UMLS:C0011854 - FACTA Search

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Query: UMLS:C0011854 (type 1 diabetes)
20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chronically hyperinsulinemic Zucker fatty rat, with peripheral insulin resistance and glucose intolerance, represents a model of noninsulin dependent diabetes mellitus (NIDDM). These animals have elevated hepatic glycogen levels. Hepatic levels of synthase phosphatase and phosphorylase phosphatase, which are diminished in the IDDM rat, were markedly increased in the obese rats. Glyburide, a sulfonylurea used in treatment of NIDDM, resulted in reduced levels of glycemia and increased insulin levels in Zucker rats. Hepatic glycogen levels were increased, as was the activation of glycogen synthase, although there were no effects of drug administration on synthase phosphatase or phosphorylase phosphatase activities. G6P levels were increased by glyburide in lean rats but not in obese animals. These effects of glyburide on liver glycogen metabolism are accounted for via potentiation of the glycogenic effects of insulin.
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PMID:Hepatic glycogen synthase phosphatase and phosphorylase phosphatase activities are increased in obese (fa/fa) hyperinsulinemic Zucker rats: effects of glyburide administration. 282 45

Insulin stimulates glucose uptake and non-oxidative glucose metabolism (predominantly glycogen synthesis) in skeletal muscle. Among other things, insulin resistance is characterized by a subnormal insulin-stimulated glucose disposal, and it appears to be associated with an increased risk for development of non-insulin-dependent diabetes mellitus (NIDDM). The aim of the present investigation has been to elucidate the mechanism of action of insulin on non-oxidative glucose metabolism both during conditions of insulin resistance and during physiological modification of glucose metabolism. To do so, the effect of insulin was investigated both with respect to its initial activation of the insulin receptor kinase and the terminal step of the signal pathway, namely stimulation of the glycogen synthase. From needle biopsies of human skeletal muscle (vastus lateralis) cellular membranes were solubilized and the insulin receptors were partially purified by affinity chromatography using wheat germ agglutinin. Subsequently insulin binding and the insulin-stimulated tyrosine kinase activity were characterized. The insulin receptor kinase activity did not change during physiological modification of the glucose metabolism (exercise training, acute exercise, growth hormone exposure or experimental hyperglycemia). No specific abnormalities of the insulin receptor kinase activity were revealed in insulin-dependent diabetes (IDDM) or in common NIDDM. In addition, insulin receptor kinase activity did not change during dietary or sulphonylurea treatment of NIDDM. Glucose deposition as glycogen in muscle is regulated by glycogen synthase (GS), which during insulin stimulation undergoes dephosphorylation and becomes more active at physiological concentrations of glucose-6-phosphate. Recently, insulin was shown to stimulate a cascade of phosphorylation-dependent kinases which ultimately activate a glycogen-bound subunit of a phosphatase (G-subunit of phosphatase-1) which promotes dephosphorylation GS by the catalytic subunit. The quantity of the GS enzyme (GStot) in muscle may be reduced in the diabetes disease. However, it may increase during physical training of insulin-dependent diabetic patients. GStot is not altered during acute exposure to insulin, hyperglycemia or muscle contraction. The insulin stimulation of GS is reduced in insulin resistant NIDDM patients. However, once the hyperglycemia and the insulin resistance is ameliorated during treatment with diet or sulphonylurea drugs the activation of GS improves. Growth hormone-induced transient insulin resistance in non-diabetic subjects, is accompanied by a reduced insulin stimulation of GS. Experimentally induced hyperglycemia in normal subjects has no influence on GS activation by insulin. After an acute exercise bout the GS in muscle becomes activated. The mechanism of this post-exercise GS activation is still unknown.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Insulin receptor function and glycogen synthase activity in human skeletal muscle. Physiology and pathophysiology. 803 33

Low molecular weight acid phosphatase encoded by the highly polymorphic locus ACP1 is a member of the protein-tyrosin phosphatase family (PTPases) which plays an essential role in the control of receptor signalling through phosphotyrosine pathways. Recent experiments have shown that purified rat liver ACP, corresponding to human ACP1, is able to hydrolyze a phosphotyrosine-containing synthetic peptide corresponding to the 1146-1158 sequence of the human insulin receptor, and shows a high affinity for it. This prompted us to analyze the degree of glycemic control in relation to ACP1 genetic variability in a sample of 214 diabetic pregnant women including IDDM, NIDDM and gestational diabetes. The ACP1 genotype was also determined in 482 non-diabetic pregnant women. In diabetic women glycemic levels in the last trimester of pregnancy appear to be significantly associated with the ACP1 genotype, and correlate positively with ACP1 enzymatic activity. The data suggest that quantitative variations of ACP1 may influence the clinical manifestations of diabetic disorders, and call for further studies on the role of this enzyme in the modulation of insulin-receptor phosphotyrosine pathways.
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PMID:Phosphotyrosine protein phosphatases and diabetic pregnancy: an association between low molecular weight acid phosphatase and degree of glycemic control. 862 Sep 37

The related tyrosine phosphatase-like proteins, islet cell antigen 512 (ICA512) and phosphatase homologue in granules of insulinoma (phogrin), are major targets of autoantibodies in patients with type 1 diabetes. In the current study, we have examined the overlapping specificities and antigenic epitopes of autoantibodies to ICA512 and phogrin and determined whether intramolecular epitope spreading occurs during the development of diabetic autoimmunity. ICA512 autoantibodies and phogrin autoantibodies were detected in 65-70% (n = 110) of patients with new-onset type 1 diabetes and 60-65% (n = 42) of prediabetic relatives of patients with type 1 diabetes. Of the sera, 10% reacted with ICA512 but not phogrin, whereas only 1% of sera reacted with phogrin but not ICA512. The binding of phogrin autoantibodies in 88 dual (ICA512 and phogrin) autoantibody-positive sera could be completely blocked by excess recombinant ICA512, whereas the blocking of ICA512 autoantibodies with recombinant phogrin was only partial (mean inhibition of 58.9 +/- 3.7%, mean +/- SE). Binding and competition analysis using multiple chimeric ICA512/phogrin constructs demonstrated that a major unique epitope for ICA512 autoantibodies is localized to amino acids 762-887. A conformational epitope associated with the carboxy-terminal 31 amino acids of ICA512 was recognized by one-third of sera, and a minor epitope is located on amino acids 601-762 of ICA512. The major epitopes for phogrin-selective autoantibodies were localized to amino acids 640-922 of phogrin. Sequential serum samples were analyzed in 22 relatives who expressed ICA512/phogrin autoantibodies. Intramolecular epitope spreading was found for 5 of 13 relatives who have progressed to type 1 diabetes. Among nine relatives who have remained nondiabetic, three demonstrated a decrease in the number of epitopes recognized. These studies highlight the complexity of autoantibody recognition of ICA512/phogrin and are consistent with the hypothesis that ICA512/phogrin may be recognized as a consequence of beta-cell destruction.
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PMID:Definition of multiple ICA512/phogrin autoantibody epitopes and detection of intramolecular epitope spreading in relatives of patients with type 1 diabetes. 958 44

IA-2 (islet cell Ag 512) and IA-2 beta (phogrin/IAR) are related autoantigens associated with type 1 diabetes. To determine the critical regions for autoantibody binding and which of these autoantigens is the primary target, mutant and chimeric constructs were used to characterize Ab epitope binding in sera from 217 new onset patients with type 1 diabetes and sequential samples from 141 islet cell Ab positive first degree relatives of patients. All 22 relatives and 121 of 129 patients with IA-2/IA-2 beta Abs had reactivity to IA-2-specific epitopes. These epitopes were in the juxtamembrane region (residues 601-682) and the protein tyrosine phosphatase (PTP)-like domain of IA-2. Chimeras showed that IA-2 residues 795-889 were important for IA-2-specific Ab binding in the PTP-like domain, and mutation of IA-2 residues 877 and 911, previously indicated as relevant for phosphatase activity, also reduced Ab binding. In contrast, Ab binding to IA-2 beta was limited to its PTP-like domain, most IA-2 beta Abs recognized epitopes shared with IA-2, and only 20 patients and 2 relatives had Abs to IA-2 beta-specific epitopes. In 4 relatives, IA-2 and/or IA-2 beta Abs developed in follow-up samples. In each of these, Abs to IA-2-specific epitopes were the first detected. In three, spreading to epitopes shared between IA-2 and IA-2 beta in subsequent samples was seen. In the 17 relatives who developed type 1 diabetes, progression to disease was associated with reactivity to multiple IA-2/IA-2 beta epitopes. These data suggest that IA-2 is the primary phosphatase-like autoantigen associated with type 1 diabetes and that studying autoantibody epitope diversity may assist in disease prediction.
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PMID:IA-2 (islet cell antigen 512) is the primary target of humoral autoimmunity against type 1 diabetes-associated tyrosine phosphatase autoantigens. 972 68

Erythrocyte Na/K ATPase activity is decreased in Type I diabetic patients; for Type II diabetic patients, literature data are controversial. Therefore, we have compared this enzymatic activity in 81 patients with Type I diabetes mellitus, 87 with Type II diabetes mellitus and 75 control subjects. Mean erythrocyte Na/K ATPase activity was lower in the Type I diabetic patients (285 +/- 8 nmol Pi x mg protein(-1) x h(-1)) than in the control subjects (395 +/- 9 nmol Pi x mg protein(-1) x h(-1)) whereas that of the Type II diabetic patients did not differ from that of control subjects. Sex, age, body mass index, and HbA1c levels did not influence erythrocyte Na/K ATPase activity. The 25 Type II diabetic patients treated with insulin, however, had lower Na/K ATPase activity than the 62 on oral treatment (264 +/- 18 vs 364 +/- 16 nmol Pi x mg protein(-1) x h(-1), p < 0.001) but similar to that of Type I diabetic patients. Among the Type II diabetic patients, stepwise regression analysis showed that fasting C-peptide level was the only factor independently correlated with Na/K ATPase activity; it explained 23% of its variance. In fact, in the insulin-treated patients, those with almost total endogenous insulin deficiency (C-peptide < 0.2 nmol x l(-1)) had the lower Na/K ATPase activity (181 +/- 21 vs 334 +/- 17 nmol Pi x mg protein(-1) x h(-1), p < 0.0001). The biological effects of treatment with C-peptide have recently led to the suggestion that this peptide could have a physiological role through the same signalling pathway as insulin, involving G-protein and calcium phosphatase and thus restoring Na/K ATPase activity. The relationship we describe between endogenous C-peptide and this activity is a strong argument for this physiological role.
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PMID:Erythrocyte Na/K ATPase activity and diabetes: relationship with C-peptide level. 975 27

Measurements have been made, in adult male diabetic patients and control subjects, of the urinary content of inositol phosphoglycans (IPGs), the IPG A-type and IPG P-type forms, which, among other actions, regulate pathways of glucose utilization, lipogenesis, triglyceride formation, and pyruvate dehydrogenase (PDH) activity. Urine samples from the entire diabetic group showed a 2- to 3-fold increase in IPG A-type, and a fall in the IPG P-type:IPG A-type ratio relative to the control group. Subdivision of the diabetic patients into lean IDDM and obese NIDDM groups revealed significant differences in the IPG P-type:IPG A-type ratio between these groups, this ratio decreasing with increases in the body mass index (BMI). Analysis of the relationships among IPGs and HbA1, blood pressure, and BMI indicated that a fall in the IPG P-type:IPG A-type ratio correlated with a rise in the HbA1 (indicative of impaired glycemic control), with increased systolic blood pressure and increased obesity, all factors linked to Syndrome X. There was a parallism between the profile of the IPG P-type:IPG A-type ratio and the well-established pattern of insulin resistance and BMI. In vitro studies of the effects of alterations in the IPG P-type:IPG A-type ratio on the activation of the pyruvate dehydrogenase complex (PDH complex) at the PDH phosphatase reaction demonstrated that IPG A-type forms antagonized the stimulation of the PDH phosphatase by IPG P-type forms, thus having a negative effect on the conversion of PDH to the active, dephosphorylated, form. This observation could provide a mechanism whereby the shifts in the IPG P-type:IPG A-type ratio reported above could change the metabolic pattern from one directed to glucose oxidation to one more directed toward energy conservation and lipid storage.
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PMID:Inositol phosphoglycans in diabetes and obesity: urinary levels of IPG A-type and IPG P-type, and relationship to pathophysiological changes. 1060 79

Development of diabetes mellitus caused by pancreatic beta-cell destruction of autoimmune origin is the result of a long lasting process. The most easily examinable feature of this stage is the occurrence of the islet cell antibodies. The sera which are positive for islet cell cytoplasmic antibodies (ICA), examined by indirect immunofluorescence, contain a mixture of antibodies. The glutamic acid decarbocylase (GAD), the tyrosin phosphatase (IA2), the insulin, and the GM2-1 glycolipid can be the targets of these antibodies. One can routinely examine the ICA, the GADA, the IA2 antibodies. The detection of antibodies against insulin (IAA) and GM-2-1 glycolipid is not invented in the routine laboratory work. The aim of the authors was the evaluation of clinical significance of occurrence of islet cell antibodies: one hundred and eighteen nondiabetic children an adult human being without known diabetic first degree relatives and 366 type 1 diabetic children and adult patients served as controls. The authors evaluated the predictive value of the different islet cell antibodies to the development of type 1 diabetes mellitus in 596 nondiabetic children with type 1 diabetic first degree relatives. The authors looked for markers of beta-cell destruction among sera of 320 diabetics manifested after 30 years of age with at least half a year of non-insulin-dependency and in the sera of 68 females suffered from gestational diabetes after 0-14 years of the index pregnancy. Finally the authors report 7 cases in which the examination of islet cell antibodies helped the diagnosis and classification of diabetes mellitus. Indirect immunofluorescence method was used for the detection of ICA, radioimmunoassay for that of GADA and IA2 antibodies. There was no positive reaction for ICA and GADA in the nondiabetic population without diabetic first degree relatives. Among the freshly diagnosed type 1 diabetic children 39% were positive for only ICA, 44% for only GADA and 80% for any antibodies. Among the freshly manifested type 1 diabetic adults ICA positivity only was observed in 21%, GADA positivity only in 7.1% and 93% for any antibodies. From the 595 nondiabetic children with type 1 diabetic first degree relatives 23 were positive for ICA, from whom 5 became diabetic during a two years observation period. These diabetic children had multiplex autoantibodies besides ICA. One child from this group, who was negative for ICA became diabetic, too. Among type 2 diabetic patients 13% were positive for ICA alone, 17% were positive for GADA alone and 27% were positive for any antibodies. The insulin dependency manifested in a short time was associated with antibody positivity. Among the gestational diabetics 10 were found positive for ICA. From them, 7 were type 1 diabetics, and 3 were type 2 diabetics at the time of the detection of antibodies. The authors suggest the need of determination of islet cell antibodies in the group of nondiabetic first degree relatives of type 1 diabetic patients (ICA, GADA, IA2 and IAA), in the group of non-insulin-dependent diabetics (ICA and GADA) as a screening for later insulin dependency, and in gestational diabetes after delivery (ICA) as screening for type 1 diabetes mellitus.
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PMID:[Detection of antibodies against pancreatic islet cells in clinical practice]. 1064 15

The liver is an attractive target organ for insulin gene expression in type 1 diabetes as it contains appropriate cellular mechanisms of regulated gene expression in response to blood glucose and insulin. We hypothesize that insulin production regulated by both glucose and insulin may be achieved using the promoter of the glucose 6-phosphatase gene (G6Pase), the expression of which in the liver is induced by glucose and suppressed by insulin. Recombinant adenoviral vectors expressing the reporter gene CAT or insulin under transcriptional direction of the G6Pase promoter were constructed. Glucose-stimulated as well as self-limiting insulin production was achieved in vector-transduced hepatoma cells in which expression of the insulin gene was controlled by the G6Pase promoter. While insulin strongly inhibited the G6Pase promoter activity under low glucose conditions, its inhibitory capacity was attenuated when glucose levels were elevated. At the physiologic glucose level of 5.5 mM glucose, vector-transduced hepatoma cells produced a self-limited level of insulin at approximately 0.2-0.3 ng/ml, which is within the range of fasting levels of insulin in normal animals. These results indicate that the G6Pase promoter possesses desirable features and may be developed for regulated hepatic insulin gene expression in type 1 diabetes.
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PMID:Glucose-stimulated and self-limiting insulin production by glucose 6-phosphatase promoter driven insulin expression in hepatoma cells. 1111 Apr 11

Recent reports indicate that genes with tissue-restricted expression, including those encoding the type 1 diabetes autoantigens insulin, glutamic acid decarboxylase (GAD), and the tyrosine-phosphatase-like protein IA-2 (or ICA512), are transcribed in the thymus. The reported modulation of diabetes susceptibility by genetically determined differences in thymic insulin levels and studies in transgenic mice provide correlative and functional evidence that thymic expression of peripheral proteins is crucial for immunological self-tolerance. However, there are no specific data about the existence, tissue distribution, phenotype, and function of those cells that express insulin and other self-antigens in the human thymus. We find that the human thymus harbors specialized cells synthesizing (pro)insulin, GAD, and IA-2, mainly localized in the medulla, and we demonstrate such cells also in peripheral lymphoid organs (spleen and lymph nodes). Phenotypic analysis qualifies these cells as antigen-presenting cells (APCs), including both dendritic cells and macrophages. These cells often appear surrounded by apoptotic lymphocytes, both in thymus and spleen, and may therefore be involved in the deletion of autoreactive lymphocytes. Our findings demonstrate the existence of, and define the tissue distribution and phenotype of, a novel subset of APCs expressing self-antigens in human lymphoid organs that appear to be involved in the regulation of self-tolerance throughout life.
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PMID:Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. 1123 56

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