Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus is an autoimmune disease that is genetically linked to the HLA class II molecule DQ in humans and to MHC I-Ag7 in nonobese diabetic mice. The I-Ag7 beta-chain is unique and contains multiple polymorphisms, at least one of which is shared with DQ alleles linked to insulin-dependent diabetes mellitus. This polymorphism occurs at position 57 in the beta-chain, in which aspartic acid is mutated to a serine, a change that results in the loss of an interchain salt bridge between alphaArg76 and betaAsp57 at the periphery of the peptide binding groove. Using mAbs we have identified alternative conformations of I-Ag7 class II molecules. By using an invariant chain construct with various peptides engineered into the class II-associated invariant chain peptide (CLIP) region we have found that formation of these conformations is dependent on the peptide occupying the binding groove. Blocking studies with these Abs indicate that these conformations are present at the cell surface and are capable of interactions with TCRs that result in T cell activation.
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PMID:The MHC class II molecule I-Ag7 exists in alternate conformations that are peptide dependent. 1092 90

Protein tyrosine phosphatase 1B (PTP1B) negatively regulates insulin signaling in part by dephosphorylating key tyrosine residues within the regulatory domain of the beta-subunit of the insulin receptor (IR), thereby attenuating receptor tyrosine kinase activity. Inhibition of PTP1B is therefore anticipated to improve insulin resistance and has recently become the focus of discovery efforts aimed at identifying new drugs to treat type II diabetes. We previously reported that the tripeptide Ac-Asp-Tyr(SO(3)H)-Nle-NH(2) is a surprisingly effective inhibitor of PTP1B (K(i) = 5 microM). With the goal of improving the stability and potency of this lead, as well as attenuating its peptidic character, an analogue program was undertaken. Specific elements of the initial phase of this program included replacement of the N- and C-termini with non-amino acid components, modification of the tyrosine subunit, and replacement of the tyrosine sulfate with other potential phosphate mimics. The most potent analogue arising from this effort was triacid 71, which inhibits PTP1B competitively with a K(i) = 0.22 microM without inhibiting SHP-2 or LAR at concentrations up to 100 microM. Overall, the inhibitors generated in this work showed little or no enhancement of insulin signaling in cellular assays. However, potential prodrug triester 70 did induce enhancements in 2-deoxyglucose uptake into two different cell lines with concomitant augmentation of the tyrosine phosphorylation levels of insulin-signaling molecules. Key elements of the overall SAR reported herein include confirmation of the effectiveness and remarkable PTP1B-specificity of the novel tyrosine phosphate bioisostere, O-carboxymethyl salicylic acid; demonstration that the tyrosine skeleton is optimal relative to closely related structures; replacement of the p-1 aspartic acid with phenylalanine with little effect on activity; and demonstration that inhibitory activity can be maintained in the absence of an N-terminal carboxylic acid. An X-ray cocrystal structure of an analogue bearing a neutral N-terminus (69) bound to PTP1B is reported that confirms a mode of binding similar to that of peptidic substrates.
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PMID:Synthesis and biological activity of a novel class of small molecular weight peptidomimetic competitive inhibitors of protein tyrosine phosphatase 1B. 1180 12

Polymorphisms of the genes involved in the metabolism of vitamin D may predispose to type 2 diabetes mellitus (T2DM). For example, there is evidence suggesting that vitamin D binding protein (DBP) amino acid variants at codons 416 (aspartic acid-->glutamic acid) and 420 (threonine-->lysine) may affect genetic susceptibility to T2DM. The aims of this study are: (1) to determine the allele, genotype, haplotype and haplotype combination frequencies of those DBP amino acid variants in a Polish population and (2) to examine their role in the genetic susceptibility to T2DM in a Polish population. Overall 393 individuals were included in this study: 231 T2DM patients and 162 controls. The sequence of DBP exon 11, which contains both examined variants, was amplified by polymerase chain reaction (PCR). Alleles and genotypes were determined based on electrophoresis of the DNA digestion products by specific restriction enzymes HaeIII and StyI. Since variants of DBP were in very strong linkage disequilibrium, haplotypes could be assigned to phase-unknown individuals. Differences in distributions between the groups were examined by chi(2) test. At codon 416 the frequency of Asp/Glu alleles was 44.6/55.4% in T2DM patients and 40.7/59.3% in controls (chi(2)=2.1, d.f.=1, P=0.28). At codon 420 the frequency of Thr/Lys alleles were 69.4/30.6% and 71.6/28.4%, (chi(2)=0.41, d.f.=1, P=0.52), respectively. Distribution of genotypes, haplotypes and haplotype combinations were similar in both groups. In conclusion, the frequency of amino acid variants at codons 416 and 420 of vitamin D binding protein gene in a Polish population is similar to other Caucasian populations, but differs significantly from other races. No evidence was found for an association between DBP frequent polymorphisms and T2DM in this population.
Diabetes Res Clin Pract 2002 Aug
PMID:Vitamin D binding protein gene and genetic susceptibility to type 2 diabetes mellitus in a Polish population. 1206 54

Many plants are used in traditional medicine as active agents against various effects induced by snakebite. Few attempts have been made however to identify the nature of plant natural products with anti-ophidian properties. Baccharis trimera (Less) DC (Asteraceae), known in Brazil as carqueja, has been popularly used to treat liver diseases, rheumatism, diabetes, as well as digestive, hepatic and renal disorders. The active component was identified as 7alpha-hydroxy-3,13-clerodadiene-16,15:18,19-diolide, C20H28O5, (clerodane diterpenoid, Bt-CD). We report now the anti-proteolytic and anti-hemorrhagic properties against snake venoms of a Bt-CD inhibitor from B. trimera. Bt-CD exhibited full inhibition of hemorrhage and proteolytic activity caused by Bothrops snake venoms. The inhibitor was able to neutralize the hemorrhagic, fibrinogenolytic and caseinolytic activities of class P-I and III metalloproteases isolated from B. neuwiedi and B. jararacussu venoms. No inhibition of the coagulant activity was observed. Bt-CD also partially inhibited the edema induced by other crude venoms, metalloproteases, basic and acidic phospholipases A2. To further elucidate the inhibitory specificity of Bt-CD against metalloproteases isolated from snake venoms, a deeper understanding of its structure and function is necessary. Furthermore, the potential use of these inhibitors to complement anti-venom as an alternative treatment of snakebite envenomations needs to be evaluated in future studies.
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PMID:Neo-clerodane diterpenoid, a new metalloprotease snake venom inhibitor from Baccharis trimera (Asteraceae): anti-proteolytic and anti-hemorrhagic properties. 1556 Aug 91

Nanomaterials have gained tremendous importance in biology and medicine because they can be used as carriers for delivering small molecules such as drugs, proteins, and genes. We report herein the binding of the hormone insulin to gold nanoparticles and its application in transmucosal delivery for the therapeutic treatment of diabetes mellitus. Insulin was loaded onto bare gold nanoparticles and aspartic acid-capped gold nanoparticles and delivered in diabetic Wistar rats by both oral and intranasal (transmucosal) routes. Our principle observations are that there is a significant reduction of blood glucose levels (postprandial hyperglycemia) when insulin is delivered using gold nanoparticles as carriers by the transmucosal route in diabetic rats. Furthermore, control of postprandial hyperglycemia by the intranasal delivery protocol is comparable to that achieved using the standard subcutaneous administration used for type I diabetes mellitus, thus showing considerable promise for further development.
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PMID:Gold nanoparticles as carriers for efficient transmucosal insulin delivery. 1637 35

Islet transplantation is associated with a high rate of early graft failure caused by early immune attack and poor functionality of islets. Apoptosis of islet cells appears soon after islet isolation and primarily involves the beta-cell. The purpose of this study was to determine the effect of ligation to extracellular matrix (ECM) proteins on survival of the islets of Langerhans following islet isolation. Islets that had been cultured for 24 h on collagen type I showed an islet survival of 59.7 +/- 8.7%, while islets that had been cultured on collagen type IV and laminin showed an islet survival of 88.6 +/- 10.3 and 94.3 +/- 5.6%, respectively. Islets that had been pretreated with anti-beta1 antibodies and argenin-glycin-aspartic acid (RGD) peptides showed a decrease in the level of apoptosis by a factor of 2.5 and 3.1, respectively, and an increase of phospho-Akt Ser 473 activity by a factor of 3.1 and 2.9, respectively, compared with untreated islets. When detached from their natural ECM surrounding in the pancreas, islet cells undergo apoptosis, unless islets are cultured on collagen IV or laminin or treated with anti-beta1 integrin antibodies or RGD peptides to mimic ECM ligation. These results indicate that inhibition of anoikis may offer opportunities to improve function and viability of islet cells.
Diabetes 2006 Feb
PMID:Integrin signaling via RGD peptides and anti-beta1 antibodies confers resistance to apoptosis in islets of Langerhans. 1644 62

Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRbeta gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRbeta mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRbeta mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.
Exp Clin Endocrinol Diabetes 2006 Nov
PMID:A novel mutation (E333D) in the thyroid hormone beta receptor causing resistance to thyroid hormone syndrome. 1717 39

Type I diabetes is a chronic autoimmune disease resulting in the destruction of insulin-producing beta cells in the pancreas. In humans, disease incidence is linked to expression of specific MHC class II alleles and in mice type I diabetes is associated with the class II allele I-A(g7). I-A(g7) contains a polymorphism that is shared by human class II alleles associated with the disease, at position 57 in the beta chain, in which aspartic acid is changed to a serine. The P9 pocket in the peptide-binding groove is in part shaped by beta57, and therefore the structure of this pocket is modified in I-A(g7). Using mAbs, we have previously determined that alternative conformations of I-A(g7) form in response to peptide binding. In this study, we have extended these findings by examining how peptides induce I-A(g7) molecules to adopt different conformations. By mutating the amino acid in the P9 position of either class II-associated invariant chain peptide (CLIP) or glutamic acid decarboxylase (GAD) 65 (207-220), we have determined that the chemical nature of the P9 anchor amino acid, either acidic or small hydrophobic, affects the overall conformation of the I-A(g7) class II molecule. T cell hybridomas specific for GAD 65 (207-220) in the context of I-A(g7) were also examined for recognition of I-A(g7) bound to GAD 65 (207-220), in which Glu(217) in the P9 position was changed to alanine. We found that although some TCRs were able to recognize both peptides in the context of I-A(g7), and thus both class II conformations, approximately one-third of the T cells tested were not able to recognize the alternate class II conformation formed with the mutated peptide. These results indicate that the I-A(g7) conformations may affect functional activation of T cells, and thus may play a role in autoimmunity.
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PMID:Conformation of MHC class II I-A(g7) is sensitive to the P9 anchor amino acid in bound peptide. 1785 34

An alpha-amylase inhibitor (alpha-AI) was isolated from white kidney beans (Phaseolus vulgaris L) by ethanol fractional precipitation, ion exchange chromatography and gel filtration column chromatography. It was a homogeneity glycoprotein demonstrated by SDS-PAGE and gel filtration on CL-6B. The glycoprotein contained 88.2% protein and was rich in aspartic acid, glutamic acid, leucine, threonine and serine. The carbohydrate moiety was consisted of Man, Glc, Gal and Xyl in a mole ratio of 2.42: 1.50: 1.52: 1.00. The glycan and the core protein backbone was connected by O-linkage as determined by beta-elimination reaction. The continuous oral administration of the alpha-AI (150 mg x kg(-1) x d(-1)) for 7 days can lower fasting blood glucose and 300 mg x kg(-1) x d(-1) alpha-AI for 7 days can improve the sugar tolerance on alloxan-dependent diabetic model rats. The result showed the alpha-AI obtained from white kidney beans had good hypoglycemic effect on alloxan induced diabetic rats and may have high potential pharmaceutical value as a regulative digestive-starch degradation in patients suffering from diabetes.
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PMID:Isolation and activity of an alpha-amylase inhibitor from white kidney beans. 1833 41

Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-A(g7) lacking a canonical aspartic acid residue at position beta57 are associated with coeliac disease and type I diabetes. However, the role of this single polymorphism in disease initiation and progression remains poorly understood. The lack of Asp 57 creates a positively charged P9 pocket, which confers a preference for negatively charged peptides. Gluten lacks such peptides, but tissue transglutaminase (TG2) introduces negatively charged residues at defined positions into gluten T-cell epitopes by deamidating specific glutamine residues on the basis of their spacing to proline residues. The commonly accepted model, proposing that HLA-DQ8 simply favours binding of negatively charged peptides, does not take into account the fact that TG2 requires inflammation for activation and that T-cell responses against native gluten peptides are found, particularly in children. Here we show that beta57 polymorphism promotes the recruitment of T-cell receptors bearing a negative signature charge in the complementary determining region 3beta (CDR3beta) during the response against native gluten peptides presented by HLA-DQ8 in coeliac disease. These T cells showed a crossreactive and heteroclitic (stronger) response to deamidated gluten peptides. Furthermore, gluten peptide deamidation extended the T-cell-receptor repertoire by relieving the requirement for a charged residue in CDR3beta. Thus, the lack of a negative charge at position beta57 in MHC class II was met by negatively charged residues in the T-cell receptor or in the peptide, the combination of which might explain the role of HLA-DQ8 in amplifying the T-cell response against dietary gluten.
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PMID:The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease. 1903 17


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