, Haryana 122002, India
| | - Vinod K. Dixit
- Department of Gastroenterology, Banaras Hindu University, Varanasi, Uttar Pradesh 221005, India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and, Research, Chandigarh 160012, India
| | - Ajay K. Jain
- Department of Gastroenterology, Choithram Hospital & Research Centre, Indore, Madhya Pradesh 452014, India
| | - Dharmesh Kapoor
- Department of Gastroenterology, Global Hospital, Hyderabad, Andhra Pradesh 500004, India
| | - Premashis Kar
- Department of Gastroenterology, LNJP Hospital, and Maulana Azad Medical College, New Delhi 110002, India
| | - Abraham Koshy
- Department of Hepatology, Lakeshore Hospital, Cochin, Kerala 682304, India
| | - Ashish Kumar
- Department of Gastroenterology and Hepatology, Sir Ganga Ram Hospital, New Delhi 110060, India
| | - Kaushal Madan
- Department of Gastroenterology, Medanta Medicity, Gurgaon, Haryana 122001, India
| | - Sri P. Misra
- Department of Gastroenterology, Moti Lal Nehru Medical College, Allahabad, Uttar Pradesh 211001 India
| | - Mohan V.G. Prasad
- Department of Gastroenterology, VGM Hospital, Coimbatore, Tamil Nadu 641005, India
| | - Aabha Nagral
- Department of Gastroenterology, Jaslok Hospital, Mumbai, Maharashtra 400026, India
| | - Amarendra S. Puri
- Department of Gastroenterology, GB Pant Hospital, New Delhi 110002, India
| | - R. Jeyamani
- Department of Gastroenterology, Christian Medical College, Vellore, Tamil Nadu 632004, India
| | - Sanjiv Saigal
- Department of Gastroenterology, Medanta Medicity, Gurgaon, Haryana 122001, India
| | - Samir Shah
- Department of Gastroenterology, Global Hospital, Mumbai, Maharashtra 400078, India
| | - Praveen K. Sharma
- Department of Medicine, Armed Forces Medical College, Pune, Maharashtra 411040, India
| | - Ajit Sood
- Department of Gastroenterology, Dayanand Medical College, Ludhiana, Punjab 141001, India
| | - Sandeep Thareja
- Department of Gastroenterology, Army Hospital (R & R), New Delhi 110010, India
| | - Manav Wadhawan
- Department of Gastroenterology and Hepatology, Indraprastha Apollo Hospital, New Delhi 110076, India
| |
Collapse
|
|
46
|
Jung HJ, Kim YS, Kim SG, Lee YN, Jeong SW, Jang JY, Lee SH, Kim HS, Kim BS. The impact of pegylated interferon and ribavirin combination treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients. Clin Mol Hepatol 2014; 20:38-46. [PMID: 24757657 PMCID: PMC3992328 DOI: 10.3350/cmh.2014.20.1.38] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 02/06/2014] [Accepted: 02/11/2014] [Indexed: 12/17/2022] Open
Abstract
Background/Aims Lipid profile and insulin resistance (IR) are associated with hepatitis C virus (HCV) and may predict the chronic hepatitis C (CHC) treatment response. The aim of this study was to determine the association between CHC treatment response and lipid profile and IR change during treatment. Methods In total, 203 CHC patients were reviewed retrospectively between January 2005 and December 2011 at Soon Chun Hyang University Hospital. The lipid profile, homeostasis model for assessment (HOMA) of IR (HOMA-IR), and HOMA of β cells (HOMA-β) were evaluated before interferon plus ribavirin therapy (BTx), at the end of treatment (DTx), and 24 weeks after the end of treatment (ATx). Results A sustained virologic response (SVR) was achieved by 81% of all patients (49/60), 60% (n=36) of whom possessed genotype 1, with the remainder being non-genotype-1 (40%, n=24). Apart from age, which was significantly higher in the non-SVR group (SVR, 48.0±11.2 years, mean±SD; non-SVR, 56.6±9.9 years; P<0.01), there were no significant differences in the baseline characteristics between the SVR and non-SVR groups. In the SVR group, low density lipoprotein-cholesterol (LDL-C) had significantly changed at DTx and ATx compared to BTx. In addition, HOMA-IR and HOMA-β were significantly changed at DTx in the SVR group. Among those with a high baseline insulin resistance (HOMA-IR >2.5), HOMA-IR was significantly changed at DTx in the SVR group. Conclusions LDL-C appears to be associated with HCV treatment in SVR patients. Furthermore, eradication of HCV may improve whole-body IR and insulin hypersecretion, as well as high baseline insulin resistance (HOMA-IR >2.5).
Collapse
Affiliation(s)
- Hee Jae Jung
- Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Young Seok Kim
- Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Sang Gyune Kim
- Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Yun Nah Lee
- Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Soung Won Jeong
- Institute for Digestive Research, Department of Internal Medicine, Soonchunhyang University Hospital Seoul, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Jae Young Jang
- Institute for Digestive Research, Department of Internal Medicine, Soonchunhyang University Hospital Seoul, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Sae Hwan Lee
- Department of Internal Medicine, Soonchunhyang University Hospital Cheonan, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Hong Soo Kim
- Department of Internal Medicine, Soonchunhyang University Hospital Cheonan, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Boo Sung Kim
- Digestive Disease Center and Research Institute, Department of Internal Medicine, Soonchunhyang University Hospital Bucheon, Soonchunhyang University College of Medicine, Bucheon, Korea
| |
Collapse
|
|
47
|
Vespasiani-Gentilucci U, Gallo P, Vincentis AD, Galati G, Picardi A. Hepatitis C virus and metabolic disorder interactions towards liver damage and atherosclerosis. World J Gastroenterol 2014; 20:2825-2838. [PMID: 24659875 PMCID: PMC3961987 DOI: 10.3748/wjg.v20.i11.2825] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/25/2013] [Accepted: 01/03/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) is one of the main causes of liver disease worldwide, and alterations of glucose metabolism have reached pandemic proportions in western countries. However, the frequent coexistence between these two conditions is more than simply coincidental, since HCV can induce insulin resistance through several mechanisms. Indeed, the virus interferes with insulin signaling both directly and indirectly, inducing the production of pro-inflammatory cytokines. Furthermore, the entire viral life cycle has strict interconnections with lipid metabolism, and HCV is responsible for a "viral" steatosis which is frequently superimposed to a "metabolic" one. Several evidences suggest that HCV-induced metabolic disorders contribute both to the evolution of liver fibrosis and, likely, to the progression of the other disorders which are typically associated with altered metabolism, in particular atherosclerosis. In the present review, we will examine in depth the links between HCV infection and insulin resistance, liver steatosis and diabetes, and analyze the impact of these interactions on the progression of liver fibrosis and atherosclerosis. Special attention will be focused on the highly debated topic of the relationship between HCV infection and cardiovascular disease. The available clinical literature on this item will be broadly reviewed and all the mechanisms possibly implied will be discussed.
Collapse
|
|
48
|
Kawaguchi Y, Mizuta T. Interaction between hepatitis C virus and metabolic factors. World J Gastroenterol 2014; 20:2888-2901. [PMID: 24659880 PMCID: PMC3961972 DOI: 10.3748/wjg.v20.i11.2888] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Revised: 11/15/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection disrupts the normal metabolism processes, but is also influenced by several of the host’s metabolic factors. An obvious and significantly detrimental pathophysiological feature of HCV infection is insulin resistance in hepatic and peripheral tissues. Substantial research efforts have been put forth recently to elucidate the molecular mechanism of HCV-induced insulin resistance, and several cytokines, such as tumor necrosis factor-α, have been identified as important contributors to the development of insulin resistance in the distant peripheral tissues of HCV-infected patients and animal models. The demonstrated etiologies of HCV-induced whole-body insulin resistance include oxidative stress, lipid metabolism abnormalities, hepatic steatosis and iron overload. In addition, myriad effects of this condition have been characterized, including glucose intolerance, resistance to antiviral therapy, progression of hepatic fibrosis, development of hepatocellular carcinoma, and general decrease in quality of life. Metabolic-related conditions and disorders, such as visceral obesity and diabetes mellitus, have been shown to synergistically enhance HCV-induced metabolic disturbance, and are associated with worse prognosis. Yet, the molecular interactions between HCV-induced metabolic disturbance and host-associated metabolic factors remain largely unknown. The diet and lifestyle recommendations for chronic hepatitis C are basically the same as those for obesity, diabetes, and metabolic syndrome. Specifically, patients are suggested to restrict their dietary iron intake, abstain from alcohol and tobacco, and increase their intake of green tea and coffee (to attain the beneficial effects of caffeine and polyphenols). While successful clinical management of HCV-infected patients with metabolic disorders has also been achieved with some anti-diabetic (i.e., metformin) and anti-lipid (i.e., statins) medications, it is recommended that sulfonylurea and insulin be avoided.
Collapse
|
|
49
|
Marks K, Kitch D, Chung RT, Hadigan C, Andersen J, Tien P, Luetkemeyer A, Alston-Smith B, Glesby MJ. Pilot study of pioglitazone before HCV retreatment in HIV/HCV genotype 1-infected subjects with insulin resistance and previous nonresponse to peginterferon and ribavirin therapy: A5239. J Acquir Immune Defic Syndr 2014; 65:345-9. [PMID: 24525470 PMCID: PMC3998202 DOI: 10.1097/qai.0000000000000073] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
: Insulin resistance is associated with nonresponse to hepatitis C virus (HCV) treatment. In this multicenter, single-arm pilot study, adult, HIV/HCV genotype 1-coinfected previous nonresponders to peginterferon/ribavirin (PegIFN/RBV) with homeostatic model assessment of insulin resistance >2.5 were treated with pioglitazone (PIO) for 24 weeks followed by PegIFN/RBV/PIO. Three of 19 subjects (15.8%) achieved undetectable HCV RNA at week 24 of PegIFN/RBV/PIO, which was not significantly different than the historical null rate of 10% (P = 0.29, lower limit of the exact 1-sided 90% confidence interval 5.9%). Over the 24 weeks of PIO monotherapy, alanine aminotransferase and aspartate aminotransferase declined significantly and correlated with improved metabolic parameters.
Collapse
Affiliation(s)
- Kristen Marks
- Division of Infectious Diseases, Weill Cornell Medical College, New York, NY
| | | | - Raymond T. Chung
- GI Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Colleen Hadigan
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | | | - Phyllis Tien
- Division of Infectious Diseases, University of California San Francisco Medical School, San Francisco, CA, and Medical Service, Department of Veterans Affairs, San Francisco, CA
| | - Annie Luetkemeyer
- HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco, CA
| | - Beverly Alston-Smith
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD
| | - Marshall J. Glesby
- Division of Infectious Diseases, Weill Cornell Medical College, New York, NY
| | | |
Collapse
|
|
50
|
Bose SK, Ray R. Hepatitis C virus infection and insulin resistance. World J Diabetes 2014; 5:52-58. [PMID: 24567801 PMCID: PMC3932427 DOI: 10.4239/wjd.v5.i1.52] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Revised: 12/20/2013] [Accepted: 01/14/2014] [Indexed: 02/05/2023] Open
Abstract
Approximately 170 million people worldwide are chronically infected with hepatitis C virus (HCV). Chronic HCV infection is the leading cause for the development of liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and is the primary cause for liver transplantation in the western world. Insulin resistance is one of the pathological features in patients with HCV infection and often leads to development of type II diabetes. Insulin resistance plays an important role in the development of various complications associated with HCV infection. Recent evidence indicates that HCV associated insulin resistance may result in hepatic fibrosis, steatosis, HCC and resistance to anti-viral treatment. Thus, HCV associated insulin resistance is a therapeutic target at any stage of HCV infection. HCV modulates normal cellular gene expression and interferes with the insulin signaling pathway. Various mechanisms have been proposed in regard to HCV mediated insulin resistance, involving up regulation of inflammatory cytokines, like tumor necrosis factor-α, phosphorylation of insulin-receptor substrate-1, Akt, up-regulation of gluconeogenic genes like glucose 6 phosphatase, phosphoenolpyruvate carboxykinase 2, and accumulation of lipid droplets. In this review, we summarize the available information on how HCV infection interferes with insulin signaling pathways resulting in insulin resistance.
Collapse
|