Infections Cause Diabetes

Type 1 Diabetes

Enterovirus RNA in serum is a risk factor for beta-cell autoimmunity and clinical type 1 diabetes: a prospective study. Childhood Diabetes in Finland (DiMe) Study Group. M Lönnrot, K Salminen, M Knip, K Savola, P Kulmala, P Leinikki, T Hyypiä, HK Akerblom, H Hyöty. J Med Virol 2000 Jun;61(2):214-220. "Viral RNA was found in 22% (11/49) of follow-up samples from prediabetic children but in only 2% (2/105) of those from controls (OR 14.9, P < 0.001). Persisting RNA positivity was not observed in any of these children. The presence of enterovirus RNA was associated with concomitant increases in the levels of autoantibodies against islet cells (OR 21.7, P < 0.01) and glutamic acid decarboxylase (OR 15.4, P < 0.05), but not in the levels of antibodies against insulin or the tyrosine phosphatase-like IA-2 protein. In contrast to the prediabetic children, those with newly diagnosed type 1 diabetes were negative for enterovirus RNA."

Lönnrot - J Med Virol 2000 abstract / PubMed

Isolation of enterovirus strains from children with preclinical Type 1 diabetes. KK Salminen, T Vuorinen, S Oikarinen, M Helminen, S Simell, M Knip, J Ilonen, O Simell, H Hyöty. Diabet Med 2004 Feb;21(2):156-164. 12 case children and 53 controls matched for HLA-DQB1 alleles. "The proportion of children who were repeatedly enterovirus RNA-positive stools was higher among case than control children (42% vs. 11% of children; P=0.02). Combined serum (antibody and RT-PCR) and stool analyses indicated at least one enterovirus infection in 83% of the case children before the appearance of autoantibodies, while only 42% of the control children had infection by the same age (P=0.006). Twelve enterovirus strains were isolated from case children and 38 strains from control children."

Salminen - Diabet Med 2004 abstract / PubMed

Evaluation Report. Special Statutory Funding Program for Type 1 Diabetes Research. National Institute of Diabetes and Digestive and Kidney Diseases, Aug. 2007. "Goal I: Identify the Genetic and Environmental Causes of Type 1 Diabetes," includes "Explore the possible role of emerging infectious agents, orphan viruses, and intestinal bacteria in the etiology of type 1 diabetes." U.S. Government research agenda is on track for a change.

Funding Program for Type 1 Diabetes Research / NIH (pdf, 348 pp)

The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TODAY study. GJ Klingensmith, L Pyle, S Arslanian, KC Copeland, L Cuttler, F Kaufman, L Laffel, S Marcovina, SE Tollefsen, RS Weinstock, B Linder; TODAY Study Group. Diabetes Care 2010 Sep;33(9):1970-1975. "Of the 1,206 subjects screened and considered clinically to have type 2 diabetes, 118 (9.8%) were antibody positive... In this trial, subjects with positive GAD-65 antibodies had lower fasting insulin, significantly lower homeostasis model assessment of insulin resistance and triglycerides and higher HDL cholesterol than in those without GAD-65 autoantibodies, suggesting less insulin resistance in the DAA-positive subjects... [T]aken together with our data, these results indicate that obese individuals with diabetes and autoimmunity are closer physiologically to their normal-weight peers with type 1 diabetes than to antibody-negative individuals with type 2 diabetes."

Klingensmith - Diabetes Care 2010 full article / PubMed Central
Klingensmith / Diabetes Care 2010 full article

Enterovirus infection and progression from islet autoimmunity to type 1 diabetes: the Diabetes and Autoimmunity Study in the Young (DAISY). LC Stene, S Oikarinen, H Hyöty, KJ Barriga, JM Norris, G Klingensmith, JC Hutton, HA Erlich, GS Eisenbarth, M Rewers. Diabetes 2010 Dec;59(12):3174-3180. "Of 140 children who seroconverted to repeated positivity for islet autoantibodies at a median age of 4.0 years, 50 progressed to type 1 diabetes during a median follow-up of 4.2 years. The risk of progression to clinical type 1 diabetes in the sample interval following detection of enteroviral RNA in serum (three diabetes cases diagnosed among 17 intervals) was significantly increased compared with that in intervals following a negative serum enteroviral RNA test (33 cases diagnosed among 1,064 intervals; hazard ratio 7.02 [95% CI 1.95-25.3] after adjusting for number of autoantibodies). Results remained significant after adjustment for ZnT8-autoantibodies and after restriction to various subgroups. Enteroviral RNA in rectal swabs was not predictive of progression to type 1 diabetes. No evidence for viral persistence was found."

Stene - Diabetes 2010 full article / PubMed Central
Stene / Diabetes 2010 full article

Enterovirus RNA in blood is linked to the development of type 1 diabetes. S Oikarinen, M Martiskainen, S Tauriainen, H Huhtala, J Ilonen, R Veijola, O Simell, M Knip, H Hyöty. Diabetes 2011 Jan;60(1):276-279. Sera from 38 type 1 diabetic children and 140 nondiabetic controls, matched by HLA-DQ. "A total of 5.1% of the samples (17 of 333) in the case group were enterovirus RNA-positive compared with 1.9% of the samples (19 of 993) in the control group (P < 0.01). The strongest risk for type 1 diabetes was related to enterovirus RNA positivity during the 6-month period preceding the first autoantibody-positive sample (odds ratio 7.7 [95% CI 1.9-31.5]). This risk effect was stronger in boys than in girls." "More samples were enterovirus RNA positive in case children with high-risk HLA DR3-DQ2/DR4-DQ8 genotype than in children who carried moderate-risk genotypes with the DR4-DQ8 haplotype (6.8 vs. 2.2%) (P < 0.002)." There was seasonal correlation between detection of antibodies and enterovirus.

Oikarinen - Diabetes 2011 full article / PubMed Central
Oikarinen / Diabetes 2011 full article

Human enterovirus RNA in monthly fecal samples and islet autoimmunity in Norwegian children with high genetic risk for type 1 diabetes: the MIDIA study. G Tapia, O Cinek, T Rasmussen, E Witsø, B Grinde, LC Stene, KS Rønningen. Diabetes Care 2011 Jan;34(1):151-155. Infants with HLA DRB1*0401-DQA1*03-DQB1*0302/DRB1*03-DQA1*05-DQB1*02 genotype, versus 54 matched controls. "The frequency of human enterovirus RNA in stool samples from case subjects before seroconversion (43 of 339, 12.7%) did not differ from the frequency in control subjects (94 of 692, 13.6%) (P = 0.97). Results remained essentially unchanged after adjustment for potential confounders, restriction to various time windows before seroconversion, or infections in the 1st year of life or after inclusion of samples collected after seroconversion. There was no difference in the average quantity of enterovirus RNA or in the frequency of repeatedly positive samples. The estimated relative risk for islet autoimmunity per enterovirus RNA-positive sample during follow-up (nested case-control analysis) was 1.12 (95% CI 0.66-1.91)."

Tapia - Diabetes Care 2011 full article / PubMed Central
Tapia - Diabetes Care 2011 full article

Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. WC Yeung, WD Rawlinson, ME Craig. BMJ 2011 Feb 3;342:d35. "[S]ystematic review of 33 prevalence studies, involving 1931 cases and 2517 controls, shows a clinically significant association between enterovirus infection and islet autoimmunity or type 1 diabetes. The association between enterovirus infection, detected with molecular methods, and diabetes was strong, with almost 10 times the odds of enterovirus infection in children at diagnosis of type 1 diabetes compared with controls (9.8, 5.5 to 17.4), while the odds of infection was also higher in children with pre-diabetes than in controls (3.7, 2.1 to 6.8)." Most studies used PCR detection of the highly conserved 5' untranslated region of the enterovirus genome, which is significantly more sensitive than serology.

Yeung / BMJ full article
Yeung - BMJ 2011 full article / PubMed Central

Exposure to the Viral By-Product dsRNA or Coxsackievirus B5 Triggers Pancreatic Beta Cell Apoptosis via a Bim / Mcl-1 Imbalance. ML Colli, TC Nogueira, F Allagnat, DA Cunha, EN Gurzov, AK Cardozo, M Roivainen, AO Beeck, DL Eizirik. PLoS Pathog 2011;7(9):e1002267. "Most candidate genes for T1D are supposed to act at the immune system level, but we have recently shown that nearly 30% of these candidate genes are also expressed in beta cells and may modulate their responses after exposure to potential environmental factors. These findings indicate that beta cells are not only targets, but also actors of T1D pathophysiology."

Colli / PLoS Pathog 2011 full article

Virus infections in type 1 diabetes. KT Coppieters, T Boettler, M von Herrath. Cold Spring Harb Perspect Med 2012 Jan;2(1):a007682. Review.

Coppieters - Cold Spring Harb Perspect Med 2012 full article / PubMed Central

Type 1 diabetes is associated with enterovirus infection in gut mucosa. M Oikarinen, S Tauriainen, S Oikarinen, T Honkanen, P Collin, I Rantala, M Mäki, K Kaukinen, H Hyöty. Diabetes 2012 Mar;61(3):687-691. Small-bowel mucosal biopsy samples from 39 type 1 diabetic patients, 41 control subjects, and 40 celiac disease patients. "Enterovirus RNA was found in diabetic patients more frequently than in control subjects and was associated with a clear inflammation response in the gut mucosa. Viral RNA was often detected in the absence of viral protein, suggesting defective replication of the virus. Patients remained virus positive in follow-up samples taken after 12 months' observation."

Oikarinen - Diabetes 2012 abstract / PubMed
Oikarinen / Diabetes 2012 full article

Type 1 diabetes associated and tissue transglutaminase autoantibodies in patients without type 1 diabetes and coeliac disease with confirmed viral infections. L Sarmiento, JA Galvan, E Cabrera-Rode, L Aira, C Correa, S Sariego, M Fonseca, I Cubas-Dueñas, LH Hung, S Resik, CM Cilio. J Med Virol 2012 Jul;84(7):1049-1053. 82 patients positve for either echovirus 16, EBV, CMV or HCV by PCR and specific IgG and 164 controls. "The prevalence of TGA in patients infected with HEV, EBV, CMV, or HCV was 55% (11/20), 25% (5/20), 9.5% (2/21), and 9.5% (2/21), respectively. GADA and IA-2A were found in 15% (3/20) and 25% (5/20) of patients infected with HEV. None of the patients infected by EBV, CMV, and HCV had GADA or IA-2A. All children infected with HEV who were positive for type 1 diabetes-associated autoantibodies were also TGA-positive. None of the sera from uninfected subjects were positive for GADA, IA-2A or TGA. In conclusion, TGA can develop during infection with HEV, EBV, CMV, or HCV, while the emergence of islet cell related autoantibodies is restricted to HEV infections."

Sarmientom - J Med Virol 2012 abstract / PubMed

Seroconversion to islet autoantibodies after enterovirus infection in early pregnancy. S Rešić Lindehammer, H Honkanen, WA Nix, M Oikarinen, KF Lynch, Jönsson, K Marsal, S Oberste, H Hyöty, Å Lernmark. Viral Immunol 2012 Aug;25(4):254-261. 365 nondiabetic mothers with islet antibodies, versus 1457 without. "In early pregnancy, mothers with h or 2/X genotypes showed an increased risk for islet autoantibodies at delivery (OR 1.85; p=0.001). After adjusting for parity, maternal age, year of birth, and season of early pregnancy, early pregnancy EV-IgM combined with DQ2/2 or 2/X increased the risk for islet autoantibodies (OR 3.10; 95% CI 1; p=0.008). EV-IgM in early pregnancy increased the risk for islet autoantibodies at delivery in non-diabetic mothers with HLA-DQ 2/2 or 2/X type 1 diabetes risk genotypes."

Rešić Lindehammer - Viral Immunol 2012 abstract / PubMed

Viruses and Type 1 diabetes: a dynamic labile equilibrium. DA Schneider, MG von Herrath. Diabetes Manag (Lond) 2013 May;3(3):217-223. Review.

Schneider - Diabetes Manag (Lond) 2013 full article / PubMed Central

Relationship Between Ljungan Virus Antibodies, HLA-DQ8, and Insulin Autoantibodies in Newly Diagnosed Type 1 Diabetes Children. AL Nilsson, F Vaziri-Sani, C Andersson, K Larsson, A Carlsson, E Cedervall, B Jönsson, J Neiderud, H Elding Larsson, SA Ivarsson, A Lernmark. Viral Immunol 2013 Jun;26(3):207-215. 676 patients age 0-18, 309 controls. "The 4(th) quartile LVAb in children <10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p<0.0001). Furthermore, in the group with 4(th) quartile LVAb, 55% were IAA positive (p=0.01) and correlation was found between 4(th) quartile LVAb and IAA in children <10 years of age (p=0.035)."

Nilsson - Viral Immunol 2013 abstract / PubMed

Risk factors and primary prevention trials for type 1 diabetes. YL Wu, YP Ding, J Gao, Y Tanaka, W Zhang. Int J Biol Sci 2013 Jul 18;9(7):666-679. Review.

Wu - Int J Biol Sci 2013 full article / PubMed Central
Wu / Int J Biol Sci 2013 full article

Pathophysiological mechanisms involving aggressive islet cell destruction in fulminant type 1 diabetes [Review]. S Tanaka, K Aida, Y Nishida, T Kobayashi. Endocr J 2013 Jul 30;60(7):837-845. Review.

Tanaka / Endocr J 2013 full article landing

Intrafamilial spread of enterovirus infections at the clinical onset of type 1 diabetes. A Salvatoni, A Baj, G Bianchi, G Federico, M Colombo, A Toniolo. Pediatr Diabetes 2013 Sep;14(6):407-416. 24 newly diagnosed diabetic children/adolescents and their family members (20 siblings and 41 parents). "EV genomes were found in the blood of 19 of 24 (79%) diabetics, 12 of 20 (60%) non-diabetic siblings, 26 of 41 (63%) parents, and 1 of 29 (3%) pediatric controls. EVs of the A, B, C, and D species were detected, with the B and C species more prevalent. Probands and virus-positive members of each family consistently shared the same EV species. During follow-up, 4 of 20 (20%) siblings of diabetic probands developed T1D with a latency of 3-25 months."

Salvatoni - Pediatr Diabetes 2013 abstract / PubMed

Coxsackievirus B4 can infect human pancreas ductal cells and persist in ductal-like cell cultures which results in inhibition of Pdx1 expression and disturbed formation of islet-like cell aggregates. F Sane, D Caloone, V Gmyr, I Engelmann, S Belaich, J Kerr-Conte, F Pattou, R Desailloud, D Hober. Cell Mol Life Sci 2013 Nov;70(21):4169-4180. "Primary ductal cells and PANC-1 cells were infectable with CVB4E2 and a RT-PCR assay without extraction displayed that a larger proportion of cells harbored viral RNA than predicted by the detection of the viral capsid protein VP1 by indirect immunofluorescence. The detection of intracellular positive- and negative-strands of enterovirus genomes in cellular extracts by RT-PCR and the presence of infectious particles in supernatant fluids during the 37 weeks of monitoring demonstrated that CVB4E2 could persist in the pancreatic duct cell line. A persistent infection of these cells resulted in an impaired expression of Pdx1, a transcription factor required for the formation of endocrine pancreas, and a disturbed formation of islet-like cell aggregates of which the viability was decreased."

Sane - Cell Mol Life Sci 2013 abstract / PubMed

Coxsackievirus B1 Is Associated With Induction of β-Cell Autoimmunity That Portends Type 1 Diabetes. OH Laitinen, H Honkanen, O Pakkanen, S Oikarinen, MM Hankaniemi, H Huhtala, T Ruokoranta, V Lecouturier, P André, R Harju, SM Virtanen, J Lehtonen, JW Almond, T Simell, O Simell, J Ilonen, R Veijola, M Knip, H Hyöty. Diabetes 2014 Feb;63(2):446-455. 183 case children with diabetes-predictive autoantibodies and 366 autoantibody-negative matched control children. "Coxsackievirus B1 was associated with an increased risk of β-cell autoimmunity. This risk was strongest when infection occurred a few months before autoantibodies appeared and it was attenuated by the presence of maternal antibodies against the virus. Two other Coxsackieviruses, B3 and B6, were associated with a reduced risk, with an interaction pattern suggesting immunological cross-protection against Coxsackievirus B1."

Laitinen - Diabetes 2014 abstract / PubMed

Coxsackievirus B1 reveals strain specific differences in plasmacytoid dendritic cell mediated immunogenicity. S Hämäläinen, N Nurminen, H Ahlfors, S Oikarinen, AB Sioofy-Khojine, G Frisk, MS Oberste, R Lahesmaa, M Pesu, H Hyöty. J Med Virol 2014 Aug;86(8):1412-1420. "CBV1 strains differed markedly in their capacity to induce innate immune responses. Out of the 18 tested CBV1 strains two induced exceptionally strong alpha interferon (IFN-α) response in PBMC cultures. The responding cell type was found to be the plasmacytoid dendritic cell. Such a strong innate immune response was accompanied by an up-regulation of several other immune response genes and secretion of cytokines, which modulate inflammation, and adaptive immune responses. These results suggest that enterovirus-induced immune activation depends on the virus strain."

Hämäläinen - J Med Virol 2014 abstract / PubMed

Enterovirus RNA in longitudinal blood samples and risk of islet autoimmunity in children with a high genetic risk of type 1 diabetes: the MIDIA study. O Cinek, LC Stene, L Kramna, G Tapia, S Oikarinen, E Witsø, T Rasmussen, PA Torjesen, H Hyöty, KS Rønningen. Diabetologia 2014 Oct;57(10):2193-2200. 45 cases and 92 controls, all with a single high-risk HLA-DQ-DR genotype. "There was no association between enterovirus RNA and islet autoimmunity in samples obtained strictly before (7.6% cases, 10.0% controls, OR 0.75 [95% CI 0.36, 1.57]), or strictly after the first detection of islet autoantibodies (10.5% case, 5.8% controls, OR 2.00 [95% CI 0.64, 6.27]). However, there was a tendency towards a higher frequency of enterovirus detection in the first islet autoantibody-positive sample (15.8%) compared with the corresponding time point in matched controls (3.2%, OR 8.7 [95% CI 0.97, 77])."

Cinek - Diabetologia 2014 abstract / PubMed

Type I diabetes mellitus: genetic factors and presumptive enteroviral etiology or protection. J Precechtelova, M Borsanyiova, S Sarmirova, S Bopegamage. J Pathog 2014;2014:738512. Major review. Includes enteroviruses, CMV, parvovirus B19, and others.

Precechtelova - J Pathog 2014 full article / PubMed Central
Precechtelova / J Pathog 2014 full article

Enterovirus infection is associated with an increased risk of childhood type 1 diabetes in Taiwan: a nationwide population-based cohort study. HC Lin, CH Wang, FJ Tsai, KP Hwang, W Chen, CC Lin, TC Li. Diabetologia 2015 Jan;58(1):79-86. Number of cases and controls not given in abstract. "Overall incidence of type 1 diabetes was higher in the EV than in the non-EV infection cohort (5.73 vs 3.89 per 100,000 person-years; incidence rate ratio 1.48 [95% CI 1.19, 1.83]), with an adjusted HR of 1.48 (95% CI 1.19, 1.83)."

Lin - Diabetologia 2015 abstract / PubMed

Monocytes of Patients with Type 1 Diabetes Harbour Enterovirus RNA. EK Alidjinou, W Chehadeh, J Weill, MC Vantyghem, C Stuckens, A Decoster, C Hober, D Hober. Eur J Clin Invest 2015 Sep;45(9):918-924. 42 T1D patients. "EV RNA was detected in whole blood and in monocytes of 7 patients and negative-strand EV RNA was found in monocytes of 6 of them. When monocytes of patients with IFNα and/or EV RNA in their blood were inoculated with CVB4, the proportion of cells stained by an anti-VP1 antibody was 8.8+/-1% whereas no VP1 was detected in the monocytes of IFNα, EV RNA negative patients. Nevertheless, when CBV4 was mixed with plasma, VP1 was detected in monocytes of all T1D patients (staining ranging from 12 to 36%)."

Alidjinou - Eur J Clin Invest 2015 abstract / PubMed

Influenza A virus antibodies show no association with pancreatic islet autoantibodies in children genetically predisposed to type 1 diabetes. A Kondrashova, N Nurminen, M Patrikainen, H Huhtala, J Lehtonen, J Toppari, J Ilonen, OG Simell, R Veijola, M Knip, H Hyöty. Diabetologia 2015 Nov;58(11):2592-2595. 95 case children with positive islet autoantibodies and 186 autoantibody-negative and non-diabetic controls. "The prevalence of influenza A virus antibodies did not differ between the case and control children (42% vs 38%; p = 0.392) and the median antibody levels were also comparable in the two groups (3.0 vs 3.8 enzyme immunoassay units)."

Kondrashova - Diabetologia 2015 abstract / PubMed

Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. L Krogvold, A Wiberg, B Edwin, T Buanes, FL Jahnsen, KF Hanssen, E Larsson, O Korsgren, O Skog, K Dahl-Jørgensen. Diabetologia 2016 Mar;59(3):492-501. "All six patients fulfilled the criteria for insulitis (5-58% of the insulin-containing islets in the six patients had ≥ 15 T cells/islet). Of all the islets, 36% contained insulin, with several resembling completely normal islets. The majority (61-83%) of T cells were found as peri-insulitis rather than within the islet parenchyma. The expression pattern of T cell genes was found to be markedly different in islets compared with the rejected kidneys. The islet-infiltrating T cells showed only background levels of cytokine/chemokine release in vitro."

Krogvold - Diabetologia 2016 abstract / PubMed

Enterovirus Exposure Uniquely Discriminates Type 1 Diabetes Patients with a Homozygous from a Heterozygous Melanoma Differentiation-Associated Protein 5/Interferon Induced with Helicase C Domain 1 A946T Genotype. BM Schulte, PR Gielen, ED Kers-Rebel, AC Prosser, K Lind, M Flodström-Tullberg, CJ Tack, LD Elving, GJ Adema. Viral Immunol 2016 Sep;29(7):389-397. "Interestingly, the data imply that the magnitude of responses to enterovirus and enterovirus-antibody complexes in PBMCs is critically influenced by the A946T polymorphism and elevated in heterozygotes compared to TT homozygous individuals in autoimmune diabetes patients, but not healthy controls."

Schulte - Viral Immunol 2016 abstract / PubMed

Incomplete immune response to coxsackie B viruses associates with early autoimmunity against insulin. MP Ashton, A Eugster, D Walther, N Daehling, S Riethausen, D Kuehn, K Klingel, A Beyerlein, S Zillmer, AG Ziegler, E Bonifacio. Sci Rep 2016 Sep 8;6:32899. Sera from 440 subjects from several studies. "Antibody responses that were anti-VP2 competent but anti-VP1 deficient were unable to neutralize CVB, and were characteristic of children who developed early insulin-targeting autoimmunity, suggesting an impaired ability to clear CVB in early childhood. In contrast, children who developed a GAD-targeting autoimmunity had robust VP1 and VP2 antibody responses to CVB. We further found that 20% of memory CD4(+) T cells responding to the GAD65247-266 peptide share identical T cell receptors to T cells responding to the CVB4 p2C30-51 peptide, thereby providing direct evidence for the potential of molecular mimicry as a mechanism for GAD autoimmunity."

Ashton - Sci Rep 2016 full article / PubMed Central
Ashton / Sci Rep 2016 full article

Type 2 Diabetes

Hepatitis C Virus Causes Insulin Resistance and Diabetes

Association of diabetes mellitus and chronic hepatitis C virus infection. AL Mason, JY Lau, N Hoang, K Qian, GJ Alexander, L Xu, L Guo, S Jacob, FG Regenstein, R Zimmerman, JE Everhart, C Wasserfall, NK Maclaren, RP Perrillo. Hepatology 1999 Feb;29(2):328-333. 1,117 patients. "In the diabetes cohort, 4.2% of patients were found to be infected with HCV compared with 1.6% of control patients (P =.02). HCV genotype 2a was observed in 29% of HCV-RNA-positive diabetic patients versus 3% of local HCV-infected controls (P <.005). In conclusion, the data suggest a relatively strong association between HCV infection and diabetes, because diabetics have an increased frequency of HCV infection, particularly with genotype 2a. Furthermore, it is possible that HCV infection may serve as an additional risk factor for the development of diabetes, beyond that attributable to chronic liver disease alone."

Mason - Hepatology 1999 abstract / PubMed

Hepatitis C virus down-regulates insulin receptor substrates 1 and 2 through up-regulation of suppressor of cytokine signaling 3. T Kawaguchi, T Yoshida, M Harada, T Hisamoto, Y Nagao, T Ide, E Taniguchi, H Kumemura, S Hanada, M Maeyama, S Baba, H Koga, R Kumashiro, T Ueno, H Ogata, A Yoshimura, M Sata. Am J Pathol 2004 Nov;165(5):1499-1508. "An increase in fasting insulin levels was associated with the presence of serum HCV core, the severity of hepatic fibrosis and a decrease in expression of insulin receptor substrate (IRS) 1 and IRS2, central molecules of the insulin-signaling cascade, in patients with HCV infection. Down-regulation of IRS1 and IRS2 was also seen in HCV core-transgenic mice livers and HCV core-transfected human hepatoma cells... In human hepatoma cells, HCV core up-regulated suppressor of cytokine signaling (SOCS) 3 and caused ubiquitination of IRS1 and IRS2. HCV core-induced down-regulation of IRS1 and IRS2 was not seen in SOCS3(-/-) mouse embryonic fibroblast cells. Furthermore, HCV core suppressed insulin-induced phosphorylation of p85 subunit of phosphatidylinositol 3-kinase and Akt, activation of 6-phosphofructo-2-kinase, and glucose uptake."

Kawaguchi - Am J Pathol 2004 full article / PubMed Central

Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study. CO Zein, C Levy, A Basu, NN Zein. Am J Gastroenterol 2005 Jan;100(1):48-55. 179 patients. "The crude percentage of DM for the cohort was 14.5%, different from the crude rate of 7.8% for the general population (p= 0.0008) and from the rate of 7.3% observed in a matched control group with non-HCV liver disease. The prevalence of DM and IFG (DM/IFG) was higher among HCV-infected patients with advanced versus those with early histological disease (p= 0.0004)... DM and IFG were not associated with anthropomorphic markers of obesity in HCV patients."

Zein - Am J Gastroenterol 2005 abstract / PubMed

Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. CS Wang, ST Wang, WJ Yao, TT Chang, P Chou. Am J Epidemiol 2007 Jul 15;166(2):196-203. 4,958 persons aged > or =40 years without diabetes (3,486 seronegative, 812 anti-HCV+, 116 with hepatitis B virus/HCV coinfection, and 544 hepatitis B surface antigen (HBsAg)+. 474 cases developed. "The 7-year cumulative incidence was 7.5% for HBsAg+, 8.6% for seronegative, 14.3% for anti-HCV+, and 14.7% for coinfected participants."

Wang / Am J Epidemiol 2007 full article

Hepatitis C virus directly associates with insulin resistance independent of the visceral fat area in nonobese and nondiabetic patients. M Yoneda, S Saito, T Ikeda, K Fujita, H Mawatari, H Kirikoshi, M Inamori Y Nozaki, T Akiyama, H Takahashi, Y Abe, K Kubota, T Iwasaki, Y Terauchi, S Togo, S Nakajima. J Viral Hepat 2007 Sep;14(9):600-607. "The results of univariate analysis revealed a significant correlation between the quantity of HCV-RNA and the HOMA-IR (r = 0.368, P = 0.0291). While a significant correlation between the visceral adipose tissue area and the HOMA-IR was also observed in the 97 control, nondiabetic, non-HCV-infected patients (r = 0.398, P < 0.0001), no such significant correlation between the visceral adipose tissue area and the HOMA-IR (r = 0.124, P = 0.496) was observed in the patients with HCV infection. Multiple regression analysis with adjustment for age, gender and visceral adipose tissue area revealed a significant correlation between the HCV-RNA and the HOMA-IR (P = 0.0446). HCV is directly associated with IR in a dose-dependent manner, independent of the visceral adipose tissue area."

Yoneda - J Viral Hepat 2007 abstract / PubMed

Risk factors for the development of diabetes mellitus in chronic hepatitis C virus genotype 4 infection. W Chehadeh, N Abdella, A Ben-Nakhi, M Al-Arouj, W Al-Nakib. J Gastroenterol Hepatol 2009 Jan;24(1):42-48. 181 HCV-positive patients and 170 control HCV-negative patients with T2D. "The prevalence of HCV-patients with T2D was 39.8%. There was no significant association of T2D with gender, nationality, obesity, HCV viral load, or antiviral therapy. Older age (>or= 50 years) and family history of diabetes were the only independent risk factor for T2D in HCV patients. However, the median age and the prevalence of obesity in HCV-positive patients with T2D were significantly lower than those in diabetic HCV-negative patients. By following-up HCV-patients receiving antiviral drugs, a significant decrease of fasting plasma glucose and glycosylated hemoglobin levels was observed in diabetic patients who achieved a sustained viral response (SVR)."

Chehadeh - J Gastroenterol Hepatol 2009 abstract / PubMed

Hepatitis C virus and type 2 diabetes. F Negro, M Alaei. World J Gastroenterol 2009 Apr 7;15(13):1537-1547. Review. "[Type 2 diabetes] is a common complication of all liver diseases, independently of the etiology, especially at the advanced stage. However, clinical and experimental data suggest a direct role of HCV in the perturbation of glucose metabolism. The first observation that cirrhotic patients infected with HCV may present with T2D more often than patients with cirrhosis of other etiology was reported in 1994 by Allison et al. Most studies using a cross-sectional design and comparing the prevalence of T2D in a population of chronic hepatitis C patients with that of a comparator group have confirmed these preliminary observations, with rare exceptions."

Negro - World J Gastroenterol 2009 full article / PubMed Central

Molecular mechanisms of insulin resistance in chronic hepatitis C. MW Douglas, J George. World J Gastroenterol 2009 Sep 21;15(35):4356-4364. Review. "It is now widely recognized that chronic hepatitis C (CHC) is associated with insulin resistance (IR) and type 2 diabetes, so can be considered a metabolic disease. IR is most strongly associated with hepatitis C virus (HCV) genotype 1, in contrast to hepatic steatosis, which is associated with genotype 3 infection." 180 million people, over 3% of the world's population, are infected.

Douglas - World J Gastroenterol 2009 full article / PubMed Central

Prevalence of type 2 diabetes in Algerian patients with hepatitis C virus infection. S Rouabhia, R Malek, H Bounecer, A Dekaken, F Bendali Amor, M Sadelaoud, A Benouar. World J Gastroenterol 2010 Jul 21;16(27):3427-3431. "The prevalence of DM was higher in HCV-infected patients in comparison with HBV-infected patients (39.1% vs 5%, P < 0.0001). Among patients without cirrhosis, diabetes was more prevalent in HCV-infected patients than in HBV-infected patients (33.5% vs 4.3%, P < 0.0001). Among patients with cirrhosis, diabetes was more prevalent in HCV-infected patients, but the difference was not significant (67.4% vs 20%, P = 0.058). The logistic regression analysis showed that HCV infection [odds ratio (OR) 4.73, 95% CI: 1.7-13.2], metabolic syndrome (OR 12.35, 95% CI: 6.18-24.67), family history of diabetes (OR 3.2, 95% CI: 1.67-6.13) and increased hepatic enzymes (OR 2.22, 95% CI: 1.1-4.5) were independently related to DM in these patients."

Rouabhia - World J Gastroenterol 2010 full article / PubMed Central

Human cytomegalovirus infection inhibits response of chronic hepatitis-C-virus-infected patients to interferon-based therapy. NG Bader el-Din, M Abd el-Meguid, AA Tabll, MA Anany, G Esmat, N Zayed, A Helmy, AR el-Zayady, A Barakat, MK el-Awady. J Gastroenterol Hepatol 2011 Jan;26(1):55-62. "CMV DNA was detected in 89.7% of non-responders and in 34.6% of sustained virological responders. Patients with reactivated CMV had significantly higher fibrosis scores (72.7%) than those with undetectable CMV DNA (23.8%, P=0.002). Patients with positive CMV had higher rates of non-response and relapse (79.5%) than those with negative CMV DNA (19%). Chronic HCV patients with latent CMV had higher rates of response (81%) to treatment than those with reactivated CMV (20.5%, P<0.001). Therefore, HCV patients with reactivated CMV and advanced fibrosis were least likely to achieve a sustained virological response following interferon therapy. This possibility is reduced to 50% of its original value in patients with reactivated CMV without fibrosis."

Bader el-Din - J Gastroenterol Hepatol 2011 abstract / PubMed

Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C. HS Conjeevaram, AS Wahed, N Afdhal, CD Howell, JE Everhart, JH Hoofnagle; Virahep-C Study Group. Gastroenterology 2011 Feb;140(2):469-477. 341 patients. "The presence of insulin resistance was associated with increasing age, body mass index (BMI), and fibrosis stage. Among patients with insulin resistance at the start of the trial, median decreases in HOMA2-IR values during treatment were 0.74 at 24 weeks and 0.89 at 48 weeks, whereas BMI decreased by 1.2 and 2.2 at the same time points (P < .001 for all). At follow-up, HOMA2-IR and BMI levels returned toward baseline values in patients who did not respond or relapsed, but HOMA2-IR values remained significantly lower in patients with sustained virologic response (SVR) (P < .001), despite increases in BMI."

Conjeevaram - Gastroenterology 2011 abstract / PubMed

Hepatitis C Virus Infection Promotes Hepatic Gluconeogenesis through an NS5A-Mediated, FoxO1-Dependent Pathway. L Deng, I Shoji, W Ogawa, S Kaneda, T Soga, DP Jiang, YH Ide, H Hotta. J Virol 2011 Sep;85(17):8556-8568. "Here, using Huh-7.5 cells either harboring HCV-1b RNA replicons or infected with HCV-2a, we showed that HCV transcriptionally upregulated the genes for phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase), the rate-limiting enzymes for hepatic gluconeogenesis. In this way, HCV enhanced the cellular production of glucose 6-phosphate (G6P) and glucose."

Deng - J Virol 2011 abstract / PubMed

Hepatitis C virus activates mTOR/S6K1 signaling pathway in inhibiting IRS-1 function for insolin resistance. SK Bose, S Shrivastava, K Meyer, BB Ray, R Ray. J Virol 2012 Jun;86(11):6315-6322. "Inhibition of IRS-1 expression was observed in HCV infected hepatocytes as compared to mock infected control. The status of tuberous sclerosis complex (TSC-1/TSC-2) was significantly decreased after HCV infection of human hepatocytes, showing a modulation of the downstream Akt pathway. Subsequent study indicated an increased level of Rheb and mTOR expression in HCV infected hepatocytes. Interestingly, phosphoS6K1 level was higher in HCV infected hepatocytes, suggesting a novel mechanism for IRS-1 inhibition. Ectopic expression of TSC-1/TSC-2 significantly recovered IRS-1 protein expression level in HCV infected hepatocytes. Further analyses indicated that HCV core protein plays a significant role in modulating the mTOR/S6K1 signaling pathway."

Bose - J Virol 2012 abstract / PubMed

Inauspicious contribution of hepatitis C virus and diabetes mellitus targeting kidneys: an update. SM Alavian, S Taheri. Iran J Kidney Dis 2012 Jul;6(4):236-254. Review. "In addition to chronic liver disease that induces high amounts
of threats to the infected patients, recently, extrahepatic manifestations of HCV infection, including renal injuries, have increasingly come into view. A retrospective cohort of over 470 000 people showed that HCV-infected patients are more likely to develop end-stage renal disease (4.3 versus 3.1 per 1000 person-year) than HCVseronegative patients. On the other hand, HCV infection among patients with a glomerular filtration rate (GFR) of 30 mL/min/1.73 m2 and less was associated with about threefold higher risk of kidney function deterioration and kidney failure. Another study showed that HCV-positive patients had a 40% higher risk for kidney failure development."

Alavian & Taheri / Iran J Kidney Dis 2012 full article (pdf, 19 pp)

Association of Hepatitis C Virus Infection with Type II Diabetes in Ethiopia: A Hospital-Based Case-Control Study. S Ali, S Abera, A Mihret, T Abebe. Interdiscip Perspect Infect Dis 2012;2012:354656. 304 diabetic patients, 300 controls. "The prevalence of HCV in type II diabetes and nondiabetic controls was 9.9% and 3.3%, respectively. In multivariate analysis, HCV seropositives have high risk of developing diabetes as compared with seronegatives (AOR = 2.997, 95% CI: (1.08, 8.315))."

Ali - Interdiscip Perspect Infect Dis 2012 full article / PubMed Central

The metabolic regulator PGC-1α links Hepatitis C virus infection to hepatic insulin resistance. A Shlomai, MM Rechtman, EO Burdelova, A Zilberberg, S Hoffman, I Solar, S Fishman, Z Halpern, EH Sklan. J Hepatol 2012 Oct;57(4):867-873. "PGC-1α was robustly induced in HCV infected cells. PGC-1α induction was accompanied by an elevated expression of the gluconeogenic gene glucose-6 phosphatase (G6Pase) and increased glucose production. The induction of gluconeogenesis is HCV dependent, since interferon treatment abolishes PGC-1α and G6Pase elevation and decreases glucose output. Moreover, PGC-1α knockdown resulted in a significant reduction of G6Pase levels in HCV full length replicon cells, emphasizing the central role of PGC-1α in the exaggerated gluconeogenic response observed in HCV patients. Treatment of HCV replicon cells with the antioxidant N-acetylcysteine resulted in reduction of PGC-1α levels, suggesting that HCV-induced oxidative stress promoted PGC-1α upregulation. Finally, both PGC-1 αand G6Pase RNA levels were significantly elevated in liver samples of HCV infected patients highlighting the clinical relevance of these results."

Shlomai - J Hepatol 2012 abstract / PubMed

Association of Serum Adipocytokines With Insulin Resistance and Liver Injury in Patients With Chronic Hepatitis C Genotype 4. MA Khattab, M Eslam, MM Aly, M Shatat, A Hussen, YI Moussa, G Elsaghir, H Abdalhalim, A Aly, S Gaber, SA Harrison. J Clin Gastroenterol 2012 Nov;46(10):871-879. 147 HCV patients and 89 controls. "CD95 immunoreactivity and adiponectin immunoreactivity were detected in all biopsies examined. Hepatic adiponectin immunostaining correlated positively with the intensity of hepatic CD95/Fas immunostaining (r=0.424; P=0.001). Hepatocyte CD95/Fas upregulation correlated with fibrosis, inflammation, and steatosis (r=0.52, P=0.0001; r=0.16, P=0.04; r=0.24, P=0.0001; respectively). Significant correlations of serum adiponectin, its receptors mRNA expression, hepatic adiponectin immunostaining, and mRNA transcription for phosphoenolpyruvate carboxykinase were identified with steatosis. A positive association between adiponectin and hepatic inflammation and fibrosis was identified. This correlation remained significant even after adjusting for age, sex, and body mass index. Among body mass index, age, and sex-matched HCV-negative controls, patients with HCV-4 have higher serum leptin, adiponectin, and high molecular weight adiponectin, and these changes are independently correlated with IR."

Khattab - J Clin Gastroenterol 2012 abstract / PubMed

A Community-Based Cross-Sectional Study: The Association of Lipids with Hepatitis C Seropositivity and Diabetes Mellitus. JL Liu, JY Chen, CT Chen, JH Wang, CY Lin, PF Chen, CH Hung, KM Kee, CM Lee, LS Tsai, SC Chen, SC Lin, SN Lu. J Gastroenterol Hepatol. 2012 Nov;27(11):1688-1694. 56,338 Taiwanese. "When subjects were divided into hyperlipidemia (CHOL, >200 or TG, >150 mg/dL; n = 33,393) or non-hyperlipidemia subgroups (CHOL, <200 and TG, <150 mg/dL; n = 22,945), anti-HCV seropositivity was identified as an independent factor only in the non-hyperlipidemia subgroup. The odds ratio was 1.35, with a 95% confidence interval of 1.17-1.55."

Liu - J Gastroenterol Hepatol. 2012 abstract / PubMed

Hepatitis C virus infection suppresses GLUT2 gene expression via down-regulation of hepatocyte nuclear factor 1α. C Matsui, I Shoji, S Kaneda, IR Sianipar, L Deng, H Hotta. J Virol 2012 Dec;86(23):12903-12911. "HCV-induced suppression of GLUT2 promoter activity was abrogated when hepatocyte nuclear factor 1α (HNF-1α)-binding motif was deleted from the GLUT2 promoter. HNF-1α mRNA levels were significantly reduced in HCV J6/JFH1-infected cells. Furthermore, HCV infection remarkably decreased the HNF-1α protein levels. We assessed the effects of proteasome inhibitor or lysosomal protease inhibitors on the HCV-induced reduction of HNF-1α protein levels. Treatment of the HCV-infected cells with a lysosomal protease inhibitor, but not with a proteasome inhibitor, restored HNF-1α protein levels, suggesting that HCV infection promotes lysosomal degradation of HNF-1α protein."

Matsui - J Virol 2012 abstract / PubMed

Associations of chronic hepatitis C with metabolic and cardiac outcomes. ZM Younossi, M Stepanova, F Nader, Z Younossi, E Elsheikh. Aliment Pharmacol Ther 2013 Mar;37(6):647-652. 173 individuals from the National Health and Nutrition Examination Surveys (NHANES), 1999-2010. "In multivariate analysis, in addition to known risk factors for insulin resistance, CH-C was independently associated with the presence of insulin resistance [OR (95% CI) = 2.06 (1.19-3.57)], DM [OR = 2.31 (1.18-4.54)] and hypertension [OR = 2.06 (1.30-3.24)]."

Younossi - Aliment Pharmacol Ther 2013 abstract / PubMed

Amino Acid substitutions in the core region associate with insulin resistance in chronic hepatitis C. CH Hung, TH Hu, CM Lee, CM Huang, CH Chen, JH Wang, SN Lu. Intervirology 2013;56(3):166-171. 56 non-diabetic chronic HCV genotype-1b patients. "Patients with a higher HOMA-IR (≥3.5) had a higher ratio of aa substitutions in core 70 (p = 0.025), a higher body mass index (p = 0.021) and serum total cholesterol level (p = 0.044) and presence of hepatic steatosis (≥5%) as compared with those with a lower HOMA-IR (<3.5). Multivariate analysis showed that independent factors of higher HOMA-IR were mutated aa70 (odds ratio 3.80, p = 0.033) and body mass index (odds ratio 1.20, p = 0.042). Patients with mutated aa70 had a higher serum tumor necrosis factor-α level than those with wild-type (p = 0.014)."

Hung - Intervirology 2013 abstract / PubMed

Virus C Hepatitis and Type 2 Diabetes: A Cohort Study in Southern Italy. L Montenegro, A De Michina, G Misciagna, V Guerra, A Di Leo. Am J Gastroenterol 2013 Jul;108(7):1108-1111. Random sample of 2,472 subjects, prospective. "HCV was associated with DM 2 only in subjects with elevated ALT (OR 0.58, 95% CI 0.31-1.08, if ALT normal; OR 1.47, 95% CI 1-2.16, if ALT elevated, controlling for age, gender, and BMI)."

Montenegro - Am J Gastroenterol 2013 abstract / PubMed

Hepatitis C virus core protein induces hepatic metabolism disorders through down-regulation of the SIRT1-AMPK signaling pathway. JW Yu, LJ Sun, W Liu, YH Zhao, P Kang, BZ Yan. Int J Infect Dis 2013 Jul;17(7):e539-545. "In HepG2 cells expressing HCV core protein, the level of ROS increased, the value of NAD(+)/NADH decreased, the activity and expression levels of mRNA and protein of SIRT1 and AMPK decreased, glucose uptake and its regulator gene GLUT2 mRNA levels decreased, glucose production and its regulator genes PEPCK and G6Pase mRNA levels increased, intracellular TG and cholesterol contents and their regulator gene (SREBP-1c, FAS, ACC, HMGR, and HMGS) mRNA levels increased, the glycolytic gene GK and fatty acid oxidation genes PPARα and CPT1A mRNA levels decreased."

Yu - Int J Infect Dis 2013 abstract / PubMed

Association between the hepatitis B and C viruses and metabolic diseases in patients stratified by age. WC Li, YY Lee, IC Chen, C Sun, FH Chiu, CH Chuang. Liver Int 2013 Sep;33(8):1194-1202. 26,305 subjects. "No significant difference in the prevalence of [metabolic syndrome] was identified in any group, except men and women >45 years who were anti-HCV positive. Various metabolic alterations in both men and women >45 years were noted, including waist circumference, body mass index, fasting blood glucose and systolic and diastolic blood pressure. Notably, high- and low-density lipoproteins were significantly lower in positive subjects compared to those weakly positive and/or negative for anti-HCV."

Li - Liver Int 2013 abstract / PubMed

Clinico-pathological significance of hepatitis C virus core antigen levels in chronic infection. E Durante-Mangoni, L Vallefuoco, R Sorrentino, D Iossa, E Perna, R Molaro, U Braschi, R Zampino, G Sodano, LE Adinolfi, R Utili, G Portella. J Med Virol 2013 2013 Nov;85(11):1913-1918. 114 patients with chronic hepatitis C. "HCVcoreAg levels were correlated significantly with HCV-RNA (r = 0.56; P < 0.0001) but also with ALT levels (r = 0.258; P < 0.01) and liver necroinflammatory activity (r = 0.205; P < 0.04). Patients harbouring HCV genotype 3 showed lower levels of HCVcoreAg than both genotype 1 and two patients. In genotype 3, a direct correlation between steatosis and HCVcoreAg was found. Levels of HCVcoreAg also varied according to the IL28B genotype."

Durante-Mangoni - J Med Virol 2013 abstract / PubMed

Interaction of IFNL3 with insulin resistance, steatosis and lipid metabolism in chronic hepatitis C virus infection. M Eslam, DR Booth, J George, G Ahlenstiel. World J Gastroenterol 2013 Nov 7;19(41):7055-7061. Review.

Eslam - World J Gastroenterol 2013 full article / PubMed Central
Eslam / World J Gastroenterol 2013 full article

Hepatitis C virus induced up-regulation of microRNA-27: A novel mechanism for hepatic steatosis. R Singaravelu, R Chen, EK Lyn, DM Jones, S O'Hara, Y Rouleau, J Cheng, P Srinivasan, N Nasheri, RS Russell, D Lorne, JP Pezacki. Hepatology 2014 Jan;59(1):98-108. "Herein, we demonstrate that HCV replication induces the expression of miR-27 in cell culture and in vivo HCV infectious models. Overexpression of the HCV proteins core and NS4B independently activates miR-27 expression. Furthermore, we establish that miR-27b overexpression in hepatocytes results in larger and more abundant lipid droplets, as observed by coherent anti-Stokes Raman scattering (CARS) microscopy. This hepatic lipid droplet accumulation coincides with miR-27b's repression of PPAR-α and ANGPTL3, known regulators of triglyceride homeostasis. We further demonstrate that treatment with a PPAR-α agonist, bezafibrate, is able to reverse the miR-27b-induced lipid accumulation in Huh7 cells."

Singaravelu - Hepatology 2014 abstract - PubMed

Increased prevalence of coronary artery disease risk markers in patients with chronic hepatitis C--a cross-sectional study. T Roed, US Kristoffersen, A Knudsen, N Wiinberg, AM Lebech, T Almdal, RW Thomsen, A Kjær, N Weis. Vasc Health Risk Manag 2014 Jan 21;10:55-62. 60 HCV patients and 60 controls. HCV patients had higher glycosylated hemoglobin level (mean 6.2 versus 5.7, difference of means 0.5; 95% CI 0.3-0.8), and a higher prevalence of metabolic syndrome (28% versus 18%, PR 1.6; 95% CI 0.8-3.0).

Roed - Vasc Health Risk Manag 2014 full article / PubMed Central
Roed / Vasc Health Risk Manag 2014 landing page

Hepatitis C Virus stimulates Low-Density Lipoprotein Receptor (LDLR) expression to facilitate viral propagation. GH Syed, H Tang, M Khan, T Hassanein, J Liu, A Siddiqui. J Virol 2014 Mar;88(5):2519-2529. "We demonstrate that HCV stimulates LDLR expression in both HCV-infected Huh7 cells and in liver tissue from chronic hepatitis C patients... Analysis of LDLR gene promoter identified a pivotal role of sterol-regulatory element binding proteins (SREBPs), in the HCV-mediated stimulation of LDLR transcription. In addition HCV negatively modulated the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that facilitates LDLR degradation. Ectopic expression of wild type PCSK9 or gain of function PCSK9 mutant negatively affected HCV replication."

Syed - J Virol 2014 abstract / PubMed

Hepatitis C virus nonstructural protein 5A favors upregulation of gluconeogenic and lipogenic gene expression leading towards insulin resistance: a metabolic syndrome. F Parvaiz, S Manzoor, J Iqbal, S McRae, F Javed, QL Ahmed, G Waris. Arch Virol 2014 May;159(5):1017-1025. "We showed that transient expression of HCV NS5A in human hepatoma cells increased lipid droplet formation through enhanced lipogenesis. We also showed increased transcriptional expression of peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and diacylglycerol acyltransferase-1 (DGAT-1) in NS5A-expressing cells. On the other hand, there was significantly reduced transcriptional expression of microsomal triglyceride transfer protein (MTP) and peroxisome proliferator-activated receptor γ (PPARγ) in cells expressing HCV NS5A. Furthermore, increased gluconeogenic gene expression was observed in HCV-NS5A-expressing cells. In addition, it was also shown that HCV-NS5A-expressing hepatoma cells show serine phosphorylation of IRS-1, thereby hampering metabolic activity and contributing to insulin resistance."

Parvaiz - Arch Virol 2014 abstract / PubMed

Eradicating hepatitis C virus ameliorates insulin resistance without change in adipose depots. KL Milner, AB Jenkins, M Trenell, J Tid-Ang, D Samocha-Bonet, M Weltman, A Xu, J George, DJ Chisholm. J Viral Hepat 2014 May;21(5):325-332. 8 normoglycaemic men with chronic HCV versus 15 HCV-negative controls. "Insulin sensitivity after viral clearance was comparable to matched controls without CHC. Post therapy, liver enzyme levels decreased but, interestingly, levels of glucagon, fatty acid-binding protein and lipocalin-2 remained elevated. Eradication of the hepatitis C virus improves insulin sensitivity without alteration in fat depots, adipokine or glucagon levels, consistent with a direct link of the virus with insulin resistance."

Milner - J Viral Hepat 2014 abstract / PubMed

The Relationship of Hepatitis C Virus Infection with Diabetes in the United States Population. CE Ruhl, A Menke, CC Cowie, JE Everhart. Hepatology 2014 Oct;60(4):1139-1149. 15,128 NHANES subjects who had data on diabetes status and serum HCV antibody (anti-HCV) or HCV RNA. "The prevalence of diabetes and pre-diabetes did not differ by HCV status. In multivariate-adjusted analysis, diabetes remained unassociated with anti-HCV (OR=1.0, 95% confidence interval (CI), 0.6-1.7) or with HCV RNA (OR=1.1, 95% CI, 0.6-1.9)."

Ruhl - Hepatology 2014 abstract / PubMed

Hepatitis C virus NS5A protein enhances gluconeogenesis through upregulation of Akt-/JNK-PEPCK signalling pathways. YC Kuo, IY Chen, SC Chang, SC Wu, TM Hung, PH Lee, K Shimotohno, MF Chang. Liver Int 2014 Oct;34(9):1358-1368. "By upregulating the expression of PEPCK gene via its transactivators FoxO1 and HNF-4a, and the coactivator PGC-1a, the NS5A promotes the production of hepatic glucose which may contribute to the development of HCV-associated type 2 diabetes mellitus."

Kuo - Liver Int 2014 abstract / PubMed

Anti-hepatitis C virus seropositivity is not associated with metabolic syndrome irrespective of age, gender and fibrosis. YL Cheng, YC Wang, KH Lan, TI Huo, YH Huang, CW Su, HC Lin, FY Lee, JC Wu, SD Lee. Ann Hepatol 2015 Mar-Apr;14(2):181-189. 30616 subjects, 2.7% [about 827] with anti-HCV and 28.8% [about 8817] with metabolic syndrome. "[A]nti-HCV seropositivity was not an independent variable for metabolic syndrome. Further stratifying the subjects by age and sex, and there was still no significant difference in HCV status between those with and without metabolic syndrome. Moreover, the stage of liver fibrosis represented by aspartate aminotransferase to platelet ratio index was also not correlated with metabolic syndrome in the subjects with anti-HCV seropositivity."

Cheng - Ann Hepatol 2015 abstract / PubMed

Chronic hepatitis C infection is associated with insulin resistance and lipid profiles. CY Dai, ML Yeh, CF Huang, CH Hou, MY Hsieh, JF Huang, IL Lin, ZY Lin, SC Chen, LY Wang, WL Chuang, ML Yu, HD Tung. J Gastroenterol Hepatol 2015 May;30(5):879-884. 160 HCV patients, 480 controls. "patients with HCV infection had a significantly higher ALT level, FPG level, insulin level, and HOMA-IR (P<0.001, P=0.023, P=0.017 and P= 0.011, respectively) and significantly lower triglycerides level (P=0.023), total cholesterol, HDL-C and LDL-C levels (all Ps<0.001)."

Dai - J Gastroenterol Hepatol 2015 abstract / PubMed

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. A Grasso, F Malfatti, G Andraghetti, S Marenco, C Mazzucchelli, S Labanca, R Cordera, R Testa, A Picciotto. Gastroenterol Res Pract 2015;2015:975695. 75 patients. "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."

Grasso - Gastroenterol Res Pract 2015 full article / PubMed Central
Grasso - Gastroenterol Res Pract 2015 full article

Substitution in Amino Acid 70 of Hepatitis C Virus Core Protein Changes the Adipokine Profile via Toll-Like Receptor 2/4 Signaling. S Uraki, M Tameda, K Sugimoto, K Shiraki, Y Takei, T Nobori, M Ito. PLoS One 2015 Jun 29;10(6):e0131346. "IL-6 production was significantly increased and adiponectin production was reduced without a change in triglyceride content by treatment with 70Q compared to 70R core protein in both murine and human adipocytes. IL-6 induction of 3T3-L1 cells treated by 70Q HCV core protein was significantly inhibited with anti-TLR2 antibody by 42%, and by TLR4 inhibitor by 40%."

Uraki - PLoS One 2015 full article / PubMed Central
Uraki / PLoS One 2015 full article

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients. TI Sheikh, T Adam, I Qadri. Asian Pac J Trop Med 2015 Aug;8(8):618-623. 8 HCV patients and 6 healthy controls. "Significantly upregulated expression of PCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression of G6PC and FOXO1 were found. CONCLUSIONS: PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients."

Sheikh / Asian Pac J Trop Med 2015 full article

Association between HCV infection and diabetes type 2 in Egypt: is it time to split up? DF Cuadros, FD Miller, N Nagelkerke, LJ Abu-Raddad. Ann Epidemiol 2015 Dec;25(12):918-923. 1442 HCV positive individuals. "We found no evidence for an association between HCV antibody status and diabetes (adjusted odds ratio [OR] = 0.87; 95% confidence interval [CI], 0.63-1.19). However, among HCV-exposed individuals, we found an evidence for an association between diabetes and active HCV infection (adjusted OR = 2.44, 95% CI, 1.30-4.57)."

Cuadros / Ann Epidemiol 2015 full article

The metabolic regulator histone deacetylase 9 contributes to glucose homeostasis abnormality induced by hepatitis C virus infection. J Chen, N Wang, M Dong, M Guo, Y Zhao, Z Zhuo, C Zhang, X Chi, Y Pan, J Jiang, H Tang, J Niu, D Yang, Z Li, X Han, Q Wang, X Chen. Diabetes 2015 Dec;64(12):4088-4098. "HDAC9 expression can be strongly induced upon hepatitis C virus (HCV) infection. HCV-induced HDAC9 upregulation enhances gluconeogenesis by promoting the expression of gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, indicating a major role for HDAC9 in the development of HCV-associated exaggerated gluconeogenic responses. Moreover, HDAC9 expression levels and gluconeogenic activities were elevated in livers from HCV-infected patients and persistent HCV-infected mice, emphasizing the clinical relevance of these results. Our results suggest HDAC9 is involved in glucose metabolism and HCV-induced abnormal glucose homeostasis and type-2 diabetes."

Chen - Diabetes 2015 abstract / PubMed

Chronic Hepatitis C Virus Infection and the Risk for Diabetes: A Community-Based Prospective Study. YJ Lin, TG Shaw, HI Yang, SN Lu, CL Jen, LY Wang, KH Wong, SY Chan, Y Yuan, G L'Italien, CJ Chen, MH Lee. Liver Int 2016 Jul 1 [Epub ahead of print]. 1917 cases among 21,559 subjects. "The cumulative risk for diabetes was 10.9% for anti-HCV seronegatives and 16.7% for anti-HCV seropositives, respectively. The HR for diabetes of anti-HCV seropositivity was 1.53 (95% CI:1.29-1.81) compared with anti-HCV seronegatives after adjustment for risk predictors. The adjusted HRs were1.63 (1.31-2.02) for anti-HCV seropositives with positive HCV RNA compared to anti-HCV seronegatives (p<0.001)."

Lin - Liver Int 2016 abstract / PubMed

Matched population-based study examining the risk of type 2 diabetes in people with and without diagnosed hepatitis C virus infection. C Schnier, S Wild, Z Kurdi, C Povey, DJ Goldberg, SJ Hutchinson. J Viral Hepat 2016 Aug;23(8):596-605. "T2DM had been diagnosed in 2.9% of anti-HCV+ves (including 3.2% of HCV RNA+ves and 2.3% of HCV RNA-ves ) and 2.7% of anti-HCV-ves . A higher proportion of T2DM was diagnosed in the peri-HCV period (i.e. around the time of HCV-diagnosis) for the anti-HCV+ves (22%) compared to anti-HCV-ves (10%). In both the pre-HCV and post-HCV periods, only those anti-HCV+ves living in less deprived areas (13% of the cohort) were found to have a significant excess risk of T2DM compared to anti-HCV-ves (adjusted odds ratio in the pre-HCV period: 4.0 for females and 2.3 for males; adjusted hazard ratio in the post-HCV period: 1.5). These findings were similarly observed for both HCV RNA+ves (chronic) and HCV RNA-ves (resolved)."

Schnier - J Viral Hepat 2016 abstract / PubMed

The Role of Cytomegalovirus

Pervasive influence of hepatitis C virus on the phenotype of antiviral CD8+ T cells. M Lucas, AL Vargas-Cuero, GM Lauer, E Barnes, CB Willberg, N Semmo, BD Walker, R Phillips, P Klenerman. J Immunol 2004 Feb 1;172(3):1744-1753. "Recent studies using MHC class I tetramers have shown that CD8(+) T cell responses against different persistent viruses vary considerably in magnitude and phenotype. At one extreme, hepatitis C virus (HCV)-specific CD8(+) T cell responses in blood are generally weak and have a phenotype that is perforin low and CCR7 high (early memory). At the other, specific responses to CMV are strong, perforin high, and CCR7 low (mature or effector memory). To examine the potential mechanisms behind this diversity, we compared CMV-specific responses in HCV-infected and healthy individuals. We find a striking difference in the phenotype of CMV-specific CD8(+) T cells between these groups. In the HCV-infected cohort, CMV-specific CD8(+) T cells lost markers associated with maturity; they had increased expression of CCR7 and reduced expression of Fas and perforin. They nevertheless responded to Ag in vitro in a manner similar to controls, with strong proliferation and appropriate acquisition of effector memory markers. The reduction in mature CD8 T cells in HCV-infected individuals may arise through either impairment or regulation of T cell stimulation, or through the early loss of mature T cells. Whatever the mechanism, HCV has a pervasive influence on the circulating CD8(+) T cell population, a novel feature that may be a hallmark of this infection."

Lucas - J Immunol 2004 abstract / PubMed

[Prevalence, clinical and therapeutical implications of active CMV infection in patients with chronic hepatitis C]. TW Lapiński, O Kovalchuk, A Parfieniuk, R Flisiak. Przegl Epidemiol 2009;63(2):305-309. 123 patients with chronic hepatitis C. "Active CMV replication was observed in 18/123 individuals (14.6%). Majority of them (16/18) have low level of CMV viraemia. There were no apparent correlations between HCV and CMV viral loads. Hemoglobin concentration, erythrocytes, leucocytes and platelet count, absolute neutrophil count and activity of alanine transaminase was similar in HCV and HCV/CMV -infected patients. Active CMV infection did not influence inflammatory activity and fibrosis in liver tissue. The early virologic response to anti-HCV therapy was independent of CMV infection."

Lapiński - Przegl Epidemiol 2009 abstract / PubMed

Access of viral proteins to mitochondria via mitochondria-associated membranes. CD Williamson, AM Colberg-Poley. Rev Med Virol 2009 May;19(3):147-164. "Proteins from two unrelated viruses, human CMV (HCMV) and HCV, are documented to traffic sequentially from the ER into mitochondria, probably through the mitochondria-associated membrane (MAM) compartment. The MAM are sites of ER-mitochondrial contact enabling the direct transfer of membrane bound lipids and the generation of high calcium (Ca2+) microdomains for mitochondria signalling and responses to cellular stress. Both HCV core protein and HCMV UL37 proteins are associated with Ca2+ regulation and apoptotic signals. Trafficking of viral proteins to the MAM may allow viruses to manipulate a variety of fundamental cellular processes, which converge at the MAM, including Ca2+ signalling, lipid synthesis and transfer, bioenergetics, metabolic flow, and apoptosis. Because of their distinct topologies and targeted MAM sub-domains, mitochondrial trafficking (albeit it through the MAM) of the HCMV and HCV proteins predictably involves alternative pathways and, hence, distinct targeting signals. Indeed, we found that multiple cellular and viral proteins, which target the MAM, showed no apparent consensus primary targeting sequences."

Williamson - Rev Med Virol 2009 abstract / PubMed

Prevalence of human cytomegalovirus co-infection in patients with chronic viral hepatitis B and C: a comparison of clinical and histological aspects. A Bayram, A Ozkur, S Erkilic. J Clin Virol 2009 Jul;45(3):212-217. 44 chronic HBV, 25 chronic HCV patients, 36 controls. "HCMV infection was demonstrated in 52.3% of chronic HBV, and 36% of chronic HCV patients. Although alanine aminotransferase (ALT) levels of HCMV-infected HBV patients were decreased slightly, they were increased in HCV patients. Histologic activity scores (necroinflammation and fibrosis) of HCMV-positive patients were higher than that of HCMV-negatives in both HBV and HCV groups. Intrahepatic HBV DNA or HCV RNA loads of the corresponding study groups were decreased in HCMV-infected patients." They concluded that replication of HBV and HCV were inhibited in HCMV-positive cases.

Bayram - J Clin Virol 2009 abstract / PubMed

CD4+ T-lymphocyte telomere length is related to fibrosis stage, clinical outcome and treatment response in chronic hepatitis C virus infection. M Hoare, WT Gelson, A Das, JM Fletcher, SE Davies, MD Curran, SL Vowler, MK Maini, AN Akbar, GJ Alexander. J Hepatol 2010 Aug;53(2):252-260. 135 HCV-RNA-positive, treatment-naïve patients and 41 healthy controls. "Shorter CD4+CD45RO+ T-lymphocyte telomeres were associated with severe fibrosis (p=0.003), independent of male sex (p=0.04), CMV positivity (p=0.003), previous HBV infection (p=0.007), and age (p=ns) in viraemic patients compared to controls. There were inverse correlations between CD4+CD45RO+ telomere length and fibrosis stage (p<0.001), portal tract inflammatory grade (p=0.035), prothrombin time (p<0.001) and bilirubin (p=0.001). One hundred and twenty-four viraemic individuals were followed prospectively to a composite endpoint of death, hepatic decompensation or HCC. Independent of age, those with shorter CD4+CD45RO+ telomeres were less likely to be complication free after 2-years than those with longer telomeres (86% versus 96%, p=0.009) with an age-adjusted hazard ratio of 0.93 (0.90-0.96). In addition, CD4+CD45RO+ telomere length predicted successful antiviral therapy (p=0.001) independent of other factors."

Hoare - J Hepatol 2010 abstract / PubMed

Human cytomegalovirus infection inhibits response of chronic hepatitis-C-virus-infected patients to interferon-based therapy. NG Bader el-Din, M Abd el-Meguid, AA Tabll, MA Anany, G Esmat, N Zayed, A Helmy, AR el-Zayady, A Barakat, MK el-Awady. J Gastroenterol Hepatol 2011 Jan;26(1):55-62. "CMV DNA was detected in 89.7% of non-responders and in 34.6% of sustained virological responders. Patients with reactivated CMV had significantly higher fibrosis scores (72.7%) than those with undetectable CMV DNA (23.8%, P=0.002). Patients with positive CMV had higher rates of non-response and relapse (79.5%) than those with negative CMV DNA (19%). Chronic HCV patients with latent CMV had higher rates of response (81%) to treatment than those with reactivated CMV (20.5%, P<0.001). Therefore, HCV patients with reactivated CMV and advanced fibrosis were least likely to achieve a sustained virological response following interferon therapy. This possibility is reduced to 50% of its original value in patients with reactivated CMV without fibrosis."

Bader el-Din - J Gastroenterol Hepatol 2011 abstract / PubMed

Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus. S Giubilato, G Liuzzo, S Brugaletta, D Pitocco, F Graziani, C Smaldone, RA Montone, V Pazzano, D Pedicino, LM Biasucci, G Ghirlanda, F Crea. Eur Heart J 2011 May;32(10):1214-1226. 166 acute coronary syndrome patients with or without DM (ACS/DM+, n= 51 and ACS/DM-, n= 115), and 60 healthy controls. The incidence of cardiovascular events (death, myocardial infarction, unstable angina) was assessed at 36 months follow-up. CD4(+)CD28(null)T-cell frequency (median, range) was higher in ACS/DM+ (12.7%, 0.1-48) vs. ACS/DM- (3.9%, 0.2-35), cDM (3.1%, 0.3-22.4), and controls (1.5%, 0.1-9.1) (P< 0.001 for all comparisons). Notably, cDM patients had significantly higher CD4(+)CD28(null)T-cell frequency than controls (P= 0.001). Glycosylated haemoglobin A(1c) was the only parameter independently associated with CD4(+)CD28(null)T-cells in cDM. The 36-month event-free survival was significantly lower in cDM patients with CD4(+)CD28(null)T-cells ≥4% (90th percentile of normal distribution) than in those with CD4(+)CD28(null)T-cells <4% (P= 0.039). Among ACS patients, the 36-month event-free survival was the lowest in those with DM and CD4(+)CD28(null)T-cells ≥4% and highest in those without DM and CD4(+)CD28(null)T-cells <4% (P< 0.001), being intermediate in those with only one of these features."

Giubilato - Eur Heart J 2011 abstract / PubMed

Susceptibility of human pancreatic β cells for cytomegalovirus infection and the effects on cellular immunogenicity. MJ Smelt, MM Faas, BJ de Haan, C Draijer, GC Hugenholtz, A de Haan, MA Engelse, EJ de Koning, P de Vos. Pancreas 2012 Jan;41(1):39-49. "β Cells were susceptible to HCMV infection. Moreover, the infection increased the cellular immunogenicity, as demonstrated by an increased MHC I and ICAM-1 expression and an increased proinflammatory cytokine release. Human cytomegalovirus-infected CM cells potently activated PBMCs. The infection-induced effects were dependent on both viral 'sensing' and viral replication."

Smelt - Pancreas 2012 abstract / PubMed

Cytomegalovirus seropositivity is associated with glucose regulation in the oldest old. Results from the Leiden 85-plus Study. S Chen, AJ de Craen, Y Raz, E Derhovanessian, AC Vossen, WG Rudi, G Pawelec, AB Maier. Immun Ageing 2012 Aug 28;9(1):18. "CMV seropositive subjects were more likely to have type 2 diabetes (17.2% vs 7.9%, p = 0.016), had a higher level of HbA1c (p = 0.014) and higher non-fasting glucose (p = 0.024) in the oldest olds. These associations remained significant after adjustment for possible confounders. CMV IgG antibody level was not significantly associated with glucose regulation (all p > 0.05)."

Chen - Immun Ageing 2012 abstract / PubMed

Prospective study of cytomegalovirus seropositivity and risk of mortality from diabetes. A Mendy, J Gasana, ER Vieira, H Diallo. Acta Diabetol 2014 Oct;51(5):723-729. Followup of 14,404 non-diabetic adults in NHANES. "At baseline, 76.8 % of subjects were CMV seropositive, and after an average follow-up of 13.7 years, diabetes mortality rate per 10,000 person-years was 6.8 (95 % CI 5.7, 8.0). Among seropositive participants, the diabetes death rate (8.4, 95 % CI 7.0, 9.9) was more than four times the rate in seronegative ones (2.0, 95 % CI 1.1, 3.6) (P value for the difference <0.001). In the adjusted Cox proportional hazards analysis, CMV seropositivity more than doubled the risk of diabetes mortality (HR 2.06, 95 % CI 1.05, 4.06)."

Mendy - Acta Diabetol 2014 abstract / PubMed

Elevated HbA1c levels and the accumulation of differentiated T cells in CMV+ individuals. JL Rector, GN Thomas, VE Burns, JB Dowd, RM Herr, PA Moss, MN Jarczok, K Hoffman, JE Fischer, JA Bosch. Diabetologia 2015 Nov;58(11):2596-2605. 1103 occupational cohort study subjects, with 400 CMV+. "Among CMV+ individuals (n = 400), elevated HbA1c was associated with increased numbers of EM (B = 2.75, p < 0.01) and EMRA (B = 2.90, p < 0.01) T cells, which was robust to adjustment for age, sex, sociodemographic variables and lifestyle factors. Elevated EM T cells were also positively associated with total cholesterol (B = 0.04, p < 0.05) after applying similar adjustments. No associations were observed in CMV- individuals."

Rector - Diabetologia 2015 abstract / PubMed

See Also:

Hepatitis Viruses are the Real Cause of "Smoking Related" Liver Cancer - studies have found HCV DNA by reverse transcriptase PCR in patients who were negative for antibodies to HCV.
CMV & other infections cause heart disease


cast 10-01-16