Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Type 1 diabetes is a metabolic disorder caused by loss of insulin-producing pancreatic beta-cells. Expression of insulin in non-beta-cells to create beta-cell surrogates has been tried to treat type 1 diabetes. Enteroendocrine K cells have characteristics similar to pancreatic beta-cells, such as a glucose-sensing system and insulin-processing proteases. In this study, we genetically engineered an enteroendocrine cell line (STC-1) to express insulin under the control of the glucose-dependent insulinotropic polypeptide promoter. We screened clones and chose one, Gi-INS-7, based on its high production of insulin. Gi-INS-7 cells expressed glucose transporter 2 (GLUT2) and glucokinase (GK) and secreted insulin in response to elevated glucose levels in vitro. To determine whether Gi-INS-7 cells can control blood glucose levels in diabetic mice, we transplanted these cells under the kidney capsule of streptozotocin (STZ)-induced diabetic mice and found that blood glucose levels became normal within 2 weeks of transplantation. In addition, glucose tolerance tests in mice that became normoglycemic after transplantation with Gi-INS-7 cells showed that exogenous glucose was cleared appropriately. These results suggest that engineered K cells may be promising surrogate beta-cells for possible therapeutic use for the treatment of type 1 diabetes.
Mol Ther 2007 Jun
PMID:Engineered enteroendocrine cells secrete insulin in response to glucose and reverse hyperglycemia in diabetic mice. 1729 98

Congenital disorders of glycosylation type Ia (CDG-Ia) is a recessive metabolic disorder caused by mutations in the PMM2 gene and characterized by a defect in the synthesis of N-glycans. The clinical presentation ranges from very severe multi-organ failure to mild neurological problems. A plethora of PMM2 mutations has been described and the vast majority are missense mutations. This selection reflects the requirement of a minimal phosphomannomutase activity to be compatible with life. We describe the characterization of two unusual truncating mutations in two CDG-Ia patients. The first patient is compound heterozygous for the PMM2 mutation p.V231M (c.691G>A) and a deep intronic point mutation (c.639-15.479C>T). The latter variant activates a cryptic splice site which results in an in-frame insertion of a pseudoexon of 123 bp between exon 7 and 8. The second patient is compound heterozygous for the mutation p.V44A (c.131T>C) and an Alu retrotransposition mediated complex deletion of approximately 28 kb encompassing exon 8. These types of mutations have not been described before in CDG-Ia patients. Their detection stresses the importance to combine PMM2 mutation screening on genomic DNA with analysis of the transcripts and/or with the enzymatic analysis of the phosphomannomutase activity. Next to the exonic deletions, which already receive more attention than before, it is likely that deep intronic mutations represent an increasingly important category of mutations.
Mol Genet Metab 2007 Apr
PMID:Characterization of two unusual truncating PMM2 mutations in two CDG-Ia patients. 1730 6

Type 2 diabetes mellitus is a complex metabolic disorder in which endogenous sex hormones may contribute to sex-dependent etiologies. We hypothesized that genetic variants related to type 2 diabetes mellitus might differ between men and women. We thus performed a large-scale association study to identify gene polymorphisms associated with type 2 diabetes mellitus in men and women separately. The study population comprised 4854 unrelated Japanese individuals (2688 men, 2166 women), including 1490 subjects with type 2 diabetes mellitus (969 men, 521 women). The genotypes for 16 gene polymorphisms were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, body mass index, and smoking status revealed that the T-->G (3' UTR) polymorphism of the thrombospondin 2 gene (THBS2), the -603A-->G polymorphism of the coagulation factor III gene (F3), and the G-->T (intron 2) polymorphism of the adipocyte, C1Q, and collagen domain containing (adiponectin) gene (ADIPOQ) were significantly associated with the prevalence of type 2 diabetes mellitus in men, and that the A-->G (Arg160Gly) polymorphism of the paraoxonase 1 gene (PON1) was significantly associated with this condition in women. A stepwise forward selection procedure demonstrated that genotypes of THBS2, F3, and ADIPOQ were significant determinants of type 2 diabetes mellitus in men, and that genotype of PON1 significantly affected this condition in women. Genotyping of these polymorphisms may prove informative for assessment of the genetic component of type 2 diabetes mellitus for men and women separately.
Int J Mol Med 2007 Apr
PMID:Gender differences in the association of gene polymorphisms with type 2 diabetes mellitus. 1733 38

Metabolic disorders, including type 2 diabetes and obesity, represent major health risks in industrialized countries. AMP-activated protein kinase (AMPK) has become the focus of a great deal of attention as a novel therapeutic target for the treatment of metabolic syndromes, because AMPK has been demonstrated to mediate, at least in part, the effects of a number of physiological and pharmacological factors that exert beneficial effects on these disorders. Thus, the identification of a compound that activates the AMPK pathway would contribute significantly to the treatment and management of such syndromes. In service of this goal, we have screened a variety of naturally occurring compounds and have identified one compound, cryptotanshinone, as a novel AMPK pathway activator. Cryptotanshinone was originally isolated from the dried roots of Salvia militorrhiza, an herb that is used extensively in Asian medicine and that is known to exert beneficial effects on the circulatory system. For the first time, in the present study, we have described the potent antidiabetic and antiobesity effects of cryptotanshinone, both in vitro and in vivo. Our findings suggest that the activation of the AMPK pathway might contribute to the development of novel therapeutic approaches for the treatment of metabolic disorders such as type 2 diabetes and obesity.
Mol Pharmacol 2007 Jul
PMID:Antidiabetes and antiobesity effect of cryptotanshinone via activation of AMP-activated protein kinase. 1742 5

Mucopolysaccharidosis II (MPS II; Hunter syndrome) is an X-linked metabolic disorder caused by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S), which catalyzes the catabolism of glycosaminoglycans (GAG) by cleaving the O-linked sulfate from dermatan sulfate and heparan sulfate. Recently, enzyme replacement therapy (ERT) with recombinant human I2S (Elaprase (idursulfase), Shire Human Genetic Therapies, Inc.), has been approved in the US and European Union for the treatment and management of MPS II. The purpose of the studies presented here was to describe some of the preclinical development of idursulfase using the I2S knock-out mouse model of MPS II designed to study the effect of dose and various dosing regimens of idursulfase on urine and tissue GAG levels. Urine and tissue samples were collected prior to idursulfase treatment and periodically throughout each study and analyzed for GAGs. The presence of anti-idursulfase antibodies in the mice serum after idursulfase use was also determined. Results showed that idursulfase, at several doses and at several dosing frequencies, caused a reduction in tissue and urine GAG levels in a dose-dependent manner. These studies also demonstrated that after IV administration, idursulfase is biologically active in the IdS-KO mouse model and is transported to key target tissues, reaching the lysosomes in an active form, and degrading the accumulated GAG. In conclusion, these results indicated that ERT with idursulfase produced in a human cell line could be useful in the treatment and management of MPS II, and were used in the design of clinical studies to evaluate the efficacy of idursulfase in MPS II patients.
Mol Genet Metab 2007 Jun
PMID:Preclinical dose ranging studies for enzyme replacement therapy with idursulfase in a knock-out mouse model of MPS II. 1745 51

Two horses (a 7-year-old Groninger warmblood gelding and a six-month-old Trakehner mare) with pathologically confirmed rhabdomyolysis were diagnosed as suffering from multiple acyl-CoA dehydrogenase deficiency (MADD). This disorder has not been recognised in animals before. Clinical signs of both horses were a stiff, insecure gait, myoglobinuria, and finally recumbency. Urine, plasma, and muscle tissues were investigated. Analysis of plasma showed hyperglycemia, lactic acidemia, increased activity of muscle enzymes (ASAT, LDH, CK), and impaired kidney function (increased urea and creatinine). The most remarkable findings of organic acids in urine of both horses were increased lactic acid, ethylmalonic acid (EMA), 2-methylsuccinic acid, butyrylglycine (iso)valerylglycine, and hexanoylglycine. EMA was also increased in plasma of both animals. Furthermore, the profile of acylcarnitines in plasma from both animals showed a substantial elevation of C4-, C5-, C6-, C8-, and C5-DC-carnitine. Concentrations of acylcarnitines in urine of both animals revealed increased excretions of C2-, C3-, C4-, C5-, C6-, C5-OH-, C8-, C10:1-, C10-, and C5-DC-carnitine. In addition, concentrations of free carnitine were also increased. Quantitative biochemical measurement of enzyme activities in muscle tissue showed deficiencies of short-chain acyl-CoA dehydrogenase (SCAD), medium-chain acyl-CoA dehydrogenase (MCAD), and isovaleryl-CoA dehydrogenase (IVD) also indicating MADD. Histology revealed extensive rhabdomyolysis with microvesicular lipidosis predominantly in type 1 muscle fibers and mitochondrial damage. However, the ETF and ETF-QO activities were within normal limits indicating the metabolic disorder to be acquired rather than inherited. To our knowledge, these are the first cases of biochemical MADD reported in equine medicine.
Mol Genet Metab 2007 Aug
PMID:Equine biochemical multiple acyl-CoA dehydrogenase deficiency (MADD) as a cause of rhabdomyolysis. 1754 May 95

Protein and peptide therapeutics are of growing importance as medical treatments but can frequently induce an immune response. This work describes the combination of complementary approaches to map the potential immunogenic regions of the yeast Rhodosporidium toruloides phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) and to engineer the protein as a human therapeutic agent for the treatment of phenylketonuria (PKU), an inherited metabolic disorder. The identification of B and T cell epitopes on the PAL protein was performed by computational predictions based on the antigenicity and hydrophilicity of proteins, as well as by experimental epitope mapping using a PepSpots peptide array (Jerini AG). Human T cell epitope mapping was performed by applying the computational EpiMatrix algorithm (EpiVax, Inc.) for MHC Class I and Class II associated T cell epitopes on PAL, which predicts which sequences are associated with binding to several different HLA alleles, a requirement for antigen presentation and subsequent primary immune response. By chemical modification through PEGylation of surface lysine residues, it is possible to cover the immunogenic regions of a protein. To evaluate this strategy, we used mass spectrometry to determine which of the immunogenic epitopes are covered by the covalent PEGylation modification strategy. This approach has allowed us to determine whether additional lysines are needed in specific residue locations, or whether certain lysine residues can be removed in order to accomplish complete molecular coverage of the therapeutic enzyme.
Mol Genet Metab 2007 Aug
PMID:Structure-based epitope and PEGylation sites mapping of phenylalanine ammonia-lyase for enzyme substitution treatment of phenylketonuria. 1756 Aug 21

Cystathionine beta synthase (CBS) deficiency is a metabolic disorder that is biochemically characterized by severe hyperhomocysteinemia. In order to show the effects of CBS deficiency onto the activity of the enzymes involved in the remethylation pathway, we used the well characterized genetic model of severe hyperhomocysteinemia in mice. We showed that CBS deficiency in mice reduced hepatic methionine synthase and betaine-homocysteine methyltransferase activities, whereas 5,10-methylene tetrahydrofolate reductase activity was increased.
Mol Genet Metab 2007 Aug
PMID:Mice deficient in cystathionine beta synthase display altered homocysteine remethylation pathway. 1756 77

Phenylketonuria (PKU) is a metabolic disorder secondary to a hepatic deficiency of phenylalanine hydroxylase (PAH) that predisposes affected children to develop severe and irreversible mental retardation. We have previously reported the complete and permanent correction of the hyperphenylalaninemic and hypopigmentation phenotypes in male, but not female, PKU mice after genome-targeted delivery of murine PAH (mPAH) complementary DNA (cDNA) in a phiBT1 bacteriophage integration system. Here we show that sequential administration of green fluorescent protein (GFP)- and red fluorescent protein (RFP)-expressing cassettes in the phiBT1 integration system led to distinct and non-overlapping populations of green and red fluorescent hepatocytes in vivo. The hyperphenylalaninemic and hypopigmentation phenotypes of female PKU mice were completely corrected after 10 weekly administrations of mPAH cDNA. Importantly, there was no apparent liver pathology in mice even after 10 consecutive administrations of the phiBT1 integration system. The results indicate that repeated administration of transgenes in the phiBT1 integration system can lead to their genome-targeted integration in a diverse population of hepatocytes and result in the elevation of transgene expression levels in a cumulative manner, which can be utilized to overcome insufficient transgene expression owing to low genome integration frequencies in a gene therapy paradigm for metabolic disorders.
Mol Ther 2007 Oct
PMID:Correction in female PKU mice by repeated administration of mPAH cDNA using phiBT1 integration system. 2773 55

Diabetes mellitus is a metabolic disorder characterized by hyperglycemia. The two main forms of the disease are distinguished by different pathogenesis, natural histories, and population distributions and indicated as either type 1 (T1DM) or type 2 diabetes mellitus (T2DM). It is well established that T1DM is an autoimmune disease whereby beta-cells of pancreatic islets are destroyed leading to loss of endogenous insulin production. Albeit less dramatic, beta-cell mass (BCM) also drops in T2DM. Therefore, it is realistic to expect that noninvasive measures of BCM might provide useful information in the diabetes-care field. Preclinical studies have demonstrated that BCM measurements by positron emission tomography scanning, using the vesicular monoamine transporter type 2 (VMAT2) as a tissue-specific surrogate marker of insulin production and [11C] Dihydrotetrabenazine (DTBZ) as the radioligand specific for this molecule, is feasible in animal models. Unfortunately, the mechanisms underlying beta-cell-specific expression of VMAT2 are still largely unexplored, and a much better understanding of the regulation of VMAT2 gene expression and of its function in beta-cells will be required before the full utility of this technique in the prediction and treatment of individuals with diabetes can be understood. In this review, we summarize much of what is understood about the regulation of VMAT2 and identify questions whose answers may help in understanding what measurements of VMAT2 density mean in the context of diabetes.
J Mol Med (Berl) 2008 Jan
PMID:VMAT2 gene expression and function as it applies to imaging beta-cell mass. 1766 59


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