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Hepatitis C Virus Infection and Human Pancreatic ß-Cell Dysfunction

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Hepatitis C Virus Infection and Human Pancreatic ß-Cell Dysfunction Pathophysiology/Complications BRIEF REPORT Hepatitis C Virus Infection and Human Pancreatic ␤-Cell Dysfunction 1 1 MATILDE MASINI, MD SILVIA DEL GUERRA, PHD showing the characteristic insulin gran- 2 1 DANIELA CAMPANI, MD MARCO BUGLIANI, PHD ules and normally preserved mitochon- 3 1 UGO BOGGI, MD SCILLA TORRI, PHD ␤ 2 1 dria. In -cells from HCV-positive MICHELE MENICAGLI, MD STEFANO DEL PRATO, MD 1 3 pancreases, the presence of virus-like par- NICOLA FUNEL, MD FRANCO MOSCA, MD 1 4 ticles was observed, mainly close to the MARIA POLLERA, MD FRANCO FILIPPONI, MD 1 1 membranes of Golgi apparatus, which, in ROBERTO LUPI, PHD PIERO MARCHETTI, MD, PHD turn, appeared hyperplastic and dilated (Fig. 1D). The mitochondria appeared round-shaped with dispersed matrix and fragmented cristae (Fig. 1D). Additional Ϯ 2 any patients with chronic hepati- and 2 women, BMI 25.8 1.6 kg/m ) ␤-cell changes were observed at the Ϯ tis C virus (HCV) develop type 2 and 10 HCV-negative (age 67 9 years, level of rough endoplasmic reticulum, Ϯ diabetes (1). This prevalence is 6 men and 4 women, BMI 26.8 2.0 which showed long and dilated tubular M 2 much higher than that observed in the kg/m ) donors were harvested and stud- membranes, with numerous electron- general population and in patients with ied with the approval of our local ethics dense ribosomes bound to the latter (not other chronic liver diseases such as hepa- committee. Histological studies were shown). These morphological changes titis B virus, alcoholic liver disease, and performed by immunohistochemistry were accompanied by reduced in vitro primary biliary cirrhosis. Furthermore, it (using the monoclonal mouse anti-HCV glucose-stimulated insulin release (Table has been shown that post-transplantation E2 protein, clone IGH222 [Innogenetics, 1); however, apoptosis was similar in con- type 2 diabetes appears to be higher Gent, Belgium]) and electron microscopy, trol as in infected islet cells (Table 1). among patients with HCV (2). However, as described elsewhere (4,5). Isolated islets the pathogenetic basis for the association were prepared by enzymatic digestion and between HCV infection and diabetes has density gradient purification, and islet func- CONCLUSIONS — Approximately not been understood. A direct involve- tional and survival studies were accom- 40% of patients with HCV infection will ment of the virus in the development of plished as previously described (5,6). display symptoms of some extrahepatic insulin resistance has been proposed, and manifestation during the illness (1). Most ␤-cell dysfunction in HCV-positive pa- extraliver manifestations of chronic HCV tients has been observed in some cases infection are immunological; however, (1). Because HCV can infect many tissues RESULTS — Histology results are the virus may have a direct cytopathic ac- other than the liver (3), we hypothesized summarized in Fig. 1. No sign of islet cell tion, because it can infect many tissues that the virus might directly damage insu- staining was found in HCV-negative pan- other than the liver (3). In the present lin-secreting cells. This article suggests creases by immunohistochemistry (Fig. article we have suggested the presence of that HCV may be present in human pan- 1A); however, focal or diffuse HCV- HCV infection in pancreatic ␤-cells of hu- creatic ␤-cells and demonstrates that islet positive islet cells were observed in HCV- man subjects, and we have provided evi- cells from HCV-positive patients have positive pancreatic glands (Fig. 1B). dence that this was associated with morphological and functional defects. Positive staining was found in 39 Ϯ 12% morphological cell changes and altered is- of 140 examined islets, and the percent- let cell function. The immunohistochem- RESEARCH DESIGN AND age of stained cells was 54 Ϯ 13% per ical method we have used to show the METHODS — The pancreases of 5 islet. The appearance of a control ␤-cell at presence of infection in islet cells has been HCV-positive (age 68 Ϯ 9 years, 3 men electron microscopy is given in Fig. 1C, previously validated (4), and the electron ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● microscopy morphological alterations of From the 1Metabolic Unit, Department of Endocrinology and Metabolism, University of Pisa and Pisa ␤ 2 the -cell are similar to those reported in University Hospital, Pisa, Italy; the Section of Transplantation Pathology, Division of Surgical, Molecular other cell types during HCV infection (7). and Ultrastructural Pathology, Department of Oncology, University of Pisa and Pisa University Hospital, Pisa, Italy; the 3Referral Center for the Treatment of Pancreas Diseases, Department of Oncology, University The insulin secretion functional defects of of Pisa and Pisa University Hospital, Pisa, Italy; and the 4Liver Transplant Unit, University of Pisa and Pisa islets from HCV-positive donors might University Hospital, Pisa, Italy. contribute to the development of diabetes Address correspondence and reprint requests to Piero Marchetti, MD, Department of Endocrinology in predisposed subjects. On the other and Metabolism, Metabolic Unit, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy. E-mail: [email protected]. hand, the absence of increased apoptosis Received for publication 30 November 2004 and accepted in revised form 29 December 2004. is in line with the observation that reduc- Abbreviations: HCV, hepatitis C virus. ing viral load is associated with improve- A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion ment of diabetes in HCV-positive patients factors for many substances. (8). In conclusion, the present article pro- © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby poses that HCV can infect human pancre- marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. atic ␤-cells and that this is accompanied 940 DIABETES CARE, VOLUME 28, NUMBER 4, APRIL 2005 Marchetti and Associates Table 1—Insulin secretion and apoptosis data of HCV-negative and HCV-positive pancreatic and diabetes, especially in predisposed islets subjects (1). Insulin release (% insulin content) Apoptosis References 3.3 mmol/l glucose 16.7 mmol/l glucose ELISA* EM† 1. Lecube A, Hernandez C, Genesca J, Es- teban JI, Jardi R, Simo R: High prevalence Ϫ HCV 1.7 Ϯ 0.3 3.8 Ϯ 0.5‡ 0.9 Ϯ 0.1 2.0 Ϯ 0.2 of glucose abnormalities in patients with HCVϩ 1.6 Ϯ 0.3 2.9 Ϯ 0.4‡§ 1.0 Ϯ 0.2 1.8 Ϯ 0.2 hepatitis C virus infection: a multivariate Data are means Ϯ SD. *Data are expressed as arbitrary units of optical density; †data are expressed as analysis considering the liver injury. Dia- percentage of apoptotic ␤-cell over total number of counted ␤-cells; ‡P Ͻ 0.01 vs. 3.3 mmol/l and §P Ͻ 0.05 betes Care 27:1171–1175, 2004 vs. 16.7 mmol/l glucose, HCVϪ by the two-tailed Student’s t test. ELISA, enzyme-linked immunosorbent 2. Bruchfeld A, Wilczek H, Elinder CG: assay; EM, electron microscopy. Hepatitis C infection, time in renal-re- placement therapy, and outcome after ␤ kidney transplantation. Transplantation by -cell dysfunction. A direct cytopathic fore suggested to explain, at least in part, 78:745–750, 2004 effect of HCV at the islet cell level is there- the association between HCV infection 3. Mayo MJ: Extrahepatic manifestations of hepatitis C infection. Am J Med Sci 325: 135–148, 2003 4. Verslype C, Nevens F, Sinelli N, Clarysse C, Pirenne J, Depla E, Maertens G, van Pelt J, Desmet V, Fevery J, Roskams T: Hepatic immunohistochemical staining with a monoclonal antibody against HCV-E2 to evaluate antiviral therapy and reinfection of liver grafts in hepatitis C vi- ral infection. J Hepatol 38:208–214, 2003 5. Marchetti P, Del Guerra S, Marselli L, Lupi R, Masini M, Pollera M, Bugliani M, Boggi U, Vistoli F, Mosca F, Del Prato S: Pancre- atic islets from type 2 diabetic patients have functional defects and increased ap- optosis that are ameliorated by met- formin. J Clin Endocrinol Metab 89:5535– 5541, 2004 6. Marchetti P, Lupi R, Federici M, Marselli L, Masini M, Boggi U, Del Guerra S, Pa- tane` G, Piro S, Anello M, Bergamini E, Purrello F, Lauro R, Mosca F, Sesti G, Del Prato S: Insulin secretory function is im- paired in isolated human islets carrying the Gly(972)3Arg IRS-1 polymorphism. Diabetes 51:1419–1424, 2002 7. Falcon V, Acost-Rivero N, Chinea G, Gavilondo J, de la Rosa MC, Menendez I, Duenas Carrera S, Vina A, Garcia W, Gra B, Noa M, Reytor E, Barcelo MT, Alvarez F, Morale-Grillo J: Ultrastructural evi- Figure 1—A and B show the results obtained by an immunoperoxidase technique for anti– dences of HCV infection in hepatocytes of HCV-E2 in pancreatic islets (original magnification ϫ400). In A, the endocrine cells from a chronically HCV-infected patients. Bio- control pancreas are completely devoid of the viral antigen. In B, the endocrine cells from an chem Biophys Res Commun 305:1085– HCV-positive pancreas show a brown, finely granular staining, indicating the presence of the HCV 1090, 2003 proteins. C and D show the results obtained by electron microscopy (original magnification 8. Bahtiyar G, Shin JJ, Aytaman A, Sowers ϫ46,000). In C, a control ␤-cell is shown, with the characteristic insulin granules (G) and normal JR, McFarlane SI: Association of diabetes mitochondria (M). In D,a␤-cell from an HCV-positive pancreas is represented, showing virus- and hepatitis C infection: epidemiologic like particles (VL) close to dilated, hyperplastic Golgi apparatus (GA) and round-shaped mito- evidence and pathophysiologic insights. chondria with dispersed matrix and fragmented cristae. Curr Diab Rep 4:194–198, 2004 DIABETES CARE, VOLUME 28, NUMBER 4, APRIL 2005 941.
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