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)

TAP2 genes are placed within the HLA complex, have limited genetic variability and encode two main groups of peptide transporter proteins, the so-called TAP2*01 alleles, with a short ATP-binding domain, and the TAP2*0201 allele with a long domain. These transporters carry antigenic peptides from cytoplasm across the endoplasmic reticulum membrane to release them into nascent HLA class I molecules, which will then travel towards the plasma membrane. The shorter TAP2*01 alleles are present in 99% of diabetics and 90% of controls; these alleles may add slight, although significant and independent, susceptibility to diabetes, particularly in subjects carrying non-Asp 57 at beta DQ. Moreover, this increased susceptibility is not due to linkage disequilibrium with other HLA markers (i.e.: DR4), which does not exist in our Spanish population.
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PMID:Susceptibility to insulin-dependent diabetes mellitus and short cytoplasmic ATP-binding domain TAP2*01 alleles. 783 51

Although the HLA class II genes are clearly associated with insulin-dependent diabetes mellitus (IDDM) in all ethnic groups, considerable variation in the associated haplotypes is observed among the ethnic groups. In Japanese, DRB1*0405-DQA1*0301-DQB1*0401, DRB1*0901-DQA1*0301-DQB1*0303 and DRB1*0802-DQA1*0301-DQB1*0302 are the major susceptibility haplotypes to IDDM, while DRB1*1501-DQA1*0102-DQB1*0602 and DRB1*1502-DQA1*0103-DQB1*0601 are the major resistance haplotypes. The hypothesis that alleles encoding amino acids other than aspartic acid at the DQB1 position 57 contribute to IDDM susceptibility is not applicable to the Japanese, mainly because the first and second susceptibility haplotypes listed above have aspartic acid at DQB1 position 57. In the 5' insulin gene polymorphism, the shorter insertion (class 1 allele) is predominant, and is not associated with diabetes in Japanese. Subdivision of the class 1 alleles also failed to show an association with IDDM in Japanese. The insulin gene region appeared to be of less value as a genetic marker for IDDM in Japanese. Little is known about other genetic markers.
Diabetes Res Clin Pract 1994 Oct
PMID:Genetic markers for insulin-dependent diabetes mellitus in Japanese. 785 39

Mexican American patients (n = 35) with insulin-dependent diabetes mellitus (IDDM) and control subjects (n = 39) were HLA-DQA and DQB typed by the polymerase chain reaction technique combined with allele-specific oligonucleotide probes. Either DQB1*0302 or DQB1*0201 was present among 91% (32/35) of the patients compared to 67% (26/39) of controls. Either DQA1*0501 or DQA1*0301 was present in all patients (100% or 35/35) compared to 29/39 (74%) (OR 12.06 Pc < 0.05) of controls. All four of these genes, in cis or trans, were present in 15/35 (43%) of the patients compared to 3/39 (8%) of controls (OR 9.0; Pc < 0.01). The presence of one or more non-susceptibility alleles showed a dose-related decrease in relative risk. Presence of aspartic acid (Asp) at position 57 of the DQ beta chain did not confer protection and non-Asp homozygosity did not confer susceptibility to IDDM in this ethnic group. In conclusion, susceptibility to IDDM in Mexican Americans is associated with particular DQA and DQB combinations, illustrates dose-dependent parameters and contradicts the critical residue hypothesis.
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PMID:Analysis of HLA-DQA1 and -DQB1 genes in Mexican Americans with insulin-dependent diabetes mellitus. 790 90

Hypertriglyceridemia is common among individuals with noninsulin-dependent diabetes mellitus (NIDDM), and heterozygous lipoprotein lipase (LPL) mutations may result in the syndrome of familial hypertriglyceridemia and low levels of high density lipoprotein (HDL) cholesterol. To test the hypothesis that heterozygous LPL mutations predispose to the hypertriglyceridemia and low HDL cholesterol levels observed among members of familial NIDDM families, we examined 36 members and 3 unrelated spouses selected from members of 20 pedigrees for triglyceride levels exceeding the age- and sex-specific 95th percentile. Eighteen pedigree members and 2 spouses were diabetic. LPL exons 1-9 were screened by single strand conformation polymorphism analysis. Six different variants were detected in exons 2, 3, 4, 8, and 9, including 4 (exons 3, 4, and 8) silent nucleotide substitutions. A common nonsense mutation (exon 9; Ser-->Ter) was present in 2 pedigrees, and a missense mutation (exon 2; Asp-->Asn) was also present in members of 2 pedigrees. Analysis of members of these families suggested an association of the exon 2 variant with hypertriglyceridemia, although this trend was no longer significant when individuals with diabetes were excluded from the analysis. The variant enzyme was not present among 83 random control individuals, and when expressed in COS-1 cells, it was similar to the wild type with respect to specific activity, heparin binding, and heat stability. Our data suggest that coding region mutations of the LPL gene cannot account for the elevated triglyceride and low HDL levels noted in diabetic individuals and their relatives in most NIDDM pedigrees, but the exon 2 Asn variant may contribute to the hypertriglyceridemia in some families.
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PMID:Molecular screening of the lipoprotein lipase gene in hypertriglyceridemic members of familial noninsulin-dependent diabetes mellitus families. 796 42

Susceptibility to insulin-dependent diabetes mellitus (IDDM) is determined by both genetic and environmental factors. The major genetic susceptibility to IDDM is conferred by genes in the HLA class II region on chromosome 6. In Caucasians, this susceptibility is thought to be determined by DQA1 and DQB1 genes including the presence of arginine at position 52 of the DQ alpha chain and the absence of aspartic acid at position 57 of the DQ beta chain. In Japanese subjects, IDDM has been found to be associated DR, DQA1, and DQB1 genes. Positive associations with arginine at position 52 of the DQ alpha chain have been demonstrated in Japanese IDDM patients. However, the majority of Japanese IDDM patients do not show positive association to the absence of aspartic acid at position 57 of the DQ beta chain. Susceptibility to IDDM in Japanese subjects appears to be due to combination of DR genes and DQA1-DQB1 haplotypes.
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PMID:[Analysis of HLA-DR, -DQA1, -DQB1 genes in Japanese IDDM patients]. 798 9

We examined the prevalence of HLA-DRB1, DQB1, DQA1 and TAP2 genes in children with insulin-dependent diabetes mellitus (type 1 diabetes). These HLA and TAP2 alleles were identified by dot-blot analysis of polymerase chain reaction (PCR)-amplified genomic DNA with sequence-specific oligonucleotide probes. The results show that those DQB1 alleles, which carry non-aspartic acid at position 57, in conjunction with DQA1 alleles carrying arginine at position 52, are strongly associated with susceptibility to type 1 diabetes. The prevalence of the TAP2* 0201 allele in diabetic patients was significantly lower than that in normal controls. Analysis of the data suggests that DQ alleles have the primary association with type 1 diabetes and that the association of TAP2 alleles with the disease is secondary.
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PMID:HLA-DQ and TAP2 genes in patients with insulin-dependent diabetes mellitus. 800 38

We examined HLA Class II antigens in 116 Japanese IDDM patients [84 typical IDDM (T-IDD); 32 slowly progressive IDDM (S-IDD)] by the hybridization protection assay (HPA) which is a novel HLA typing method based on hybridization of acridinium-ester-labeled DNA probes to amplified DNA. We detected HLA-DRB1, -DQA1 and -DQB1 genes by this method which is capable of analyzing over 50 samples within 4 h with high sensitivity. Positive associations were found in DRB1*0405, DRB1*0802, DRB1*0901, DQA1*0301, DQB1*0303 and DQB1*0401, negative correlations in DRB1*0403, DR2, DR12, DRB1*0801 or 03, DQA1*0101 or 02, DQA1*0501, DQB1*0301 and DQB1*0602 alleles. The absence of aspartic acid (Asp) at position 57 of the DRB1 chain and the presence of arginine (Arg) at position 52 of the DQA1 chain correlated positively with both types of IDDM. There were no significant differences in HLA between T-IDD and S-IDD. These results suggest that the absence of Asp at position 57 of the DRB1 chain and the presence of Arg at position 52 of the DQA1 chain are significant Japanese IDDM patients and that DRB1*0802, in which the amino acid at position 57 is aspartic acid, may play a role in the pathogenesis of IDDM. Also, T-IDD and S-IDD have common bases in the HLA gene.
Diabetes Res Clin Pract 1994 Mar
PMID:Analysis of MHC class II antigens in Japanese IDDM by a novel HLA-typing method, hybridization protection assay. 807 Mar 5

The particular histocompatability antigen (HLA) gene(s) that may confer systemic lupus erythematosus (SLE) susceptibility remains unknown. In the present study, 58 unrelated patients and 69 controls have been analyzed for their class I and class II serologic antigens, class II (DR and DQ) DNA restriction fragment length polymorphism, their deduced DQA1 and B1 exon 2 nucleotide sequences and their corresponding amino acid residues. By using the etiologic fraction (delta) as an almost absolute measure of the strongest linkage disequilibrium of an HLA marker to the putative SLE susceptibility locus, it has been found that the strength of association of the HLA marker may be quantified as follows: DQA1*0501 (associated to DR3) or DQB1*0201 (associated to DR3) > non Asp 57 beta DQ/Arg 52 alpha DQ > DR3 > non Asp 57 beta DQ. Thus, molecular HLA DQ markers tend to be more accurate as susceptibility markers than the classical serologic markers (DR3). However, dominant or recessive non Asp 57 beta DQ susceptibility theories, as previously postulated for insulin-dependent diabetes mellitus, do not hold in our SLE nephritic population; indeed, three patients bear neither Arg 52 alpha DQ nor Asp 57 beta DQ suscepibility factors. On the other hand, nonsusceptibility factors are included in our population in the A30B18CF130-DR3DQ2(Dw25) haplotype and not in A1B8CS01-DR3DQ2(Dw24); this distinctive association has also been recorded in type I diabetes mellitus and may reflect the existence of common pathogenic HLA-linked factors for both diseases only in the A30B18CF10DR3DQ2(Dw25) haplotype. Finally, the observed increase of deleted C4 genes (and not 'null' C4 proteins) in nephritic patients shows that C4 genes are disease markers, but probably without a pathogenic role.
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PMID:Differential contribution of C4 and HLA-DQ genes to systemic lupus erythematosus susceptibility. 810 32

Enterostatin is a peptide which has been found to decrease food intake with a specificity for the fat contained in the food. In this work we have investigated the effect of enterostatin (Val-Pro-Asp-Pro-Arg) and its proteolytic fragments, des-arg-enterostatin (Val-Pro-Asp-Pro) and the tripeptide Asp-Pro-Arg, on insulin secretion. It was found that enterostatin and desarg-enterostatin inhibited insulin secretion from isolated rat islets by 55.3% (P < 0.05) and 53.6% (P < 0.05) at 1.6 x 10(-4) M concentration, while the tripeptide Asp-Pro-Arg at 1.6 x 10(-4) M concentration had no significant effect and increased insulin secretion by 33.0%. Enterostatin at 200 ng after intraventricular administration was found to inhibit the intake of a high-fat diet by 45.0%, while des-arg-enterostatin (200 ng) had no effect, in agreement with previous findings. The tripeptide Asp-Pro-Arg (200 ng) had no effect on the intake of a high-fat diet compared to saline injection. The ability of enterostatin to inhibit high-fat food intake and decrease insulin secretion may be important for the prevention of obesity and type II diabetes, conditions linked through hyperinsulinemia.
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PMID:Enterostatin--its ability to inhibit insulin secretion and to decrease high-fat food intake. 811 74

Recent studies have shown that mutations in human beta-cell glucokinase that impair the activity of this key regulatory enzyme of glycolysis can cause early-onset non-insulin-dependent diabetes mellitus (NIDDM). The amino acid sequence of human glucokinase has 31% identity with yeast hexokinase, a related enzyme for which the crystal structure has been determined. This homology has allowed us to model the three-dimensional structure of human glucokinase by analogy to the crystal structure of yeast hexokinase B. This model of human glucokinase provides a basis for understanding the effects of mutations on its enzymatic activity. Residues in the active site and on the surface of the binding cleft for glucose are highly conserved in both enzymes. Regions far from the active site are predicted to differ in conformation, and 10 insertions or deletions that range in size from 1 to 7 residues are located on the protein surface between elements of secondary structure. The model structure suggests that human glucokinase binds glucose in a similar manner to yeast hexokinase. The glucose-binding site contains a conserved aspartic acid, two conserved glutamic acids, and two conserved asparagines that form hydrogen bond interactions with the hydroxyls of the glucose similar to those observed in other sugar-binding proteins. Mutation of residues in the predicted glucose-binding site has been found to greatly reduce enzymatic activity. This model will be useful for future structure/function studies of glucokinase.
Diabetes 1994 Jun
PMID:Molecular model of human beta-cell glucokinase built by analogy to the crystal structure of yeast hexokinase B. 819 64


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