Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT00572 (Asn)
 11,732 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this study we demonstrate that haptoglobin, a serum glycoprotein secreted by the liver, has altered structure in the BB/Wor diabetic rat. SDS-PAGE of haptoglobin (a tetramer composed of two glycosylated beta-chains each containing two sites for Asn-linked oligosaccharides connected by disulfide bonds with two nonglycosylated alpha-chains) clearly shows that the beta-chain of haptoglobin from diabetic rats is smaller than normal, with a molecular mass of 39 instead of 40 kDa. Both acute and chronic diabetic rats exhibit the defect. Defective haptoglobin appears in the serum within 4 days of onset of the disease, but insulin therapy prevents the defect. Removal of Asn-linked oligosaccharides with peptide: N-glycosidase F from Flavobacterium meningosepticum abolished the size difference between the beta-chains from normal and diabetic haptoglobin, with the molecular mass in both cases shifting to 30 kDa. Haptoglobin from both normal and diabetic rats was resistant to digestion by endoglycosidase H from Streptomyces griseus, which cleaves high mannose-type chains. Removal of sialic acid with neuraminidase treatment resulted in a reduction in the molecular mass in both cases, but without eliminating the size difference between the two. These results demonstrate that haptoglobin from diabetic BB/Wor rats contains a structural abnormality which correlates with onset of the disease. The defect is most likely due to an alteration in Asn-linked oligosaccharides, probably involving a change in the neutral sugars of complex-type oligosaccharide chains. This finding represents the first example of an altered Asn-linked oligosaccharides in diabetes.
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PMID:Diabetic BB/Wor rat haptoglobin exhibits a probable structural abnormality in Asn-linked oligosaccharides. 202 25

To overcome the difficulties encountered in quantifying the insulin receptor number by Scatchard analysis, a radioimmunoassay (RIA) for the human insulin receptor (hIR) has been developed that uses an antibody raised against a synthetic peptide (Gly-Lys-Lys-Asn-Gly-Arg-Ile-Leu-Thr-Leu-Pro-Arg-Ser-Asn-Pro-Ser) corresponding to the carboxyl terminal of the hIR. A second peptide (Tyr-Gly-Arg-Ile-Leu-Thr-Leu-Pro-Arg-Ser-Asn-Pro-Ser) was used as a standard and allowed preparation of monoiodinated derivative of theoretical specific activity for use as the radioactive ligand. The assay is specific, highly reproducible, and sensitive, with a detection limit of 10 fmol of receptor. One mole of purified receptor, measured by Scatchard analysis or amino acid analysis, is read as one mole of receptor in the RIA with peptide being the standard. The assay is effective with receptor from multiple sources and could determine the decrease in number of insulin receptors seen in IM-9 lymphocytes after treatment with insulin (downregulation).
Diabetes 1989 Aug
PMID:Peptide-based radioimmunoassay for insulin receptor. Detection of insulin-stimulated downregulation in IM-9 lymphocytes. 266 3

The mechanisms of hypoglycaemic action of a 'second-generation' sulphonylurea, gliclazide, and a synthetic human growth hormone fragment, hGH 6-13 (Leu-Ser-Arg-Leu-Phe-Asp-Asn-Ala), were compared at the cellular level in rats. Both compounds were shown to be hypoglycaemic in vivo although their molecular structures were totally different. Gliclazide was markedly insulinotropic, as are all hypoglycaemic sulphonylureas, whereas hGH 6-13 had no visible effect on basal levels of plasma insulin. However, in vitro studies with isolated pancreatic islets revealed that hGH 6-13 significantly augmented insulin secretion in the presence of exogenous glucose. One other major difference was that gliclazide had no direct effect on insulin receptor function while the synthetic hGH 6-13 increased the binding of insulin to specific receptors on isolated cells. Results suggested that the human growth hormone fragment hGH 6-13 could be a potential anti-diabetes drug with the ability to potentiate circulating insulin action and to achieve blood glucose normalisation.
Diabetes Res Clin Pract 1988 May 19
PMID:A comparison of cellular actions between gliclazide and a hypoglycaemic peptide fragment of human growth hormone (hGH 6-13). 304 43

The pancreatic effect of a hypoglycaemic fragment of human growth hormone containing the amino acid sequence Leu-Ser-Arg-Leu-Phe-Asp-Asn-Ala (hGH 6-13), was investigated. In partially pancreatectomized rats, hGH 6-13 (3 mg/kg body weight) enhanced glucose utilization in blood as demonstrated in intravenous glucose tolerance tests (IVGTTs). However, the basal levels of plasma insulin in the animals were apparently not affected by acute administration of the hGH fragment and only slightly modulated with prolonged hGH fragment treatment. Direct studies with the isolated pancreatic islets from normal and hGH 6-13 treated rats showed that hGH 6-13 did not influence in vitro or ex vivo insulin release in the absence of glucose but significantly potentiated the glucose-induced insulin secretion of the pancreatic islets from treated animals. An increase of 42% in glucose oxidation of the isolated pancreatic islets after exposure to hGH 6-13 was observed. This study reveals significant differences in the molecular mechanism of the hypoglycaemic action between the hGH fragments and orally active sulphonylureas. The findings suggest that the hypoglycaemic hGH fragments, structurally unrelated to sulphonylureas, could be a new group of effective agents to achieve blood glucose normalization without the risk of hyperinsulinaemia, as their pancreatic effect is glucose-dependent.
Diabetes Res 1988 Mar
PMID:Pancreatic effect of a hypoglycaemic fragment of human growth hormone (hGH 6-13). 304 17

A series of synthetic peptides corresponding to the amino-terminal sequence of human growth hormone (hGH) has been studied for insulin-potentiating effects using three different bioassay systems: (1) intravenous insulin tolerance tests, (2) insulin binding to specific receptors of hepatic plasma membranes and isolated hepatocytes, and (3) modulation of insulin-dependent glycogen synthase and glycogen phosphorylase in muscle and adipose tissue. The results establish that the minimum active sequence is the hexapeptide (hGH 8-13) containing H2N-Arg-Leu-Phe-Asp-Asn-Ala-COOH and strongly indicate that the insulin-potentiating action of the active peptides is to increase the binding of insulin to specific receptors and thus modulate the action of glycogen synthase and phosphorylase, producing hypoglycemia as the result of increased glycogen storage in liver, muscle, and adipose tissue.
Diabetes 1980 Oct
PMID:The minimal amino acid sequence of the insulin-potentiating fragments of human growth hormone: its mechanism of action. 677 19

We have recently identified a new member of the Ras/GTPase superfamily termed Rad which has unique sequence features and is overexpressed in the skeletal muscle of humans with type II diabetes (Reynet, C., and Kahn, C. R. (1993) Science, 262, 1441-1444). When expressed in bacteria as a glutathione S-transferase fusion protein, Rad bound [alpha-32P]GTP quickly and saturably. Binding was specific for guanine nucleotides and displayed unique magnesium dependence such that both GTP and GDP binding were optimal at relatively high Mg2+ concentrations (1-10 mM). Rad had low intrinsic GTPase activity which was greatly enhanced by a GTPase-activating protein (GAP) activity present in various tissues and cell lines. Several known GAPs had no stimulatory effect toward Rad. Conversion of Ser to Asn at position 66 in Rad (equivalent to position 12 in Ras) resulted in a total loss of GTP binding. Mutation of Pro61 (equivalent to Gly12 in Ras) or Gln109 (equivalent to Gln61 in Ras) had no effect on Rad GTPase activity, whereas creation of a double mutation at these positions resulted in exceptionally high intrinsic GTPase activity. In vitro, Rad was phosphorylated by the catalytic subunit of cAMP-dependent protein kinase (PK). Phosphopeptide mapping indicated two PKA phosphorylation sites near the COOH terminus. Rad also co-precipitated a serine/threonine kinase activity from extracts of various tissues and cell lines which catalyzed phosphorylation on Rad but was not inhibited by PKA inhibitor. Thus, Rad is a GTP-binding protein and a GTPase which has some structure/function similarities to Ras, but displays unique features. Rad may also be phosphorylated on serine/threonine residues by PKA and other kinases, as well as regulated by its own GAP which is present in many tissues and cell types.
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PMID:Characterization of Rad, a new member of Ras/GTPase superfamily, and its regulation by a unique GTPase-activating protein (GAP)-like activity. 787 54

Hypertriglyceridemia is common among individuals with noninsulin-dependent diabetes mellitus (NIDDM), and heterozygous lipoprotein lipase (LPL) mutations may result in the syndrome of familial hypertriglyceridemia and low levels of high density lipoprotein (HDL) cholesterol. To test the hypothesis that heterozygous LPL mutations predispose to the hypertriglyceridemia and low HDL cholesterol levels observed among members of familial NIDDM families, we examined 36 members and 3 unrelated spouses selected from members of 20 pedigrees for triglyceride levels exceeding the age- and sex-specific 95th percentile. Eighteen pedigree members and 2 spouses were diabetic. LPL exons 1-9 were screened by single strand conformation polymorphism analysis. Six different variants were detected in exons 2, 3, 4, 8, and 9, including 4 (exons 3, 4, and 8) silent nucleotide substitutions. A common nonsense mutation (exon 9; Ser-->Ter) was present in 2 pedigrees, and a missense mutation (exon 2; Asp-->Asn) was also present in members of 2 pedigrees. Analysis of members of these families suggested an association of the exon 2 variant with hypertriglyceridemia, although this trend was no longer significant when individuals with diabetes were excluded from the analysis. The variant enzyme was not present among 83 random control individuals, and when expressed in COS-1 cells, it was similar to the wild type with respect to specific activity, heparin binding, and heat stability. Our data suggest that coding region mutations of the LPL gene cannot account for the elevated triglyceride and low HDL levels noted in diabetic individuals and their relatives in most NIDDM pedigrees, but the exon 2 Asn variant may contribute to the hypertriglyceridemia in some families.
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PMID:Molecular screening of the lipoprotein lipase gene in hypertriglyceridemic members of familial noninsulin-dependent diabetes mellitus families. 796 42

We identified two patients with pathogenic single nucleotide changes in two different mitochondrial tRNA genes: the first mutation in the tRNA(Asn) gene, and the ninth known mutation in the tRNA(Leu(UUR)) gene. The mutation in tRNA(Asn) was associated with isolated ophthalmoplegia, whereas the mutation in tRNA(Leu(UUR)) caused a neurological syndrome resembling MERRF (myoclonus epilepsy and ragged-red fibers) plus optic neuropathy, retinopathy, and diabetes. Both mutations were heteroplasmic, with higher percentages of mutant mtDNA in affected tissues, and undetectable levels in maternal relatives. Analysis of single muscle fibers indicated that morphological and biochemical alterations appeared only when the proportions of mutant mtDNA exceeded 90% of the total cellular mtDNA pool. The high incidence of mutations in the tRNA(Leu(UUR)) gene suggests that this region is an "etiologic hot spot" in mitochondrial disease.
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PMID:Two novel pathogenic mitochondrial DNA mutations affecting organelle number and protein synthesis. Is the tRNA(Leu(UUR)) gene an etiologic hot spot? 825 46

Glucokinase plays a key role in the regulation of glucose metabolism in insulin-secreting pancreatic beta-cells and in the liver. Recent studies have shown that mutations in this enzyme can lead to the development of a form of non-insulin-dependent diabetes mellitus that is characterized by an autosomal dominant mode of inheritance and onset during childhood. Here, we report the catalytic properties of five additional missense mutations associated with diabetes (Glu70-->Lys, Ser131-->Pro, Ala188-->Thr, Trp257-->Arg and Lys414-->Glu), one polymorphism present in both normal and diabetic subjects (Asp4-->Asn), and three site-directed mutations (Glu177-->Lys, Glu256-->Ala, and Lys414-->Ala). The Trp257-->Arg mutation generated an enzyme that had an activity that was less than 0.5% of that for native human beta-cell glucokinase. By contrast, the Glu70-->Lys, Ser131-->Pro, Ala188-->Thr, and Lys414-->Glu mutations had a Vmax that was 20-100% of normal but a Km for glucose that was 8-14-fold greater than the native enzyme. There was no effect of the Asp4-->Asn polymorphism or the Glu177-->Lys substitution on glucokinase activity. The Lys414-->Ala substitution had no effect on Vmax but increased the Km for glucose 2-fold and the Glu256-->Ala substitution caused a approximately 200-fold decrease in Vmax. These studies have led to the identification of additional residues involved in glucokinase catalysis and substrate binding.
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PMID:Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants. 832 92

A 74-year-old male patient with diabetes mellitus and hypertension who had been treated for a long period was admitted to our hospital. Laboratory data on admission revealed high values for fasting blood sugar and fructosamine, 219 mg/dl and 389 mumol/l respectively, while the concentration of glycated hemoglobin (HbA1c) was low (3.0%). High performance liquid chromatography and isoelectric focusing analysis of the patient's Hb disclosed abnormal Hb with the content being 41.3%. The structural analysis indicated that this abnormal Hb was Hb Riyadh [beta 120 (GH3) Lys-->Asn]. The low value of HbA1c despite the high blood glucose level may be attributed to this abnormal hemoglobin.
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PMID:A diabetic case of Hb Riyadh with a low HbA1c value. 850 23


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