Fulminant Type 1 Diabetes Research Articles

Differences in the humoral autoreactivity to zinc transporter 8 between childhood- and adult-onset type 1 diabetes in Japanese patients

The aim of this study was to evaluate the humoral autoreactivity to zinc transporter 8 (ZnT8) depending on the clinical phenotype of type 1 diabetes (T1D). ZnT8 autoantibodies (ZnT8A) were determined by radioimmunoassay using carboxy-terminal ZnT8 constructs in 57 childhood-onset, 97 adult-onset, and 85 fulminant T1D. The ZnT8A frequency was higher in childhood-onset patients and decreased with increasing age of onset from 70% to 24% (P(trend)<0.005). None of the patients with fulminant T1D was positive for ZnT8A. There were at least two distinct ZnT8A epitope patterns associated with the aa325-restriction, childhood-onset patients have aa325-nonrestricted response more frequently compared to the adult-onset group (P<0.05). The level of ZnT8A was inversely associated with the copy number of HLA-DR4 allele (P<0.05). These results suggest differences in the humoral autoreactivity to ZnT8 depending on the clinical phenotype, which should provide strategy for autoantibody measurement in subjects to allow early diagnosis of autoimmune T1D.

Prevalence and clinical features of fulminant type 1 diabetes

Objective To investigate the prevalence and clinical features of fulminant type 1 diabetes.Methods Using data retrieved from Second Xiangya Hospital of Central South University,all patients diagnosed with type 1 diabetes from Jan.1,2001 to Dec.31,2007 were identified.The patients were divided into fulminant type 1 diabetes (F1D) group,typical type 1 diabetes (T1A) group,and idiopathic type 1 diabetes(T1B) group.Their clinical features were compared.Results Eight patients (9.1%) fulfilled the criteria for fulminant type 1 diabetes among 87 newly diagnosed type 1 diabetes,and the percentage of fulminant type 1 diabetes reached 14.0% among type 1 diabetic patients with age of onset of 18 years or older.Patients of F1D group had a markedly higher plasma glucose concentration compared with patients of T1A group and T1B group(P=0.004).Serum amylase was higher in F1D group than that in T1A group(P = 0.021).Four (50%) patients were GADA positive,among whom 1 patient was Coxsackie B virus (CVB) IgM positive and 1 patient was Herpes Simplex virus 1 (HSV1) IgM positive.Conclusions Fulminant type 1 diabetes accounts for about 10% of the type 1 diabetes in the Chinese individuals with ketosis-or ketoacidosis-onset.Patients with this subset of diabetes had severe metabolic derangement.Viral infection and autoimmunity may be involved in the pathogenesis of fulminant type 1 diabetes. Key words: Diabetes mellitus,type 1; Fulminant diabetes mellitus; Ketoacidosis; Autoantibody; Viral infection

Immunological features of fulminant type 1 diabetes

To investigate the immunological features of fulminant type 1 diabetes. Twenty patients with fulminant type 1 diabetes (F1D) were recruited based upon the criteria proposed by Hanafusa, and 40 patients with classical type 1 diabetes were matched with age, gender and duration for comparison. GADA, IA2A and ZnT8A were determined with radioligand assay, and GAD-reactive T cells were measured by enzyme-linked immunospot (ELISPOT) assay. The HLA-DQ were analyzed by sequence-based genotyping (SBT). Eight of 20 patients with F1D were antibody-positive, including 7 GADA positive, 4 ZnT8A positive, and 3 both GADA and ZnT8A positive. The index of 3 GADA positive patients were less than 0.4 at first visit, two turned to be negative by two or three years. While the GADA index of the patient was 0.343 at onset and increased to 1.467 three years later. Among subjects with F1D (3/6) and classical type 1 diabetes (3/6), were recorded significant GAD-stimulated responses by ELISPOT assay. The frequencies of HLA-DQA1*0102-DQB1*0601 and DQA1*03-DQB1*0401 were significantly higher in F1D than those in classical type 1 diabetes (P = 0.005, P = 0.035, respectively). Humoral and cellular immunoreactivity and susceptible HLA-DQ genotype existed in part of F1D patients, indicating autoimmunity may involve in the pathogenesis of F1D.

Insulitis in Human Type 1 Diabetes

Pancreatic tissues were analyzed immunohistologically in patients with autoimmune and fulminant type 1 diabetes (T1D) and control subjects. Both beta and alpha cells were decreased in fulminant T1D, but only beta cells were significantly decreased in autoimmune T1D. Insulitis was seen in both subtypes of T1D, but it remained longer in autoimmune than in fulminant T1D. Lymphocytic infiltration to the exocrine pancreatic tissue was observed only in fulminant T1D, whereas immunologically abnormal findings, such as increased expression of MHC class I molecule and Fas antigen in islet cells and Fas-ligand expression in infiltrating lymphocytes, were detected only in autoimmune T1D. From these findings, together with clinical features, it could be concluded that in autoimmune T1D, beta cells are assumed to be destroyed through a long-standing autoimmune process, whereas in fulminant T1D, beta cells seem to be destroyed very rapidly, probably by a destructive process triggered by viral infection.

A case of fulminant type 1 diabetes mellitus after influenza B infection

A 64-years-old man referred to a hospital because of high-grade fever. He was diagnosed as having influenza B by “POCTEM Influenza A/B”, a rapid influenza diagnostic kit which detect some antigens of influenza virus. Six days after medication of oseltamivir phosphate, his flu-symptoms disappeared, but he complained sever thirsty. And after 2 days, he suffered from loss of consciousness and was admitted to the hospital. Laboratory data on admission showed diabetes ketoacidosis, slight elevation of HbA1c level despite sever hyperglycemia, and increase of serum amylase concentration. Anti GAD antibody and anti IA-2 antibody were not detected. Urinary C-peptide excretion was undetectable and serum C-peptide levels were also undetectable after glucagon and arginin load, suggesting disappearance of endogeneous insulin secretion. Class II HLA was susceptible to fulminant type1 diabetes. Based on these findings, we diagnosed him with fulminant type1 diabetes. In Japan, only three viruses in three cases have been reported to be the trigger in the development of fulminant type 1 diabetes. They were human herpes virus 6, herpes simplex virus and Coxsackie B3 virus. This is the fourth report of fulminant type 1 diabetes developed after the established diagnosis of viral infection and the first after influenza B virus infection. The fact that fulminant type 1 diabetes developed after the infection of such a common virus suggest that factors within host will play more important roles than virus itself in the etiology of fulminant type 1 diabetes.

Cblb Gene Analysis in Japanese Type 1 Diabetes with Younger Age of Onset.

To clarify the contribution of Cblb to the development of type1 diabetes (T1D), we investigated Japanese younger-onset T1D patients. We sequenced the cblb gene in 10 T1D patients and screened the identified mutations in 109 Japanese T1D patients and 100 normal subjects. In addition to four previously reported synonymous single nucleotide polymorphisms (SNPs), we identified two novel nonsynonymous variants (786 C>T (A155V) and 1718 A>G (N466D)). The A155V mutation was found in one subject with Basedow’s disease whose mother also carried both the mutation and Basedow’s disease. The N466D mutation was found in 6 T1D cases including a subject who was classified as fulminant T1D. We found no significant differences in the allele frequency of these SNPs among T1D and control subjects, suggesting that the contribution of cblb to the genetic susceptibility to T1D might not be high for Japanese younger–onset T1D.

Fulminant type 1 diabetes mellitus caused by drug hypersensitivity syndrome with human herpesvirus 6 infection

Drug hypersensitivity syndrome (DHS) is an idiosyncratic and life-threatening adverse drug reaction characterized by skin rash and multiorgan involvement. In rare cases, fulminant type1 diabetes mellitus (DM) may develop after DHS. Among proposed pathogenesis, human herpesvirus 6 (HHV-6) infections may play a role in the development of DHS. We report a case of DHS associated with HHV-6 reactivation, complicated with a rare sequela of irreversible fulminant type 1 DM. No diabetes-related autoantibodies were detected. Early detection and intervention for this serious complication should be given in patients with DHS. Fulminant type1 DM associated with DHS is reviewed. The role of HHV-6 in DHS associated with fulminant type 1 DM is also discussed.

High titres of IgA antibodies to enterovirus in fulminant type-1 diabetes

We have recently proposed that fulminant type-1 diabetes is a novel subtype of type-1 diabetes with abrupt onset of insulin-deficient hyperglycaemia without islet-related autoantibodies. The pathogenesis is still unknown, but flu-like symptoms are frequently observed before the onset of disease of this subtype. Enterovirus infection is a candidate environmental factor causing type-1 diabetes. The aim of this study was to determine whether enterovirus infection contributes to the development of fulminant type-1 diabetes. We investigated 19 patients with recent-onset fulminant type-1 diabetes, 18 patients with recent-onset typical type-1A diabetes, and 19 healthy controls. IgM, IgG, and IgA subclasses of antibodies to enterovirus were determined by ELISA. IgA antibody titres to enterovirus were significantly higher in fulminant type-1 diabetes than in typical type-1A diabetes (p=0.033) and controls (p=0.0003). IgM antibodies to enterovirus were not detected in any subject. IgG titres were lower in autoimmune diabetes than fulminant type and controls (p=0.014 and 0.019, respectively). High titres of enterovirus IgA antibodies in serum suggest recurrent enterovirus infection in fulminant type-1 diabetic patients, indicating higher susceptibility to enteroviral infections among them. Such infections might have pathogenetic importance in the triggering of fulminant type-1 diabetes.