Slowly Progressive Insulin-dependent Diabetes Mellitus Research Articles

Update information on type 1 diabetes in children/adolescents and adults.

Update information on type 1 diabetes in children/adolescents and adults.

Development of slowly progressive insulin-dependent diabetes mellitus (SPIDDM) during the course of frequent relapsing nephrotic syndrome in a 14-year-old boy

Development of slowly progressive insulin-dependent diabetes mellitus (SPIDDM) during the course of frequent relapsing nephrotic syndrome in a 14-year-old boy

Current clinical state of type 1 diabetes in Saitama prefecture.

In Japan, epidemiologicalstudies on type 1 diabetes (T1D) have mainly focused on the disease in childhood. Meanwhile, limited information is available regarding the clinical features of adolescent and adult T1D. Therefore, we aimed to investigate their current clinical state in Saitama prefecture near Tokyo, Japan. We conducted a cross-sectional, hospital-based, multicenter study. Eight institutions participated in the study, all of which treated relatively large numbers of T1D patients. We identified 1241 T1D patients aged 16 or over: 814 with acute-onset T1D (AT1D), 362 with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), and 65 with fulminant T1D (FT1D). Based on the patient's medical records, various clinical parameters and complications were investigated. Of 1241 patients, 739 (59.5%) werefemales. Among all patients, the median age, onset age, and disease duration were 51, 38, and 13years, respectively. The patients had a median BMI of 22.6kg/m2, and 26.1% were obese, corroborating previous nationwide surveys. Moreover, the median HbA1c was 7.8%, similar to previous nationwide surveys. Among patients with AT1D, SPIDDM, and FT1D, 85.6%, 72.1%, and 81.5% carried out multiple daily insulin injection, respectively, while 10.3%, 2.2%, and 18.5% were subject to continuous subcutaneous insulin infusion. The proportions of retinopathy, nephropathy, and neuropathy were 26.3%, 20.8%, and 21.5%. The glycemic control in T1D patients in Saitama was equivalent to that observed in previous nationwide surveys. Moreover, approximately one-quarter of T1D patients had obesity. Future studies should address whether our findings reflect those throughout Japan. The online version contains supplementary material available at 10.1007/s13340-021-00557-8.

Significance of peripheral mononuclear cells producing interferon-γ in response to insulin B:9–23-related peptides in subtypes of type 1 diabetes

Type 1 diabetes is largely caused by β-cell destruction through anti-islet autoimmunity. Reportedly, interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) specific to four insulin B-chain amino acid 9–23-related peptides (B:9–23rPep) were increased in type 1 diabetes participants. This study aimed to investigate the PBMC frequencies in subtypes of type 1 diabetes using enzyme-linked immunospot assay. In this cross-sectional study, peripheral blood samples were obtained from 148 participants including 72 with acute-onset type 1 diabetes (AT1D), 51 with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), and 25 with type 2 diabetes. The frequency of B:9–23rPep-specific IFN-γ-producing PBMCs was significantly higher in AT1D participants than in SPIDDM and type 2 diabetes participants. Meanwhile, a significant inverse correlation was observed between the PMBC frequencies and insulin secretion capacity in SPIDDM participants. These findings suggest that the increased peripheral B:9–23rPep-specific IFN-γ immunoreactivity reflects decreased functional β-cell mass and greater disease activity of type 1 diabetes.

Distinct Inflammatory Changes of the Pancreas of Slowly Progressive Insulin-dependent (Type 1) Diabetes.

The aim of this study was to identify the distinct pathological changes on the endocrine and exocrine pancreas of slowly progressive insulin-dependent diabetes mellitus (SPIDDM) or latent autoimmune diabetes in adults. The pancreases from 12 islet autoantibody-positive SPIDDM patients and 19 age-matched subjects with no diabetes were examined histologically for islet inflammation/insulitis, expressions of cytokines, and enterovirus VP1 protein, exocrine pancreatic inflammation, pancreatic ductal changes, major histocompatibility complex class I hyperexpression, and amylin-positive amyloid in the islets. Insulitis dominant for CD8 T-cells and CD68 macrophages was observed in all SPIDDM cases irrespective of duration of diabetes and weight of residual beta cells. Major histocompatibility complex class I hyperexpression on residual beta cells was observed in SPIDDM. All SPIDDM exocrine pancreases showed extensive inflammation, dilated pancreatic ducts, and periductal fibrosis. As many as 75% (9/12) of pancreases had pancreatic intraepithelial neoplasia, which is assumed to be associated with ductal obstruction/narrowing and exocrine pancreatic inflammation, in SPIDDM. Amylin-positive amyloid deposition was not detected in SPIDDM. Persistent insulitis with preserved beta cells and major histocompatibility complex class I hyperexpression and exocrine pancreatic inflammation with pancreatic intraepithelial neoplasia are distinct histological features of SPIDDM pancreas.

Incidence of diabetes mellitus and neoplasia in Japanese short-statured children treated with growth hormone in the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS).

.The primary goal of the Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) was to assess the safety and effectiveness of Humatrope®, a GH preparation, in the treatment of pediatric patients with short stature. We report our findings in the GH-treated Japanese pediatric population focusing on the incidence of type 2 diabetes (T2D) and occurrence of neoplasms. A total of 2,345 Japanese patients were assessed for safety. During a mean observation period of 3.2 yr, T2D occurred in 3 patients (0.13%) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) related to underlying mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in 1 patient (0.04%). Neoplasms were reported in 13 patients (0.56%), including 1 patient with brain tumor (germinoma) and 5 with craniopharyngiomas (4 recurrences); the remainder were benign, typically dermatological, neoplasms. The incidence of diabetes mellitus determined in the study did not differ from previous reports in GH-treated pediatric patients, and there was no apparent increase in the risk of new neoplastic lesions or malignant tumors.

Urinary Glucose Screening for Early Detection of Asymptomatic Type 2 Diabetes in Jeonbuk Province Korean Schoolchildren.

This study aimed to investigate the prevalence of glucosuria and the characteristics of diabetes in schoolchildren as detected by a school urine glucose screening program implemented from 2010 to 2013 in the Jeonbuk province area of Korea. A total of 110 children without known diabetes were analyzed. They were checked with an oral glucose tolerance test (OGTT) with other laboratory tests and their clinical data were collected. A total of 707,238 schoolchildren from a school population of 1,064,999 were screened for glucosuria. In total, over a 4-year period, 545 schoolchildren (0.077%) were positive for glucosuria on the second urine test. The prevalence of glucosuria was more common among middle and high schoolchildren than among elementary schoolchildren. Among 110 students who completed the OGTT to confirm diabetes, 40 were diagnosed with diabetes mellitus (DM); 39 children, type 2 diabetes mellitus (T2DM) and 1 child, slowly progressive insulin dependent diabetes mellitus (SPIDDM). The mean annual incidence of diabetes was 5.6 per 100,000 schoolchildren and adolescents. The subjects with diabetes diagnosed through the urine screening test showed minimal or no symptoms of diabetes. The students with diabetes were more likely to be woman and obese, and they have a higher body mass index, higher cholesterol, triglyceride, insulin, C-peptide, and fasting glucosuria values than the students with normal glucose tolerance. We identified 40 new cases of diabetes in the Korean schoolchildren with asymptomatic glucosuria on urine glucose screening. This finding shows that school urine glucose screening is a feasible and simple method for early detection of asymptomatic T2DM.

Clinical, Endocrinological and Immunological Characteristics of Japanese Patients With Autoimmune Polyglandular Syndrome Type 3a

Background: Autoimmune polyglandular syndrome (APS) is an autoimmune disease that involves multiple organ failure. In APS3, autoimmune thyroid disease occurs with other autoimmune diseases, but not with Addison disease. APS3a is defined as APS3 including autoimmune diabetes. The information about clinical backgrounds of APS3a is very limited. We studied to understand clinical, endocrinological and immunological characteristics of Japanese patients with APS3a. Methods: We reviewed our previously published case reports about APS3a, and picked up patients with type 1 diabetes and autoimmune diabetes, who showed the positivity for anti-glutamic acid decarboxylase antibody (anti-GAD ab) or anti-islet antigen 2 antibody (anti-IA2 ab) or anti-thyroglobulin antibody (anti-TG ab) or anti-thyroid peroxidase antibody (anti-TPO ab) or anti-thyroid stimulating hormone receptor antibody (anti-TR ab) between January 2010 and January 2016. We collected data including age, sex, anti-GAD ab, anti-IA2 ab, HbA1c, serum fasting C-peptide immunoreactivity (CPR), urinary CPR, treatment for diabetes, anti-TPO ab, anti-TG ab, anti-TR ab, thyroid stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), findings of thyroid ultrasonography and treatment for thyroid diseases. Results: Present study revealed a remarkable female predominance in APS3a. Among patients with autoimmune diabetes, slowly progressive insulin-dependent diabetes mellitus (SPIDDM) was the most common type of diabetes, and almost 80% of patients with APS3a showed the positivity for anti-GAD ab. Among patients with autoimmune thyroid diseases, almost 80% of patients had possible Hashimoto thyroiditis. Almost 70% of patients with APS3a showed the positivity for anti-TPO ab. Almost 20% of APS3a patients had possible Grave’s disease, and 83% of patients with possible Grave’s disease showed overt Grave’s disease. In patients with possible Grave’s disease, the positive rate of anti-TR ab was 100%. Conclusion: We revealed clinical, endocrinological and immunological characteristics of patients with APS3a in Japan. J Endocrinol Metab. 2016;6(2):46-51 doi: http://dx.doi.org/10.14740/jem348e

A Case of Slowly Progressive Insulin-dependent Diabetes Mellitus (SPIDDM) with Low Anti-GAD Antibody Titer Detected during Treatment of Organizing Pneumonia

A Case of Slowly Progressive Insulin-dependent Diabetes Mellitus (SPIDDM) with Low Anti-GAD Antibody Titer Detected during Treatment of Organizing Pneumonia

Pathological changes in the pancreas of fulminant type 1 diabetes and slowly progressive insulin‐dependent diabetes mellitus (SPIDDM): innate immunity in fulminant type 1 diabetes and SPIDDM

The contribution of innate immunity responsible for beta-cell destruction in fulminant type 1 diabetes (FT1D) and slowly progressive insulin-dependent diabetes mellitus (SPIDDM) is unclear. Islet-cell expression of Toll-like receptors (TLRs) including TLR3 and TLR4, the cytoplasmic retinoic acid-inducible protein I (RIG-I)-like helicases, RIG-I, melanoma differentiation-associated gene-5 and laboratory of genetics and physiology 2 in the affected islets were studied immuno-histochemically on three pancreases obtained 2-5 days after the onset of FT1D and a pancreas from a patient with SPIDDM. Laboratory of genetics and physiology 2 and RIG-I strongly expressed in beta cells in all three FT1D pancreases infected with enterovirus (VP1 antigen). Melanoma differentiation-associated gene-5 was hyper-expressed in all subsets of islet cells including beta cells and alpha cells. TLR3 and TLR4 were expressed in mononuclear cells that infiltrated to islets. IFN-alpha/beta was strongly expressed in islet cells. In contrast, pancreas of a patient with SPIDDM, enterovirus and expression of innate immune receptors including RIG-I, melanoma differentiation-associated gene-5, hyperexpression of laboratory of genetics and physiology 2 and mononuclear cells, which were positive for TLR3 and TLR4, and infiltration to the islets were not detected. These findings demonstrate that retinoic acid-inducible protein I (RIG-I)-like helicases and TLRs play a crucial role on beta-cell destruction in enterovirus-induced FT1D. The presence of distinct mechanism(s) of slowly progressive beta-cell failure in SPIDDM was suggested.

Slowly Progressive Insulin-dependent Diabetes Mellitus Associated with Pernicious Anemia

A 59-year-old man was found to have diabetes mellitus five months after the diagnosis of pernicious anemia. Although the urinary C-peptide level corresponded to a non-insulin-dependent stage (39.9 microg/day), the markedly extremely elevated titers of GAD antibody suggested that this case very likely represented a non-insulin-dependent stage of slowly progressive insulin-dependent diabetes mellitus (SPIDDM). Because thyroid and adrenal functions were normal, this our case was not considered to be polyglandular autoimmune syndrome (PGAS). We report this case because patients with pernicious anemia and SPIDDM in the absence of PGAS are rare in Japan.

Autoimmune polyglandular syndrome type 3 complicated by mineralocorticoid-responsive hyponatremia of the elderly

We experienced the first case with autoimmune polyglandular syndrome type 3 (anti-thyroid peroxidase antibody-positive hypothyroidism and anti-glutamic acid decarboxylase antibody-positive diabetes) complicated by mineralocorticoid-responsive hyponatremia of the elderly. This case is also a rare slowly progressive insulin-dependent diabetes mellitus (SPIDDM) case, for which the patient has been treated for many years with sulfonylurea or glinide. Our observation also demonstrated that glucose metabolism in autoimmune diabetes such as SPIDDM is influenced by appetite, thyroid function and glucocorticoid effect.

Latent autoimmune diabetes in adults: the search for interventions continues

This Practice Point commentary discusses the findings of a study by Maruyama et al., in which treatment with insulin was compared to sulfonylurea in 60 patients with slowly progressive insulin-dependent diabetes mellitus (SPIDDM), a presumed form of latent autoimmune diabetes in adults (LADA). Patients who received insulin had a lower rate of progression to insulin dependency than patients who received sulfonylurea (10% versus 43%, P = 0.003). Here, I review the history of LADA and the current approach to diagnosis and treatment. Diagnosis of LADA is generally by the detection of glutamic acid decarboxylase antibodies in adults who present with the clinical features of type 2 diabetes mellitus, providing presumptive evidence of autoimmunity. Treatment of LADA is usually with insulin, an approach supported by the findings of the study. Nonetheless, some evidence suggests that sulfonylurea actually accelerates loss of β-cell function. Whether this effect had a role in the results obtained by the Maruyama et al. is not yet clear.

Immunopathological and Genetic Features in Slowly Progressive Insulin‐Dependent Diabetes Mellitus and Latent Autoimmune Diabetes in Adults

In 1982 we proposed the presence of a subtype of type 1 diabetes [slowly progressive insulin-dependent diabetes mellitus (SPIDDM)], which was characterized by persistently positive islet cell antibody, late age of onset, noninsulin-dependent diabetes, and slowly progressive beta cell failure. Since then many studies demonstrated that this subtype of type 1 diabetes is prevalent in many ethnic groups and was later called the latent autoimmune diabetes in adults (LADA). Recent epidemiological studies reported that about 10% of patients with apparent type 2 diabetes have at least one autoantibodies against islet-specific antigen with high potential to progress to insulin-dependent state. Between SPIDDM and LADA some differences are reported in terms of some genetic predispositions including HLA class II and class I genes, vitamin D receptor gene, and CTLA4 genes. Common features in SPIDDM and LADA including preserved beta cells at the onset of diabetes and weak T cell response to residual beta cells suggest that these subtypes of type 1 diabetes are suitable candidates for prevention treatment for further progression of beta cell failure.

Thiazolidinediones May Not Reduce Diabetes Incidence in Type 1 Diabetes

Thiazolidinediones improve glycemic control by reducing insulin resistance. Some studies have demonstrated that troglitazone had a preventative effect on diabetes in NOD (non-obese diabetic) mice. One of the mechanisms proposed for the prevention of diabetes by thiazolidinediones is an effect on T-helper 1/T-helper 2 (Th1/Th2) balance. In this article, we attempted to clarify whether pioglitazone is also effective in preventing diabetes as compared to metformin, which has no immunological effect. Female NOD mice were administered pioglitazone or metformin orally, and the insulitis score, cytokines secreted from splenocytes, cytokine expression levels in the pancreas, and the incidence of diabetes after acceleration by cyclophosphamide were analyzed. We could not find any advantage of pioglitazone in preventing Th1 skewing and the development of diabetes over metformin. Therefore, further research should take place before the application of thiazolidinediones to human slowly progressive insulin-dependent diabetes mellitus (SPIDDM) patients.

Measurement of GAD Antibody and HLA Antigens in Classification of Diabetes

Since acute-onset insulin-dependent diabetes mellitus (IDDM) usually demonstrates a greater number of HLA antigens related to IDDM than slowly progressive IDDM (SPIDDM), the type of diabetes may be affected by a dosage effect of HLA antigens. The purpose of this study is to elucidate the dosage effect of HLA antigens in modifying the type of diabetes. We assayed antibodies to glutamic acid decarboxylase (GADab) in 253 non-insulin-dependent diabetes mellits (NIDDM) patients and 17 IDDM patients. We assayed HLA antigens (class I A, B, C antigens, class II DR, DQ antigens) in 7 of 8 GADab-positive NIDDM patients and 3 GADab-positive acute-onset IDDM patients, whose disease etiologies may be related to the background of autoimmunity. We tried to score the association of HLA antigens with IDDM as positive or negative in each patient. If the patients had one HLA antigen related to IDDM, they were given one point. If they had one HLA antigen showing a negative association with IDDM, one point was subtracted from the score. HLA scores of GADab-positive patients with NIDDM tended to have a lower score, but exceptionally there were a few higher HLA scores among NIDDM patients. Both GADab-positive and negative IDDM patients tended to have higher HLA scores.Our results suggest that measurement of HLA antigens as well as GADab can be of clinical value in predicting the type of diabetes. Moreover, it may be possible to detect patients who should receive insulin during the early stage of GADab-positive NIDDM.