HCV, HAART, & Diabetes:

What is the Association Between Diabetes & HCV & HAART?

These studies appear to show some conflicting findings on an association between diabetes & HCV

Is there a relationship between HAART-associated insulin resistance and hyperglycemia and HCV or lipodystrophy? HAART can elevate lipids and lead to glucose abnormalities. There appears to be an association between lipids & possibly diabetes (despite the conflicting study results herein) and HCV. So, can HAART lead to worsening fibrosis through lipid & glucose abnormalities? Do HAART caused lipid abnormalities lead to damage or inflammation of the liver, which in turns worsen fibrosis? As well, can HCV enhance lipodystrophy, since HCV may injure cells associated with fat processing?

HYPERGLYCEMIA AND INSULIN RESISTANCE IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS INFECTION: EFFECTS OF INTERFERON-ALPHA THERAPY.
     Alaa Ismaeil, Yosry Abdelrahman, Afaf Ahmed Abdel-Hady, Nadia Abou-Zekri, Mohammed Nader Allam, Moataz Hassan Hassanien, Theodor Bilharz Research Institute, Giza Egypt

Introduction:
Hepatitis C virus (HCV) infection was suggested as an additional risk factor for the development of diabetes. Hyperinsulinemia and insulin resistance are well-described features of cirrhosis. Insulin has been shown to stimulate sympathetic nervous activity in healthy normal subjects. The aim of the present study was to evaluate the impact of chronic HCV infection on blood glucose and plasma catecholamine concentrations, as well as on plasma insulin state. The response to therapeutic administration of interferon-alpha (IFN-alpha) was also assessed. 

Methods:
The study was conducted on 50 subjects; 10 apparently healthy subjects as controls and 40 patients proved to have chronic HCV infection. Fasting blood sugar (FBS), plasma insulin, insulin autoantibodies and catecholamine (norepinephrine, NE; epinephrine, E; and dopamine, DA) concentrations were determined in all subjects; and in patients were re-evaluated 6 months after antiviral therapy (IFN-alpha: 3 MU three times weekly, and ribavirin: 1-1.2 g daily).

Results:
Significant elevations of FBS, plasma insulin autoantibodies, NE, E, and DA were recorded in patients as compared to controls. Positive correlation was observed between FBS and plasma insulin autoantibodies. After antiviral administration, only plasma insulin autoantibodies showed a significant decrease. Cases with positive response to antiviral therapy, [become seronegative for HCV-mRNA; responders, n = 17], showed significant decrease in FBS and plasma insulin autoantibodies. Both values, however, were still significantly elevated as compared to the controls.

Conclusions:
Chronic HCV infection is associated with insulin resistance, not deficiency, that might contribute to hyperglycemia. Sympathetic activation observed in patients with chronic HCV infection is neither related to HCV infection per se, nor to plasma insulin levels.

AFTER HIGH GLUCOSE IN THE LIVER. RELEVANCE FOR THE PATHOGENESIS OF FIBROSIS DEVELOPMENT IN NON-ALCOHOLIC STEATO-HEPATITIS (NASH).
     Valerie Paradis, Hosp Bicetre, Le Kremlin-Bicetre France; Delphine Dargere, Frank Bonvoust, Michel Vidaud, CNRS Esa 8037, Paris France; Pierre Bedossa, Hosp Bicetre, Le Kremlin-Bice France

Hyperglycemia is a well-known factor involved in the development of renal fibrosis in diabetic patients. Indeed, it has been shown that glucose stimulates collagen transcription in mesangial cells and fibroblasts. In the liver, nonalcoholic steatohepatitis (NASH), often observed in diabetic patients, might progress in some cases to fibrosis and cirrhosis.

The aim of the study was to evaluate the role of hyperglycemia in the development of liver fibrosis. Since CTGF is a potential intermediate factor between high glucose and fibrosis, we also assessed the CTGF response to hyperglycemia. Immunohistochemical study was performed on liver biopsies from patients with NASH (15 cases) using anti-CTGF antibodies. A strong staining was observed in all cases studied. A sinusoidal and perisinusoidal staining was detected in areas of inflammation and fibrogenesis. As an animal model of diabetes, Zucker/Zucker rats were studied. Standard histopathology, CTGF immunostaining, western blot and quantitative RT-PCR for CTGF mRNA were performed both in Zucker/Zucker rats and control littermates.

Histopathological analysis showed a pericentrolobular steatosis associated with perisinusoidal fibosis in the liver of Zucker/Zucker rats. Western-blot of liver protein extracts from Zucker/Zucker rats showed a significant increase in the specific CTGF 38 kD band by comparison to control obese non diabetic littermates. Immunostaining also demonstrated a significant sinusoidal staining. Similarly, mRNA quantification, performed by a real-time RT-PCR procedure, demonstrated a two to three folds up-regulation of CTGF mRNA in diabetic rats in association with a similar increase in collagen a(I)1 mRNA. To gain further insights in the role of hyperglycemia on CTGF regulation, primary hepatic stellate cells isolated from adult Sprague-Dawley rats were incubated in presence of high glucose (30 mM).

Results showed that CTGF mRNA was two to three folds up-regulated in presence of high glucose in the media. In conclusion, this study supports the role of hyperglycemia in the development of liver fibrosis. It also confirms the involvement of CTGF in hyperglycemia-induced fibrosis. Such mechanism should have some relevance in NASH.

THE ASSOCIATION OF DIABETES MELLITUS WITH HEPATITIS C VIRUS INFECTION IN A SEROPREVALENCE SURVEY OF THE GENERAL U.S. POPULATION 1988 TO 1994.
     Charles H Beymer, Univ of Washington Sch of Medicine, Seattle, WA; Edward J Boyko, Jason A Dominitz, Univ of Washington and VA Puget Sound HCS, Seattle, WA

Introduction:
An association between hepatitis C virus (HCV) infection and diabetes mellitus (DM) has been demonstrated in clinic based cross-sectional studies.

Aim:
To determine if HCV and DM are associated in a population based survey.

Methods:
Using data from the Third National Health and Nutrition Examination Survey (NHANES III), we examined the anti-HCV status of 16,529 persons. Since this study focused on type 2 DM only, persons with onset of diabetes before age 20 years, and who therefore would be most likely to have type 1 DM, were eliminated from this analysis. Since the prevalence of either HCV or type 2 DM is very low among persons < 20 years of age, the analysis was also restricted to persons age 20 years.

DM was defined as present if any of the following conditions were present: self-reported clinician-diagnosis of DM; fasting plasma glucose > 125 mg/dl; oral glucose tolerance test (OGTT) 2-h plasma glucose > 199 mg/dl; or random serum glucose > 170 mg/dl. Each analysis incorporated subject selection design features (primary sampling unit, stratum) and appropriate sample weights based on the subsample employed in the analysis.

By design, a sub-sample of survey participants were invited for an OGTT, accounting for the observation that 46% and 40% of subjects with a HCV serology test had a fasting and 2-h plasma glucose measured, respectively.

Results:
388 persons tested positive for HCV, while 2,281 met our diagnostic criteria for type 2 DM. Subjects with type 2 DM were older (p<0.0001), more likely to be female (p<0.02), and had on average higher body mass index (BMI, p<0.0001) and waist-to-hip ratio (WHR, p<0.0001). Diabetic and non-diabetic subjects were similar with regard to white or black race and anti-HCV prevalence (see table). Measures of glycemia (hemoglobin A1c, 2-hour, and fasting plasma glucose) were analyzed in relation to hepatitis C serology using linear regression analysis. No association was seen between these measures of glycemia and hepatitis C seropositivity in univariate analysis or in a multivariate analysis adjusted for age, gender, race, BMI, and WHR (see table).

Conclusions:
The results of this analysis based on NHANES III national survey data do not support an association between HCV and presence of DM. Furthermore, no association was seen between this infection and three measures of glycemia. These results argue against a potential role for HCV in the etiology of type 2 DM.

Table: Characteristics of Study Subjects Age 20 or Over in the NHANES III in Relation to Presence of Diabetes Mellitus and Hepatitis C Seropositivity

Dependent Variable N Odds Ratio (95% CI) p-value
Diabetes Mellitus (DM) 16,529 0.80 (0.50-1.29)  0.353
DM, Adjusted* 15,657 1.15 (0.68-1.95)  0.599
DM, Fasting Glucose  7,534 0.91 (0.37-2.21)  0.827
DM, Fasting Glucose, Adjusted*  7,227 1.21 (0.43-3.38)  0.710
 

Coefficient (95% CI)

Hemoglobin A1c 15,873  0.023 (-0.108-0.153)  0.730
Hemoglobin A1c, Adjusted* 15,138  0.052 (-0.082-0.187)  0.437
2-h Glucose  6,645 -6.94   (-23.83-9.96 )  0.413
2-h Glucose, Adjusted*  6,461 3.80 (-12.90-20.51 )  0.649
Fasting Glucose  7,534 4.21   (-4.20-12.61 )  0.319
Fasting Glucose, Adjusted*  7,227 4.51   (-3.51-12.56 )  0.266

*Adjusted for age, gender, race, BMI and WHR.