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)

To gain insight into the mechanisms responsible for the loss of the glucagon response to insulin-induced hypoglycemia in type 1 diabetes, glucagon responses to 4 different stimuli were examined over 3 months of diabetes in alloxan-treated mice. At 1, 6, and 12 weeks after alloxan (60 mg/kg), phloridzin (0.1 g/kg) was administered to overnight fasted diabetic mice to match the glucose levels of those in nondiabetic control mice before administration of the acute stimuli. Despite the elevation of baseline glucagon levels produced by the phloridzin treatment, the glucagon responses to insulin (2 U/kg intraperitoneally [IP])-induced hypoglycemia was not impaired at 1 week. However, the response was reduced by greater than 60% after 6 and 12 weeks of diabetes (P <.05). In contrast, the glucagon response to arginine (0.25 g/kg intravenously [IV]) was not reduced after 1, 6, or 12 weeks of diabetes, ruling out a generalized impairment of the A-cell responses. The glucagon response to the neuroglucopenic agent, 2-deoxyglucose (2-DG; 500 mg/kg IV) was impaired, like that to insulin-induced hypoglycemia, after 6 and 12 weeks of diabetes (P <.05), suggesting that supersensitivity to the potential inhibitory effects of exogenous insulin is not the mechanism responsible for the impairment. Finally, the glucagon response to the cholinergic agonist, carbachol (0.53 micromol/kg IV), was not impaired in the diabetic animals, arguing against a defect in the A-cell's responsiveness to autonomic stimulation. The data suggest that the impairment of the glucagon response to insulin-induced hypoglycemia in alloxan diabetic mice is not due to a generalized impairment of A-cell responsiveness, to desensitization by a suppressive action of insulin, or to impairment of the A-cell response to autonomic stimuli. The remaining mechanisms which are likely to explain the late loss of the glucagon response to insulin-induced hypoglycemia include (1) a defect in the A-cell recognition of glucopenic stimuli, or (2) a defect in the autonomic inputs to the A cell that are known to be activated by glucopenic stimuli.
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PMID:Differential impairment of glucagon responses to hypoglycemia, neuroglycopenia, arginine, and carbachol in alloxan-diabetic mice. 1178 66

We have recently described a novel phenotype in a group of subjects with type 1 diabetes that is manifested by glucose >11.1 mmol/l 120 min after an oral glucose load, but with normal fasting glucose levels. We now describe the metabolic characteristics of these subjects by comparing parameters of islet hormone secretion and glucose disposal in these subjects to age-matched nondiabetic control subjects. The patients with type 1 diabetes had fasting glucose, insulin, and glucagon values similar to those of control subjects. Additionally, the insulin secretory response to intravenous arginine at euglycemia was similar in the control and diabetic groups (264 +/- 33.5 and 193 +/- 61.3 pmol/l; P = 0.3). However, marked differences in beta-cell function were found in response to hyperglycemia. Specifically, the first-phase insulin response was lower in diabetic subjects (329.1 +/- 39.6 vs. 91.3 +/- 34.1 pmol/l; P < 0.001), as was the slope of glucose potentiation of the insulin response to arginine (102 +/- 18.7 vs. 30.2 +/- 6.1 pmol/l per mmol/l; P = 0.005) and the maximum insulin response to arginine (2,524 +/- 413 vs. 629 +/- 159 pmol/l; P = 0.001). Although plasma levels of glucagon-like peptide (GLP)-1 and gastric inhibitory peptide (GIP) did not differ between control and diabetic subjects, the incretin effect was lower in the diabetic patients (70.3 +/- 5.4 vs. 52.1 +/- 5.9%; P = 0.03). Finally, there was a lack of suppression of glucagon in the patients after both oral and intravenous glucose administration, which may have contributed to their postprandial hyperglycemia. Glucose effectiveness did not differ between patients and control subjects, nor did insulin sensitivity, although there was a tendency for the patients to be insulin resistant (9.18 +/- 1.59 vs. 5.22 +/- 1.17 pmol.(-1).min(-1); P = 0.08). These data characterize a novel group of subjects with type 1 diabetes manifested solely by hyperglycemia following an oral glucose load in whom islet function is normal at euglycemia, but who have marked defects in both alpha- and beta-cell secretion at hyperglycemia. This pattern of abnormalities may be characteristic of islet dysfunction early in the development of type 1 diabetes.
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PMID:Impaired beta-cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose. 1191 12

Interleukin 1 (IL-1) is a pleiotropic cytokine with the potential to destroy pancreatic beta-cells, and thought to be involved in the pathogenesis of type I diabetes mellitus. Expression of inducible nitric oxide synthase (iNOS) and subsequent NO formation induced by IL-1beta may impair an islet function in rodents. Inhibition of iNOS may protect against cytokine-induced beta-cell suppression, although cytokines might also induce NO-independent impairment. To examine the role of NO in the IL-1beta treated cells, rat islets were treated with various concentrations (0, 0.5, 5, 50, 500 pmol/L) of IL-1beta with or without NG-monomethyl-L-arginine (NMMA; a competitive inhibitor of nitiric oxide synthase) for 2 or 6 h. Insulin secretion was stimulated in islets treated with 5, 50, and 500 pmol/ L of IL-1beta for 2 h and 0.5 pmol/L for 6 h, respectively. The stimulatory effect of IL-1beta on the insulin secretion of rat islets was not prevented by NMMA. Nitrate concentration was increased in a time- and concentration-dependent manner. Nitrate production was inhibited by NMMA. iNOS mRNA expression was increased at concentrations more than 5 pmol/L of IL-1beta in a dose dependent manner. iNOS mRNA was detectable after 2 h and peaked at 6 h but decreased after 24 h. These results suggested that the stimulatory effect of IL-1beta on the insulin secretion of rat islets is independent of iNOS-related NO production of IL-1beta and the enzyme activity of nitric oxide synthase.
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PMID:The stimulatory effect of IL-1beta on the insulin secretion of rat pancreatic islet is not related with iNOS pathway. 1198 73

IDDM is positively associated with HLA-DQA1*0301-DQB1*0302 (DQ8) and DQA1*0501-DQB1*0201 (DQ2) and negatively associated with DQA1*0102-DQB1*0602 (DQ6). The aim of the present study was to analyze the importance of several polymorphic residues and domains of DQalpha and DQbeta, in addition to residue 52 DQalpha and residue 57 DQbeta, with regard to susceptibility or resistance in new-onset 0- to 15-year-old Swedish children with IDDM (n = 425) and matched controls (n = 367). HLA genotyping identified several polymorphic residues of the DQalpha and DQbeta to be either positively or negatively associated with IDDM, including Arg 52 DQalpha and Asp 57 DQbeta. Leu 69 DQalpha was positively (OR 7.02, P < 0.0001), Ala 69 DQalpha was negatively (OR 0.22, P < 0.0001), Gln 47 DQalpha was positively (OR 5.8, P < 0.0001), Cys 47 DQalpha was positively (OR 2.2, P < 0.0001), Lys 47 DQalpha was negatively (OR 0.47, P < 0.005), and Arg 47 DQalpha was negatively (OR 0.22, P < 0.005) associated with IDDM. Similarly, residues at 11, 18, 45, 48, 50, 53, 55, 61, 64, 66, 76, and 80 were either positively or negatively associated with IDDM. Likewise, for DQbeta, Leu 53 DQbeta was positively (OR 11.01, P < 0.0001), Gln 53 DQbeta was negatively (OR 0.22, P < 0.0005), Arg 70 DQbeta was positively (OR 11.01, P < 0.0001), and Gly 70 DQbeta was negatively (OR 0.19, P < 0.0001) associated like other residues at 71, 74, 84, 85, 86, 89, and 90 DQbeta with IDDM. Certain domains in the DQalpha, RFTIL (at DQalpha positions 52, 61, 64, 66, and 69), were present in 95% of patients compared to 69% of controls (OR 9.01, P(c) < 0.0001), and DQbeta domain GR (at DQbeta positions 45 and 70) was present in 95% of patients and 68% of controls (OR 8.68, P < 0.0001), which correlated better than the individual amino acid residues with IDDM. A combination of the DQalpha and DQbeta chain domains was present in 94% of patients compared to 60% of controls (OR 10.6, P < 0.001). In conclusion, domains in the DQalpha, DQbeta, or both in the DQ molecule explain susceptibility or resistance to IDDM better than individual amino acid residues of DQA1 and DQB1.
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PMID:The combination of several polymorphic amino acid residues in the DQalpha and DQbeta chains forms a domain structure pattern and is associated with insulin-dependent diabetes mellitus. 1202 Nov 43

Cytokines released from activated antigen-presenting cells and T-lymphocytes are crucially involved in the pathogenesis of type 1 diabetes. Previous studies have shown that proinflammatory cytokines play an important role in the induction of autoimmunity and beta-cell damage. Inhibition of insulin expression has been described, but their effects on other major target autoantigens, such as the tyrosine phosphatase-like protein IA-2, is not known. In the present study, we established sensitive real-time RT-PCR to measure IA-2, insulin, and inducible nitric oxide (NO) synthase (iNOS) mRNA expression. Rat insulinoma INS-1 cells were stimulated with IL-1beta, TNF-alpha, interferon (IFN)-gamma, and IL-2 as well as with two combinations of these cytokines (C1: IL-1beta + TNF-alpha + IFN-gamma; C2: TNF-alpha + IFN-gamma). Treatment with IL-1beta, TNF-alpha, or IFN-gamma alone caused a significant down-regulation of IA-2 and insulin mRNA levels in a time and dose-dependent manner, whereas IL-2 had no effect. Exposure to cytokine combinations strongly potentiates the inhibitory effects. Incubation of cells with C1 and C2 for 24 h induces a significant inhibition of IA-2 mRNA levels by 78% and 58%, respectively. Under these conditions, an up to 5 x 10(4)-fold increase of iNOS gene expression was observed. The hypothesis that the formation of NO is involved in IA-2 regulation was confirmed by the finding that the coincubation of C1 with 4 mM L-N(G)-monomethyL-L-arginine, an inhibitor of the iNOS, partly reversed the down-regulation of IA-2. Further, incubation with the synthetic NO-donor S-nitroso-N-acetyl-D-L-penicillamine significantly decreased IA-2 mRNA level to 51% of basal levels. In conclusion, we have demonstrated for the first time that IL-1beta, TNF-alpha, and IFN-gamma exert a strong inhibitory effect on expression of the diabetes autoantigen IA-2. The action of IL-1beta may be partly mediated by the activation of the NO pathway.
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PMID:Effect of proinflammatory cytokines on gene expression of the diabetes-associated autoantigen IA-2 in INS-1 cells. 1223 95

OBJECTIVE-Impaired endothelial function of resistance and conduit arteries can be detected in patients with type 1 diabetes. We studied whether a persistent improvement of endothelial function can be achieved by regular physical training. RESEARCH DESIGN AND METHODS-The study included 26 patients with type 1 diabetes of 20 +/- 10 years' duration and no overt angiopathy; 18 patients (42 +/- 10 years old) participated in a bicycle exercise training program, and 8 patients with type 1 diabetes (33 +/- 11 years old) served as control subjects. Vascular function of conduit arteries was assessed by flow-mediated and endothelium-independent dilation of the brachial artery and of resistance vessels by the response of ocular fundus pulsation amplitudes to intravenous N(G)-monomethyl-L-arginine (L-NMMA) at baseline, after 2 and 4 months of training, and 8 months after cessation of regular exercise. RESULTS-Training increased peak oxygen uptake (VO(2max)) by 13% after 2 months and by 27% after 4 months (P = 0.04). Flow-mediated dilation (FMD) of the brachial artery increased from 6.5 +/- 1.1 to 9.8 +/- 1.1% (P = 0.04) by training. L-NMMA administration decreased fundus pulsation amplitude (FPA) by 9.1 +/- 0.9% before training and by 13.4 +/- 1.5% after 4 months of training (P = 0.02). VO(2max), FMD, and FPA were unchanged in the control group. Vascular effects from training were abrogated 8 months after cessation of exercise. CONCLUSIONS-Our study demonstrates that aerobic exercise training can improve endothelial function in different vascular beds in patients with long-standing type 1 diabetes, who are at considerable risk for diabetic angiopathy. However, the beneficial effect on vascular function is not maintained in the absence of exercise.
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PMID:Exercise training improves vascular endothelial function in patients with type 1 diabetes. 1235 80

Proinflammatory cytokine induction of NO synthesis may contribute to the destruction of pancreatic beta cells leading to type 1 diabetes. The NO synthase substrate arginine can also be metabolized to ornithine and urea in a reaction catalyzed by cytosolic (AI) or mitochondrial (AII) isoforms of arginase. Recent evidence suggests that the rate of NO generation is dependent on the relative activities of NO synthase and arginase. The objectives of this study were (i). to identify the arginase isoforms expressed in rat and human islets of Langerhans and a rat beta cell line, RINm5F and (ii). to investigate the competition for arginine between NO synthase and arginase in IL-1beta-treated rat islets. Arginase activity was detected in rat islets (fresh tissue, 346 mU/mg protein; cultured, 587 mU/mg), cultured human islets (56 mU/mg), RINm5F cells (376 mU/mg), rat kidney (238 mU/mg), and rat liver (6119 mU/mg). Using Western blots, AI was shown to be the predominant isoform expressed in rat islets and in RINm5F cells while human islets expressed far more AII than AI. Rat islets were cultured in medium containing 1.14, 0.1, and 0.01 mM arginine and treated with IL-1beta and the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH). IL-1beta-induced NO generation was unaffected by ABH at 1.14 mM arginine, but significantly increased at 0.1 and 0.01 mM arginine. These findings suggest that the level of islet arginase activity can regulate the rate of induced NO generation and this may be relevant to the insulitis process leading to beta cell destruction in type 1 diabetes.
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PMID:Arginase expression and modulation of IL-1beta-induced nitric oxide generation in rat and human islets of Langerhans. 1244 78

Insulin-dependent diabetes mellitus (type-1 diabetes) is an inflammatory autoimmune disease associated with vascular permeability changes leading to many complications including nephropathy, retinopathy, hypertension, hyperalgesia and neuropathy. The bradykinin B(1) receptor was recently found to be upregulated during the development of the diabetes and to be involved in its complications. Kinins are known to be important mediators of a variety of biological effects including cardiovascular homeostasis, inflammation and nociception. In the present study, we studied the effect of the selective B(1) receptor agonist, des-Arg(9)-bradykinin, and its specific antagonists, Ac-Lys-[D-beta Nal(7), Ile(8)]des-Arg(9)-bradykinin (R-715) and Ac-Orn-[Oic(2), alphaMe Phe(5), D-beta Nal(7), Ile(8)]des-Arg(9)-bradykinin (R-954), on diabetic hyperalgesia. Diabetes was induced in male CD-1 mice by injecting a single high dose of streptozotocin (200 mg kg(-1), i.p.) and the nociception was assessed using the hot plate and the tail flick tests, 1 week following the injection of streptozotocin. Our results showed that induction of diabetes by streptozotocin provoked a marked hyperalgesia in diabetic mice expressed as about 11% decrease in hot plate reaction time and 26% decrease in tail flick reaction time. Following acute administration of R-715 (200-800 microg kg(-1), i.p.) and R-954 (50-600 microg kg(-1), i.p.), this hyperalgesic activity was blocked and the hot plate and tail flick latencies of diabetic mice returned to normal values observed in control healthy mice. In addition, the acute administration of des-Arg(9)-bradykinin (200-600 microg kg(-1), i.p.) significantly potentiated diabetes-induced hyperalgesia, an effect that was totally reversed by R-715 (1.6-2.4 mg kg(-1), i.p.) and R-954 (0.8-1.6 mg kg(-1), i.p.). These results provide a major evidence for the implication of the bradykinin B(1) receptors in the development of hyperalgesia associated with diabetes and suggest a novel approach to the treatment of this diabetic complication using the bradykinin B(1) receptor antagonists.
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PMID:Role of bradykinin B(1) receptors in diabetes-induced hyperalgesia in streptozotocin-treated mice. 1246 57

The human transporter associated with antigen processing (TAP1 and TAP2) genes are located in the human leukocyte antigen (HLA) class II region of the genome and encode proteins that form a heterodimer essential for the transport of endogenous peptides into the endoplasmic reticulum for assembly with HLA class I molecules. Type 1 diabetes is an autoimmune disease that is associated with the HLA region of the genome, with HLA class II genes conferring the greatest statistical risk. The presentation of self-peptides by HLA class I molecules is defective in individuals with this disease, and both TAP1 and TAP2 are potential contributors to this defect. Denaturing gradient gel electrophoresis (DGGE) was applied to screen all 11 exons and the 3' flanking region of TAP2 for polymorphisms in individuals with type 1 diabetes patients and controls. Seventy polymorphisms, including 51 in introns, 4 in the 3' flanking region, and 15 in exons, were identified. Sequencing of polymorphic DNA fragments revealed several new polymorphisms, including a Gln --> Arg substitution at codon 611 and a GT --> GC polymorphism affecting the donor splice site of intron 4, that might be of functional significance. None of the polymorphisms examined differed in frequency between individuals with type 1 diabetes and controls.
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PMID:Polymorphisms of human TAP2 detected by denaturing gradient gel electrophoresis. 1250 27

The Arg(972) insulin receptor substrate-1 (IRS-1) variant has been hypothesized to play a role in pancreatic beta-cell stimulus-coupled insulin secretion and survival. We analyzed the relations between type 1 diabetes and the Arg(972) IRS-1 variant. The frequency of the IRS-1 Arg(972) variant was investigated in two independent sets of unrelated patients: a case-control study and a collection of type 1 diabetes simplex families. In the former group, frequency of the IRS-1 Arg(972) variant was significantly increased in the patients (P = 0.0008), conferring an OR of 2.5. Transmission disequilibrium analysis of data obtained from the family set revealed that the Arg(972) IRS-1 variant was transmitted from heterozygous parents to affected probands at a frequency of 70.2% (P < 0.02). Arg(972) IRS-1 frequency showed no significant correlation with HLA genotypic risk for type 1 diabetes. Arg(972) IRS-1 type 1 diabetic patients also had lower fasting plasma concentrations of C-peptide at the time of diagnosis with respect to patients carrying the wild-type IRS-1 (0.49 +/- 0.058, n = 34, and 0.76 +/- 0.066, n = 134, respectively [means +/- SE]; P = 0.051). Our findings suggest a role for Arg(972) IRS-1 in conferring risk for the development of type 1 diabetes.
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PMID:The Gly972-->Arg IRS-1 variant is associated with type 1 diabetes in continental Italy. 1260 35


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