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)

We identified a heterozygous missense mutation that substituted aspartic acid (GAC) for alanine (GCC) at codon 1048 of the insulin receptor gene in a patient who displayed typical symptoms of Type A syndrome of insulin resistance. The proband's mother and younger brother were also found to be heterozygous for the mutation. We constructed the identified mutant insulin receptor cDNA by site-directed mutagenesis, transfected the mutant cDNA into COS 7 cells, and found that kinase activity of the mutant insulin receptors was markedly impaired. Ala1048 is located in the kinase domain of the insulin receptor beta-subunit and is conserved in most of protein-tyrosine kinases. Besides, neighboring Glu1047 is invariant in all protein kinases and is thought to be involved in interaction with ATP. Photoaffinity labeling of the mutant insulin receptor with ATP analogue, 8-azido (alpha-32P)ATP was not influenced by the mutation, suggesting that the mutation did not inhibit ATP binding but possibly interfered with subsequent phosphoryl transfer. Insulin-stimulated phosphorylation of exogenous substrate by partially purified insulin receptors prepared from COS 7 cells that were cotransfected with wild-type and mutant insulin receptor cDNAs was markedly impaired, whereas autophosphorylation was decreased by approximately 50% of wild-type receptors. These results indicated that the identified heterozygous substitution of Asp for Ala1048 in insulin receptor was responsible for insulin resistance of this patient.
Diabetes 1993 Dec
PMID:Ala1048-->Asp mutation in the kinase domain of insulin receptor causes defective kinase activity and insulin resistance. 824 30

Homogenates of pancreatic islets catalyzed breakdown of L-glutamate to GABA with a rate of 0.24 +/- 0.04 nmol.min-1 x mg-1 protein at 37 degrees C. The formation of GABA was stimulated by addition of pyridoxal phosphate in the range 0.05-1 microM (0.97 +/- 0.02 nmol.min-1 x mg protein-1 at a saturating cofactor concentration), which indicates that the process was catalyzed by glutamic acid decarboxylase. The half-maximal effect was obtained with 0.1 microM PLP. Kinetic analyses of the results showed that the Vmax and Km for the reaction were 1.12 nmol.min-1 x mg protein-1 and 0.66 mM, respectively. The pH optimum was 7.0. Subcellular fractionation revealed that 51% of GAD activity was present in the cytosol, 17% in microsomes, 9% in secretory granules, 5% in mitochondria, and 11% in cell debris. Comparison of the kinetic properties of the cytosolic and microsomal forms of the enzyme showed that their Km for glutamate was the same, but that the cytosolic GAD had a lower Km for PLP. GABA synthesis in the nominal absence of PLP was enhanced by malate (twofold increase at 5 mM) and citrate (threefold increase at 5 mM), but was unaffected by ATP and chloride. However, if the islet homogenate was prepared and incubated in the presence of PLP, neither malate nor citrate influenced enzyme activity. Aspartate and AOA were powerful inhibitors of glutamate breakdown. Freshly isolated islets contained approximately 4 mM GABA, whereas the concentration was < 0.1 mM in whole pancreas.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Oct
PMID:GABA production in rat islets of Langerhans. 837 91

We report on HLA-DQB1 typing in IDDM patients of north east Italian region using an enzymatic method based on the detection of hybridization reaction between PCR amplified DNA from whole blood and allele specific oligonucleotides by an antibody directed against double stranded DNA (DNA-enzyme immunoassay or DEIA). The method is reliable, simple and sensitive as the classical radioactive method with the advantage of using a universal non radioactive detection reagent. Nineteen families, each including one subject with juvenile insulin-dependent diabetes mellitus (IDDM) were analyzed. A strong association between absence of an aspartic acid (Asp) in position 57 of DQB1 beta chain in homozygous conditions and susceptibility to IDDM was found. In contrast with some previous observations, however, no significant association was found between Asp/non-Asp heterozygous genotype and IDDM. No patients were found with an homozygous Asp/Asp genotype, known to be protective in caucasoid population. Of particular interest was the DQB1 allelic distribution in our population sample. The non-Asp allele most frequently found in IDDM subjects was the DQB1 0201 allele and this finding was statistically significant (Pc value < 0.05, relative risk = 5.01). No significant association was found for any other allele including the DQB1 0302 (Pc value = not significant although with relative risk = 3.28) previously reported as the most frequent allele in IDDM caucasoid patients.
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PMID:HLA-DQB1 typing of north east Italian IDDM patients using amplified DNA, oligonucleotide probes and a rapid DNA-enzyme immunoassay (DEIA). 841 76

Although inflammatory or degenerative changes in salivary glands have been demonstrated in genetic animal models of diabetes mellitus and in experimental diabetes, no information is available in diabetics on the possible leakage in saliva of cytosolic enzymes as markers of salivary cell injury. Aspartate (GOT) and alanine (GPT) aminotransferases and lactate dehydrogenase (LDH) were determined in saliva samples collected by the Salivette method from well-controlled insulin-dependent (IDDM n = 11) and non-insulin-dependent (NIDDM n = 18) diabetic patients and from age-cross-matched healthy subjects (n = 33). In IDDM salivary concentrations of GOT (112.55 +/- 23.94 UI/L) and LDH (1120.27 +/- 168.31 UI/L) were similar to those found in the NIDDM (90.94 +/- 19.64, and 1255.43 +/- 221.40 UI/L respectively), but higher (p < 0.05) than those observed in normal subjects (33.09 +/- 3.71, and 423.58 +/- 39.94, UI/L respectively). GPT was higher in NIDDM than IDDM, which in turn was higher than in normal subjects (42.78 +/- 14.72, 16.45 +/- 3.74 and 6.85 +/- 1.52 UI/L respectively). Salivary and serum values of GOT, GPT and LDH were not correlated. Determination of cytosolic enzymes in saliva may be useful for monitoring the diabetic involvement of salivary glands.
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PMID:Aminotransferases and lactate dehydrogenase in saliva of diabetic patients. 844 46

We examined the apolipoprotein E polymorphism of an obese patient presenting non-insulin-dependent diabetes, hypertension and moderate lipid disturbances. The apolipoprotein E genotyping carried out from leukocyte DNA using PCR amplification and restriction enzyme digestion demonstrated homozygosity for the rare apoE1[Gly127-->Asp; Arg158--> Cys] (Weisgraber allele). The nucleotide change results in a glycine to aspartic acid substitution at amino acid 127 in the apolipoprotein E2.
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PMID:Genotyping of a patient homozygous for a rare apolipoprotein E1 [Gly127-->Asp; Arg158-->Cys] (Weisgraber allele). 875 Jun 11

MHC associations with IDDM in the Korean population were studied to investigate genetic susceptibility to this disorder. The frequencies of HLA-DR3, -DR4 and -DR9 were significantly higher in diabetic patients. However, the frequency of DR2 was significantly decreased in diabetic patients. DQA1*0301 and DQA1*0501 were positively and DQA1*0102 and DQA1*0201 negatively associated with IDDM. DQB1*0301 and DQB1*0601 were negatively associated with IDDM. Heterodimers DQA1*0301-DQB1*0201, DQA1*0501-DQB1*0201 and DQA1*0501-DQB1*0302 were positively associated with DQA1*0102-DQB1*0601 negatively associated with IDDM. The frequencies of DR3-DQA1*0301-DQB1*0201 and -DQA1*0501-DQB1*0201 were significantly higher in diabetic patients. The frequencies of DR4-DQA1*0301-DQB1*0201 and DR9-DQA1*0301-DQB1*0303 were significantly higher in diabetic patients. The presence of non-aspartic acid at position 57 of the DQ beta-chain was not associated with susceptibility to IDDM. However, the frequency of Arg 52 homozygotes was significantly higher in diabetic patients. These results suggest a role of the MHC molecule and also suggest racial differences in susceptibility to IDDM even within the Asian populations.
Diabetes Res Clin Pract 1996 Mar
PMID:Role of HLA class II alleles in Korean patients with IDDM. 879 97

Rat myoblast primary cultures were tested as a model for proinsulin synthesis and processing and unregulated insulin delivery for insulin-dependent diabetes mellitus (IDDM) gene therapy. Three human proinsulin cDNA constructs containing genetically engineered furin endoprotease cleavage sites between the B-chain and C-peptide (IFur) and between the C-peptide and A-chain (IIFur) and/or containing a histidine B10 to aspartic acid point mutation were subcloned into a mammalian expression vector (pCMV) containing the cytomegalovirus (CMV) promoter. The altered cleavage sites enable the insulin to be processed by the ubiquitous endoprotease furin. The histidine B10 to aspartic acid mutation creates a more stable form of insulin leading to an increase in insulin accumulation. Myoblasts transfected with a proinsulin cDNA construct mutated at all three sites (pCMV.IFur.IIFur.B10), a construct with only the furin sites (pCMV.IFur.IIFur), and a construct containing only the mutation at the B10 position (pCMV.B10) accumulated 852 +/- 16, 150 +/- 13, and 883 +/- 39 microU (pro)insulin/ml, respectively, in the culture medium during a 48-hr incubation. (Pro)insulin was detected in the culture medium within 2 hr post-transfection. Significant (pro)insulin release continued for 1 week and gradually diminished over a month. Approximately 50% of the proinsulin released from rat myoblasts transfected with pCMV.IFur.IIFur.B10 was completely processed into mature insulin based on densitometric analysis of autoradiographs of gels containing immunoprecipitated 35S-Cys-labeled (pro)insulin. However, only a trace of the proinsulin encoded by pCMV.B10 was processed. In an isolated rat adipocyte [14C]glucose oxidation assay, insulin released from myoblasts transfected with pCMV.IFur.IIFur.B10 was active biologically, displaying more biological activity than normal human insulin. Plasmid expression was studied by transfecting myoblasts with the beta-galactosidase (beta-Gal) gene in pCMV, allowing them to divide and fuse into multinucleated myotubes, followed by staining for beta-Gal. Approximately 80% of myotubes expressed beta-Gal. The results indicate that proinsulin encoded by genetically modified proinsulin cDNA is processed into mature insulin, which is secreted at high levels, making myoblasts a viable target cell for gene therapy of IDDM.
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PMID:Synthesis and processing of genetically modified human proinsulin by rat myoblast primary cultures. 882 70

We report a point mutation in the ligand-binding domain of the TR beta 1 gene in an affected patient and his daughter. The phenotype was borderline hyperthyroid with periodic aggravation of symptoms. In the cognate variant TR beta (TR beta-CN) amino acid codon 322 was exchanged from aspartic acid to asparagine. TR beta-CN revealed strongly decreased T3-binding activity. At low T3 levels TR beta-CN transactivated a palindromic thyroid hormone response element (TRE-PAL) only to a limited extend, whereas full activity was retained at a high T3 concentration. At low T3 levels, TR beta-CN exerted a dominant negative effect on wild-type TR beta, whereas this effect was diminished in the presence of high T3 concentrations. TR beta-CN could not be activated by retinoid X receptor (RXR) beta in the presence of T3, whereas addition of 9cis-retinoic acid (9c-RA) resulted in the transactivation of TRE-PAL through RXR beta independently of the presence of TR beta-CN. In conclusion, the time dependent variable THR phenotype of patient CN might be influenced by the differential expression of RXRs and the T3 and 9c-RA hormonal status.
Exp Clin Endocrinol Diabetes 1996
PMID:Periodically hyperthyroid phenotype in thyroid hormone resistance is associated with mutation D322N in the thyroid hormone receptor beta gene: transcriptional properties of the mutant and the role of retinoid X receptor. 898 Oct 16

The WHO DiaMond Molecular Epidemiology Sub-Project is testing the hypothesis that the geographic differences in IDDM incidence reflect population variation in the frequency of IDDM susceptibility genes (i.e., DQA1 and DQB1 alleles with sequences coding for arginine (R) in position 52 of the DQ alpha-chain, and an amino acid other than aspartic acid (ND) in position 57 of the DQ beta-chain, respectively) using a standardized case-control design. Data from twelve populations which have completed (or have nearly completed) recruitment and HLA molecular analyses are presented. There was an approximate 2-fold increase in the frequencies of DGA1*0301, DQB1*0201 and DQB11*0302 among IDDM cases compared to non-diabetic controls in most populations. Interestingly, DQA*0301 was more common in low versus moderate-high incidence countries. DQB1*0201 and DQB1*0302 were more prevalent in the moderate-high incidence areas. DQA1*R and DQB1*ND were both consistent markers of IDDM risk, with stronger associations in moderate-high versus low incidence areas. In general, individuals homozygous for both DQA1*R and DQB1*ND had the highest genotype-specific IDDM incidence rates, which approximated risk estimates for first degree relatives in several countries. These data revealed considerable variation in the frequencies of DQB1 and DQA1 alleles across countries, which likely contribute to the global patterns of IDDM incidence.
Diabetes Res Clin Pract 1996 Oct
PMID:Molecular IDDM epidemiology: international studies. WHO DiaMond Molecular Epidemiology Sub-Project Group. 901 79

HLA-DQA11 and DQB1 alleles coding for arginine (R) in position 52, and an amino acid other than aspartic acid (ND) in position 57, respectively, are strong genetic markers for IDDM in Caucasians. However, their contribution to the occurrence of the disease in Asian populations is less clear. As part of the WHO DiaMond Molecular Epidemiology Sub-Project, HLA-DQ molecular typing was performed for IDDM cases and non-diabetic controls from three populations in the Western Pacific Rim Region where incidence rates have been established (Hokkaido, Japan; Seoul, Korea; Auckland, New Zealand). DQA1*R homozygosity was significantly associated with IDDM in all areas. DQB1*ND homozygosity was also related to IDDM in Korea and New Zealand, but not in Japan. Individuals who were homozygous for DQA1*R and DQB1*ND were at highest IDDM risk in Korea and New Zealand, with the most striking findings in Auckland. In Japan, individuals carrying two DQA1*R, but only one DQB1*ND allele, were most likely to develop IDDM. These data revealed considerable genetic heterogeneity between Japan and Korea and suggest that DQA1*R and DQB1*ND alleles may explain a larger proportion of IDDM incidence in Caucasian compared to Asian populations.
Diabetes Res Clin Pract 1996 Oct
PMID:Molecular epidemiology of IDDM in the Western Pacific Rim Region. WHO DiaMond Molecular Epidemiology Sub-Project Group. 901 80


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