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)

Arginine vasopressin (AVP) hypersecretion in response to metoclopramide or to insulin-induced hypoglycaemia has been described in type I diabetes mellitus. In the present study, we examined whether residual endogenous insulin secretion may play a role in the control of this abnormal AVP secretory pattern. For this purpose, 21 insulin-dependent diabetic men and 10 age- and weight-matched normal men were tested with MCP (20 mg in an i.v. bolus). On a different occasion, subjects were tested with insulin (0.15 IU kg-1). The diabetic patients were subdivided into C-peptide negative patients (CpN, 11 patients without detectable endogenous pancreatic beta cell activity) (group I) and C-peptide positive patients (CpP, 10 patients with residual endogenous insulin secretion) (group II). Experiments started after optimization of the metabolic status of the diabetic men by 3 days of treatment with continuous subcutaneous insulin infusion. The basal concentrations of AVP were similar in all groups. The administration of MCP induced a striking elevation in plasma AVP levels in the normal controls and in the diabetic subjects of groups I and II. However, the AVP rise was significantly higher in group I and group II than in normal controls. Furthermore, group I diabetics showed higher AVP increments than group II. Insulin induced a similar hypoglycaemic nadir in all subjects at 30 min, even though the diabetic subjects of groups I and II had a delayed recovery in blood glucose levels. The hypoglycaemic pattern was similar in group I and II. Hypoglycaemia induced a striking AVP increase in the normal controls.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Influence of residual C-peptide secretion on the arginine vasopressin response to hypoglycaemia and metoclopramide in insulin-dependent diabetes. 758 12

Prolactin (PRL) is well known for its stimulatory effects on various components of the immune response. Experimentally induced high levels of PRL have been shown to correlate with the worsening of several autoimmune diseases. In contrast, lowering PRL levels may protect from the autoimmune process. We investigated in both sexes of NOD mice a spontaneous model of autoimmune type 1 diabetes, the effects of two drugs, a dopaminergic agonist, bromocriptine (BRC, 10 mg/kg), which is assumed to inhibit PRL secretion, and a dopaminergic antagonist, metoclopramide (MCP, 5 mg/kg), which in contrast stimulates PRL secretion, on the incidence of diabetes, the severity of insulitis, and PRL and glucose levels. Chronic treatment of NOD mice with MCP slightly aggravated development of diabetes. The dopamine antagonist tended to accelerate the onset of diabetes in females and significantly increased the number of islets with peri-insulitis in both sexes. The weak deleterious effects exerted by MCP in NOD mice may be related to its stimulatory action on PRL release. Contrary to the expected results, the dopamine agonist BRC did not protect from autoimmune diabetes. In contrast, the drug appeared to accelerate diabetes onset in males and significantly increased the number of islets showing insulitis in both sexes. This study underlines the complexity of the action of BRC which in NOD mice only transiently inhibits the release of PRL. Moreover, the aggravating actions of BRC may be related to the marked hyperglycemic effect of the drug observed in male and female NOD mice.
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PMID:Attempts to pharmacologically modulate prolactin levels and type 1 autoimmune diabetes in the non-obese diabetic (NOD) mouse. 882 12

In uremia, accelerated muscle protein degradation results from activation of the ATP-ubiquitin proteasome proteolytic pathway. Like uremia, other conditions (e.g., acidosis and diabetes) activate this pathway in rat muscles and are associated with excess glucocorticoids (GC) and impaired insulin action. To define the stimuli responsible for muscle wasting in IDDM, the roles of glucocorticoids, insulinopenia and acidosis in streptozotocin (STZ) - induced diabetes were studied. Proteolysis in isolated epitrochlearis muscles from acutely (3d) diabetic rats was 52% higher than pair-fed, sham-injected rats; this increase was eliminated by an inhibitor of the proteasome or by blocking ATP synthesis. In muscles of STZ-diabetic rats, the levels of ubiquitin-conjugated proteins and mRNAs encoding ubiquitin, the ubiquitin-carrier protein, E2(14k) and the C3, C5 and C9 proteasome subunits were increased. Transcription of ubiquitin and C3 proteasome subunit genes in muscle was also increased by IDDM. Oral NaHCO(3) eliminated acidemia but did not prevent accelerated muscle proteolysis. Corticosterone excretion was higher in IDDM rats and adrenalectomy (ADX) prevented these catabolic responses; physiologic doses of glucorcoticoids restored the excessive protein catabolism in ADX-STZ rats. Giving IDDM rats replacement insulin also normalized protein degradation in muscles. In conclusion, reduced insulin together with physiologic levels of glucocorticoids activate the ubiquitin-proteasome pathway by a mechanism that includes enhancing ubiquitin conjugation and proteolysis by the proteasome. The balance between these stimuli could regulate muscle proteolysis in uremia.
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PMID:The balance between glucocorticoids and insulin regulates muscle proteolysis via the ubiquitin-proteasome pathway. 1068 43

Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The non-obese diabetic (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse lymphocytes that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect both prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor alpha (TNF-alpha). The proteasome dysfunction is both tissue and developmental stage specific and likely contributes to disease pathogenesis and tissue targeting.
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PMID:A role for NF-kappaB and the proteasome in autoimmunity. 1114 Apr 62

In NOD (nonobese diabetic) mice, a model of autoimmune diabetes, various immunomodulatory interventions prevent progression to diabetes. However, after hyperglycemia is established, such interventions rarely alter the course of disease or allow sustained engraftment of islet transplants. A proteasome defect in lymphoid cells of NOD mice impairs the presentation of self antigens and increases the susceptibility of these cells to TNF-alpha-induced apoptosis. Here, we examine the hypothesis that induction of TNF-alpha expression combined with reeducation of newly emerging T cells with self antigens can interrupt autoimmunity. Hyperglycemic NOD mice were treated with CFA to induce TNF-alpha expression and were exposed to functional complexes of MHC class I molecules and antigenic peptides either by repeated injection of MHC class I matched splenocytes or by transplantation of islets from nonautoimmune donors. Hyperglycemia was controlled in animals injected with splenocytes by administration of insulin or, more effectively, by implantation of encapsulated islets. These interventions reversed the established beta cell-directed autoimmunity and restored endogenous pancreatic islet function to such an extent that normoglycemia was maintained in up to 75% of animals after discontinuation of treatment and removal of islet transplants. A therapy aimed at the selective elimination of autoreactive cells and the reeducation of T cells, when combined with control of glycemia, is thus able to effect an apparent cure of established type 1 diabetes in the NOD mouse.
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PMID:Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. 1143 53

Type 1 diabetes (also known as insulin-dependent diabetes mellitus or juvenile-onset diabetes) is usually caused by T cell-mediated autoimmunity, with a prediabetic state characterized by the production of autoantibodies specific for proteins expressed by pancreatic beta cells. The nonobese patient with diabetes (NOD) mouse is a spontaneous model of type 1 diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) region of the genome. A specific proteasome defect has been identified in NOD mouse in select lymphocytic and monocytic lineages that results from down-regulation of expression of the proteasome subunit LMP2, which is encoded by a gene in the MHC genomic region. This defect prevents the proteolytic processing required for the production and activation of the transcription factor nuclear factor-kappaB (NF-kappaB), which plays important roles in immune and inflammatory responses, as well as increases the susceptibility of the affected cells to apoptosis induced by tumor necrosis factor-alpha (TNF-alpha). The novel role of the proteasome in dysfunction in autoimmunity is presented and documented to be both tissue and developmental stage specific. We propose a role of the proteasome as a step in disease pathogenesis and tissue targeting.
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PMID:Defective function of the proteasome in autoimmunity: involvement of impaired NF-kappaB activation. 1146 44

We investigated the expression of Th1- and Th2-associated chemokine receptors on peripheral blood lymphocytes at diagnosis and in the first phase of type 1 diabetes. Peripheral blood mononuclear cells (PBMCs) of 25 patients with newly diagnosed type 1 diabetes, 10 patients with longstanding type 1 diabetes, and 35 healthy control subjects were examined for expression of the chemokine receptors CXCR4 (naive T-cells), CCR5 and CXCR3 (Th1 associated), and CCR3 and CCR4 (Th2 associated) on CD3+ lymphocytes. Furthermore, we analyzed chemokine serum levels (monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and RANTES [regulated on activation, normal T-cell expressed and secreted]) and phytohemagglutinin (PHA)-stimulated cytokine secretion of Th1- (gamma-interferon [IFN-gamma] and tumor necrosis factor-alpha [TNF-alpha]) and Th2 (interleukin [IL]-4 and -10)-associated cytokines by PBMC. The patients with newly diagnosed type 1 diabetes were followed for these parameters at 6-12 months after diagnosis. The PBMCs of patients with newly diagnosed but not with longstanding type 1 diabetes showed reduced expression of the Th1-associated chemokine receptors CCR5 (P < 0.001 vs. control subjects) and CXCR3 (P < 0.002 vs. control subjects). This reduction correlated with reduced IFN-gamma and TNF-alpha production of PBMCs after PHA stimulation and reversed 6-12 months after diagnosis to normal levels. CCR4 cells were reduced in both newly diagnosed and longstanding type 1 diabetic patients, which correlated to reduced PHA-stimulated IL-4 production. MIP-1alpha and MIP-1beta levels were considerably elevated in a subgroup of patients with newly diagnosed diabetes. We assume that Th1-associated peripheral T-cells are reduced in a narrow time window at the time of diagnosis of diabetes, possibly due to extravasation in the inflamed pancreas. Thus, chemokine receptor expression of peripheral blood lymphocytes may be a useful surrogate marker for the immune activity of type 1 diabetes (e.g., in intervention trials).
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PMID:Reduced expression of Th1-associated chemokine receptors on peripheral blood lymphocytes at diagnosis of type 1 diabetes. 1214 60

Insulin-dependent diabetes mellitus is known to go along with enhanced muscle protein breakdown. Since evidence has been presented that the ubiquitin-proteasome system is significantly involved in muscle wasting under this condition, we have investigated, whether this biological role goes along with alterations of the proteasome system in skeletal muscle of streptozotocin-diabetic rats. Previously, we have found a drop of overall proteasome activity in muscle extracts of rats after induction of diabetes but no change in total amount of 20S proteasome was detected. In the present investigation under the same diabetic conditions we have measured a significant decrease in the amount of proteasome activator PA28, a finding that explains the loss of total proteasome activity. Since increased mRNA levels of proteasome subunits have been measured in muscle tissue of rats after induction of diabetes, we have isolated and purified 20S proteasomes from muscle tissue of control and 6 days diabetic rats. The specific chymotrypsin-like, trypsin-like, and peptidylglutamylpeptide-hydrolysing activities of proteasomes from diabetic and control rats were found to be not significantly different. Therefore, we have fractionated 20S proteasomes into their subtypes and detected that induction of diabetes mellitus effects a redistribution of subtypes of all three proteasome populations but only the increase in subtype V (immuno-subtype) was statistically significant. This altered subtype pattern obviously meets the requirements to the system under wasting conditions. Since this process goes along with de novo biogenesis of 20S proteasomes, it most likely explains the phenomenon of elevated mRNA concentrations of proteasome subunits after induction of diabetes mellitus.
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PMID:Alteration of 20S proteasome-subtypes and proteasome activator PA28 in skeletal muscle of rat after induction of diabetes mellitus. 1267 65

The cytokine IL-1beta suppresses rodent islets of Langerhans in vitro. Presently we used inhibitors of the proteasome to investigate if these compounds could counteract the suppressive effects of the cytokine. Thus, isolated rat islets were cultured and pre-treated with proteasome inhibitors and subsequently exposed for 48 h to 25 U/ml human IL-1beta. After this period functional tests were carried out. The rate of glucose oxidation (pmol/10 islets x 90 min) was suppressed by IL-1beta (115 +/- 17 vs. control 380 +/- 57). Pre-treatment with 10 microM of the proteasome inhibitor MG115 (N-carbobenzoxyl-leu-leu-norvalinal) and 100 microM of the calpain inhibitor norLEU (N-acetyl-leu-leu-norleucinal; known to affect proteasome activity) counteracted the suppressive effects (253 +/- 17 and 262 +/- 10 respectively). The calpain inhibitor alIMET (N-acetyl-leu-leu-methional) had no effect. MG115 (10 microM) and norLEU (100 microM) blocked nitric oxide formation induced by IL-1beta, while alIMET was without effect. We also investigated if IL-1beta could influence the expression of two inducible proteasome subunits, namely LMP2 and LMP7, and found that the cytokine increased the mRNA expression of the proteasome subunit LMP2 in islets, and that the proteasome inhibitor MG115 prevented this increase. In conclusion our study shows that IL-1beta increases the transcription of the proteasome subunit LMP2, and that the proteasome is involved in IL-1beta induced suppression of islet function. Moreover, the observation that inhibitors of the proteasome protect islets against IL-1beta induced inhibition of glucose metabolism, suggests that these compounds might be worthwile to explore in future therapies against the development of type 1 diabetes.
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PMID:Involvement of the proteasome in IL-1beta induced suppression of islets of Langerhans in the rat. 1290 36

In models of type 1 diabetes, cytokines induce pancreatic beta-cell death by apoptosis. This process seems to be facilitated by a reduction in the amount of the islet-brain 1/JNK interacting protein 1 (IB1/JIP1), a JNK-scaffold with an anti-apoptotic effect. A point mutation S59N at the N terminus of the scaffold, which segregates in diabetic patients, has the functional consequence of sensitizing cells to apoptotic stimuli. Neither the mechanisms leading to IB1/JIP1 down-regulation by cytokines nor the mechanisms leading to the decreased capacity of the S59N mutation to protect cells from apoptosis are understood. Here, we show that IB1/JIP1 stability is modulated by intracellular calcium. The effect of calcium depends upon JNK activation, which primes the scaffold for ubiquitination-mediated degradation via the proteasome machinery. Furthermore, we observe that the S59N mutation decreases IB1/JIP1 stability by sensitizing IB1/JIP1 to calcium- and proteasome-dependent degradation. These data indicate that calcium influx initiated by cytokines mediates ubiquitination and degradation of IB1/JIP1 and may, therefore, provide a link between calcium influx and JNK-mediated apoptosis in pancreatic beta-cells.
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PMID:Calcium- and proteasome-dependent degradation of the JNK scaffold protein islet-brain 1. 1450 25


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