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Unique pathological changes in the pancreas of fulminant type 1 diabetes.

ABSTRACT: Distinct features of the pancreas of fulminant type 1 diabetes (FT1DM) include (1) enterovirus infection of the islets and exocrine acinar tissue. (2) Activated innate immune responses: MDA5 and RIG-I expression and TLR4 and TLR9 expression in the islets of FT1DM. (3) Combined activation of the STAT/JNK and NFkB pathways, resulting in Type I interferon (IFN) and proinflammatory cytokine (i.e., IFNγ) expression in islet beta cells and MHC class I hyper-expression. (4) Activation of dendritic cells followed by effector cell infiltration of CD8⁺ T cells and CD68⁺ macrophages, resulting in apoptosis and neurosis of islet cells and exocrine acinar cells. (5) Many chemo-attractants (i.e., CXCL10) and chemotactic activators (i.e., l-plastin) were induced by a viral infection. (6) Mutual stimulating effect of cytokines expressed in beta cells in autocrine and paracrine mechanisms may enhance beta-cell destruction through the STA1-caspase pathway. (7) Proteomics analysis using laser capture microdissection followed by mass spectrometry found 38 molecules in inflamed islets of FT1DM, which were not highlighted before. Our pathologically verified model of beta-cell destruction in FT1DM will contribute to anti-virus therapy of type 1 diabetes in the near future.

SUBMITTER: Kobayashi T

PROVIDER: S-EPMC7538509 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Genetics of fulminant type 1 diabetes.

Project description:Since fulminant type 1 diabetes was reported as a distinct subtype of type 1 diabetes in 2000, the Committee on Type 1 diabetes, Japan Diabetes Society has continuously recruited patients and conducted genomic research to elucidate the genetic basis of fulminant type 1 diabetes. The contribution of the human leukocyte antigen complex (HLA) to genetic susceptibility to fulminant type 1 diabetes was compared with that of other subtypes in 2009. The alleles and haplotypes associated with fulminant type 1 diabetes were found to be different from acute-onset and slowly progressive type 1 diabetes. DRB1*15:01-DQB1*06:02, a protective haplotype against acute-onset type 1 diabetes, does not provide protection against fulminant type 1 diabetes and DRB1*08:02-DQB1*03:02, a susceptible haplotype to acute-onset type 1 diabetes, does not confer susceptibility to fulminant type 1 diabetes. Recently, the first genome-wide association study (GWAS) of fulminant type 1 diabetes was performed in Japanese individuals. A strong association was observed with multiple single nucleotide polymorphisms (SNPs) in the HLA region, and the strongest association was observed with rs9268853 in the class II DR region. In addition, 11 SNPs outside the HLA region showed some evidence of association with the disease. In particular, rs11170445 in CSAD/lnc-ITGB7-1 on chromosome 12q13.13 showed an association at a genome-wide significance level. Fine mapping revealed that rs3782151 in CSAD/lnc-ITGB7-1 showed the lowest P value. CSAD/lnc-ITGB7-1 was found to be strongly associated with susceptibility to fulminant, but not classical, autoimmune type 1 diabetes, implicating this locus in the distinct phenotype of fulminant type 1 diabetes.

| S-EPMC7538480 | biostudies-literature

Gene expression Fulminant type 1 diabetes vs classical type 1A diabetes

2014-01-01 | GSE44313 | GEO

Gene expression Fulminant type 1 diabetes vs classical type 1A diabetes

Project description:We determined the genes that were differentially expressed between fulminant type 1 diabetes and classical type 1A diabetes using gene expression microarray in peripheral blood cells. Ten patients with type 1 diabetes (5 fulminant and 5 classical type 1A) were enrolled in this study. All patients had recovered from ketosis or ketoacidosis at disease onset and had been receiving intensive insulin injection therapy for at least 1 month, which means that all patients and healthy controls were free of metabolic derangements at the time of blood sampling. To determine the genes that were differentially expressed between classical type 1A and fulminant type 1 diabetes, a volcano plot analysis (fold change >1.5 and p-value <0.05) was performed.

2014-01-01 | E-GEOD-44313 | biostudies-arrayexpress

Proteomic Analysis of Disease Stratified Human Pancreas Tissue Indicates Unique Signature of Type 1 Diabetes.

Project description:Type 1 diabetes (T1D) and type 2 diabetes (T2D) are associated with functional beta cell loss due to ongoing inflammation. Despite shared similarities, T1D is an autoimmune disease with evidence of autoantibody production, as well as a role for exocrine pancreas involvement. Our hypothesis is that differential protein expression occurs in disease stratified pancreas tissues and regulated proteins from endocrine and exocrine tissues are potential markers of disease and potential therapeutic targets. The study objective was to identify novel proteins that distinguish the pancreas from donors with T1D from the pancreas from patients with T2D, or autoantibody positive non-diabetic donors. Detailed quantitative comprehensive proteomic analysis was applied to snap frozen human pancreatic tissue lysates from organ donors without diabetes, with T1D-associated autoantibodies in the absence of diabetes, with T1D, or with T2D. These disease-stratified human pancreas tissues contain exocrine and endocrine tissues (with dysfunctional islets) in the same microenvironment. The expression profiles of several of the proteins were further verified by western blot. We identified protein panels that are significantly and uniquely upregulated in the three disease-stratified pancreas tissues compared to non-disease control tissues. These proteins are involved in inflammation, metabolic regulation, and autoimmunity, all of which are pathways linked to, and likely involved in, T1 and T2 diabetes pathogenesis. Several new proteins were differentially upregulated in prediabetic, T1D, and T2D pancreas. The results identify proteins that could serve as novel prognostic, diagnostic, and therapeutic tools to preserve functional islet mass in Type 1 Diabetes.

| S-EPMC4547762 | biostudies-literature

gene expression Fulminant type 1 diabetes vs classical type 1A diabetes vs healthy controls

2014-01-01 | GSE44314 | GEO

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

Project description:OBJECTIVE: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

| S-EPMC6143218 | biostudies-literature

gene expression Fulminant type 1 diabetes vs classical type 1A diabetes vs healthy controls

Project description:We determined the genes that were differentially expressed between fulminant type 1 diabetes and classical type 1A diabetes or healthy control using gene expression microarray in peripheral blood cells. Ten patients with type 1 diabetes (5 fulminant and 5 classical type 1A) and 6 healthy controls were enrolled in this study. All patients had recovered from ketosis or ketoacidosis at disease onset and had been receiving intensive insulin injection therapy for at least 1 month, which means that all patients and healthy controls were free of metabolic derangements at the time of blood sampling. To determine the genes that were differentially expressed among fulminant type 1 diabetes, classical type 1A and healthy controls, a volcano plot analysis (fold change >1.5 and p-value <0.05) was performed.

2014-01-01 | E-GEOD-44314 | biostudies-arrayexpress

Integrative Analyses of Genes Associated with Fulminant Type 1 Diabetes.

Project description:ObjectiveFulminant type 1 diabetes (FT1D) is a type of type 1 diabetes, which is characterized by rapid onset of disease and severe metabolic disorders. We intend to screen for crucial genes and potential molecular mechanisms in FT1D in this study.MethodWe downloaded GSE44314, which includes six healthy controls and five patients with FT1D, from the GEO database. Identification of differentially expressed genes (DEGs) was performed by NetworkAnalyst. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of DEGs were screened by an online tool-Database for Annotation, Visualization, and Integration Discovery (DAVID). Protein-protein interaction (PPI) network and hub genes among DEGs were analyzed by NetworkAnalyst. And we also use NetworkAnalyst to find out the microRNAs (miRNAs) and transcription factors (TFs) which regulate the expression of DEGs.ResultWe identified 130 DEGs (60 upregulated and 70 downregulated DEGs) between healthy controls and FT1D patients. GO analysis results revealed that DEGs were mostly enriched in generation of precursor metabolites and energy, neurohypophyseal hormone activity, and mitochondrial inner membrane. KEGG pathway analysis demonstrated that DEGs were mostly involved in nonalcoholic fatty liver disease. Results indicated that NCOA1, SRF, ERBB3, EST1, TOP1, UBE2S, INO80, COX7C, ITGAV, and COX6C were the top hub genes in the PPI network. Furthermore, we recognized that LDLR, POTEM, IFNAR2, BAZ2A, and SRF were the top hub genes in the miRNA-target gene network, and SRF, TSPAN4, CD59, ETS1, and SLC25A25 were the top hub genes in the TF-target gene network.ConclusionOur study pinpoints key genes and pathways associated with FT1D by a sequence of bioinformatics analysis on DEGs. These identified genes and pathways provide more detailed molecular mechanisms of FT1D and may provide novel therapeutic targets.

| S-EPMC7559223 | biostudies-literature

Dietary Changes During COVID-19 Lockdown in Adults With Type 1 Diabetes on a Hybrid Artificial Pancreas.

Project description:In this retrospective analysis, we examine the impact of the lockdown of the coronavirus pandemic (COVID-19) on eating habits in individuals with type 1 diabetes (T1D) on a hybrid artificial pancreas (HAP). Dietary composition before and during lockdown was assessed by 7-day food records of 12 participants with T1D on HAP (three men and nine women, ages 38 ± 13 years, HbA1c 6.8 ± 0.3%, M ± SD). Continuous glucose monitoring (CGM) metrics and lifestyle changes (online questionnaire) were also assessed. Compared to prelockdown, reported body weight tended to increase during lockdown with no changes in total energy intake. Participants significantly decreased animal protein intake (-2.1 ± 3.7% of total energy intake, p = 0.048), but tended to increase carbohydrate intake (+17 ± 28 g/day, p = 0.052). These changes were induced by modifications of eating habits at breakfast and lunch during weekdays. Patients consumed more cereals (+21 ± 33 g/day, p = 0.038), whole grain (+22 ± 32 g/day, p = 0.044), and sweets (+13 ± 17 g/day, p = 0.021), and less animal protein sources (-42 ± 67 g/day, p = 0.054). Participants showed a more regular meal timing and decreased physical activity. Blood glucose control remained optimal (time-in-range 76 ± 8 vs. 75 ± 7% before lockdown), and daily total insulin infusion increased (42 ± 10 vs. 39 ± 12 I.U., p = 0.045). During the lockdown, patients with T1D on HAP modified dietary habits by decreasing animal protein and increasing carbohydrate intake. This increase, mainly concerning whole grain and low-glycemic-index products, did not influence blood glucose control.

| S-EPMC8578275 | biostudies-literature

Progression of gestational diabetes mellitus to pregnancy-associated fulminant type 1 diabetes: a case report.

Project description:Pregnancy-associated fulminant type 1 diabetes (PF) occurs during pregnancy or within 2 weeks of delivery. Although it occurs infrequently, it is associated with high fetal mortality rate. Few studies have examined whether PF is associated with gestational diabetes mellitus (GDM). A 29-year-old woman diagnosed with GDM at 24 weeks of gestation developed a fever, sore throat, nausea and vomiting at 29 weeks of gestation. Ketoacidosis was considered based on her blood ketone and glucose levels and the results of a blood gas analysis. Since the patient's islet function declined rapidly, fluid replacement, insulin therapy, and other treatments were administered. The patient was ultimately diagnosed with PF, and has required ongoing insulin therapy. She delivered a healthy baby girl by elective cesarean section at 37-week gestation. Her blood glucose has been satisfactorily controlled over the 12 months since her acute presentation. PF is characterized by poor maternal and infant outcomes and a high stillbirth rate. Blood glucose should be regularly monitored in pregnant women with GDM. A sudden increase in blood glucose may indicate the possibility of PF, which needs to be managed in a timely manner to avoid adverse pregnancy outcomes.

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