Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Noninsulin dependent diabetes mellitus (NIDDM) is associated with an entirely different set of genetic alterations from insulin-dependent diabetes mellitus (IDDM). Over 90% of IDDM carry HLA type DR3, DR4 or both. Several theories have been proposed to explain how the genetic alterations are translated into a beta cell destructive process. All involve the elaboration of a beta cell autoantigen. A major current research focus is on the development of pharmacologic approaches to the control of the beta cell destructive process (cyclosporine A). This has led to a shift in interest to the early identification of individuals at risk for IDDM. Many questions remain to be answered. In our paper emphasis is placed on epidemiological research. In Allegheny County, Pennsylvania, we have found an incidence of 1.73 cases/1000 (incidence rate of 15/100,000/year). There were marked geographical variations (incidence rate of 1/100,000/year in Asian countries, of 40/100,000/year in Finland). This suggests that there are major environmental determinants leading to expression of disease in genetically susceptible individuals. There are no geographical differences in the main age of onset, the sex ratio and the clinical patterns in the initial course of newly detected IDDM. In all parts of the world islet cell antibodies are positive in 60-80% of newly diagnosed IDDM. Migration of children from their native homeland with a low incidence rate to a country with high incidence rate was accompanied by an increase of incidence. The following potential environmental factors have been considered: viral infections, environmental toxins, nutrients, and stress. In our view IDDM occurs in genetically susceptible individuals.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:What do epidemiologic observations tell us about the etiology of insulin dependent diabetes mellitus? 240 77

By an indirect immunofluorescence method with In-111 cells (hamster insulinoma cell line), circulating islet cell surface antibodies (ICSA) were detected in 7 (20%) out of 36 patients with non-insulin dependent diabetes mellitus (NIDDM), 9% of 68 chronic thyroiditis (CT) patients, or 16% of 19 NIDDM patients associated with CT, but not in 18 normal subjects. Sera from five out of nine ICSA-positive patients examined further also showed cell-surface immunofluorescence on TPC-1 cells (human thyroid papillary adenocarcinoma cell line), and prior absorption of the sera with In-111 cells abolished the immunofluorescence. The 64 kDa protein from In-111 cells or human thyroid follicular cells was immunoprecipitated with ICSA-positive sera. In one case of NIDDM associated with CT, 64 kDa protein was detected in both cells. The results indicate that some ICSA in NIDDM patients recognize the same or a very closely-related autoantigen(s) in both islet beta-cells and thyroid follicular cells, suggesting an explanation, at least in part, for the autoimmune mechanism(s) in clinical association of NIDDM and CT.
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PMID:A possible common cell surface autoantigen in islet beta-cells and thyroid follicular cells in patients with non-insulin dependent diabetes mellitus and chronic thyroiditis. 888 24

Antibodies to autonomic nervous system structures have previously been detected using a complement fixation immunofluorescence test in the sera of patients with insulin-dependent diabetes mellitus (IDDM) and non-insulin dependent diabetes mellitus (NIDDM). These antibodies might play a role in the aetiology of autonomic neuropathy. Sera from 45 IDDM, 40 NIDDM and 52 control subjects were tested by immunofluorescence for antibodies to human sympathetic ganglia, human adrenal medulla and rabbit vagus nerve. The use of human sympathetic ganglia was compared with rabbit tissue for the detection of sympathetic ganglia antibodies; the results for these autonomic nervous system antibodies were also compared with results using an ELISA. There was no relationship between the presence of antibodies detected by ELISA and those detected by immunofluorescence, but of 14 IDDM patients with thyroid antibodies, 12 had autonomic nervous system antibodies detected by either immunofluorescence or ELISA (p < 0.005 compared to patients without thyroid antibodies). To further characterize the autoantigen(s), immunoblotting was performed. An adrenal antigen corresponding to 74 kDa was detected in sera from three patients, only one of whom had antibodies detectable by ELISA and immunofluorescence. One IDDM serum showed specific binding to a vagus nerve antigen corresponding to 33 kDa. No specific binding to sympathetic ganglia antigen was demonstrated. Antibodies against autonomic nervous system antigens are an inconsistent feature of diabetes, and appear more associated with coincidental autoimmunity against other organs such as the thyroid.
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PMID:Analysis of antibodies against components of the autonomic nervous system in diabetes mellitus. 934 50

Glutamic acid decarboxylase (GAD) catalyzes the formation of gamma-aminobutyric acid (GABA), which is a major transmitter in the central nervous system. Two forms of GAD (GAD65 and GAD67) are known to be expressed in human tissues and GAD65 is predominantly expressed in pancreatic beta-cells. Recent findings revealed that GAD functions as an autoantigen in human autoimmunity, especially in insulin-dependent diabetes mellitus (IDDM). GAD is a key antigen for the development of autoimmunity against beta-cells and the production of GADAb precedes other autoantibodies such as IAA and ICA512/IA-2Ab prior to the clinical onset of IDDM. At onset, GADAb is detected in 50-80% of patients using RIA or RBA method. Factors that influence the positivities and titers of GADAb at onset, such as onset age, sex, presence of autoimmunity against thyroid, HLA type, have been reported. After onset, GADAb titer decreased more slowly than that of ICA512/IA-2Ab. These findings suggest that autoantibodies against beta-cells, such as GADAb, may develop independently. The presence of GADAb in relatives of IDDM patients and NIDDM patients predicts the development of beta-cell destruction in combination with other anti-islet autoantibodies.
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PMID:[GAD antibody in IDDM]. 959 23

The IA-2 is a major autoantigen of type 1 diabetes belonging to the protein tyrosine phosphatase family. We report on the humoral autoimmunity to an alternatively-spliced variant of IA-2 (IA-2 variant) and autoimmune-mediated diabetes age of onset association with IA-2 autoantibody epitope specificities, in 144 recent-onset patients with type 1 diabetes and 54 GAD autoantibody-positive patients with type 2 diabetes. The cytoplasmic domain of IA-2 (IA-2ic) detected a somewhat greater proportion of patients expressing autoantibodies than IA-2 variant (56%vs. 52% of patients with type 1 diabetes and 17%vs. 9% of GAD autoantibody-positive patients with type 2 diabetes). Conversely, only 1% of IA-2 variant autoantibody-positive patients failed to react to IA-2ic construct. Among 80 patients with type 1 diabetes who were positive for autoantibodies to IA-2ic, 8% recognized the juxtamembrane region (JM, representing amino acids 601-629) only, 64% bound the protein tyrosine phosphatase (PTP)-like domain of IA-2 only, and 29% bound both JM and PTP epitopes. Autoantibodies to the PTP-like domain were prevalent in children and adolescents with type 1 diabetes. The age of disease onset in patients with IA-2JM autoantibodies only, was significantly higher than those in patients reacted with the PTP-like domain of IA-2 (P< 0.02). Among GAD autoantibody-positive patients with type 2 diabetes reacted with IA-2ic, 44% bound the JM region only, and 33% bound epitopes in the PTP-like domain only; 22% had autoantibodies to both regions. The frequency of GAD autoantibody-positive patients with type 2 diabetes positive for autoantibodies to the JM region only, was significantly higher than that in patients with type 1 diabetes (P< 0.01). IA-2PTP autoantibodies were significantly associated with HLA-DR4, while the additional reactivity to IA-2JM was associated with HLA-DR9 allele. These results suggest that autoantibody recognition of IA-2 epitopes in autoimmune diabetes is associated with age of disease onset, which may reflect the intensity of the beta-cell destruction process.
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PMID:Association between IA-2 autoantibody epitope specificities and age of onset in Japanese patients with autoimmune diabetes. 1177 57

MMDM patients are typically young at onset with low body mass index, require insulin treatment for glycemic control, have insulin resistance, and do not develop ketosis on withdrawal of insulin. WHO's revised classification in 1999, based on the etiopathogenesis of the disease, identifies only two categories: type 1 diabetes and type 2 diabetes. MMDM could be considered as type 1b diabetes. Genetic and immunological studies were done on MDDM patients (n = 72) from Cuttack and healthy controls to understand and to justify its inclusion in the category of type 1b diabetes. Antibodies (Abs) to tyrosine pyrophosphatase (IA2-Abs), glutamate decarboxylase 65 (GAD65-Abs), and other minor markers like ICA12 Abs and tissue transglutaminase Abs (TTG-Abs) were studied. HLA-DR and DQ were studied for the genetic markers. Of the MMDM patients 30% were positive for either GAD65 or IA-2 antibodies, and 14% were positive for ICA12 antibodies. All three antibody markers together accounted for 39% of PDDM patients, as some patients were positive for more than one autoantibody. TTG antibodies (specific for Celiac disease) were present in 14/71 (20%) of MMDM patients compared to 3/122 (2%) controls. All four autoantibodies accounted for 53% of PDDM patients, leaving 47% of patients free of known autoantibodies. The autoantibody-negative PDDM patients were analyzed for HLA and MICA markers, showing that DR7-DQ9 and MICA allele 9 are increased in this group compared to healthy controls, which suggests an autoimmune response to an unknown dietary autoantigen. We conclude from our data that an autoimmune mechanism is involved in the etiology of MMDM. In addition, the presence of silent celiac disease seen with MMDM patients, which has not yet been reported, is significant. It is important to note that subclinical celiac disease exists with diabetes mellitus and must be considered in the diagnosis of MMDM.
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PMID:Molecular mechanisms involved in the etiopathogenesis of malnutrition-modulated diabetes mellitus. 1202 Oct 93

The recent identification of tissue transglutaminase (tTG) as the autoantigen for celiac disease-associated anti-endomysial antibodies (EMA) has allowed the use of rapid immunoassay to detect the presence of autoantibodies, anti-tTG, in the serum of patients. In this study, we examined the prevalence of IgG or IgA anti-tTG in sera from patients with elevated levels of IgM rheumatoid factors, which are autoantibodies reactive with the Fc portion of IgG. We report here on four cases of anti-tTG positivity for patients with elevated IgM rheumatoid factor (RF) without evidence of celiac sprue. The study population consisted of 65 patients (26 men, 39 women; mean age, 49 years; range 4 - 92 years) with elevated RF (>20 U/ml ), and 23 healthy subjects (12 men, 11 women; mean age, 46 years; range, 21 - 54 years). IgG and IgA anti- tTG levels were detected using a commercially available ELISA kit (Immuno-Biological Laboratories, Germany). Out of 65 patients, one (1.5%) and three (4.6%) patients were positive for IgG and IgA anti-tTG antibodies, respectively, and this was a higher frequency than occurred in healthy subjects (0/23). The clinical features of the four cases positive for IgG or IgA anti-tTG were as follows: The first case (female, 63 yrs) positive for IgA anti-tTG antibody suffered from rheumatoid arthritis, type II diabetes mellitus, iron deficiency anemia and gastric indigestion without symptoms of malabsorption. She denied any gluten sensitivity on her diet. Her esophagogastroduodenoscopic biopsy showed mucosal atrophy with no elongated crypts or infiltration of inflammatory cells in the lamina propria. The remaining three cases positive for anti-tTG antibodies had interstitial pneumonia, a herniated lumbar disc, and mild scoliosis, respectively. They all denied any malabsorption symptoms or gluten sensitivity. Jejunal biopsy could not be performed in all four cases.
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PMID:Tissue transglutaminase autoantibodies in patients with IgM rheumatoid factors. 1551 14

Troglitazone is a thiazolidinedione antidiabetic agent with insulin-sensitizing activities that was withdrawn from the market in 2000 due to its association with idiosyncratic hepatotoxicity. To address the suspected autoantibody production associated with troglitazone, we investigated autoantibodies in sera from patients with type II diabetes mellitus with troglitazone-induced liver dysfunction. Two female patients (47- and 70-year-old) ceased taking troglitazone (400 mg/day) after 23.5 and 16 weeks, respectively, due to increased serum ALT. Using two-dimensional electrophoresis and amino acid sequence analyses, aldolase B was identified as an autoantigen that reacted with antibodies in sera from both patients. The titer of anti-aldolase B remained high for several weeks after stopping troglitazone administration. The mean reactivity of autoantibodies to aldolase B determined by ELISA with sera of patients with chronic hepatitis (n = 40) and liver cirrhosis (n = 40) was significantly higher (p < 0.05 and p < 0.001, respectively) than with sera of healthy subjects (n = 80). These findings suggest that liver injury may cause the appearance of autoantibodies to aldolase B which may then aggravate the hepatitis. In addition, the anti-aldolase B titer might indicate the severity of liver dysfunction.
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PMID:Detection of autoantibody to aldolase B in sera from patients with troglitazone-induced liver dysfunction. 1611 20

Type 1A diabetes (T1D) results from autoimmunity targeted at a limited number of molecules that are expressed in the pancreatic beta cell. Putative novel autoantigen candidates were identified from microarray expression profiling of human and rodent islet cells. The highest ranking candidate was Slc30A8 (zinc transporter 8; ZnT8), which was screened by radioimmunoprecipitation assays against new-onset T1D and prediabetic sera. Such assays detected 63% of subjects with new-onset diabetes, but fewer than 2% of controls, 3% of those with type 2 diabetes, and 10% of patients with other autoimmune disorders. ZnT8 autoantibodies were found, however, in 26% of T1D subjects previously classified as autoantibody-negative on the basis of existing markers (GADA, IA2 A, IAA, and ICA). We conclude that SLC30A8 provides an important additional and independent predictive marker for T1D.
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PMID:SlC30A8 is a major target of humoral autoimmunity in type 1 diabetes and a predictive marker in prediabetes. 1912 Mar 7

Diabetes mellitus is caused by deficiency of insulin secretion from the pancreatic islet beta cells and/or insulin resistance in liver, muscle and adipocytes, resulting in glucose intolerance and hyperglycemia. Several protein tyrosine phosphatases, such as PTP1B (PTPN1), TCPTP (PTPN2), LYP (PTPN22), PTPIA-2, PTPMEG2 (PTPN9) or OSTPTP are involved in insulin signaling pathway, insulin secretion and autoreactive attack to pancreatic beta cells. Genetic mutation or overexpression of these phosphotases has been found to cause or increase the risk of diabetes mellitus. Some population with high risk for type 2 diabetes has overexpressed PTP1B, a prototypical tyrosine phosphatase which down-regulates insulin and leptin signal transduction. Animal PTP1B knockout model and PTP1B specific inhibitor cellular studies indicate PTP1B may serve as a therapeutic target for type 2 diabetes. TCPTP shares more than 70% sequence identity with PTP1B in their catalytic domain. TCPTP dephosphorylates tyrosine phosphorylated substrates overlapping with PTP1B but also has its own distinct dephosphorylation sites and functions. Recent research indicates TCPTP may have role in type 1 diabetes via dysregultaion of cytokine-mediated immune responses or pancreatic beta cell apoptosis. The tyrosine phosphatase LYP, which down-regulates LCK activity in T cell response, can become mutated as R620W which is highly correlated to type 1 diabetes. LYP R620W may be a gain of function mutation which suppresses TCR signaling. Patients bearing the R620W mutant have impaired T cell responses and increased populations of (CD45RO+CD45RA-) CD4+ T cells. A detailed elucidation of mechanism of R620W in type 1 diabetes and specific LYP inhibitor development will help characterize LYP R620W as a therapeutic target. A receptor tyrosine phosphatase, PTPIA-2/beta is a major autoantigen of type 1 diabetes. A diagnosis kit identifying PTPIA-2/beta autoantibodies is valuable in early detection and prevention of type 1 diabetes. In addition, other phosphatase like OSTPTP and PTPMEG2 are involved in type 2 diabetes via regulation of insulin production, beta cell growth or insulin signaling. Research into understanding the mechanism of these tyrosine phosphatases in diabetes, such as their precise functions in the regulation of insulin secretion, the insulin response and the immune response will strengthen our knowledge of diabetes pathophysiology which may result in new diagnostic and therapeutic strategies for diabetes.
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PMID:[Research progress of several protein tyrosine phosphatases in diabetes]. 2040 54


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