Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Seventeen patients with Cushing's disease (CD) were treated from 1978 to 2000. There were 11 males and 6 females aged 6.8-18.8 years (mean age 13.0 +/- 5.9 years). Presenting features were: weight gain (100%); growth failure (71%); hirsutism (53%); striae (53%); hypertension (47%). Mean age of patients with striae was 15.2 +/- 2.3 years, without striae 10.3 +/- 3.3 years. Median height SDS was -1.81 (range -0.28 to -4.17), 53% having height SDS < -1.8. The height velocity in 6 subjects was subnormal (0.9-3.8 cm/year). Median BMI SDS was 2.29 (range 1.72-5.06). Cushing's disease was confirmed by detectable serum ACTH, median 28 ng/l (range 12-99, NR <10-50) (n = 15); loss of cortisol circadian rhythm values at midnight ranging from 216 to 1,080 nmol/l (NR <50) (n = 15); lack of cortisol suppression (NV < 50 nmol/l) during low-dose dexamethasone suppression test (LDDST) (0.5 mg 6-hourly x 8) (n = 14); and >50% suppression of cortisol compared with the basal value during high-dose dexamethasone suppression test (HDDST) (2 mg 6-hourly x 8) (n = 14). A CRH test (1 microg/kg i.v.) showed an increase of cortisol from 12 to 217% (median 73.5%) (n = 16). Pituitary imaging (CT/MRI) showed an image consistent with microadenoma in 6/17 patients, but there was concordance between pituitary imaging and surgical findings in 1/11 patients (9%). Inferior petrosal sinus sampling (IPSS) for ACTH after CRH was performed in 11 subjects (age 10.7-18.8 years). Central to peripheral ACTH ratios were >2 (2.5-157.2) in 10/11 patients. The inter-petrosal sinus ACTH gradient was >1.4 in 10 patients (2.1-20.8), indicating lateralization of ACTH secretion. In 10 patients (91%), the side of the tumour on IPSS was predictive of findings at surgery. Therapy consisted of transsphenoidal microadenomectomy (TSS) in 16 patients and bilateral adrenalectomy (1978) in 1. Following TSS alone, 7 patients were cured (cortisol <50 nmol/l) and 2 were in remission (cortisol <300 nmol/l), i.e. 56%. Seven had persisting hypercortisolaemia and underwent pituitary irradiation (4,500 cGy). Therapeutic outcome for a median of 8 years (0.5-24 years) resulted in cure of CD in 14/17 patients (82%) and remission in 1. Linear growth after TSS +/- pituitary irradiation in 10 subjects showed no short-term catch-up growth, with peak growth hormone (GH) 0.5-20.9 mU/l to insulin tolerance test (ITT)/glucagon. Eight patients were treated with human growth hormone (hGH) (14 U/m(2)/week) combined in 3 with GnRH analogue. The mean final (n = 6) or latest (n = 4) height SDS was -1.36. The difference between final/latest height SDS and target height SDS was 0.93 +/- 1.13, i.e. less (p = 0.005) than the difference between height SDS and target height SDS at presentation, i.e. 1.72 +/- 1.26, indicating long-term catch-up growth.
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PMID:Cushing's disease in childhood: presentation, investigation, treatment and long-term outcome. 1140 58

Pycnodysostosis is a rare hereditary bone abnormality with an autosomal recessive mode of inheritance. We report the clinical, radiologic, and endocrine status of 8 children with this rare disease. All patients had the characteristic phenotype of the disorder including short stature (8 of 8), increased bone density (7 of 8), separated cranial sutures (8 of 8), large fontanel with delayed closure (8 of 8), obtuse mandibular angle (8 of 8), delayed teeth eruption (8 of 8), enamel hypoplasia (7 of 8), dysplastic acromial ends of the clavicles (6 of 8), frontal bossing (6 of 8), ocular proptosis (8 of 8), and dysplastic nails (8 of 8). Developmental evaluation according to the revised Denever developmental screening showed normal motor, fine motor-adaptive language, and personal social abilities in all the children. All had normal hepatic and renal functions. Serum calcium and phosphorus concentrations were normal. Two children had low serum alkaline phosphatase concentration. Short stature is a characteristic feature of pycnodysostosis. Seven of the 8 children were born short (length standard deviation score [SDS] = -3 to -1.5). Deceleration of linear growth was significant during the first 3 years of life. All the children had height SDS below -3 at the end of their third year of life. Although short stature is a feature of this genetic disorder, defective growth hormone (GH) secretion in response to provocation with clonidine and glucagon was found in 4 of the 8 patients. These 4 patients had pituitary hypoplasia on the magnetic resonance imaging (MRI) of their brain. In addition, 3 of these 4 patients had demyelination of the cerebrum. Patients with pycnodysostosis (n = 8) had low circulating concentrations of insulin-like growth factor-1 (IGF-1) compared with normal age-matched short children with constitutional short stature (CSS). IGF-I increased significantly after injecting GH for 3 days in these patients. Physiologic replacement with GH (18 U/m(2)/week) divided in daily evening doses subcutaneously increased IGF-1 concentration and improved linear growth velocity and height standard deviation scores (HtSDS) in the 4 children with GH deficiency. These data ruled out GH resistance and proved the usefulness of GH therapy in the management of short stature in these patients. In summary, some patients with pycnodysostosis have partial GH deficiency and low IGF-1 concentration. GH therapy markedly increases IGF-I secretion and improves their linear growth. MRI study of the brain including the hypothalamic-pituitary area is recommended in these children because of the high incidence of pituitary hypoplasia and cerebral demyelination.
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PMID:Pycnodysostosis: clinical, radiologic, and endocrine evaluation and linear growth after growth hormone therapy. 1147 77

A unique factor, human T cell hypoglycaemic factor (hTCHF), has been shown to produce hypoglycaemia during the convalescent stage in the plasma of patients with Japanese encephalitis virus (JEV) infection. The present study was undertaken to investigate the ability of T cells from fresh peripheral blood mononuclear cells (PBMC) of such patients to produce hTCHF. The PBMC, as well as the individual subpopulations, were cultured for 24 h and the culture supernatants (CS) were assayed for hypoglycaemic activity. The activity was observed in the CD8+ T cells. The hypoglycaemia in JE-confirmed patients coincided with the gradual rise in circulating glucagon level, with no significant alterations in insulin, growth hormone and cortisol levels. The hTCHF was purified by ion exchange chromatography and the purified protein was observed as a approximately 25 kDa band on SDS-PAGE. Secretory hTCHF in the sera of patients and T cell CS was present in 88% of convalescent serum samples. We conclude that during the convalescent stage of JEV infection, a unique factor, hTCHF, is secreted by activated CD8+ T cells from patients and that this is responsible for the development of hypoglycaemia.
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PMID:Alteration in plasma glucose levels in Japanese encephalitis patients. 1205 8

Ethanol has profound acute effects on hepatic metabolism. While many of these effects are mediated via the redox imbalance that accompanies hepatic ethanol oxidation via the alcohol dehydrogenase (ADH) pathway, there is increasing evidence that ethanol also perturbs hepatic metabolism via its modulation of cyclic AMP-mediated signalling pathways. This paper examines the effects of ethanol on glucagon-stimulated protein phosphorylation using SDS-PAGE to analyse the 32P-labelling of cytosolic peptides in isolated rat hepatocytes pre-equilibrated with 32PO4(3-). We show that ethanol has biphasic effects on glucagon-stimulated protein phosphorylation. At a low concentration (50 mM), ethanol decreased the phosphorylation of certain peptides, whereas at higher concentrations (100-200 mM) it increased the 32P-labelling of all of the eleven glucagon-stimulated cytosolic peptides. The non-metabolizable alcohol 2-methylpyrazole-2-ol had no effects on glucagon-stimulated protein phosphorylation. The ADH inhibitor 4-methylpyrazole at 150 mM ethanol concentration abolished the potentiating effect of ethanol on the glucagon-stimulated phosphorylation of most peptides. In conclusion, the results indicate that ethanol alters glucagon-receptor-dependent protein phosphorylation in isolated hepatocytes via a complex mechanism that is partially dependent on ethanol oxidation via ADH.
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PMID:Effects of ethanol on glucagon-stimulated protein phosphorylation in isolated hepatocytes. 1464 35

Interaction of natural peptide ligands with class 2 GPCRs, which are targets of biologically important hormones such as glucagon, secretin, and corticotropin-releasing factor (CRF), occurs with a common orientation, in that the ligand C-terminus binds to the extracellular receptor N-terminus, whereas the ligand N-terminus binds to the receptor juxtamembrane domain. N-Terminal truncation, by eight amino acids in the case of CRF, leads to antagonists, suggesting those residues constitute the receptor activating sequence. Here, we identified by photoaffinity cross-linking using p-benzoyl-l-phenylalanine (Bpa) analogues of urocortin (Ucn) the most affine CRF receptor agonist, interaction domains of CRF(1) receptor with Bpa residues at exclusive positions. Specific cleavage patterns of the corresponding ligand-receptor complexes, obtained using several cleavage methods in combination with SDS-PAGE for fragment size determination, showed that a Bpa group located N-terminally or in position 12 binds at the second and such in position 17 or 22 at the first extracellular receptor loop. Our results indicate that the very N-terminal ligand residues (1-11), which are responsible for receptor activation, are oriented to the juxtamembrane domain by interaction of amino acid residues 12, 17, and 22. Our findings contradict a recently proposed interaction model derived from ligand interaction with a soluble receptor N-terminus, indicating that conclusions drawn from such a reduced system may be of limited value to understand the interaction with the full-length receptor.
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PMID:Photoaffinity cross-linking of the corticotropin-releasing factor receptor type 1 with photoreactive urocortin analogues. 1630 Apr 6

Although paediatric Cushing's disease is rare, it is associated with severe morbidity in childhood and presents a major diagnostic and therapeutic challenge for the paediatric endocrinologist. Growth failure remains an important feature of paediatric Cushing's disease, both at diagnosis and after successful treatment. However, the development of specific diagnostic tests and important therapeutic advances has contributed significantly to the current management. Transsphenoidal pituitary surgery (TSS) is now accepted as first-line therapy for both adult and paediatric Cushing's disease, offering the best opportunity for cure while preserving normal pituitary function. The cure rate following TSS in our centre is currently 62%; therefore, a significant proportion of children following TSS will remain uncured. Our favoured second-line therapy is pituitary radiotherapy, which is effective, rapid and appears to spare anterior pituitary function, with the exception of GH secretion. Growth failure was a symptom at diagnosis in 74% of patients; mean height SDS -1.81 (-0.28 to -4.17) compared with mean BMI SDS 2.29 (1.72-5.06). Height velocity (HV) was also subnormal; range 0.9-3.8 cm/yr. Chronic hypercortisolaemia suppresses linear growth and a history of symptoms for >2 years was obtained in 72% of our paediatric patients with Cushing's disease. In our series, 9 out of 10 patients did not demonstrate catch-up growth 0.64 years after TSS or pituitary radiotherapy and peak serum GH level to glucagon/ITT stimulation was 0.5-20.9 mU/l. Assessment of GH secretion over a period of 6 to 108 months after cure of paediatric Cushing's disease suggests that impaired GH secretion may persist into adult life. Investigation of possible GHD is performed in our unit in all post-cure patients who do not show optimal catch-up growth. If GH secretion is subnormal, GH replacement is started early and continued until final height, when GH secretion is reassessed. In our series of 10 patients, 9 received GH therapy, combined in 3 with a GnRH analogue to arrest puberty. The results of this treatment were satisfactory with mean height deficit compared with target height improving significantly from mean -1.72 +/- 1.26 SDS at diagnosis to -0.93 +/- 1.13 SDS (p=0.005) at final height or latest assessment, indicating that a favourable final height can be achieved.
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PMID:Growth and growth hormone secretion in paediatric Cushing's disease. 1700 7

Glucagon-like peptide-1 (7-36) amide (GLP-1), a gut hormone released into the blood stream after feeding, can stimulate insulin secretion by potentiating the insulinotropic action of glucose. An expression vector pET-22bG8, encoding a fusion protein containing eight tandem repeat GLP-1 ([Ser(8), Gln(26), Asp(34)]-GLP-1) analogues, was constructed and transformed into the Escherichia coli BL21(DE3) strain over-expressing the His-tagged fusion protein under the IPTG promoter. SDS-PAGE and Western blot analysis demonstrated that the His-tagged GLP-1 fusion protein migrated as a single protein with a molecular weight of 32 kDa. Following chronic (10 days) oral administration (20 mg kg(-1) day(-1)) of the fusion protein to diabetic rats, serum glucose levels were significantly lowered from 26 +/- 2.5 to 7.9 +/- 1.4 mmol/l. Further studies are needed to evaluate the potential use for GLP-1 analogue short peptide in the treatment of diabetes mellitus.
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PMID:Oral administration of a fusion protein containing eight GLP-1 analogues produced in Escherichia coli BL21(DE3) in streptozotocin-induced diabetic rats. 1758 4

Glucagon-like peptide-1 (GLP-1), an incretin secreted by intestinal L-cells, can effectively lower blood glucose levels in patients with diabetes. A fusion gene, consisting of 10 tandem repeated GLP-1 analog genes, was expressed at a high level in the yeast Pichia pastoris. SDS polyacrylamide gel electrophoresis (SDS-PAGE), and Western Blotting results showed that fusion protein migrated as a single protein band with a molecular weight of 36 kDa. A biological activity test showed that the GLP-1 analog could significantly lower the level of serum glucose when GLP-1 purified analog was injected into diabetic rats. A potential strategy for large-scale production of fusion protein containing the 10 GLP-1 analogs as discovered, and a single GLP-1 analog was obtained from fusion protein digested with trypsin. This should be inspired foreign expression of medicinal short peptides and be valuable in further research on GLP-1 analog drugs in the treatment of diabetes mellitus.
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PMID:High-level expression of fusion protein containing 10 tandem repeated GLP-1 analogs in yeast Pichia pastoris and its biological activity in a diabetic rat model. 1758 76

Glucagon-like peptide-1 (GLP-1) is a 30-residue peptide hormone secreted by intestinal L-cells in response to nutrient ingestion. In the present study, overlapping PCR technology was employed to construct two GLP-1 mutants (GLP-1(A2G))2 and human albumin (HSA) genes in vitro without linker. The spliced gene, (GLP-1(A2G))2-HSA, was over expressed under the control of promoter AOX1 and Mat alpha signal peptide in Pichia pastoris. SDS-PAGE and Western blotting were applied to assay the recombinant fusion protein in the culture broth. The results demonstrated that the recombinant (GLP-1(A2G))2-HSA concentration in the broth could reach a level of 245.0 mg/L and the expressed fusion protein was capable of cross-reacting with anti-human GLP-1 and anti-human albumin antibody. The recombinant (GLP-1(A2G))2-HSA protein was purified by ultrafiltration, columns of Q-sepharose fast flow and Superdex 75 size-exclusion. The recombinant (GLP-1(A2G))2-HSA protein obtained could lower in vivo glucose concentration in blood and stimulate in vitro islet cell proliferation. In mouse model, the fusion protein was detectable in plasma even 308 h after a single subcutaneous dose of 1.25 mg/kg. The result showed that the terminal biological half-time of the protein was about 54.2 h which is 650-fold longer than that of GLP-1. The pharmacokinetic analysis of the protein suggests its promising application in clinical medicine.
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PMID:Expression, purification, and characterization of recombinant human serum albumin fusion protein with two human glucagon-like peptide-1 mutants in Pichia pastoris. 1855 14

Plant cathepsin B-like cysteine protease (CBCP) plays a role in disease resistance and in protein remobilization during germination. The ability of animal cathepsin B to function as a dipeptidyl carboxypeptidase has been attributed to the presence of a dihistidine (His110-His111) motif in the occluding loop, which represents a unique structure of cathepsin B. However, a dihistidine motif is not present in the predicted sequence of the occluding loop of plant CBCP, as determined from cDNA sequence analysis, and the loop is shorter. In an effort to investigate the enzymatic properties of plant CBCP, which possesses the unusual occluding loop, we have purified CBCP from the cotyledons of daikon radish (Raphanus sativus) by chromatography through Sephacryl S-200, DEAE-cellulose, hydroxyapatite and organomercurial-Sepharose. The molecular mass of the enzyme was estimated to be 28 kDa by SDS/PAGE under reducing conditions. The best synthetic substrate for CBCP was t-butyloxycarbonyl Leu-Arg-Arg-4-methylcoumaryl 7-amide, as is the case with human cathepsin B. However, the endopeptidase activity of CBCP towards glucagon and adrenocorticotropic hormone showed broad cleavage specificity. Human cathepsin B preferentially cleaves model peptides via its dipeptidyl carboxypeptidase activity, whereas daikon CBCP displays both endopeptidase and exopeptidase activities. In addition, CBCP was found to display carboxymonopeptidase activity against the substrate o-aminobenzoyl-Phe-Arg-Phe(4-NO(2)). Daikon CBCP is less sensitive (1/7000) to CA-074 than human cathepsin B. Expression analysis of CBCP at the protein and RNA levels indicated that daikon CBCP activity in cotyledons is regulated by post-transcriptional events during germination.
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PMID:Purification and characterization of cathepsin B-like cysteine protease from cotyledons of daikon radish, Raphanus sativus. 1895 67


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