Chronic hepatitis C virus (HCV) infection is a multifaceted disease, which is associated with numerous extrahepatic manifestations, of which essential mixed cryoglobulinemia with or without membranoproliferative glomerulonephritis, and porphyria cutanea tarda are well known (1). Recent epidemiological studies have added another clinical condition, type 2 diabetes mellitus (DM), to the spectrum of HCV-associated diseases. In 1994, Allison et al. first reported an increased prevalence of DM in patients with HCV-associated liver cirrhosis as compared to patients with cirrhosis due to hepatitis B virus, alcohol, cholestatic liver disease or autoimmune hepatitis (2). Subsequently, various reports have confirmed the association between DM and HCV infection, even in the absence of cirrhosis (3–9). In these studies, the prevalence of DM in patients with liver disease secondary to HCV infection has been reported to vary from 20% to 50%, in contrast to the 2.5% to 25% prevalence found in patients with non-HCV-related liver disease.
Similar to the general population, several reports have also suggested an association between HCV infection and new onset posttransplant diabetes mellitus (PTDM) after liver and kidney transplantation (10–15). PTDM is a common complication after organ transplantation, and it has been associated with significant deleterious effects on long-term patient and graft survival. A recent meta-analysis of 10 studies in 2502 kidney recipients confirmed a significant and independent relationship between anti-HCV seropositive status and PTDM (16). Moreover, preliminary evidence shows that the induction of a pretransplant-sustained viral response by interferon-alpha treatment in HCV-positive dialysis patients awaiting kidney transplant may be associated with a lower risk of PTDM (17).
Despite the current epidemiologic evidence linking DM with HCV, the precise mechanism of this association remains unclear. Possible pathophysiologic mechanisms that have been suggested include induction of insulin resistance, diminished hepatic glucose uptake and glycogenesis, as well as a direct cytopathic effect of HCV on islet-cells inducing beta-cell dysfunction (18–22). Some evidence indicates that a predominant effect of the virus is the induction of insulin resistance, caused by inhibitory actions of the virus on insulin regulatory pathways within the liver, possibly mediated by proinflammatory cytokines (18,22). However, after transplantation, the mechanism underlying the association between HCV and PTDM is likely to be multifactorial and complex and may be different from those in immunocompetent HCV-positive individuals, owing to concomitant immunosuppression. We have recently found an evidence for increased insulin resistance in HCV-infected liver transplant recipients (23). In another study of kidney transplant recipients, HCV-infected recipients were found to have increased insulin resistance, however, there were no HCV-negative controls for comparison (24).
The aim of our study was to explore the initial mechanisms involved in PTDM in HCV infection in kidney transplant recipients. For this purpose, a 3-h intravenous glucose tolerance (IVGTT) was performed. Insulin sensitivity (the inverse of insulin resistance), pancreatic insulin secretion, pancreatic antibodies and proinflammatory cytokines were compared between nondiabetic HCV-positive and -negative kidney transplant recipients.