Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Celiac disease (CD) is a complex inflammatory disorder of the small intestine, induced by dietary gluten in genetically susceptible individuals. CD is strongly associated with HLA-DQ2 and it has recently been established that gut-derived DQ2-restricted T cells from patients with CD predominantly recognize gluten-derived peptides in which specific glutamine residues are deamidated to glutamic acid by tissue transglutaminase. Recently, intestinally expressed human genes with high homology to DQ2-gliadin celiac T-cell epitopes have been identified. Single or double point mutations which would increase the celiac T-cell epitope homology, and mutation in these genes, leading to the expression of glutamic acid at particular positions, could hypothetically be involved in the initiation of CD in HLA-DQ2-positive children. Six gene regions with high celiac T-cell epitope homology were investigated for single-nucleotide polymorphisms using direct sequencing of DNA from 20 CD patients, 27 type 1 diabetes mellitus (T1DM) patients with associated CD, 24 patients with T1DM without CD and 110 healthy controls, all of Caucasian origin. No variants in any of these genes in any of the investigated groups were found. We conclude that gut-expressed human celiac epitope homologous peptides are unlikely to represent non-HLA risk factors in the development of celiac disease in Caucasians.
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PMID:No allelic variation in genes with high gliadin homology in patients with celiac disease and type 1 diabetes. 1530 43

Haplotype blocks characterized from 78 single-nucleotide polymorphisms (SNPs) in a 1- to 2-centiMorgan region in the human diabetes susceptibility gene IDDM17 were tested for association with type 1 diabetes mellitus (T1DM). Two haplotypes in two adjacent blocks in AMACO, a von Willebrand factor homologue, appear to be associated with the absence of T1DM; transmission tests support this hypothesis. Interestingly, in both haplotype blocks, a single SNP distinguishes the protective haplotype from the other haplotypes. One SNP is noncoding, whereas the other SNP causes a change from glutamic acid to glycine. Future work in identifying the protective allele includes association tests of block haplotypes in other populations.
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PMID:IDDM17: polymorphisms in the AMACO gene are associated with dominant protection against type 1A diabetes in a Bedouin Arab family. 1569 9

Prevention of type 1 diabetes mellitus requires early intervention in the autoimmune process directed against beta cells of the pancreatic islets of Langerhans. This autoimmune inflammatory process is thought to be caused by the effect of Th1 cells and their secreted cytokines (e.g. interferon) and to be suppressed by Th2-secreted anti-inflammatory cytokines (e.g. IL-4, IL-10). Various methods aimed specifically at halting or modulating this response have been attempted. An alternative method is the re-induction of tolerance towards the putative self antigen that causes the disease. Proposed antigens such as insulin, glutamic acid decarboxilase (GAD) and the heat shock protein 60 (Hsp60)-derived peptide 277 have been used successfully in murine diabetes models and in initial clinical trials in early diabetes patients. Here, we review the results of these trials.
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PMID:Immune modulation for prevention of type 1 diabetes mellitus. 1573 55

Islet transplantation for type 1 diabetes can enable the achievement of near-normal glycemic control without severe hypoglycemic episodes. How much an islet (beta-cell) graft may be contributing to glycemic control can be quantified by stimulatory tests of insulin (or C-peptide) secretion. Glucose-potentiation of arginine-induced insulin secretion provides a measure of functional beta-cell mass, the beta-cell secretory capacity, as either AIR(pot) or AIR(max), but requires conduct of a hyperglycemic clamp. We sought to determine whether acute insulin responses to intravenous glucose (AIR(glu)) or arginine (AIR(arg)) could predict beta-cell secretory capacity in islet recipients. AIR(arg) was a better predictor of both AIR(pot) and AIR(max) (n=10, r2=0.98, P<0.0001 and n=7, r2=0.97, P<0.0001) than was AIR(glu) (n=9, r2=0.78, P=0.002 and n=6, r2=0.76, P=0.02). Also, the measures of beta-cell secretory capacity were highly correlated (n=7, r2=0.98, P<0.0001). These results support the use of AIR(arg) as a surrogate indicator of beta-cell secretory capacity in islet transplantation.
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PMID:Acute insulin responses to glucose and arginine as predictors of beta-cell secretory capacity in human islet transplantation. 1804 22

The risk determinants of type 1 diabetes, initiators of autoimmune response, mechanisms regulating progress toward beta cell failure, and factors determining time of presentation of clinical diabetes are poorly understood. We investigated changes in the serum metabolome prospectively in children who later progressed to type 1 diabetes. Serum metabolite profiles were compared between sample series drawn from 56 children who progressed to type 1 diabetes and 73 controls who remained nondiabetic and permanently autoantibody negative. Individuals who developed diabetes had reduced serum levels of succinic acid and phosphatidylcholine (PC) at birth, reduced levels of triglycerides and antioxidant ether phospholipids throughout the follow up, and increased levels of proinflammatory lysoPCs several months before seroconversion to autoantibody positivity. The lipid changes were not attributable to HLA-associated genetic risk. The appearance of insulin and glutamic acid decarboxylase autoantibodies was preceded by diminished ketoleucine and elevated glutamic acid. The metabolic profile was partially normalized after the seroconversion. Autoimmunity may thus be a relatively late response to the early metabolic disturbances. Recognition of these preautoimmune alterations may aid in studies of disease pathogenesis and may open a time window for novel type 1 diabetes prevention strategies.
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PMID:Dysregulation of lipid and amino acid metabolism precedes islet autoimmunity in children who later progress to type 1 diabetes. 1907 94

The purpose of this study was to evaluate pharmacokinetic and pharmacodynamic profiles of pure insulin aspart and three different formulations of insulin aspart and protaminated insulin aspart: biphasic insulin aspart 30 (BIAsp30), biphasic insulin aspart 50 (BIAsp50) and biphasic insulin aspart 70 (BIAsp70). Nineteen type 1 diabetes patients received individually identical doses of the four different insulin aspart preparations on 4 separate days in this randomized crossover study. Having achieved overnight stable blood glucose control by intravenous infusions of human insulin, one of the trial insulins was injected subcutaneously and a standard meal was given in the morning. Plasma glucose and serum insulin aspart were recorded the following 12 hr. During the first 4 hr after injection with the trial insulin, the area under the curve for levels of insulin aspart (AUC(ins)) was significantly higher during insulin aspart treatment as compared to the other three insulin treatments, followed by BIAsp70, BIAsp50 and BIAsp30 (P < 0.05). Over the last 4 hr, the AUC(ins) for BIAsp30 was significantly higher as compared to the other insulin preparations (P < 0.05). By contrast, during the initial 4 hr, the area under the curve for levels of glucose (AUC(glu)) was highest after injection with BIAsp30 compared to the other three treatments (P < 0.05), while during the last 4 hr the highest AUC(glu) was seen following insulin aspart (P < 0.05). We conclude that when insulin aspart is pure or formulated with protamine in three different ratios, the pharmacokinetic profiles are readily distinguishable. These differences in pharmacokinetics are reflected in the pharmacodynamic profiles.
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PMID:A comparison of pharmacokinetics and pharmacodynamics of biphasic insulin aspart 30, 50, 70 and pure insulin aspart: a randomized, quadruple crossover study. 1917 69

The proline-, glutamic acid-, serine- and threonine-rich (PEST) family of protein tyrosine phosphatases (PTPs) includes proline-enriched phosphatase (PEP)/lymphoid tyrosine phosphatase (LYP), PTP-PEST, and PTP-hematopoietic stem cell fraction (HSCF). PEP/LYP is a potent inhibitor of T-cell activation, principally by suppressing the activity of Src family protein tyrosine kinases (PTKs). This function seems to be dependent, at least in part, on the ability of PEP to bind C-terminal Src kinase (Csk), a PTK also involved in inactivating Src kinases. Interestingly, a polymorphism of LYP in humans (R620W) is a significant risk factor for autoimmune diseases including type 1 diabetes, rheumatoid arthritis, and lupus. The R620W mutation may be a 'gain-of-function' mutation. In non-hematopoietic cells, PTP-PEST is a critical regulator of adhesion and migration. This effect correlates with the aptitude of PTP-PEST to dephosphorylate cytoskeletal proteins such as Cas, focal adhesion associated-kinase (FAK), Pyk2, and PSTPIP. While not established, a similar function may also exist in immune cells. Additionally, overexpression studies provided an indication that PTP-PEST may be a negative regulator of lymphocyte activation. Interestingly, mutations in a PTP-PEST- and PTP-HSCF-interacting protein, PSTPIP1, were identified in humans with pyogenic sterile arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome and familial recurrent arthritis, two autoinflammatory diseases. These mutations abrogate the ability of PSTPIP1 to bind PTP-PEST and PTP-HSCF, suggesting that these two PTPs may be negative regulators of inflammation.
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PMID:PEST family phosphatases in immunity, autoimmunity, and autoinflammatory disorders. 1929 Sep 36

In this study, we compared the rate of insulin requirement among adults with type 1 diabetes (T1D) in 24 Ukrainian regions. The glutamic acid decaroxylase 65 antibody (GADA), insulin antibody (IA), and plasma c-peptide levels were investigated. The data included the prevalent cases of T1D in Ukraine at the end of 2006. Only persons aged over 14 years at the time of inclusion into the Ukrainian register and diagnosed with diabetes before 30 years of age were included in this study (n=26796). A total of 86 T1D patients (42 males; 44 females) with a mean age of 27.5 years (0.86) and a mean diabetes duration of 10.3 (0.72) years (SE), were randomly selected from four regional diabetes registers. The GADA, IA, and the plasma c-peptide levels were also determined. The logistic regression model was used, and the odds ratio (OR) and 95% confidence interval (CI) were calculated. Furthermore, the differences in the T1D prevalence among the 24 Ukrainian regions were obtained (p<0.001). In the "minimal" regional cluster (MIC), the prevalence rate was 6 (5-6), and in the "maximal" (MAC) regional cluster, it was -9 (8-9) per 10000 adults. For patients with a disease duration (DD) of up to 15 years (n=13677), the daily insulin dose (DID) was observed to increase linearly with DD (R=0.899, p<0.001). The median insulin doses were standardized according to DD, and the values were lowest in the MIC and highest in the MAC populations: 45.89 (45.28-47.19) and 56.59 (53.33-57.88) U/24 h, respectively (p<0.01). Furthermore, the level of HbA1c in the MAC of T1D patients was observed to be higher than that in the MIC (9.52+/-2.24%, n=240, and 8.57+/-3.29%, n=111, respectively; p<0.01). In addition, the GADA levels and persistence in the MAC patients (n=38) were higher than that in the MIC patients (n=48): 14.1+/-4.6 and 3.2+/-1.2 U/ml, respectively, mean+/-SE; p=0.028; OR=9.66 (3.31-28.17), p<0.001. Adjusting for age, gender, and duration of diabetes affected the results only slightly. Furthermore, the IA and c-peptide levels and their persistence were not observed to be associated with TD1 prevalence.
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PMID:Correlation between the prevalence of type 1 diabetes with the daily insulin dose and the autoimmune process against glutamic acid decarboxylase in adults. 1978 23

Immunomodulatory strategies in the management of type 1 diabetes mellitus (T1DM) have as their primary target the prevention of initiating islet autoimmunity (primary-), the secondary one is the progression to diabetes (secondary-) in non-diabetic persons at risk, and the decline of beta-cell function in new-onset patients (tertiary-prevention). This article reviews four recent immunointervention trials in patients with T1DM. (1) The Pre-POINT study is a primary prevention trial that will test whether vaccination with oral or nasal insulin can prevent the progression of islet autoimmunity and of T1DM in autoantibody-negative children who are genetically at high diabetes risk. (2) The Cord Blood study is a tertiary immunointervention trial that will test whether administration of autologous umbilical cord blood to children with T1DM can lead to regeneration of pancreatic islet insulin-producing beta-cells and improved blood glucose control. (3) The GAD Vaccination study will test whether vaccination with alum-formulated rhGAD65 (recombinant human glutamic acid decarboxylate) can preserve beta-cell function in 320 children with newly diagnosed T1DM, as has been suggested in a recent phase II study. (4) The AIDA study will test the beta-cell protective effect of interleukin-1-receptor antagonist Anakinra in 80 patients with T1DM, which has recently been shown to improve beta-cell function in patients with type 2 diabetes.
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PMID:[Survey of recent clinical trials of the prevention and immunointervention of type 1 diabetes mellitus]. 2016

Type 1 diabetes mellitus (DM1) is an autoimmune disease characterized by a lack of insulin production by beta pancreatic cells. Immunological mechanisms play a key role in DM1 physiopathology, even in asymptomatic patients where different autoantibodies directed against several components of beta cells have been found. The human leucocitary antigen, islet cells autoantibodies, insulin autoantibodies, glutamic acid decarboxilase autoantibodies and the rapid intravenous glucose tolerance test can be used to identify individuals with high risk for developing DM1. Ganglioside GM2-1 and the tyrosine phosphatase enzyme (IA2/ICA512) antigens determination are also employed to assess DM1 individual risk. This risk is significantly higher when three or four autoantibodies are found. Nowadays, the islet cell autoantibodies are employed as markers for DM1. This work analyzes the immunological aspects related to DM1, and highlights recent developments in this field.
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PMID:[Mechanism of immunological injury in type 1 diabetes]. 2055 Aug 61


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