Characteristics of Interferon-Associated Diabetes Mellitus in Past 30 Years: A Review

Abstract

Interferon (IFN) is a broad-spectrum antiviral agent that activates cell surface receptors and causes cells to produce antiviral proteins, inhibiting viral replication. Interferon use has long been associated with diabetes. The PubMed database was searched for articles related to diabetes and interferon from March 30, 2020. Patients were divided into type 1 diabetes group and type 2 diabetes group. We reviewed the relevant literature to compare interferon-associated T1D and interferon-associated T2D differences. Interferon treatment shortened the incubation period of T2D and changed the original T2D to T1D. The onset of interferon-associated T1D required longer periods of IFN treatment than interferon-associated T2D, and the interferon-associated T1D group had higher GADA positive rates, lower BMI, lower fasting blood glucose, and greater insulin dependence (p<0.05). More patients in the T1D group were positive for HLA-DRB1*04, DRB1*03, DRB1*09, DRB1*14, HLA-DQB1*04, HLA-DQB1*02, HLA-DQB1*03, and HLA-DQB1*05. The combined detection of GAD antibodies and HLA alleles may be an effective method to predict the incidence of T1D after IFN treatment.

Key words

interferon - diabetes - autoimmune disease - hepatitis C - glutamate decarboxylase antibody

Publication History

Received: 16 August 2021

Accepted after revision: 13 January 2022

Article published online:
11 March 2022

• References

• 1 World Health Organisation Global surveillance and control of hepatitis C. Report of a WHO consultation organised in collaboration with the viral hepatitis prevention board, Antwerp, Belgium. J Viral Hepat 1999; 6: 35-47
• 2 Bottazzo GF, Dean BM, McNally GM. et al. In situ characterisation of autoimmune phenomena in the pancreas in diabetic insulitis. N Engl J Med 1985; 353: 360-363
• 3 EASL (European Association on the studies on the Liver) EASL international consensus conference on hepatitis C. Paris, 26–27 February 1999. Consensus statement. J Hepatol 1999; 31: 3-8
• 4 Russo MW, Fried MW. Side effects of therapy for chronic hepatitis C. Gastroenterology 2003; 124: 1711-1719
• 5 Fattovich G, Giustina G, Favarato S. et al. A survey of adverse events in 11,241 patients with chronic viral hepatitis treated with α interferon. J Hepatol 1996; 24: 38-47
• 6 Trans HA, Reeves GEM, Gibson R. et al. Development of thyroid diseases in the treatment of chronic hepatitis C with a interferon may be a good prognosticator in achieving a sustained virological response: A metaanalysis. J Gastroenterol Hepatol 2009; 24: 1163-1168
• 7 Manns MP, Wedemeyer H, Cornberg M. Treating viral hepatitis C: efficacy, side effects and complications. Gut 2006; 55: 1350-1359
• 8 Fabris P, Betterle C, Floreani A. et al. Development of type 1 diabetes mellitus during interferon alpha therapy for chronic HCV hepatitis. Lancet 1992; 340: 548
• 9 Nakamura K, Kawasaki E, Imagawa A. et al. Type 1 diabetes and interferon therapy: a nationwide survey in Japan. Diabetes Care 2011; 34: 2084-2089
• 10 Eibl N, Gschwantler M, Ferenci P. et al. Development of insulin-dependent diabetes mellitus in a patient with chronic hepatitis C during therapy with interferon-alpha. Eur J Gastroenterol Hepatol 2001; 13: 295-298
• 11 Fabris P, Betterle C, Greggio NA. et al. Insulin-dependent diabetes mellitus during alpha-interferon therapy for chronic viral hepatitis. J Hepatol 1998; 28: 514-517
• 12 Fujioka T, Honda M, Yoshizaki T. et al. A case of type 1 diabetes onset and recurrence of Graves’ disease during pegylated interferon-alpha plus ribavirin treatment for chronic hepatitis C. Intern Med 2010; 49: 1987-1990
• 13 Guerci AP, Guerci B, Levy-Marchal C. et al. Onset of insulin-dependent diabetes mellitus after interferon-alfa therapy for hairy cell leukaemia. Lancet 1994; 343: 1167-1168
• 14 Kawazoe T, Araki M, Lin Y. et al. New-onset type 1 diabetes mellitus and anti-aquaporin-4 antibody positive optic neuritis associated with type 1 interferon therapy for chronic hepatitis C. Intern Med 2012; 51: 2625-2629
• 15 Kose S, Gozaydin A, Akkoclu G. et al. Chronic hepatitis B with type I diabetes mellitus and autoimmune thyroiditis development during interferon alpha therapy. J Infect Dev Ctries 2012; 6: 364-368
• 16 Lopes EP, Oliveira PM, Silva AE. et al. Exacerbation of type 2 diabetes mellitus during interferon-alfa therapy for chronic hepatitis B. Lancet 1994; 343: 244
• 17 Lv YY, Shi BY, Guo H. Abrupt onset of type 1 diabetes mellitus during recombinant interferon-alpha 2b therapy in a patient with chronic hepatitis B. World J Gastroenterol 2008; 14: 4713-4715
• 18 Oka R, Hiroi N, Shigemitsu R. et al. Type 1 diabetes mellitus associated with pegylated interferon-alpha plus ribavirin treatment for chronic hepatitis C: case report and literature review. Clin Med Insights Endocrinol Diabetes 2011; 4: 39-45
• 19 Popescu C, Popescu GA, Arama V. Type 1 diabetes mellitus with dual autoimmune mechanism related to pegylated interferon and ribavirin treatment for chronic HCV hepatitis. J Gastrointestin Liver Dis 2013; 22: 101-104
• 20 Ranganathan R, Janarthanan K, Rajasekaran S. Onset of Type 1 Diabetes Mellitus During Pegylated-interferon Alfa and Ribavirin Therapy for Chronic Hepatitis C Virus Infection. J Clin Exp Hepatol 2012; 2: 86-87
• 21 Recasens M, Aguilera E, Ampurdanes S. et al. Abrupt onset of diabetes during interferon-alpha therapy in patients with chronic hepatitis C. Diabet Med 2001; 18: 764-767
• 22 Scavone G, Zaccardi F, Manto A. et al. A case of chronic hepatitis C developing insulin-dependent diabetes, thyroid autoimmunity and stiff-person syndrome as complications of interferon therapy. Diabetes Res Clin Pract 2010; 89: e36-e38
• 23 Seifarth C, Benninger J, Bohm BO. et al. Augmentation of the immune response to islet cell antigens with development of diabetes mellitus caused by interferon-alpha therapy in chronic hepatitis C. Z Gastroenterol 1999; 37: 235-239
• 24 Soultati AS, Dourakis SP, Alexopoulou A. et al. Simultaneous development of diabetic ketoacidosis and Hashitoxicosis in a patient treated with pegylated interferon-alpha for chronic hepatitis C. World J Gastroenterol 2007; 13: 1292-1294
• 25 Tosone G, Borgia G, Gentile I. et al. A case of pegylated interferon alpha-related diabetic ketoacidosis: can this complication be avoided?. Acta Diabetol 2007; 44: 167-169
• 26 Uonaga T, Yoshida K, Harada T. et al. Case of type 1 diabetes mellitus following interferon beta-1a treatment for multiple sclerosis. Intern Med 2012; 51: 1875-1877
• 27 Uto H, Matsuoka H, Murata M. et al. A case of chronic hepatitis C developing insulin-dependent diabetes mellitus associated with various autoantibodies during interferon therapy. Diabetes Res Clin Pract 2000; 49: 101-106
• 28 Frankart L, Lejeune D, Donckier J. Diabetes mellitus and interferon therapy. Diabet Med 1997; 14: 405
• 29 Narvaez I, Perez B, Alcalde M. et al. Chronic viral hepatitis, interferon, diabetes mellitus, and celiac disease. Am J Gastroenterol 2003; 98: 2336-2337
• 30 Kado S, Miyamoto J, Komatsu N. et al. Type 1 diabetes mellitus caused by treatment with interferon-beta. Intern Med 2000; 39: 146-149
• 31 Yamazaki M, Sato A, Takeda T. et al. Distinct clinical courses in type 1 diabetes mellitus induced by peg-interferon-alpha treatment for chronic hepatitis C. Intern Med 2010; 49: 403-407
• 32 Nakamura K, Kawasaki E, Abiru N. et al. Trajectories of anti-islet autoantibodies before development of type 1 diabetes in interferon-treated hepatitis C patients. Case reports and a literature review. Endocr J 2010; 57: 947-951
• 33 Radhakrishnan S, Upadhyay A, Mohan N. et al. Late development of diabetes mellitus after interferon-alfa and ribavirin therapy for chronic hepatitis C: a case report. Med Princ Pract 2005; 14: 281-283
• 34 Yagyu H, Okada K, Sato S. et al. Pegylated interferon-alpha2b and ribavirin combination therapy induces Hashitoxicosis followed by type 1 diabetes mellitus. Diabetes Res Clin Pract 2012; 95: e52-e54
• 35 Tahrani A, Bowler L, Singh P. et al. Resolution of diabetes in type 2 diabetic patient treated with IFN-alpha and ribavirin for hepatitis C. Eur J Gastroenterol Hepatol 2006; 18: 291-293
• 36 Krug J, Fritzsch J, Aust G. Induction of insulin antibodies and insulin allergy under alpha-interferon treatment of renal cell carcinoma in a patient with insulin-treated diabetes mellitus – a case report. Int Arch Allergy Immunol 1995; 106: 169-172
• 37 Zornitzki T, Malnick S, Lysyy L. et al. Interferon therapy in hepatitis C leading to chronic type 1 diabetes. World J Gastroenterol 2015; 21: 233-239
• 38 Muraishi K, Sasaki Y, Kato T. et al. Classification and characteristics of interferon-related diabetes mellitus in Japan. Hepatol Res 2011; 41: 184-188
• 39 Tasi TN, Hsieh CH. Development of reversible diabetes mellitus after cessation of interferon-alpha therapy for chronic hepatitis C infection. N Z Med J 2004; 117: U1230
• 40 Sossau D, Kofler L, Eigentler T. Type 1 diabetes mellitus caused by treatment with low-dose interferon-alpha in a melanoma patient. Melanoma Res 2017; 27: 516-518
• 41 Costa JM, Moraes MS, Saldanha AC. et al. Diabetes mellitus associated with pentamidine isethionate in diffuse cutaneous leishmaniasis. Rev Soc Bras Med Trop 1995; 28: 405-407
• 42 Blanchard E, Vickers CR, Samaras K. et al. Not so sweet: autoimmune diabetes mellitus on triple therapy for chronic hepatitis C infection. Diabet Med 2015; 32: e1-e3
• 43 Alsabbagh ME, Eisa N, Alraiyes AH. et al. Chronic hepatitis C therapy: a rare complication revisited. BMJ Case Rep 2013;
• 44 Bosi E, Minelli R, Bazzigaluppi E. et al. Fulminant autoimmune Type 1 diabetes during interferon-alpha therapy: a case of Th1-mediated disease?. Diabet Med 2001; 18: 329-332
• 45 Lo YC, Chang SY, Sheng WH. et al. Association of pancreatic autoantibodies and human leukocyte antigen haplotypes with resolution of diabetes mellitus after therapy for hepatitis C virus infection in patients with HIV infection: case report and review of literature. Eur J Gastroenterol Hepatol 2009; 21: 478-481
• 46 Mofredj A, Howaizi M, Grasset D. et al. Diabetes mellitus during interferon therapy for chronic viral hepatitis. Dig Dis Sci 2002; 47: 1649-1654
• 47 Zheng Y, Wang Z, Xie Z. et al. Fulminant type 1 diabetes caused by peginterferon α-2a therapy in hepatitis C. J Diabetes 2018; 10: 419-420
• 48 Whitehead RP, Hauschild A, Christophers E. et al. Diabetes mellitus in cancer patients treated with combination interleukin 2 and alpha-interferon. Cancer Biother 1995; 10: 45-51
• 49 Nylen ES, Marathe IC, Khan IA. et al. Sudden onset of diabetic ketoacidosis during consensus interferon therapy for chronic viral hepatitis C. Am J Med Sci 2008; 335: 329-330
• 50 Gori A, Caredda F, Franzetti F. et al. Reversible diabetes in patient with AIDS-related Kaposi’s sarcoma treated with interferon alpha-2a. Lancet 1995; 345: 1438-1439
• 51 Cozzolongo R, Betterle C, Fabris P. et al. Onset of type 1 diabetes mellitus during peginterferon alpha-2b plus ribavirin treatment for chronic hepatitis C. Eur J Gastroenterol Hepato 2006; 18: 689-692
• 52 Wang XL, Mu YM, Lu ZH. et al. Type 1 diabetes caused by interferon alpha-2alpha in polycythemia vera therapy. Diabetes Care 2010; 33: e141
• 53 Jabr FI, Ordinario MM. Sudden onset of diabetic ketoacidosis during pegylated interferon alfa therapy. Am J Med 2003; 115: 158-159
• 54 Bhatti A, McGarrity TJ, Gabbay R. Diabetic ketoacidosis induced by alpha interferon and ribavirin treatment in a patient with hepatitis C. Am J Gastroenterol 2001; 96: 604-605
• 55 Chedin P, Cahen-Varsaux J, Boyer N. Non-insulin-dependent diabetes mellitus developing during interferon-alpha therapy for chronic hepatitis C. Ann Intern Med 1996; 125: 521
• 56 Tohda G, Oida K, Higashi S. et al. Interferon-alpha and development of type 1 diabetes: a case without insulin resistance. Diabetes Care 1998; 21: 1774
• 57 Holt RIG, DeVries JH, Hess-Fischl A. et al. The management of type 1 diabetes in adults. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2021; 64: 2609-2652
• 58 Schreuder TC, Gelderblom HC, Weegink CJ. et al. High incidence of type 1 diabetes mellitus during or shortly after treatment with pegylated interferon alpha for chronic hepatitis C virus infection. Liver Int 2008; 28: 39-46
• 59 Okanoue T, Sakamoto S, Itoh Y. et al. Side effects of high-dose interferon therapy for chronic hepatitis C. J Hepatol 1996; 25: 283-291
• 60 Piquer S, Hernández C, Enriquez J. et al. Islet cell and thyroid antibody prevalence in patients with hepatitis C virus infection: effect of treatment with interferon. J Lab Clin Med 2001; 137: 38-42
• 61 McHutchison JG, Gordon SC, Schiff ER. et al. Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group. N Engl J Med 1998; 339: 1485-1492
• 62 Koivisto VA, Pelkonen R, Cantell K. Effect of interferon on glucose tolerance and insulin sensitivity. Diabetes 1989; 38: 641-647
• 63 Fabris P, Floreani A, Tositti G. et al. Type 1 diabetes mellitus in patients with chronic hepatitis C before and after interferon therapy. Aliment Pharmacol Ther 2003; 18: 549-558
• 64 He H, Ni Y, Chen J. et al. Sex difference in cardiometabolic risk profile and adiponectin expression in subjects with visceral fat obesity. Transl Res 2010; 155: 71-77
• 65 Pinelli L, Drei F, Gonfiantini E. et al. Insulin dependent diabetes mellitus epidemiology: HLA genotype study in 12 north eastern Italian families with two siblings affected by type 1 diabetes. Eur J Epidemiol 1989; 5: 456-461
• 66 Petrone A, Bugawan TL, Mesturino CA. et al. The distribution of HLA class II susceptible/protective haplotypes could partially explain the low incidence of type 1 diabetes in continental Italy (Lazio region). Tissue Antigens 2001; 58: 385-394
• 67 Huang X, Yuang J, Goddard A. et al. Interferon expression in the pancreases of patients with type I diabetes. Diabetes 1995; 44: 658-664
• 68 Foulis AK, Farquharson MA, Meager A. Immunoreactive alpha-interferon in insulin-secreting beta cells in type 1 diabetes mellitus. Lancet 1987; 2: 1423-1427
• 69 Chehadeh W, Weill J, Vantyghem MC. et al. Increased level of interferon-alpha in blood of patients with insulin-dependent diabetes mellitus: relationship with coxsackievirus B infection. J Infect Dis 2000; 181: 1929-1939
• 70 Devendra D, Eisenbarth GS. Interferon alpha – a potential link in the pathogenesis of viral-induced type 1 diabetes and autoimmunity. Clin Immunol 2004; 111: 225-233
• 71 Foulis AK, Farquharson MA, Hardman R. Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1987; 30: 333-343
• 72 Ogawa K, Hige S, Nakanishi M. et al. Immunological and mutagenic actions of ribavirin monotherapy preceding combination therapy with interferon for patients with chronic hepatitis C. Antivir Ther 2009; 14: 513-522
• 73 Ogihara T, Katagiri H, Yamada T. et al. Peg-interferon (PEGIFN) plus ribavirin combination therapy, but neither interferon nor PGE-IFN alone, induced type 1 diabetes in a patient with chronic hepatitis C. Intern Med 2009; 48: 1387-1390
• 74 Betterle C, Fabris P, Zanchetta R. et al. Autoimmunity against pancreatic islets and other tissues before and after interferon-alpha therapy in patients with hepatitis C virus chronic infection. Diabetes Care 2000; 23: 1177-1181
• 75 Yamada K, Takane-Gyotoku N, Yuan X. et al. Mouse islet cell lysis mediated by interleukin-1-induced Fas. Diabetologia 1996; 39: 1306-1312
• 76 Yamada K, Otabe S, Inada C. et al. Nitric oxide and nitric oxide synthase mRNA induction in mouse islet cells by interferon-gamma plus tumor necrosis factoralpha. Biochem Biophys Res Commun 1993; 197: 22-27