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)

There has been great interest in the ex vivo expansion of human long-term repopulating hematopoietic stem cells (LTR-HSCs) for a variety of clinical applications such as umbilical cord blood transplantation. The glucoprotein130 signal, activated by a complex of interleukin 6 (IL-6) and soluble IL-6 receptor (IL-6/sIL-6R), acts dramatically in synergy with the c-Kit or Flk2/Flt3 signal to expand immature human HSCs. We demonstrate a significant ex vivo expansion of human LTR-HSCs capable of repopulating in newly discovered nonobese diabetes/Shi-severe combined immunodeficient (NOD/Shi-SCID) mice. The proportion of human CD45+ cells in recipient marrow was 10 times higher in animals receiving the cultured cells with stem cell factor, Flk2/Flt3 ligand, thrombopoietin, and IL-6/sIL-6R than in those receiving comparable numbers of fresh cord blood CD34+ cells. The expansion rate provided by this combination was estimated to be 4.2-fold by a limiting dilution method. Addition of IL-3 to the culture with the cytokine combination abrogated the repopulating ability of the expanded cells. The culture method with the IL-6/sIL-6R complex and other cytokines may pave the way for ex vivo expansion of human transplantable HSCs suitable for clinical applications.
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PMID:Ex vivo expansion of human hematopoietic stem cells. 1137 56

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

We have carried out a detailed sequence and functional analysis of a novel human facilitative glucose transporter, designated GLUT10, located in the Type 2 diabetes-linked region of human chromosome 20q12-13.1. The GLUT10 gene is located between D20S888 and D20S891 and is encoded by 5 exons spanning 26.8 kb of genomic DNA. The human GLUT10 cDNA encodes a 541 amino acid protein that shares between 31 and 35% amino acid identity with human GLUT1-8. The predicted amino acid sequence of GLUT10 is nearly identical in length to the recently described GLUT9 homologue, but is longer than other known members of the GLUT family. In addition, we have cloned the mouse cDNA homolog of GLUT10 that encodes a 537 amino acid protein that shares 77.3% identity with human GLUT10. The amino acid sequence probably has 12 predicted transmembrane domains and shares characteristics of other mammalian glucose transporters. Human and mouse GLUT10 retain several sequence motifs characteristic of mammalian glucose transporters including VP497ETKG in the cytoplasmic C-terminus, G73R[K,R] between TMD2 and TMD3 (PROSITE PS00216), VD92RAGRR between TMD8 and TMD9 (PROSITE PS00216), Q242QLTG in TMD7, and tryptophan residues W430 (TMD10) and W454 (TMD11), that correspond to trytophan residues previously implicated in GLUT1 cytochalasin B binding and hexose transport. Neither human nor mouse GLUT10 retains the full P[E,D,N]SPR motif after Loop6 but instead is replaced with P186AG[T,A]. A PROSITE search also shows that GLUT10 has lost the SUGAR TRANSPORT 2 pattern (PS00217), a result of the substitution G113S in TMD4, while all other known human GLUTs retain the glycine and the pattern match. The significance of this substitution is unknown. Sites for N-linked glycosylation are predicted at N334ATG between TMD8 and TMD9 and N526STG in the cytoplasmic C-terminus. Northern hybridization analysis identified a single 4.4-kb transcript for GLUT10 in human heart, lung, brain, liver, skeletal muscle, pancreas, placenta, and kidney. By RT-PCR analysis, GLUT10 mRNA was also detected in fetal brain and liver. When expressed in Xenopus oocytes, human GLUT10 exhibited 2-deoxy-D-glucose transport with an apparent Km of approximately 0.3 mM. D-Glucose and D-galactose competed with 2-deoxy-D-glucose and transport was inhibited by phloretin. The gene localization and functional properties suggest a role for GLUT10 in glucose metabolism and Type 2 diabetes.
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PMID:Sequence and functional analysis of GLUT10: a glucose transporter in the Type 2 diabetes-linked region of chromosome 20q12-13.1. 1159 15

Beta 3-adrenergic receptors (beta 3 ARs) are important structures in the human body but the role they play is not yet very clear. Stimulation of beta 3 AR in adipose tissue causes greater energy expenditure and increases thermogenesis and lipolysis. Mutation of the gene coding beta 3 AR in position 64 with thymidine instead of cytosine leads to the replacement of tryptophan (Trp 64) with arginine (Arg 64) and may be the cause of greater increase in body mass and the decrease in basic metabolism. The data however, is differentiated in populations and cannot be conclusive. The connection has been discovered between the state of the beta 3 ARs and the blood lipid concentration (also differing in populations). In some patients beta 3 AR mutation is correlated with high arterial diastolic pressure, increased incidence of noninsulin-dependent diabetes in younger, increased insulin resistance and diabetes in pregnant. beta 3-AR agonists might be used in treatment of many diseases, which obviously demands further investigations.
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PMID:[The role of beta 3-adrenergic receptors in the human organism]. 1176 88

Indoleamine 2,3-dioxygenase (IDO) catalyzes the breakdown of the amino acid tryptophan into kyneurenine. It has been shown that IDO production by placental trophoblasts prevents the attack of maternal T-cells activated in response to the paternal HLA alleles expressed by the tissues of the fetus. In this article, we show that adenoviral gene transfer of IDO to pancreatic islets can sufficiently deplete culture media of tryptophan and consequently inhibit the proliferation of T-cells in vitro. Experiments in vivo have also demonstrated that transplantation of IDO-expressing islets from prediabetic NOD mouse donors into NODscid recipient mice is associated with a prolongation in islet graft survival after adoptive transfer of NOD diabetogenic T-cells. This protection is attributed to the depletion of tryptophan at the transplantation site beneath the kidney capsule. These results suggest that local modulation of tryptophan catabolism may be a means of facilitating islet transplantation as a therapy for type 1 diabetes.
Diabetes 2002 Feb
PMID:Indoleamine 2,3-dioxygenase expression in transplanted NOD Islets prolongs graft survival after adoptive transfer of diabetogenic splenocytes. 1181 42

In the tryptophan-niacin conversion, 2-amino-3-carboxymuconate-6-semiardehyde decarboxylase (ACMSD; formerly termed picolinic carboxylase) is an important enzyme regulating the generation of quinolinate. In a series of experiments, we investigated alterations of ACMSD expression in rats by feeding a high protein diet and by inducing diabetes with streptozotocin (STZ). Male Sprague-Dawley rats (5-wk-old) were fed a diet containing 40% casein for 11 d, and hepatic ACMSD activity and mRNA expression were determined at intervals. The enzyme activity had increased at d 2, and it continued to increase through d 11. ACMSD mRNA expression had increased at d 1 and the elevated levels were maintained through d 11. Shifting from the 40% casein diet to a 20% casein diet restored hepatic ACMSD activity and mRNA expression to normal levels within 5 d and 2 d, respectively. In another series of experiments, male Wistar rats were injected with STZ (50 mg/kg) and the time-course (d 0, 1, 2, 4, 8 and 14) of the change in hepatic ACMSD activity and mRNA expression were examined. The activity increased dramatically after d 4, while mRNA expression was significantly elevated at d 2, followed by slight increases through d 14. Insulin administration (2 U/12 h) reduced the elevated ACMSD activity and fully suppressed the elevated ACMSD mRNA expression due to STZ injection. These results indicated that the fluctuation of hepatic ACMSD mRNA expression was followed by that of ACMSD activity.
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PMID:Expression of rat hepatic 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase is affected by a high protein diet and by streptozotocin-induced diabetes. 1204 25

The major lenticular protein alpha-crystallin has chaperone activity. With increasing age this chaperone function is compromised. Diabetes and glucocorticoid therapy are risk factors for cataract and are associated with raised sugar and glucocorticoid levels, respectively. These molecules react with proteins. Long-lived lenticular proteins are particularly susceptible to such attack. To investigate this possibility we carried out incubations of alpha-crystallin with fructose 6-phosphate and prednisolone-21-hemisuccinate and investigated the effect of modification on chaperone ability. Fructose 6-phosphate and prednisolone-21-hemisuccinate compromised chaperone activity as measured by the beta L-crystallin thermal aggregation assay. Tryptophan fluorescence provided evidence that the structure of alpha-crystallin had been modified by both compounds.
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PMID:The effect of modification of alpha-crystallin by prednisolone-21-hemisuccinate and fructose 6-phosphate on chaperone activity. 1206 Dec 73

Diabetic ketoacidosis (DKA) is a severe metabolic disturbance of insulin-dependent diabetes mellitus (IDDM) which has a significant effect on amino acid metabolism. Amino acids serve as precursors for various neurotransmitters which are involved in affective disorders, and patients with IDDM are known to have an increased prevalence of affective disorders. We monitored the plasma concentrations of 23 amino acids in six adolescents prior to treatment of DKA and at 6, 24 and 120 hours after initiation of treatment. The well-known increase in the concentrations of the glucogenic amino acids and the decrease in the branched-chain amino acids were observed in response to treatment of DKA. Low levels of tryptophan were found prior to treatment of DKA. Treatment increased the plasma tryptophan levels, but the mean concentration remained low throughout the sampling period. Only the glutamate-derived amino acids (glutamate, proline and glutamine) from the Krebs cycle pool were significantly affected by treatment. Glutamine declined initially, but recovered as the plasma pH normalized. Our results indicate that DKA causes a depletion of plasma tryptophan. This depletion may predispose some patients with IDDM to have affective disorders secondary to a neurotransmitter imbalance.
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PMID:Diabetic ketoacidosis depletes plasma tryptophan. 1210 94

Generation of new blood vessels from pre-existing vasculature (angiogenesis) is accompanied in almost all states by increased vascular permeability. This is true in physiological as well as pathological angiogenesis, but is more marked during disease states. Physiological angiogenesis occurs during tissue growth and repair in adult tissues, as well as during development. Pathological angiogenesis is seen in a wide variety of diseases, which include all the major causes of mortality in the west: heart disease, cancer, stroke, vascular disease and diabetes. Angiogenesis is regulated by vascular growth factors, particularly the vascular endothelial growth factor family of proteins (VEGF). These act on two specific receptors in the vascular system (VEGF-R1 and 2) to stimulate new vessel growth. VEGFs also directly stimulate increased vascular permeability to water and large-molecular-weight proteins. We have shown that VEGFs increase vascular permeability in mesenteric microvessels by stimulation of tyrosine auto-phosphorylation of VEGF-R2 on endothelial cells, and subsequent activation of phospholipase C (PLC). This in turn causes increased production of diacylglycerol (DAG) that results in influx of calcium across the plasma membrane through store-independent cation channels. We have proposed that this influx is through DAG-mediated TRP channels. It is not known how this results in increased vascular permeability in endothelial cells in vivo. It has been shown, however, that VEGF can stimulate formation of a variety of pathways through the endothelial cell, including transcellular gaps, vesiculovacuolar organelle formation, and fenestrations. A hypothesis is outlined that suggests that these all may be part of the same process.
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PMID:Regulation of microvascular permeability by vascular endothelial growth factors. 1216 26

The complications (thromboembolism and jaundice), averse effects (metabolic disorders, hypertension and bleeding) and the risks (cancer and teratologic effects) of oral contraceptives are summarized and compared to those of other methods. Venous thrombosis is more frequent than arterial thrombosis; both are rare but can be severe; risk is decreased with minidose pills. Cholostatic jaundice is likely only in those with history of such jaundice in pregnancy. Decreased oral glucose tolerance similar to diabetes of pregnancy, similarly, is more common with high dose pills. Triglycerides, pre-beta lipoproteins and t otal cholesterol levels are increased to the upper limit of normal, but stabilize after 3 months of pill intake in normal women. Mixed hyperlipidemia in some women can be detected by the cholesterol to triglycerides ratio after 8 and 12 hours of fasting. Other possible side effects are hypertension, elevated thyroid hormone, depression due to abnormal tryptophan metabolism, acne, cholasma, varices, spotting, amenorrhea. The risk of cancer is still unknown, but that of chromosomal defects in unfounded. To avoid these complications, the physician must observe the contraindications of history of thromboembolism, heart disease, jaundice, hypertension and cancer, and follow patients regularly by gynecologic exam, glucose tolerance and blood lipid tests and take blood pressure. In comparison, diaphragms give 15% failure rates, and copper IUDs less than 1%, but about 10% expulsions and 10% removals for bleeding.
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PMID:[Complications of contraception]. 1225 11


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