interferon ( ifn ) exerts antiviral , antiproliferative , and immunomodulatory actions,1 and is used extensively for the treatment of chronic hepatitis c ( hcv ) . ribavirin ( rbv ) , an antiviral agent , has been reported to reinforce the therapeutic effect of ifn in patients with chronic hcv.2 in recent years , combined pegylated interferon ( peg - ifn)+rbv therapy has been used as a primary treatment for chronic hcv . however , ifn - induced autoimmune disease has been highlighted as one of the problems with this therapy . in 1992 , fabris et al reported the case of a patient with hcv who developed type 1 diabetes mellitus following treatment with ifn.3 since then , cases of type 1 diabetes mellitus associated with ifn monotherapy or combined ifn+rbv therapy have been reported sporadically . ifn therapy is usually discontinued when type 1 diabetes mellitus is diagnosed in these patients . however , a few cases in which ifn therapy was continued even after the diagnosis of type 1 diabetes mellitus have also been reported . we report here the case of a patient who developed type 1 diabetes mellitus during combined peg - ifn+rbv therapy for hcv , who showed no worsening of diabetes despite continued use of ifn . a 63-year - old man presented to our hospital with excessive thirst , polydipsia , and polyuria . he had been diagnosed as having acute hepatitis b at age 35 years , at which time a liver biopsy had resulted in massive bleeding requiring blood transfusion . at age 48 years , he was diagnosed as having chronic hcv ( genotype 1b ) . ifn therapy for chronic hcv was administered at ages 50 years and 60 years , but the treatment failed to achieve negative conversion of serum hcv - rna . at age 63 years , peg - ifn+rbv was administered , and serum hcv - rna became negative eight weeks after the start of this treatment . from week 16 onwards , physical findings on admission were height 165 cm , body weight 66 kg , body mass index 24.2 kg / m , and blood pressure 120/72 mmhg . mild anemia was noted ( red blood cell count and hemoglobin 379  10/l and 11.2 g / dl , respectively ) , but there were no abnormalities of the other blood cell parameters . fasting plasma glucose was 16.2 mmol / l , serum glycosylated hemoglobin was 10.0% ( japan diabetes society ) , and serum glycoalbumin was 39.3% . there were no abnormalities in serum electrolyte profile , liver function , or renal function . the c - peptide level was 0.68 ng / ml ( normal 1.00 2.00 ng / ml ) , fasting immunoreactive insulin was 3.0 u / ml(normal 3.0616.9 u / ml ) , and the serum antiglutamic acid decarboxylase antibody titer was markedly elevated at 27,700 u / ml ( normal < 1.5 u / ml ) . hla dna typing revealed drb1 * 0101/*0405 , which was not inconsistent with the diagnosis of type 1 diabetes mellitus . because the patient had hcv genotype 1b , which needed 48 weeks of combined peg - ifn+rbv therapy,4 the treatment was continued even after diagnosis of diabetes mellitus , until 48 weeks with careful observation of plasma glucose levels . intensive insulin therapy was started immediately after the diagnosis for treatment of type 1 diabetes mellitus . the patient initially required 22 u of insulin per day ( insulin glargine 10 u , insulin as part 444 u ) ; however , the dosage could be gradually reduced after completion of peg - ifn+rbv therapy . at present , plasma glucose is well controlled ( glycosylated hemoglobin 5.7%6.5% ) , with only 6 u of insulin aspart needed per day . serum antiglutamic acid decarboxylase antibody titers also decreased gradually from the initial 27,700 u / ml to about 900 u / ml at four years after the diagnosis . it has been reported that insulin resistance may develop as a result of interference in intracellular insulin signaling by hcv proteins , mainly viaserine phosphorylation of irs-1 and impairment of the downstream akt signaling pathway.5 according to a report by mehta et al , the incidence of type 2 diabetes mellitus is about three times higher in hcv - infected individuals than in noninfected individuals overthe age of 40 years.6 in contrast it has also been reported that the incidence of type 1 diabetes mellitus as a complication is lower than that of type 2 diabetes mellitus.7 it has also been reported that the pancreas - associated autoantibody ( including antiglutamic acid decarboxylase antibody ) positivity rate in hcv patients is 3% before the start of ifn therapy but increases to 7% thereafter.1 thus , ifn therapy seems to be associated with the onset of diabetes mellitus mediated by the autoimmune system . whether or not the type 1 diabetes mellitus that developed in the present case was associated with ifn+rbv therapy no evidence of development of diabetes mellitus was seen during the first two sessions of ifn therapy ; however , considering that the blood glucose level began to rise four months after the administration of ifn+rbv therapy , it is unlikely that this patient would developed diabetes mellitus before the start of this therapy , and the most reasonable interpretation would be that the ifn+rbv therapy was causatively associated with the onset of type 1 diabetes mellitus . because pancreas - associated autoantibodies had not been measured before the start of ifn+rbv therapy , it is unknown whether the timing of the start of this therapy coincided with onset of type 1 diabetes mellitus or whether the patient had developed slowly progressive type 1 diabetes before the start of the ifn+rbv . twenty - eight cases of type 1 diabetes mellitus diagnosed after the start of ifn+rbv therapy have thus far been reported in the english language literature.3,825 we reviewed the data for each of these cases , focusing on the length of time from the start of ifn+rbv therapy to the onset of type 1 diabetes mellitus , continuation/ discontinuation of ifn therapy after the onset of type 1 diabetes , weaning / nonweaning from insulin therapy after discontinuation of ifn+rbv , presence / absence of pancreas - associated autoantibodies before and after ifn+rbv therapy , and the hla haplotype of the patients ( table 1 ) . while in most cases ifn+rbv therapy had been discontinued immediately after the diagnosis of type 1 diabetes,3,816,18,2024 the treatment had been continued in two cases , including the present case.25 insulin therapy could be discontinued later in only two of the 19 cases in which ifn+rbv therapy had been stopped immediately after the diagnosis of type 1 diabetes.8,23 weaning from insulin therapy appears to be difficult in cases of type 1 diabetes mellitus developing after the start of ifn+rbv therapy , and it has been reported that weaning was impossible in 75% of such cases.1 a report of cases of type 1 diabetes mellitus developing after completion of ifn+rbvtherapy19 suggests that discontinuation of ifn+rbv therapy does not always suppress the onset of type 1 diabetes mellitus . after the onset of type 1 diabetes , insulin secretion was improved three months later by strict control of diabetes in case 2 , and insulin treatment could be canceled 14 months later in case 24 . therefore , if strict blood glucose control is possible regardless of continuation/ discontinuation of ifn+rbv therapy , it would seem possible to reduce the insulin dose required eventually , as achieved in the present case ( probably the so - called  honeymoon phenomenon  ) . in this sense , strict control of diabetes as shown in table 1 , among the 28 reported patients , 19 had undergone measurement of pancreas - associated autoantibodies before the start of ifnrbv therapy,3,913,1517,1921 which revealed 10 antibody - positive cases3,9,11,13,14,16,19 and nine antibody - negative cases.1012,17,1921 on the other hand , after the start of treatment , autoantibodies were positive in 27 of the 28 cases . autoantibodies remained negative in only one case ; however , a diagnosis of type 1 diabetes mellitus was made on the basis of the clinical course and capacity for insulin secretion . 11 although checking for pancreas - associated autoantibodies before the start of ifn+rbv therapy may seem valid , it would appear to be difficult to predict the onset of type 1 diabetes mellituson the basis of the results . rather than checking for pancreas - associated autoantibodies , checking for the hla haplotype before the start of this therapy may be more useful to predict the onset of type 1 diabetes mellitus , in view of reports that the hla haplotype may be closely involved in the onset of type 1 diabetes mellitus associated with ifn+rbv therapy.1,19 however , because checking of the hla haplotype is an expensive investigation and type 1 diabetes mellitus is a rare complication of ifn+rbv therapy , it may be difficult to perform this test in all cases . it would therefore be advisable to bear in mind the possibility of onset of type 1 diabetes mellitus when ifn+rbv therapy is administered . ifn causes a shift in the th1/th2 balance to a th1-predominant state , which results in induction of th1-type cytokines , such as ifn- and interleukin 2 . these cytokines activate macrophages , natural killer cells , and cytotoxic t lymphocytes , resulting in exaggerated cellular immune responses.1,26,27 the th1-predominant state also seems to amplify autoimmune responses , accelerating  cell destruction in the pancreas . alternatively , it is possible that th1-type cytokines induce the fas antigen on the  cell surface , resulting in cellular apoptosis , or that free radicals formed by the actions of cytokines serve as cytotoxic factors for  cells.28,29 rbv also has the effect of causing a shift in the th1/th2 balance to a th1-predominant state , reinforcing ifn - induced activation of cellular immunity in a synergistic manner.30 in the present case , three sessions of ifn+rbv therapy were administered ; however , hyperglycemia was not noted during the first two sessions . although it is highly probable that addition of rbv to ifn therapy caused the onset of type 1 diabetes mellitus in the present case , further data is needed to examine whether or not ifn+rbv therapy might be associated with an elevated risk of developing type 1 diabetes mellitus as compared with use of ifn therapy alone . we encountered a patient who was diagnosed as having type 1 diabetes mellitus during combined peg - ifn+ rbv therapy , in whom no aggravation of diabetes was found despite continued use of ifn+rbv therapy . prediction of the onset of type 1 diabetes mellitus is difficult based on the baseline measurement of pancreas - associated autoantibodies alone . therefore , it would be advisable to bear in mind the possibility of onset of type 1 diabetes mellitus in all patients treated with ifn+rbv .
combined pegylated interferon ( peg - ifn)+ribavirin ( rbv ) therapy has been used as a primary treatment for chronic hepatitis c. however , ifn - induced autoimmune disease , including type 1 diabetes mellitus , has been highlighted as one of the problems with this therapy . 
 here we report the case of a patient who developed type 1 diabetes mellitus during combined peg - ifn+rbv therapy for hepatitis c but who showed no exacerbation of diabetes despite continued use of ifn . a 63-year - old man with chronic hepatitis c and a nonresponder to previous ifn treatments , 
 was admitted to our hospital because of excessive thirst , polydipsia , and polyuria 24 weeks after the start of peg - ifn+rbv therapy . 
 high levels of blood glucose and glycosylated hemoglobin and low levels of c - peptide and immunoreactive insulin were observed . 
 the serum antiglutamic acid decarboxylase antibody titer was 27,700 u / ml . 
 we diagnosed ifn - induced type 1 diabetes mellitus ; however peg - ifn+rbv therapy was continued for 48 weeks . 
 serum hcv remains negative five years after this treatment . 
 intensive insulin therapy was started immediately after the diagnosis of type 1 diabetes . 
 although the patient initially required 22 u / day of insulin , the dosage could be gradually reduced after completion of peg - ifn+rbv therapy and blood glucose remained well controlled . 
 prediction of onset of type 1 diabetes mellitus on the basis of baseline measurement of pancreas - associated autoantibodies is difficult . 
 therefore , it would be advisable to consider the possibility of onset of type 1 diabetes mellitus in all patients receiving ifn+rbv therapy .