Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although it has been confirmed that insulin dependent diabetes mellitus (IDDM) is a kind of autoimmune disease, islet cell autoantibodies (ICAs), insulin autoantibodies (IAA) and anti-GAD-glutamic acid decardaxylase antibodies have been found in the sera of patients with IDDM and immunotherapies have been used in some patients with IDDM, yet the manner in which the dysfunctional immunosystem acts on beta cells and causes damage to them remains to be clarified. Recently, possible involvement of the abnormal production of IL-6 in autoimmune symptoms was suggested in patients with cardiac myxomas, Castleman's disease and rheumatoid arthritis. However reports of IL-6 abnormal production in patients with IDDM are rare. In the present study, we examined whether or not an abnormal expression of IL-6 mRNA was present in mononuclear cells (PBMNCs) of the peripheral blood of patients with IDDM. We devised a highly sensitive, specific and semiquantitative protocol, ie, reverse transcription and polymerase chain reaction (RT-PCR). We have used such an assay to measure the relative expression levels of IL-6 mRNA in PBMNCs from 12 early IDDM patients (duration < 6 mon, 8.20 +/- 3.85 yr), 29 newly-diagnosed NIDDM patients (54.85 +/- 9.12 yr), 23 normal children (8.20 +/- 3.26 yr) and 12 normal adults (31.92 +/- 11.22 yr). In this assay significantly high expression levels of IL-6 mRNA were found in PBMNCs from patients with IDDM (P < 0.05). The relative levels were 0.91 +/- 0.19; 0.10 +/- 0.06; 0.43 +/- 0.08; 0.10 +/- 0.07, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Expression levels of IL-6 mRNA in PBMNCs from patients with IDDM, NIDDM and normals by RT-PCR procedure. 814 5

To clarify whether glutamic acid decarboxylase65 antibodies (GAD65 Ab) and insulin autoantibodies (IAA) are good predictive markers for insulin-dependency in NIDDM, we studied GAD65 Ab and IAA in NIDDM patients treated with diet alone or in combination with oral hypoglycemic agents. GAD65 Ab were found in 12 or 29 (5.2%, P = 0.079 vs. control) NIDDM patients and IAA in 8 of 229 (3.5%). The frequency of GAD65 Ab and IAA positivity in NIDDM did not differ significantly from those of healthy controls (2/150, 1.3%, 2/150, 1.3%, respectively), but the frequency of patients who were positive for either GAD65 Ab or IAA, or both, was significantly higher than that of normal controls (17/229, 7.4% and 4/150, 2.7%, respectively, P < 0.05). In addition, the prevalences of GAD65 Ab and of IAA in those patients whose disease durations, since the diagnosis of diabetes, were less than one year were significantly higher than those of controls (4/30, 13.3%, P < 0.05, 4/30, 13.3%, P < 0.05, respectively). We found no differences between GAD65 Ab positive- and negative-patients in either BMI or serum C-peptide levels. Over a one to five year follow-up period (mean 2.0 yrs), serum C-peptide levels gradually decreased necessitating insulin treatment in three of the patients positive for GAD65 Ab and/or IAA (3/17, 17.6%; two were positive for both GAD65 Ab and IAA and one was positive for GAD65 Ab only). In contrast, only five patients negative for the two antibodies developed insulin requirement (5/212, 2.4%, P < 0.01). These results suggest that GAD65 Ab and IAA are good markers for predicting the development of insulin dependency in NIDDM patients and that the predictive value for insulin-dependency in NIDDM is enhanced by measuring both antibodies.
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PMID:Glutamic acid decarboxylase65 (GAD65) antibodies and insulin auto-antibodies in Japanese patients with non-insulin-dependent diabetes mellitus. 915 13

Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes mellitus (NIDDM) characterised bylan early age of onset (< 25 years) and an autosomal dominant mode of inheritance. MODY is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4 alpha) [MODY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1 alpha) [MODY3]. A nonsense mutation in the HNF-4 alpha gene has recently been shown to cause MODY in a single large North American pedigree (RW). We screened a large UK Caucasian MODY family which showed weak evidence of linkage to the MODY1 locus on chromosome 20q (lod score for ADA 0.68 at theta = 0) for mutations in the coding region of the HNF-4 alpha gene by direct sequencing. A missense mutation resulting in the substitution of glutamine for glutamic acid was identified in exon 7 (E276Q). The mutation was present in all of the diabetic members of the pedigree plus two unaffected subjects and was not detected in 75 normal control subjects or 95 UK Caucasian subjects with late-onset NIDDM. This is the first missense mutation to be described in the HNF-4 alpha gene.
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PMID:A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young. 924 9

The adenosine (A1) receptor agonist, GR79236 (N-[(1S,trans)-2-hydroxycyclopentyl]adenosine), inhibits catecholamine-induced lipolysis in vitro, but the short-term metabolic and haemodynamic effects have not been previously reported in the fructose fed model of insulin resistance, dyslipidaemia and hypertension. This study reports the effects of GR79236 (1 mg/kg/day for 8 days) on nonesterified free fatty acid and triglyceride metabolism, oral and i.v. glucose tolerance, blood pressure and heart rate, and insulin sensitivity, in normal rats and rats fed a fructose-enriched diet. In normal rats, GR79236 significantly reduced fasting glucose (25%), free fatty acid (50%) and triglyceride (55%) concentrations, and improved glucose tolerance (AUC[glu] 21.2 +/- 1.3 vs. 16.5 +/- 1.1 mmol h/l, p < 0.05). Fructose feeding induced a state of insulin resistance and dyslipidaemia, as shown by an increase in steady-state plasma glucose levels (7.1 vs. 6.1 mmol/l), impaired i.v. glucose tolerance and a 3-fold rise in fasting triglyceride levels; fructose-fed rats also developed a significant increase in blood pressure. GR79236 ameliorated the effects of fructose feeding on fatty acid and triglyceride levels, and blood pressure, and improved i.v. glucose tolerance in fructose-fed rats. The hypotriglyceridaemic effect was due to a reduction in triglyceride secretion rate (17.3 +/- 1.7 vs. 30.2 +/- 1.1). Thus, in normal rats and in a dietary-induced rodent model of insulin resistance, dyslipidaemia and hypertension, GR79236 has lipid-lowering and glucose-lowering activity, as well as haemodynamic effects, which are potentially useful for treating both the metabolic and haemodynamic features of insulin resistance and NIDDM in humans.
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PMID:Short-term metabolic and haemodynamic effects of GR79236 in normal and fructose-fed rats. 942 21

Mutations of the hepatocyte nuclear factor-1 alpha (HNF1 alpha) gene are an important cause of autosomal dominant diabetes with onset before age 25 yr [maturity-onset diabetes of the young (MODY)], and some regions of the HNF1 alpha gene appear to be hot spots for mutations. To evaluate the role of HNF1 alpha in the more common familial type 2 diabetes, we studied 62 families of Northern European origin by linkage analysis and molecular screening. Linkage was rejected under dominant models consistent with either late-onset type 2 diabetes or early-onset dominant diabetes. We used single strand conformation polymorphism analysis to screen 53 diabetic members of 36 families who reported diabetes diagnosed before age 40 yr, 9 members of 2 Utah families with typical MODY, and 24 additional members of families with possible linkage. One MODY family showed the previously reported frameshift mutation (P291fsinsC) in exon 4. Among the individuals with more typical type 2 diabetes, we identified the previously reported common polymorphisms, a new intronic polymorphism, and 3 common amino acid variants. We also identified 2 novel missense mutations that segregated with type 2 diabetes in 1 family each: lysine for glutamic acid substitution at codon 619 in exon 10 (E619K), and an arginine for threonine substitution at codon 537 in exon 8 (R537T) in a second family. The exon 8 mutation showed relatively low penetrance, and the role in this family remains uncertain. No coding mutations were identified in the family members screened on the basis of linkage but without early-onset diabetes. Although HNF1 alpha mutations are not a common cause of familial type 2 diabetes, they may account for 5% of families in which at least 1 member has onset of type 2 diabetes before age 40 yr. Incomplete penetrance and a high sporadic frequency make linkage an inefficient screening tool.
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PMID:Linkage and molecular scanning analyses of MODY3/hepatocyte nuclear factor-1 alpha gene in typical familial type 2 diabetes: evidence for novel mutations in exons 8 and 10. 962 39

Genetic studies have shown that mutations in the gene encoding hepatocyte nuclear factor (HNF)-4alpha, a member of the steroid/thyroid hormone receptor superfamily, give rise to early-onset type 2 diabetes (MODY1). The functional properties of mutant HNF-4alpha proteins and the molecular mechanisms by which they impair insulin secretion are largely unknown. In the present study, we have investigated transcriptional activation, DNA binding properties, and protein dimerization activity of three HNF-4alpha missense mutations--HNF4(R127W), HNF4(V255M), and HNF4(E276Q)--that have been associated with type 2 diabetes. We demonstrate that HNF4(E276Q) has lost its ability to bind to HNF-4 consensus binding sites and activate transcription. HNF4(E276Q) had no effect on the functional activity of wild-type HNF-4alpha in the pancreatic beta-cell line HIT-T15, but it exhibited weak dominant-negative activity in other cell types. Analysis of HNF4(E276Q) protein showed that it exists in two forms: a full length 54-kDa protein and a 40-kDa COOH-terminal protein lacking the NH2-terminal transactivation domain and the DNA binding domain. Immunoprecipitation experiments indicate that this truncated protein can bind to wild-type HNF-4alpha and may be responsible for the weak dominant-negative effects seen in these cells. In addition, we show that the transcriptional transactivation of HNF4(R127W) and HNF4(V255M) is indistinguishable from that of wild-type HNF-4alpha, suggesting that they are sequence polymorphisms. Our results demonstrate that HNF4(E276Q) is a loss-of-function mutation and that it identifies glutamic acid 276 in alpha-helix 8 of the ligand-binding domain of HNF-4alpha protein as a critical residue for DNA binding, transcriptional activation, and protein stability in vivo.
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PMID:Functional characterization of the MODY1 gene mutations HNF4(R127W), HNF4(V255M), and HNF4(E276Q). 1038 54

To analyze the contribution of MHC class II genes in type 2 diabetes mellitus (DM) with end stage renal disease (ESRD), we examined the distribution of HLA-DRB1, DQA1, DQB1 loci in Mexican Mestizos of Central Mexico, using PCR-SSOP and PCR-SSP. Three groups were included: 47 type 2 diabetic ESRD patients; 42 patients with ESRD and 50 type 2 DM patients with no kidney complication. The results were compared with those of 101 controls of the same area. The median since DM was first diagnosed, was 18 years prior to the onset of ESRD. The frequencies of DRB1*1502 and DQB1*0501 were increased in DM patients with ESRD (p = 0.004; RR = 7.4, CI = 1.5-37; EF = 0. 13; p = 0.007; RR = 2.9, CI = 2.3-3.5, EF = 0.21, respectively). In contrast, DRB1*0407 was decreased in the same group (p = 0.0008, RR = 0.2; CI = 0.035-0.70, PF = 0.19). Diabetic patients with DRB1*1502 are 8.8 times more likely to develop ESRD, independently of the duration time of DM. DRB1*1502 contributes to the susceptibility to ESRD while DRB1*0407 is involved in protection. The residue at DRB1-74 differs in these alleles: DRB1*0407 has glutamic acid and DRB1*1502 has an alanine, suggesting that this substitution may be important for both, peptide anchoring and for presentation to the T cells.
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PMID:Contribution of HLA class II genes to end stage renal disease in mexican patients with type 2 diabetes mellitus. 1108 16

Four apolipoprotein (apo) E variants have been reported to be associated with lipoprotein glomerulopathy (LPG), which is characterized by type III hyperlipoproteinemia (type III HLP) and proteinuria and frequently leads to nephrotic syndrome. We report the histologic findings in the kidneys of a type III HLP patient with an apo E variant, apo E Toranomon, in which the glutamine at residue 187 in apo E is substituted by glutamic acid (Q187E). The patient also had type 2 diabetes mellitus. No evidence of lipoprotein thrombi suggestive of LPG was detected, however, and the histologic diagnosis was diabetic nephrosclerosis. This unique case illustrates that not all apo E variants result in LPG, and the location of mutations in the apo E protein is one of the important determinants for the development of LPG.
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PMID:A patient with apolipoprotein E2 variant (Q187E) without lipoprotein glomerulopathy. 1187 95

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.
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PMID:Vitamin D binding protein gene and genetic susceptibility to type 2 diabetes mellitus in a Polish population. 1206 54

The aim of the study was to investigate the participation of human leukocyte antigen (HLA) class II alleles in the expression of type 2 diabetic and in nondiabetic subjects with and without family history of diabetes. The purpose was to evaluate any HLA association and to look for different patterns of insulin resistance and insulin secretion, comparing subjects with a low probability of developing diabetes, as a result of their family history. We recruited 87 healthy subjects without family history of diabetes, 48 healthy subjects with family history, and 47 type 2 diabetic patients. All of them were Mexican Mestizos of central Mexico. Using a standard 75-g oral glucose tolerance test, insulin resistance was determined and insulin secretion was assessed with the HOMA model. DRB1, DQA1 and DQB1 alleles were typed using polymerase chain reaction-sequence-specific oligonucleotide probe (PCR-SSOP) and sequence specific primers (PCR-SSP). Nondiabetic subjects had similar HOMA-IR and DeltaI 30/DeltaG 30 index (HOMA). A significant decreased frequency of DRB1*0403 (p = 0.01; odds ratio [OR] = 0.20) was demonstrated in type 2 diabetic patients, and DRB1*0701 (p = 0.02; OR = 0.17) in nondiabetics with family history of diabetes. These alleles associated with protection against type 2 diabetes, share glutamic acid at position-74 and were previously demonstrated to contribute to protection against type I diabetes.
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PMID:Protective effect of DRB1 locus against type 2 diabetes mellitus in Mexican Mestizos. 1250 21


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