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

Paraoxonase is an HDL-associated enzyme implicated in the pathogenesis of atherosclerosis by protecting lipoproteins against peroxidation. Its biallelic gene polymorphism at codon 192 (glutamine/arginine) has been associated with coronary artery disease (CAD). To further evaluate the role of this paraoxonase gene polymorphism for CAD in type 2 diabetes, we determined the paraoxonase genotype in 288 type 2 diabetic patients (170 with and 118 without angiographically documented CAD). The paraoxonase 192 Gln/Arg genotype was assessed using polymerase chain reaction followed by AlwI digestion. The frequency of the Gln allele was 0.656 in the CAD patients and 0.746 in the controls (chi2 = 5.36, P = 0.02). Compared with the Gln/Gln genotypes, the age-adjusted odds ratio for CAD was 1.78 (95% CI 1.08-2.96, P = 0.02) in subjects carrying at least one Arg allele. In the multivariate analysis, this association was even stronger after correction for the possible confounders age, sex, smoking history, and hypertension. Among current and former smokers, the odds ratio (OR) for having CAD among patients with at least one Arg allele was 3.58 (1.45-9.53, P < 0.01). The paraoxonase Arg allele was not associated with the history of myocardial infarction (OR 1.20 [0.73-1.99, NS]), but was with the extent of CAD (OR for three-vessel disease 1.92 [1.15-3.27, P = 0.01]). Our data indicate that the 192 Arg allele of the human paraoxonase gene is a risk factor for CAD but not myocardial infarction in type 2 diabetic patients, a risk factor further modified by cigarette smoking. This risk could possibly be explained by a reduced ability of the paraoxonase Arg isoform to protect lipoproteins against peroxidation.
 ...
PMID:Paraoxonase 192 Gln/Arg gene polymorphism, coronary artery disease, and myocardial infarction in type 2 diabetes. 1007 66

The SOX (sex-determining region [SRY]-type high mobility group [HMG] box) family of transcription factors play key roles in determining cell fate during organ development. In this study, we have identified a new human SOX gene, SOX13, as encoding the type 1 diabetes autoantigen, islet cell antigen 12 (ICA12). Sequence analysis showed that SOX13 belongs to the class D subgroup of SOX transcription factors, which contain a leucine zipper motif and a region rich in glutamine. SOX13 autoantibodies occurred at a significantly higher frequency among 188 people with type 1 diabetes (18%) than among 88 with type 2 diabetes (6%) or 175 healthy control subjects (4%). Deletion mapping of the antibody epitopes showed that the autoantibodies were primarily directed against an epitope requiring the majority of the protein. SOX13 RNA was detected in most human tissues, with the highest levels in the pancreas, placenta, and kidney. Immunohistochemistry on sections of human pancreas identified SOX13 in the islets of Langerhans, where staining was mostly cytoplasmic. In mouse pancreas, Sox13 was present in the nucleus and cytoplasm of beta-cells as well as other islet cell types. Recombinant SOX13 protein bound to the SOX consensus DNA motif AACAAT, and binding was inhibited by homodimer formation. These observations-along with the known molecular interactions of the closely related protein, rainbow trout Sox23-suggest that SOX13 may be activated for nuclear import and DNA binding through heterodimer formation. In conclusion, we have identified ICA12 as the putative transcription factor SOX13 and demonstrated an increased frequency of autoantibody reactivity in sera from type 1 diabetic subjects compared with type 2 diabetic and healthy control subjects.
 ...
PMID:Sex-determining region Y-related protein SOX13 is a diabetes autoantigen expressed in pancreatic islets. 1087 Nov 92

The prevaleance of morbid obesity (body mass index of 35.0 or greater) is low in Japan (0.2-0.3%), and little systematic investigation of its cause in this population has been carried out. Leptin plays a central role in regulation of body weight; mice deficient in leptin develop marked obesity. We sought mutations in the leptin gene in 53 morbidly obese Japanese (maximum body mass index 35-60) including 46 with type 2 diabetes. Direct DNA sequencing was performed following polymerase chain reaction amplification. Apart from a silent mutation at codon 25 (CAA/CAG, glutamine) detected in eight subjects, no mutations were detected. We found a significantly higher prevalence of the variant leptin 25CAG allele among the 53 obese subjects (0.085) studied than in 132 nonobese control subjects (0.011, P<0.001). In Japanese populations mutations in the protein coding sequence of the leptin gene are unlikely to be a major cause of morbid obesity. However, the leptin 25CAG allele may be linked to morbid obesity in this population. Specifically, genetic variation located near the leptin gene may be involved in pathogenesis. The leptin polymorphism 25CAG appears to be a new genetic marker for obesity susceptibility, at least in Japanese.
 ...
PMID:A polymorphic marker in the leptin gene associated with Japanese morbid obesity. 1114 Mar 77

Paraoxonase 1 (PON1) is an HDL-associated enzyme which protects HDL and LDL particles from lipid peroxidation. Its enzymatic serum activity varies 10-40-fold between individuals, and its biallelic gene polymorphism at codon 192 (glutamine-->arginine, Gln/Arg) has been associated with coronary artery disease in diabetic patients. To evaluate the role of this PON1 gene polymorphism in cerebrovascular disease, we determined the PON1 192 genotype in 149 patients with hemodynamically relevant extracranial artery stenosis and in 241 controls. The PON1 192 Gln/Arg genotype was determined using polymerase chain reaction followed by Alw I digestion and polyacrylamide gel electrophoresis. Among all subjects, there was no association between the PON1 192 Gln/Arg genotype and cerebrovascular disease (Odds ratio for Arg/Arg and Gln/Arg vs Gln/Gln 0.99, 95%-CI 0.70-1.39). In contrast, in the subgroup of type 2 diabetic patients the PON1 192 Arg allele conferred about twice the risk of cerebrovascular stenosis compared to those homozygous for the Gln allele (Odds ratio 2.00, 95%-CI 0.92-4.38). Our data indicate that in the general population the PON1 192 Gln/Arg gene polymorphism cannot be regarded as a major risk marker for cerebrovascular disease. The observed interaction with type 2 diabetes, however, is supporting the hypothesis that the effect of the PON1 192 Arg allele on atherosclerosis is modulated by other risk factors like diabetes.
 ...
PMID:Paraoxonase 1 192 Gln/Arg gene polymorphism and cerebrovascular disease: interaction with type 2 diabetes. 1140 95

Troglitazone is a peroxisome proliferator-activated receptor-gamma agonist that has been shown to halt mesangium expansion in experimental models of type 2 diabetes mellitus and to act directly on rat mesangial cells. Because glutamine serves as the precursor for cellular biosynthetic processes, we asked whether troglitazone would inhibit mesangial cell glutamine metabolism under these conditions. Confluent monolayers of rat mesangial cells were incubated in RPMI medium in the presence of troglitazone or vehicle (DMSO). Troglitazone effected a dose-dependent reduction in glutamine utilization and in alanine formation, associated with a decrease in monolayer collagen-glycosaminoglycan content. Despite the reduced glutamine uptake, ammonium formation did not decrease, consistent with increased glutamate flux through the deamination pathway. Assayable activity of the alanine aminotransferase decreased by 63%, whereas assayable glutamate dehydrogenase remained unchanged. In control monolayers, the sum of ammonium plus alanine plus glutamate nitrogen released accounted for <75% of the glutamine nitrogen uptake. In troglitazone-treated monolayers, all of the glutamine nitrogen taken up could be accounted for as ammonium nitrogen released into the medium. These results are consonant with troglitazone reducing glutamine metabolism and specifically the transamination pathway in rat mesangial cells associated with a reduction in collagen-glycosaminoglycan content.
 ...
PMID:Troglitazone inhibits glutamine metabolism in rat mesangial cells. 1173 5

The current study investigated the fate of a [U-(13)C]palmitate tracer extracted by forearm muscle in type 2 diabetic and control subjects. We studied seven healthy lean male subjects and seven obese male subjects with type 2 diabetes using the forearm muscle balance technique with continuous intravenous infusion of the stable isotope tracer [U-(13)C]palmitate under baseline conditions and during intravenous infusion of the nonselective beta-agonist isoprenaline (ISO; 20 ng *kg(-1) lean body mass* min(-1)). In skeletal muscle of control subjects, there was a significant release of (13)C-labeled oxidation products in the form of (13)CO(2) (15% of (13)C uptake from labeled palmitate) and a significant release of (13)C-labeled glutamine (release of (13)C-labeled atoms from glutamine was 6% of (13)C uptake from labeled palmitate), whereas in type 2 diabetic subjects there was no detectable release of (13)CO(2) and (13)C-glutamine, despite a significant uptake of [U-(13)C]palmitate (60% of control value). There was net uptake of arterial (13)C-labeled glutamate by forearm muscle in both groups. Also, the ISO-induced increase in arterial glutamine enrichment and arterial concentration of (13)C-glutamine was more pronounced in the diabetic group relative to control subjects. In view of the diminished ISO-induced release of (13)C-glutamine from type 2 diabetic muscle, the latter data indicate that more [U-(13)C]palmitate entered the liver in the diabetic group and was incorporated into newly synthesized glutamine and glutamate molecules. Thus, the lack of release of (13)C-labeled oxidation products by type 2 diabetic muscle during beta-adrenergic stimulation, despite significant [U-(13)C]palmitate uptake, indicates differences in the handling of fatty acids between type 2 diabetic subjects and healthy control subjects.
 ...
PMID:The fate of [U-(13)C]palmitate extracted by skeletal muscle in subjects with type 2 diabetes and control subjects. 1187 80

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.
 ...
PMID:A patient with apolipoprotein E2 variant (Q187E) without lipoprotein glomerulopathy. 1187 95

This review summarizes the state of knowledge on D-glucosamine-6P synthesis catalyzed by glucosamine-6P synthase. The mechanisms of L-glutamine hydrolysis, ammonia transfer and fructose-6P conversion into D-glucosamine-6P are analyzed with the E. coli enzyme in light of recent X-ray structures. With 92 references this paper covers the literature up to June 2001 and emphasizes the potential implication of the mammalian glucosamine-6P synthase in type 2 diabetes.
 ...
PMID:From Lobry de Bruyn to enzyme-catalyzed ammonia channelling: molecular studies of D-glucosamine-6P synthase. 1190 40

Transglutaminase 2 (TGase 2) is a Ca+2-dependent enzyme that catalyzes both intracellular and extracellular cross-linking reactions by transamidation of specific glutamine residues. TGase 2 is known to be involved in the membrane-mediated events required for glucose-stimulated insulin release from the pancreatic beta cells. Here we show that targeted disruption of TGase 2 impairs glucose-stimulated insulin secretion. TGase 2-/- mice show glucose intolerance after intraperitoneal glucose loading. TGase 2-/- mice manifest a tendency to develop hypoglycemia after administration of exogenous insulin as a consequence of enhanced insulin receptor substrate 2 (IRS-2) phosphorylation. We suggest that the increased peripheral sensitivity to insulin partially compensates for the defective secretion in this animal model. TGase 2-/- mouse phenotype resembles that of the maturity-onset diabetes of young (MODY) patients. In the course of screening for human TGase 2 gene in Italian subjects with the clinical features of MODY, we detected a missense mutation (N333S) in the active site of the enzyme. Collectively, these results identify TGase 2 as a potential candidate gene in type 2 diabetes.
 ...
PMID:Role of transglutaminase 2 in glucose tolerance: knockout mice studies and a putative mutation in a MODY patient. 1220 28

Serum paraoxonase (PON) is a high-density lipoprotein-bound enzyme that can prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides and thus exert an anti-atherogenic effect. Recent studies have suggested that glutamine(Q isoform)/arginine(R isoform) polymorphism at position 192 of PON(1) gene is associated with macrovascular disease of type 2 diabetes mellitus (T2DM). We re-investigated this relationship using carotid intima-media thickness (IMT) as a surrogate continuous variable for macroangiopathy. The genotype and allele frequency of PON(1) 192 Q/R polymorphism was assayed by polymerase chain reaction-restriction fragment length polymorphism in 152 type 2 diabetic patients and 128 healthy subjects from a population of Chinese Han nationality in ChengDu area. The carotid IMT was measured by B-mode ultrasonography in type 2 diabetic patients. No differences were found in PON(1) gene Q/R polymorphism in the type 2 diabetic patients when compared with the control group. The mean carotid IMT in type 2 diabetic subjects with the QQ, QR and RR genotype was 0.65+/-0.27, 0.83+/-0.27 and 1.05+/-0.32 mm, respectively. One-way ANOVA showed that IMT was significantly greater in the RR subgroup than in both QR and QQ subgroups (P<0.01). Multivariate logistic regression analysis showed R allele to be the main determinant of IMT variability (OR 4.0 95% CI 2.10-7.40 P=0.005). Our data support the view that 192 R allele of PON(1) gene is a risk factor for macrovascular disease of T2DM in Chinese.
 ...
PMID:Gln-Arg192 polymorphism of paraoxonase 1 is associated with carotid intima-media thickness in patients of type 2 diabetes mellitus of Chinese. 1284 20


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>