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)

Cytokines, in particular IL-1, released mainly by infiltrating macrophages, can be one of the key mediators of immune-induced beta-cell destruction in IDDM. IL-1 is able to induce suppression of insulin release and biosynthesis in cultured rat pancreatic islets. In addition, the cytokine shows clear cytotoxic effects leading to beta-cell death. The proposed mechanisms of action of IL-1 after binding to the beta-cell receptors are varied. Concerning the cytotoxic effects of the cytokine, the role of oxygen free radicals, mainly derived from arachidonate metabolism (see Fig. 1) is clear, and possibly potentiated by a cytosolic Na(+)-mediated alkalinization of the beta-cell exposed to the cytokine. In fact, an increased influx of Na+ may explain some of the cytotoxicity since it results in concomitant water uptake leading to swelling of the endoplasmic reticulum. NO formation also seems to be related to the cytokine-induced cytotoxicity since inhibition of the NO synthase abolishes the effects of the cytokine (see Fig. 1). In relation to the inhibitory effects of the cytokine on the beta-cell, different studies point toward almost all known second messenger systems already described for several hormones, such as cAMP formation, increased phospholipase C activity, changes in cytosolic Ca++, and altered gene transcription (see Fig. 1). Of particular interest is the protease activation associated with IL-1 (a serine protease) that seems to be clearly connected with the effects of the cytokine upon the beta-cell. In conclusion, the different studies devoted to the problem of IL-1 signal transduction on the beta-cell seem to indicate that the action of the cytokine on the pancreatic insulin-secreting cells is not associated with an individual second messenger system but rather seems to be related to a plurifactorial transduction system.
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PMID:Interleukin-1 and beta-cell function: more than one second messenger? 142 86

Recent observations suggest a role for interleukin-1 (IL-1), a polypeptide product of macrophage/monocytic cells, in the immune-mediated destruction of pancreatic islet beta-cells observed in type 1 diabetes. In this study, we investigated the effects of IL-1 on both alpha- and beta-cell secretory functions in rat islet cell monolayer cultures. Insulin release was 97% inhibited after 6 h of incubation in RPMI-1640 medium (11 mM glucose) containing 1 U/ml IL-1 and 96% inhibited after 24 h of incubation in medium containing 0.1 U/ml IL-1. The cell content of insulin in the monolayers was decreased by 66% (P less than 0.01) after 4 days of incubation in 10 U/ml IL-1; however, after a further 8-day incubation in IL-1-free medium, cell insulin content recovered fully. In contrast, cell glucagon content was decreased by 77% (P less than 0.001) after 4 days of incubation in 10 U/ml IL-1 and did not recover after a further 8-day incubation in IL-1-free medium. After an 18-h preincubation in medium with 0.1 and 1 U/ml IL-1, insulin release responses to 16.7 mM glucose were abolished in 4-h incubations, whereas responses to 0.1 mM 3-isobutyl-1-methylxanthine were normal, and after a further 2 and 5 days of incubation in IL-1-free medium, insulin responses to 16.7 mM glucose recovered fully. Similarly, the inhibitory effect of 16.7 mM glucose on glucagon release was lost after an 18-h preincubation in 0.1 and 1 U/ml IL-1, and did not recover fully after 2 and 5 days in IL-1-free medium, whereas the stimulatory effect of 3-isobutyl-1-methylxanthine on glucagon release was not affected by IL-1. We conclude that 1) IL-1 inhibits glucose-dependent and not cAMP-dependent mechanisms of insulin and glucagon release; 2) inhibition of glucose-stimulated insulin release by IL-1 is reversible, whereas the effect on glucose-modulated glucagon release is not; and 3) IL-1 causes a reversible decrease in the insulin content of islet cells and an irreversible decrease in glucagon content. These actions of IL-1 do not appear to account for the beta-cell-specific destruction of islets characteristic of type 1 diabetes.
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PMID:Interleukin-1 inhibits glucose-modulated insulin and glucagon secretion in rat islet monolayer cultures. 245 40

The influence of diabetes mellitus on phosphodiesterase (PDE) activity in human sc adipose tissue was investigated in 8 patients with insulin-dependent (IDDM) and 9 with noninsulin-dependent (NIDDM) diabetes mellitus. The results were compared with data from 10 healthy normal weight subjects. The apparent maximal PDE activity (Vmax) of the low Km form of PDE was 60% lower (P less than 0.01) in untreated IDDM and NIDDM than in the control state. After treatment of IDDM and NIDDM, the Vmax of the low Km PDE was normalized. In untreated IDDM and NIDDM, the Vmax of the low Km PDE was correlated to the cAMP level (r = 0.8). This correlation was not observed after antidiabetic treatment or in the control state. The apparent Vmax values of the high Km form of PDE were similar in the diabetic states and in control subjects. The results suggest that the low Km PDE is inhibited in untreated IDDM and NIDDM. In these conditions, PDE may be one factor responsible for regulation of the cAMP level.
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PMID:Phosphodiesterase activity in human subcutaneous adipose tissue in insulin- and noninsulin-dependent diabetes mellitus. 628 60

Incubation of washed platelets in Tyrode buffer, pH 7.5, with insulin (200 microU/ml) and CaCl2 (1.2 mM) at 37 degrees C for 3 h resulted in a threefold increase of plasminogen activator activity in the supernatant over the basal level as determined by both the amidolytic assay and the proteolysis of alpha-casein through the formation of plasmin from plasminogen. This plasminogen activator showed no plasmin-like activity and was inhibited by anti-tissue plasminogen activator antibody as well as by type 1 plasminogen activator inhibitor. The substrate specificity and the inhibition of the enzymic activity by various inhibitors indicated that the platelet plasminogen activator (pPA) was related to tissue-type plasminogen activator of relative molecular weight 56,000. Fibrinolytic activity of pPA and its insulin-dependent release were demonstrated by the shortening of euglobulin lysis time and by the clot lysis time of platelet-rich plasma from normal and type I diabetes mellitus patients. Treatment of platelet membranes with insulin also increased the release of pPA. Increased levels of adenosine 3',5'-cyclic monophosphate (cAMP) in platelets by incubation with various agents completely inhibited the insulin-induced release of the activator. On the other hand, inhibition of platelet aggregation by aspirin had no effect on the release of pPA, indicating that the effect of cAMP was not due to the inhibition of platelet aggregation by the nucleotide.
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PMID:Insulin-induced release of plasminogen activator from human blood platelets. 753 Sep 14

The majority of the impaired symptoms in hypoglycaemia unawareness, such as palpitations, tachycardia and tremor, are caused by increased release of adrenaline (ADR) and noradrenaline (NA), and induced by stimulation of beta-adrenergic receptors. Binding of ADR or NA to the beta-adrenergic receptor generates a signal, transmitted via a guanine nucleotide binding protein complex (G-protein), which in turn activates adenylate cyclase with increased production of cAMP. The aim of this study was to show whether IDDM-patients with hypoglycaemia unawareness had deficient coupling between beta2-adrenergic receptors and G-proteins compared to IDDM-patients with hypoglycaemia unawareness and healthy controls. The IDDM-patients were subgrouped as hypoglycaemia aware or unaware based on questionnaire answers, clinical information and the results of isoprenaline sensitivity tests. Mononuclear leukocytes (MNL) were isolated from venous blood. By saturation binding experiments, using [125I]-(-)-iodopindolol ((-)-IPIN), total receptor number (Bmax) and affinity (Kd) were determined. By displacement experiments the relative number of low- and high-affinity receptors for the beta-adrenergic agonist (-)-isoprenaline ((-)-ISO) were determined. We found no difference in Bmax- or Kd-values. for (-)-IPIN between the subgroups. However, there was a reduced capability to form high-affinity binding complexes with (-)-ISO in MNL from IDDM-patients with hypoglycaemia unawareness. It was concluded that hypoglycaemia unawareness in IDDM was associated with dysfunction of the proximal beta2-adrenergic signal pathway.
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PMID:Dysfunction in the beta 2-adrenergic signal pathway in patients with insulin dependent diabetes mellitus (IDDM) and unawareness of hypoglycaemia. 864 18

The report is a discussion of previously published and newly analyzed results concerning the association between heart diseases and alterations in the force-frequency relation (FFR). The optimum stimulation frequency of the FFR is measured and compared in isolated left ventricular myocardium from non-failing hearts with atrial septal defect, coronary artery disease (without and with insulin dependent diabetes mellitus) and from failing hearts with mitral regurgitation, or idiopathic dilated cardiomyopathy. Specifically, we examine the role of altered control of the excitation-contraction coupling system in blunting the force-frequency relation. We use the percent slope of the FFR as a measure of changes in the frequency sensitivity of this control. Our finding of a linear, direct relation between optimum stimulation frequency and % slope across all disease types suggests both parameters are coupled to the same underlying mechanism. To investigate the possible role of altered control of the calcium pump in this mechanism, we analyzed the detailed relation between isometric twitch relaxation kinetics and stimulation frequency in mitral regurgitation myocardium (MR). In the presence of 0.5 microM forskolin the depressed slope and optimum frequency of the FFR and the prolonged half-time of twitch relaxation were all restored to values found in non-failing myocardium. We use the kinetics of isometric twitch relaxation as an index of changes in pumping rate that occur in response to changes in stimulation frequency or in intracellular cyclic adenosine monophosphate concentration. A mathematical model based on the Hill relations for calcium pump uptake rate and for isometric tension as a function of intracellular pCa is developed to simulate isometric twitch relaxation in MR and non-failing myocardium. The success of this model in simulating non-failing and failing twitch relaxation supports a proposed mechanism for the prolonged relaxation time and depressed FFR in MR involving depressed protein kinase-A activity (due to lowered cAMP or to a defect in the Ser16 site of phospholamban) as a mechanism of altered control of the calcium pump in MR heart disease.
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PMID:Role of cAMP in modulating relaxation kinetics and the force-frequency relation in mitral regurgitation heart failure. 920 49

The importance of bioassays measuring stimulating and blocking autoantibodies to the TSH-receptor (TSH-R) by their effect on cAMP production in CHO cells transfected with the recombinant TSH-R is increasingly recognized. The standard technique for this bioassay is cumbersome, as it involves purification of serum IgG with polyethylene glycol (PEG) and resuspension in hypotonic buffer. We have therefore established a simpler approach for the detection of stimulating and blocking autoantibodies using JP09 CHO cells and unfractionated human serum. The cAMP concentration was measured by a highly sensitive commercial radioimmuno assay. Thyroid stimulating autoantibodies (TSAb) were present in 107 out of 126 patients with Graves' disease (85%) and in 4 out of 40 patients with Hashimoto's thyroiditis (10%). Specificity was confirmed by the fact that only 1 patient with insulin dependent diabetes mellitus (IDDM) out of 64 patients with different non-thyroid autoimmune disorders (46 with IDDM, 10 with stiff man syndrome and 8 with rheumatoid arthritis) and 2 out of 100 healthy controls (2%) were positive in this assay. In the subgroup of hyperthyroid Graves' disease patients 76 out of 83 (92%) had TSAb and the same number had TSH binding inhibiting immunoglobulin (TBII), as assessed by the commercial TRAK assay. Although both antibody types showed only a weak correlation (r = 0.30), a combination of TSAb and TBII detected 98% of all Graves' patients and 99% of the hyperthyroid subgroup. Thyroid blocking autoantibodies (TBAb) were measured in 4 out of 24 TSAb negative patients with Graves' disease (17%), who were hypothyroid and positive for TBII. A comparison of our bioassay with the standard bioassay using PEG precipitation showed a good correlation (r = 0.76,p < 0.001), demonstrating the feasibility of the simplified assay for the routine detection of TSAb and TBAb in Graves' disease.
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PMID:Application of a bioassay with CHO cells for the routine detection of stimulating and blocking autoantibodies to the TSH-receptor. 956 61

IA-2, a member of the protein tyrosine phosphatase family, represents a major target autoantigen in type 1 diabetes. To study the regulation of IA-2 gene expression, we used INS-1 insulinoma cells to analyze beta-cell signal transduction pathways as well as the effect of metabolic and hormonal factors involved in the regulation of the insulin secretory pathway. Quantitative competitive reverse transcriptase-polymerase chain reaction revealed that an increase of cellular cAMP mediated by forskolin (10 micromol/l, 24 h) or 3-isobutyl-1-methylxanthine (100 micromol/l, 24 h) induced maximal stimulation of IA-2 mRNA levels (451 +/- 85 and 338 +/- 86% compared with basal conditions; P < 0.001). In contrast, activation of protein kinase C (PKC) by short-term treatment with phorbol 12-myristate 13-acetate (PMA) (1 micromol/l, 6 h) did not alter IA-2 expression, whereas depletion of PKC by prolonged culturing (24 h) exerted a significant inhibition (57 +/- 24%; P < 0.05). cAMP-dependent upregulation was confirmed by the findings that glucagon (10 micromol/l, 24-48 h) increased levels of IA-2 mRNA (190 +/- 35%; P < 0.05), whereas short-term incubation with high glucose concentration showed no effect. However, prolonged incubation in high glucose (21 mmol/l) induced a time- and dose-dependent increase of IA-2 mRNA expression, reaching maximal values after 144 h (285 +/- 68%; P < 0.05). These studies demonstrate that stimuli of insulin secretion that operate by activation of adenylate cyclase generating cAMP significantly increase IA-2 gene expression. In contrast, activation of PKC by high glucose concentration or PMA exerted no effect, suggesting that IA-2 gene expression is not simply coupled to insulin secretion, but may be involved in the fine regulation of beta-cell function. These findings may be important to clarify the function of IA-2 in beta-cells and elucidate mechanisms involved in the induction of autoimmunity to IA-2.
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PMID:Regulation of the diabetes-associated autoantigen IA-2 in INS-1 pancreatic beta-cells. 1090 70

Diabetes mellitus is uncommon in infancy and newborn period. The two common forms seen are the transient and permanent forms of diabetes mellitus of the newborn. They have to be differentiated from the transient hyperglycemic states (Blood sugar > 125 mg/dl) seen in newborns who receive parenteral glucose infusions and in those with septicemia and CNS disorders. Transient diabetes mellitus of the newborn (TDNB) is defined as hyperglycemia occurring within the first month of life lasting at least 2 weeks and requiring insulin therapy. Most of these cases resolve spontaneously by 4 months. It has a reported incidence of 1 in 45,000 to 60,000 live births. The most likely etiology is a maturational delay of cAMP mediated insulin release. The clinical features include small for datedness, proneness for birth asphyxia, open-eye alert facies, dehydration, emaciation, polyuria and poydipsia. These children are prone to septicemia and urinary tract infections. They have hyperglycemia, glucosuria, absent or mild ketonuria, low basal insulin, C-peptide and IGF-1 levels. Treatment consists of hydration and judicious administration of insulin with close monitoring. Thirty percent of these children are likely to develop permanent neonatal diabetes. Compared to transient form, permanent diabetes mellitus is uncommon. It is usually due to pancreatic dysgenesis often associated with other malformations and rarely due to type 1 diabetes mellitus. The diagnosis is based on the demonstration of both exocrine and endocrine pancreatic dysfunction. These children are managed as type 1 diabetes mellitus. They are prone to develop the vascular complications of diabetes at an earlier date.
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PMID:Diabetes mellitus in newborns and infants. 1093 65

Poorly controlled or untreated type I diabetes mellitus is characterized by hyperglycemia and is associated with decreased bone mass and osteoporosis. We have demonstrated that osteoblasts are sensitive to hyperglycemia-associated osmotic stress and respond to elevated extracellular glucose or mannitol by increasing c-jun and collagen I expression. To determine whether MAPKs are involved in this response, MC3T3-E1 osteoblasts were treated with 16.5 mm glucose, mannitol, or contrast dye for 1 h. Immunoblotting of phosphorylated p38 demonstrated activation of p38 MAPK by hyperosmotic stress in vitro and in vivo. Activation peaked at 20 min, remained detectable after 24 h, and was protein kinase C-independent. Activating transcription factor-2 (ATF-2) activation followed the same pattern as phospho-p38. Transactivation of cAMP response element (CRE)- and c-jun promoter (containing a CRE-like element)-reporter constructs increased following hyperosmotic treatment. SB 203580 (a p38 MAPK inhibitor) blocked ATF-2 phosphorylation, CRE transactivation, and c-jun promoter activation. Hyperosmotic activation of collagen I promoter activity was also inhibited by SB 203580, consistent with the involvement of c-jun in collagen I up-regulation. Therefore, we propose that hyperglycemia-induced increases in p38 MAPK activity and ATF-2 phosphorylation contribute to CRE activation and modulation of c-jun and collagen I expression in osteoblasts.
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PMID:P38 and activating transcription factor-2 involvement in osteoblast osmotic response to elevated extracellular glucose. 1214 42


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