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.
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."
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.
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."
Virus infections in type 1 diabetes. KT Coppieters, T Boettler, M
von Herrath. Cold Spring Harb Perspect Med 2012 Jan;2(1):a007682.
Review.
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."
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. "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 / PubMedHepatitis 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."
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."
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."
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."
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)."
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."
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.
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."
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."
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."
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."
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 Mar 28 [Epub ahead of
print]. "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."
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."
[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."
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."
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.
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."
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."
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 Jan 8 [Epub ahead of print]. 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."
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."
cast 04-30-12