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)

Xanthurenic acid (XA), kynurenic acid (KA) and creatinine in fasting urine were determined by reversed phase high pressure liquid chromatography in order to investigate the distortion of tryptophan metabolites in diabetes mellitus. The results of ten patients with non-insulin dependent diabetes mellitus and ten normal healthy subjects were compared. No tryptophan load test was performed in this study, because tryptophan loading produces further latent shortage of active vitamin B6 which results in exacerbation of the disease. The ratios of XA to KA and to creatinine were 0.35 +/- 0.099 (mean +/- S.D.) and 0.99 +/- 0.321 in the diabetic patients. The corresponding figures in the normal subjects were 0.17 +/- 0.064 and 0.55 +/- 0.22. Both ratios were significantly higher in the diabetic patients than in normal subjects (p less than 0.001 and p less than 0.01, respectively). This means that XA was excessively excreted in diabetic patients resulting in distortion of tryptophan metabolism. Our findings indicated that the ratios are useful to monitor excess XA excretion and also for detection of diabetes.
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PMID:Studies on the urinary excretion of xanthurenic acid in diabetics. 652 81

Because the supplementation of pyridoxine (vitamin B6) improves the glucose tolerance in gestational diabetes and adult onset diabetes, pyridoxine deficiency has been considered to be one of the factors that cause diabetes mellitus. We produced pyridoxine deficient rats by giving pyridoxine-free food with deoxypyridoxine which competitively the activity of pyridoxal phosphate. In these pyridoxine deficient rats plasma insulin during the glucose tolerance test was significantly low as compared with controls. In vitro experiments of pancreas perfusion showed that secretion of insulin and glucagon was impaired in the pyridoxine deficiency. Since the restriction of diet-calorie caused a decrease in arginine-induced secretion of insulin and glucagon from the isolated pancreas, the impairment of the endocrine pancreas may depend on malnutrition. Pyridoxine deficiency is surely one of the factors that impair the endocrine pancreas by multifactorial derangement of metabolism besides the tryptophan-nicotinic acid pathway.
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PMID:The endocrine pancreas in pyridoxine deficient rats. 703 87

Recently, a missense mutation replacing tryptophan with arginine at codon 64 of the beta 3-adrenergic receptor gene was shown to be associated with insulin resistance in nondiabetic subjects and to an earlier onset of NIDDM in Pima Indians. We studied whether the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene in a cohort of young healthy Danes was associated with high birth weight, accelerated weight gain during childhood and adolescence, present obesity, or impaired insulin sensitivity. The protocol included 380 unrelated white subjects in whom insulin sensitivity and secretion were measured during a combined intravenous glucose and tolbutamide tolerance test. A number of biochemical and anthropometric characteristics were determined for each subject. The subjects were genotyped for the codon 64 polymorphism by applying polymerase chain reaction restriction fragment-length polymorphism screening with the use of endonuclease BstN1. The allelic frequency of the mutated allele was 7% (95% CI: 5-10%), and it was similar in obese and nonobese subjects. The beta 3-adrenergic receptor gene variant was not related to birth weight or weight gain during childhood or adolescence. In its heterozygous form, the gene variant was not associated with an altered insulin sensitivity index (SI) or other features of the insulin resistance syndrome (BMI, blood pressure, fasting serum lipid levels, or fasting serum fibrinolytic variables). Three homozygous carriers of the polymorphism were identified, and each had a significantly higher BMI (27.4 +/- 1.3 vs. 23.5 +/- 3.7 kg/m2 [mean +/- SD]; P = 0.032), lower SI [4.9 +/- 2.9 vs. 15.4 +/- 9.0 10(-5) x (min x pmol/l)-1; P = 0.013], and higher fasting serum C-peptide (730 +/- 155 vs. 471 +/- 158 pmol/l; P = 0.016) than the wild-type carriers. The homozygous carriers also had significantly higher levels of fasting serum triglyceride (P = 0.042) and serum LDL cholesterol (P = 0.013). When adjustments were made for age, sex, BMI, and VO2max in a multiple regression analysis, a significantly negative association was found between homozygosity for the codon 64 variant and the SI (P = 0.009). We conclude that in young healthy Danes, the homozygous form but not the heterozygous form of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor may be associated with obesity and, independent of BMI, with a low SI. Since only three homozygous carriers were identified among 380 subjects, the results must be interpreted with caution, and studies of larger population samples are needed.
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PMID:Insulin sensitivity and body weight changes in young white carriers of the codon 64 amino acid polymorphism of the beta 3-adrenergic receptor gene. 869 Jan 60

Type 2 diabetes mellitus is characterized by impaired glucose uptake. With a photometric method of recording the erythrocyte suspension absorption during the course of glucose transport across the membranes, we observed that the initial rate of glucose zero-trans entry was decreased significantly in 30 Chinese type 2 diabetic patients as compared to 25 healthy controls. The rate of glucose infinite-cis efflux exhibited no difference between the patients and controls. The measurement of temperature dependence of glucose transport showed that the activation energy for glucose entry was increased in diabetic patients. The inhibitory constant of glucose entry by cytochalasin B (CB) in patients was similar to that of the controls. However, we found that the inhibitory constant was increased significantly in the patient erythrocytes after phloretin treatment. After the erythrocytes were made into stripped white ghosts, the fluorescence quenching experiment was performed. Glucose, CB and phloretin can quench the fluorescence of tryptophan residues in the glucose transporter 1, GLUT1. The abnormality of fluorescence quenching in the erythrocyte membranes of patients was observed. The transfer tendency of tryptophan residues from the hydrophilic environment to the hydrophobic environment was decreased in patient ghosts as binding with glucose, and the opposite tendency appeared as CB and phloretin instead of glucose. We conclude that the decreased in glucose entry in the erythrocyte membranes of diabetic patients was due to the GLUT1 change in structure - mostly the outer domain of the glucose transporter.
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PMID:The abnormality of glucose transporter in the erythrocyte membrane of Chinese type 2 diabetic patients. 1082 51

A missense mutation of the beta3-adrenergic receptor gene (ADRB3) resulting in a tryptophan/arginine exchange at position 64 (Trp64Arg polymorphism) has recently been associated with greater capacity to gain weight, a low resting metabolic rate, higher blood pressure, and an early onset of type 2 diabetes. These findings prompted us to examine the relationship between this mutation, blood pressure, and vascular complications in German patients with type 2 diabetes. White patients with type 2 diabetes mellitus (n = 417) were enrolled in the study. The Trp64Arg polymorphism of the ADRB3 gene was detected by polymerase chain amplification and subsequent restriction digest with BstN I. Stepwise logistic regression analysis of the entire study population revealed a significant interaction between gender and genotype (P = .019). We therefore performed separate analyses for men and women. There was a significant relationship between hypertension and the ADRB3 Trp64Arg variant in men (P = .015), but not in women. Furthermore, blood pressure levels in male patients with the minor allele had higher blood pressure levels (P < .05), despite a significantly greater number of antihypertensive medications (P = .01). There was no association between ADRB3 genotype and vascular complications in these patients. In conclusion, our data are compatible with a contribution of this genetic variant of ADRB3 to hypertension in male patients with type 2 diabetes. Further studies will be needed to determine the role of this polymorphism as a predictor of hypertension or vascular complications in patients with type 2 diabetes.
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PMID:The Trp64Arg polymorphism of the beta3-adrenergic receptor gene is associated with hypertension in men with type 2 diabetes mellitus. 1098 54

Carboxypeptidase E (CPE) is involved in the biosynthesis of peptide hormones and neurotransmitters, including insulin. One of the features of type 2 diabetes mellitus (T2DM) is an elevation in the proinsulin level and/or proinsulin/insulin molar ratio, suggesting that mutations in proinsulin processing enzymes may contribute to the development of T2DM. We scanned CPE for mutations in a collection of Ashkenazi T2DM families and identified five novel single nucleotide polymorphisms (SNPs). An SNP in the 283(rd) codon, c.847C>T, changes arginine to tryptophan (R283W). The residue Arg283 is conserved among CPE orthologs as well as most enzymatically active metallocarboxypeptidases. Of the 272 Ashkenazi T2DM pedigrees screened, we found four families segregating R283W. Within these four families, patients who inherited one copy of this variant had much earlier age of onset for T2DM. The R283W CPE protein cleaves peptide substrates with substantially lower efficiencies and is less stable at elevated temperature. In addition, the R283W CPE variant has a narrower pH optimum and is much less active at pH 6.0-6.5, indicating that the R283W CPE variant would be substantially less active than wild type CPE in the trans-Golgi network and immature secretory vesicles where the enzyme functions in vivo. To summarize, we uncovered a rare non-conservative missense mutation in CPE and demonstrated that the mutant protein has altered enzymatic properties. We predict that this mutant could cause hyperproinsulinism and diabetes in the homozygous state.
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PMID:Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. 1146 36

Using unnatural amino acid mutagenesis, the binding site for serotonin at the novel Caenorhabditis elegans receptor MOD-1 has been probed. As with the closely related serotonin receptor 5-HT3, MOD-1 makes use of a strong cation-pi interaction between the ammonium of serotonin and the indole side chain of a tryptophan. However, the specific Trp used by MOD-1 is different from that used for 5-HT3 (and the nAChR), aligning with a residue more than 40 amino acids distant in sequence space and on a different "loop" of the agonist binding site. This suggests a significant rearrangement of the ligand on binding these two closely related receptors. It is suggested that, unlike enzymes, receptors and other signaling molecules may need only to deliver an agonist to a general binding region, rather than establishing precise drug-receptor interactions.
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PMID:Different binding orientations for the same agonist at homologous receptors: a lock and key or a simple wedge? 1278 21

We investigated amino acid metabolism in the Zucker diabetic fatty (ZDF Gmi fa/fa) rat during the prediabetic insulin-resistant stage and the frank type 2 diabetic stage. Amino acids were measured in plasma, liver, and skeletal muscle, and the ratios of plasma/liver and plasma/skeletal muscle were calculated. At the insulin-resistant stage, the plasma concentrations of the gluconeogenic amino acids aspartate, serine, glutamine, glycine, and histidine were decreased in the ZDF Gmi fa/fa rats, whereas taurine, alpha-aminoadipic acid, methionine, phenylalanine, tryptophan, and the 3 branched-chain amino acids were significantly increased. At the diabetic stage, a larger number of gluconeogenic amino acids had decreased plasma concentrations. The 3 branched-chain amino acids had elevated plasma concentrations. In the liver and the skeletal muscles, concentrations of many of the gluconeogenic amino acids were lower at both stages, whereas the levels of 1 or all of the branched-chain amino acids were elevated. These changes in amino acid concentrations are similar to changes seen in type 1 diabetes. It is evident that insulin resistance alone is capable of bringing about many of the changes in amino acid metabolism observed in type 2 diabetes.
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PMID:Amino acid metabolism in the Zucker diabetic fatty rat: effects of insulin resistance and of type 2 diabetes. 1538 98

In humans, mice, and other mammals, the melanocortin system consists of four peptide hormones with a core amino acid sequence of histidine-phenylalanine-arginine-tryptophan and five melanocortin receptors. Both the melanocortin hormones and their receptors are produced in diverse tissues throughout the body. The ligand of primary interest for treatment of insulin resistance is alpha-melanocyte-stimulating hormone (alpha-MSH), which is derived, as are all melanocortins, from tissue-specific post-translational proteolytic processing of the pro-opiomelanocortin (POMC) precursor protein. Recent results have shown that alpha-MSH is the complement of leptin in the endocrine circuit, regulating bodyweight, food intake, and metabolic rate. alpha-MSH can decrease bodyweight, weight gain, and food intake in mice with diet-induced and genetic obesity. As obesity is a major risk factor for type 2 diabetes mellitus, it was reasonable to investigate the endocrine agents involved in obesity for their involvement in diabetes. alpha-MSH analogs have also been shown to affect blood glucose levels in some mouse models of obesity. For instance, the POMC null mouse is extremely sensitive to insulin in an insulin tolerance test, while being otherwise euglycemic. The results from rodent studies with alpha-MSH suggest reciprocal effects: alpha-MSH appears to increase sensitivity to insulin when present in the CNS, while alpha-MSH in the periphery is necessary for insulin resistance. Should these trends be validated in humans, alpha-MSH-based therapeutics specifically active in the CNS or peripheral circulation may be promising for the treatment of type 2 diabetes.
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PMID:The role of melanocyte-stimulating hormone in insulin resistance and type 2 diabetes mellitus. 1639 14

CGS 35601 (L-tryptophan, N-[[1-[[(2S)-2-mercapto-4-methyl-1-oxopentyl]amino]-cyclopentyl]carbonyl]) is one of a few single molecules capable of inhibiting the activities of angiotensin-converting enzyme (ACE), neutral endopeptidase (NEP) and endothelin converting enzyme (ECE) simultaneously, with IC(50) values of 22, 2, and 55 nM, respectively. Through the inhibition of ACE and ECE, it blocks the conversion of angiotensin I (AI) and big endothelin-1 (big ET-1) into the two most potent peptidic vasoconstrictors, angiotensin II (AII) and ET-1, respectively. By inhibiting NEP, CGS 35601 also prevents the degradation of peptidic vasodilators such as bradykinin (BK), natriuretic peptides (NPs) and adrenomedullin (ADM) and, hence, modulates the secondary release of other vasoactive mediators such as nitric oxide (NO) and prostaglandins. In chronic (30 days) experiments, CGS 35601 is well tolerated with a very good safety profile in healthy normotensive, hypertensive and type 2 diabetic rats. The antihypertensive efficacy of CGS 35601 was demonstrated in chronically instrumented, unrestrained and conscious rat models of hypertension (SHR and DSS) and type 2 diabetes (ZDF-fatty). It lowered blood pressure effectively as well as modulated plasma concentrations of a number of circulating vasoactive peptidic mediators that are keys to the regulation of the vascular tone. These data suggest that CGS 35601, a triple vasopeptidase inhibitor (VPI), may represent a novel class of antihypertensive drugs and may have the potential to reduce morbidity and mortality from cardiovascular disorders, diabetes and subsequent renal complications. Similar in vivo ACE, NEP, and ECE inhibitory activities were also observed with the orally active prodrug, CGS 37808 (L-tryptophan, N-[[1-[[(2S)-2-(acetylthio)-4-methyl-1-oxopentyl]amino]cyclopentyl]-carbonyl]-, methyl ester.
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PMID:CGS 35601, a triple inhibitor of angiotensin converting enzyme, neutral endopeptidase and endothelin converting enzyme. 1661 31


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