Slow-onset Type Research Articles

4 years between diagnosis and insulin therapy in a case of slow onset type 1 diabetes mellitus

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Agricultural perspectives of climate change induced disasters in Doti, Nepal

Natural disasters are among the major risk factors in aggravating human and livestock lifes as well as agricultural production in most of the developing and poor countries. A community level survey was conducted in Doti district to assess the rural communities perception towards the disasters induced by climate change in agriculture and livestock production and productivity. Discussions with two focal groups, at village level and with district based stakeholders revealed that there is a conceptual difference between the perception of disasters at the government level and the farmers level. Most of the farmers have realized the major disasters of slow onset type (drought and famine) to be more common than the rapid onset type (landslides and floods). There has been a change in the cropping pattern with decreased winter rain and short monsoon rain. The local communities have suffered due to drought which has lead to fewer water holes for animals and less water for irrigation. Farmers have gradually decreased the number of larger ruminants like cattle and buffalo and are inclined towards smaller animals like sheep and goat. Animal diseases as well as insects-pests of crops are also on the rise.

The age of onset of diabetes and glutamic acid decarboxylase titer measured long after diagnosis are associated with the clinical stage of slow-onset type 1 diabetes

AimsDiabetes mellitus is divided into 3 clinical stages: not insulin requiring, insulin requiring for control, and insulin requiring for survival. We investigated the clinical characteristics of patients with slow-onset type 1 diabetes (T1D) to examine which clinical factors influence the clinical stage. MethodsOne hundred fifty patients with slow-onset T1D were divided into 3 groups based on disease stage, and clinical features were compared among these groups. The patients were also divided into 4 groups based on the age of onset and the glutamic acid decarboxylase antibody (GAD-Ab) titer, which was measured long after diagnosis (mean, 9.2 years). The frequencies of the 3 stages were compared among these 4 groups. ResultsThe age of onset and the log (GAD-Ab) titer differed significantly among the 3 stages. The number of patients not requiring insulin was significantly higher and the number of those requiring insulin for survival was significantly lower in the group in which the age of onset was ≥50 and the log (GAD-Ab) titer <0.6, while the opposite pattern was observed in the group in which the age of onset was <50 and the log(GAD-Ab) titer ≥0.6. ConclusionsOur results suggest that the combination of the age of onset and GAD-Ab titer measured long after diagnosis might predict the clinical stage of slow-onset T1D.

Susceptibility to Fatty Acid-Induced β-Cell Dysfunction Is Enhanced in Prediabetic Diabetes-Prone BioBreeding Rats: A Potential Link Between β-Cell Lipotoxicity and Islet Inflammation

β-Cell lipotoxicity is thought to play an important role in the development of type 2 diabetes. However, no study has examined its role in type 1 diabetes, which could be clinically relevant for slow-onset type 1 diabetes. Reports of enhanced cytokine toxicity in fat-laden islets are consistent with the hypothesis that lipid and cytokine toxicity may be synergistic. Thus, β-cell lipotoxicity could be enhanced in models of autoimmune diabetes. To determine this, we examined the effects of prolonged free fatty acids elevation on β-cell secretory function in the prediabetic diabetes-prone BioBreeding (dp-BB) rat, its diabetes-resistant BioBreeding (dr-BB) control, and normal Wistar-Furth (WF) rats. Rats received a 48-h iv infusion of saline or Intralipid plus heparin (IH) (to elevate free fatty acid levels ~2-fold) followed by hyperglycemic clamp or islet secretion studies ex vivo. IH significantly decreased β-cell function, assessed both by the disposition index (insulin secretion corrected for IH-induced insulin resistance) and in isolated islets, in dp-BB, but not in dr-BB or WF, rats, and the effect of IH was inhibited by the antioxidant N-acetylcysteine. Furthermore, IH significantly increased islet cytokine mRNA and plasma cytokine levels (monocyte chemoattractant protein-1 and IL-10) in dp-BB, but not in dr-BB or WF, rats. All dp-BB rats had mononuclear infiltration of islets, which was absent in dr-BB and WF rats. In conclusion, the presence of insulitis was permissive for IH-induced β-cell dysfunction in the BB rat, which suggests a link between β-cell lipotoxicity and islet inflammation.

ZnT8 and type 1 diabetes [Review

Zinc is essential for the proper storage, secretion, and the action of insulin and is transported from cytoplasm to insulin secretory granules in the pancreatic β-cells by SLC30A zinc transporters (ZnT). ZnT8 is specifically expressed in the pancreatic β-cells and has been identified as a novel target autoantigen in patients with type 1 diabetes. Autoantibodies to ZnT8 (ZnT8A) are detected in 50-60% of Japanese patients with acute-onset and 20% with slow-onset type 1 diabetes. Furthermore, humoral autoreactivity to ZnT8 is unique in terms of a key determinant, which is not reported on other islet autoantigens such as insulin, glutamic acid decarboxylase, or the protein tyrosine phosphatase-related molecules IA-2. Type 2 diabetes-associated nonsynonymous single nucleotide polymorphism in SLC30A8 (the gene of ZnT8), rs13266634 (Arg325Trp), modulates ZnT8A specificities thereby indicating that this amino acid substitution has the critical role in antibody binding. The humoral autoreactivity to ZnT8 depends on the clinical phenotype, which may provide clues to understand the role of this protein in the pathogenesis of type 1 diabetes.

Zinc transporter 8 autoantibodies in fulminant, acute‐onset, and slow‐onset patients with type 1 diabetes

The aim of this study was to determine the prevalence and role of autoantibodies to zinc transporter 8 (ZnT8A) in three forms (fulminant, acute-onset, and slow-onset) of Japanese patients with type 1 diabetes. One-hundred and ninety-six new-onset patients with type 1 diabetes were studied: 85 were fulminant, 81 acute-onset, and 30 slow-onset type 1 diabetes. ZnT8A were determined by radioimmunoassay using a hybrid ZnT8 carboxy-terminal construct (aa268-369) carrying 325Trp and 325Arg. Furthermore, ZnT8A epitopes were analysed using ZnT8 constructs incorporating the known aa325 variants (Trp, Arg, and Gln). ZnT8A were detected in 58% patients with acute-onset and 20% with slow-onset type 1 diabetes (p<0.0005). In contrast, none of sera from fulminant type 1 diabetes were reactive to ZnT8 construct. Conversion of Arg or Trp to Gln at aa325 abolished reactivity in 59% of patients with an age of onset>10 years, which was significantly higher than that in patients≤10 years of age (33%, p<0.05). These results suggest that ZnT8A are an additional useful marker for acute-onset type 1 diabetes, but not a diagnostic marker for fulminant type 1 diabetes, and ZnT8A epitope recognition is different according to the onset age.

Effect of human leukocyte antigen class II genes on insulin deficiency in slow-onset type 1 diabetes in the Japanese population

The aim of this study is to determine the contribution of human leukocyte antigen (HLA) class II genes to insulin deficiency in slow-onset type 1 diabetes (T1D). Our results suggest that the susceptibility conferred by HLA subtypes to slow-onset T1D differs between insulin-deficient patients and non-insulin-deficient patients.

Aggressive and devastating neuropathy: the consequence of untreated slow-onset type 1 diabetes

Though type 1 diabetes (T1D) is described to be a disease of acute onset, there is strong evidence for a period of subclinical hyperglycaemia leading up to diagnosis. We describe two clinical cases with a prolonged and insidious onset of T1D, where neurological complications were present at the time of diagnosis. In both, there was an initial rapid and debilitating progression in neurological as well as other microvascular complications, but with a subsequent stabilization in complications over the next few years. These rare and unusual cases illustrate the variable nature of the natural history of T1D as well as its microvascular complications.

Effect of human leukocyte antigen class II genes on acute-onset and slow-onset type 1 diabetes in the Japanese population

The contribution of the human leukocyte antigen (HLA) subtype to slow-onset type 1 diabetes (T1D), which includes latent autoimmune diabetes in adults (LADA), remains unclear in the Japanese population. We compared the frequencies of HLA DR-DQ haplotypes and genotypes of 72 acute-onset T1D patients, 100 slow-onset T1D patients, and 292 control subjects. The frequencies of DRB1*0405-DQB1*0401 (DR4) and DRB1*1302-DQB1*0604 (DR13) haplotypes were significantly higher in acute-onset patients, whereas that of the DRB1*1502-DQB1*0601 haplotype was significantly lower than those in slow-onset diabetes patients and controls. In contrast, DRB1*0802-DQB1*0302 (DR8) and DRB1*0901-DQB1*0303 (DR9) haplotypes were significantly more frequent, and the DRB1*1501-DQB1*0602 haplotype was extremely rare, in acute-onset patients and slow-onset diabetes patients. Genotype analysis revealed that DR4/9, DR4/13, and DR9/13 in acute-onset patients indicated high odds ratios (6.81, 12.0, and 15.6, respectively), whereas DR4/8 was significantly more frequent in slow-onset diabetes patients, but not in acute-onset patients. Our study demonstrated for the first time that the DR8 haplotype confers susceptibility to slow-onset T1D in the Japanese population. Moreover, there potentially are hierarchies for predisposing haplotypes, namely, DR13 > DR4 > DR9 > DR8 and for protective haplotypes, namely, DRB1*1501-DQB1*0602 > DRB1*1502-DQB1*0601.

Combination of HLA-A24, -DQA1*03, and -DR9 Contributes to Acute-Onset and Early Complete β-Cell Destruction in Type 1 Diabetes

To elucidate the genetic factors contributing to heterogeneity of the rate of beta-cell destruction in type 1 diabetes, we investigated the relationship between the time course of complete beta-cell loss and HLA class I and II alleles. HLA allele frequencies were also examined among subgroups classified by the mode of onset. The subjects were 266 type 1 diabetic patients (among whom 196 patients were studied longitudinally) and 136 normal control subjects. Earlier complete loss of beta-cell function was observed in patients who possessed both HLA-A24 and HLA-DQA1*03 and in patients who had HLA-DR9, compared with those without these HLA alleles (P=0.0057 and 0.0093, respectively). Much earlier complete beta-cell loss was observed in the patients who possessed all of HLA-A24, -DQA1*03, and -DR9 compared with the remaining patients (P=0.0011). The combination of HLA-A24, -DQA1*03, and -DR9 showed a higher frequency in acute-onset than slow-onset type 1 diabetes (P=0.0002). In contrast, HLA-DR2 was associated with a slower rate of progression to complete beta-cell loss. These results indicate that the combination of HLA-A24, -DQA1*03, and -DR9 contributes to the acute-onset and early complete beta-cell destruction, whereas HLA-DR2 has a protective effect against complete beta-cell loss in type 1 diabetes.

Systematic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): Association between a promoter polymorphism and type 1 diabetes in Asian populations

The protein tyrosine phosphatase, nonreceptor 22 gene (PTPN22) maps to human chromosome 1p13.3-p13.1 and encodes an important negative regulator of T-cell activation, lymphoid-specific phosphatase (Lyp). Recently, the minor allele of a single-nucleotide polymorphism (SNP) at nucleotide position 1858 (rs2476601, +1858C > T) was found to be associated with type 1 diabetes. However, the degree of the association is variable among ethnic populations, suggesting the presence of other disease-associated variants in PTPN22. To examine this possibility, we carried out a systemic search for PTPN22 using direct sequencing of PCR-amplified products in the Japanese population. Association and linkage studies were also conducted in 1,690 Japanese samples, 180 Korean samples, and 472 Caucasian samples from 95 nuclear families. We identified five novel SNPs, but not the +1858C > T SNP. Of these two frequent SNPs, -1123G > C, and +2740C > T were in strong linkage disequilibrium (LD), and the -1123G > C promoter SNP was associated with acute-onset but not slow-onset type 1 diabetes in the Japanese population (odds ratio [OR] = 1.42, 95% CI = 1.07-1.89, P = 0.015). This association was observed also in Korean patients with type 1 diabetes (Mantel-Haenszel chi2= 6.543, P = 0.0105, combined OR = 1.41 95% CI = 1.09-1.82). Furthermore, the affected family-based control (AFBAC) association test and the transmission disequilibrium analysis of multiplex families of European descent from the British Diabetes Association (BDA) Warren Repository indicated that the association was stronger in -1123G > C compared to +1858C > T. In conclusion, the type 1 diabetes association with PTPN22 is confirmed, but it cannot be attributed solely to the +1858C > T variant. The promoter -1123G > C SNP is a more likely causative variant in PTPN22.

Nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) P22 Phox C242T gene polymorphism in type 1 diabetes.

Type 1 diabetes is caused by the immune-mediated destruction of insulin-secreting pancreatic beta cells and is thought to be an autoimmune disease resulting from a complex interaction of genetic and environmental factors. In animal models of type 1 diabetes, macrophages and their products, superoxides, have central roles in the beta cell destruction, but in humans their roles remain unclear. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase produces superoxide in macrophages, and its essential component, p22 phox, is a critical enzyme for superoxide production. The C242T polymorphism in the p22 phox coding gene has been reported to be associated with reduced oxidase activity. We therefore investigated whether the p22 phox gene polymorphism affected the susceptibility to and clinical course of type 1 diabetes. We examined 287 Japanese type 1 diabetic patients and 425 unrelated nondiabetic subjects. In addition, we allocated the diabetic patients to the following three groups: (1) acute-onset type 1 diabetes with at least one autoantibody (GADA, IA-2, IAA); (2) acute-onset type 1 diabetes without autoantibodies; and (3) slow-onset type 1 diabetes with autoantibody. We could not find a significant difference in p22 phox genotype and T allele frequency between overall type 1 diabetic patients and control subjects. Regardless of the onset pattern and autoantibody positivity of type 1 diabetes, no difference in p22 phox genotype and T allele frequency was found among the groups. In conclusion, the p22 phox C242T gene polymorphism did not affect the susceptibility to and clinical course of Japanese type 1 diabetes.

Vitamin D receptor gene polymorphism affects onset pattern of type 1 diabetes.

Type 1 diabetes mellitus is recognized as a T-cell-mediated autoimmune disease. Vitamin D compounds are known to suppress T-cell activation by binding to the vitamin D receptor (VDR); and thus, VDR gene polymorphisms may be related to T-cell-mediated autoimmune diseases. We, therefore, investigated a VDR gene polymorphism in type 1 diabetes. We examined the VDR gene Bsm I polymorphism in 203 type 1 diabetic patients and 222 controls, and the association between the VDR gene polymorphism and type 1 diabetes and their onset pattern. We found a significantly higher frequency of B allele in type 1 diabetics overall, compared with controls (P = 0.0010). Moreover, there was a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls (P = 0.0002), whereas this difference was not observed between slow-onset type 1 diabetics and controls. Regardless of the existence of islet-associated autoantibody, we found a significant difference in B-allele frequency between acute-onset type 1 diabetics and controls. In conclusion, we found an association between a VDR gene polymorphism and acute-onset type 1 diabetes. Assessment of this VDR gene polymorphism may contribute to prediction of the onset pattern in individuals with a high risk of type 1 diabetes.

Islet autoantibodies in Latvian subjects with non-insulin-dependent diabetes mellitus: slow-onset type 1 diabetes or polyendocrine autoimmunity?

In Latvia diabetes mellitus is diagnosed using the WHO's clinical criteria; assays for the detection of autoantibodies are not available, and hence slowly progressive autoimmune diabetes is likely to be missed. Autoantibodies against glutamic acid decarboxylase (GAD65) and protein tyrosine phosphatase (IA-2) among patients with clinically diagnosed NIDDM identify group of patients with slow-onset type 1 diabetes or LADA. The aim of this study was to estimate the risk of polyendocrine autoimmunity among clinically diagnosed NIDDM patients from Latvia. One hundred NIDDM patients and 100 healthy controls were tested for GAD65 and IA-2 autoantibodies as well as 21-hydroxylase (21-OH) and tissue transglutaminase (TTG) antibodies by RIA assay. Age at onset was >or= 30 years, and duration of disease less than 5 years. Of 100 patients, 85 were on oral hypoglycemic agents and 15 were on insulin. Body mass index (BMI) under 19 was recorded in 1% (1 of 100 cases), while overweight (BMI > 25.5 in females and 27 in males) was documented in 45% (45 of 100 cases). GAD65 antibodies were found in 30 of 100 (30%) and IA-2 antibodies in 40 of 100 (40%) patients. Either GAD65 or IA-2 antibodies were found in 55 of 100 (55%). None of the patients carried antibodies against 21-OH and only 1 of 100 (1%) carried antibodies against TTG. From the results obtained in our study we conclude that in Latvian adult NIDDM subjects, islet autoantibodies identify groups of slow-onset type 1 diabetes but not polyendocrine autoimmunity.

Molecular Manipulation of Autoantibody Testing in Type 1 Diabetes: Two for One

Diabetes mellitus is an epidemic that, according to estimates, will have a prevalence of 5.4% of the global population by the year 2025 (1). The number of adults with diabetes in the world is expected to rise from 135 million in 1995 to 300 million by 2025. Although the majority of the escalation will be attributable to type 2 diabetes, the prevalence of type 1 diabetes is also increasing. Data pooled from 27 countries reveal that the incidence of type 1 diabetes is rising by 3% per year (2), predominantly in children and young adults. In addition, several studies report that ∼10% of type 2 diabetes patients have islet autoantibody markers of type 1 diabetes, which predict insulin dependency (3)(4). Because the number of patients classified with type 2 diabetes is 10- to 20-fold greater than those deemed to have type 1 diabetes, this group of possible slow-onset type 1 diabetes is likely to have a significant impact on the severity of the diabetes epidemic. Despite advances in diabetes treatment and monitoring that permit improved glycemic control, insulin therapy is inadequate to prevent patients from developing eye, kidney, nerve, and cardiovascular disease. Moreover, tight control, which cannot be achieved by all patients, is associated with a substantially increased risk of hypoglycemia (5). A desirable goal in the management of diabetes is to prevent the disease before clinical onset. Although several strategies aimed at prevention are under evaluation (6)(7), this will be attained only if type 1 diabetes can be diagnosed before the appearance of clinical manifestations of the disease. …

Early Phase of Juvenile IDDM–Environmental and Genetic Intervention–

AbstractThe clinical appearance in the early phase of two cases of juvenile IDDM detected by urine glucose screening are described. Their postprandial blood glucose and HbAj were maintained without insulin therapy for several months below 180 mg/dl and 8.7% respectively. At three and six months after diagnosis both cases became ketoacidotic and their glucose tolerance deteriorated with a marked decrease of postprandial serum CPR level.There was no high insulin requirement with low CPR level at the time of diagnosis in 12 such patients with the above mentioned slow onset type IDDM. The insulin requirement steadily increased and serum CPR decreased from 12 months after diagnosis. The so‐called honeymoon period was not observed in this group.However, at the time of diagnosis in 24 patients with typical abrupt onset IDDM, there was a high insulin dose requirement with a low level of postprandial CPR value followed by an early decline in the insulin requirement with a temporary increase of CRP value.HLA‐DR4 or DRW9 or both were more freqently observed in patients with abrupt onset type IDDM than in slow onset type IDDM. It may probably be that genetic background as well as environmental factors affect the clinical picture in the early phase of IDDM in children.