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)

A series of very potent derivatives of the 30-amino acid peptide hormone glucagon-like peptide-1 (GLP-1) is described. The compounds were all derivatized with fatty acids in order to protract their action by facilitating binding to serum albumin. GLP-1 had a potency (EC(50)) of 55 pM for the cloned human GLP-1 receptor. Many of the compounds had similar or even higher potencies, despite quite large substituents. All compounds derivatized with fatty acids equal to or longer than 12 carbon atoms were very protracted compared to GLP-1 and thus seem suitable for once daily administration to type 2 diabetic patients. A structure-activity relationship was obtained. GLP-1 could be derivatized with linear fatty acids up to the length of 16 carbon atoms, sometimes longer, almost anywhere in the C-terminal part without considerable loss of potency. Derivatization with two fatty acid substituents led to a considerable loss of potency. A structure-activity relationship on derivatization of specific amino acids generally was obtained. It was found that the longer the fatty acid, the more potency was lost. Simultaneous modification of the N-terminus (in order to obtain better metabolic stability) interfered with fatty acid derivatization and led to loss of potency.
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PMID:Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. 1079 83

Few studies have tried to characterize the efficacy of parenteral support of critically ill infants during short period of intensive care. We studied seventeen infants during five days of total parenteral hyperalimentation. Subsequently, according to the clinical conditions, the patients received nutritional support by parenteral, enteral route or both up to the 10th day. Evaluations were performed on the 1st, 5th, and 10th days. These included: clinical data (food intake and anthropometric measurements), haematological data (lymphocyte count), biochemical tests (albumin, transferrin, fibronectin, prealbumin, retinol-binding protein) and hormone assays (cortisol, insulin, glucagon). Anthropometric measurements revealed no significant difference between the first and second evaluations. Serum albumin and transferrin did not change significantly, but mean values of fibronectin (8.9 to 16 mg/dL), prealbumin (7.7 to 18 mg/dL), and retinol-binding protein (2.4 to 3. 7 mg/dL) increased significantly (p < 0.05) from the 1st to the 10th day. The hormonal study showed no difference for insulin, glucagon, and cortisol when the three evaluations were compared. The mean value of the glucose/insulin ratio was of 25.7 in the 1st day and 15. 5 in the 5th day, revealing a transitory supression of this hormone. Cortisol showed values above normal in the beginning of the study. We conclude that the anthropometric parameters were not useful due to the short time of the study; serum proteins, fibronectin, prealbumin, and retinol-binding protein were very sensitive indicators of nutritional status, and an elevated glucose/insulin ratio, associated with a slight tendency for increased cortisol levels suggest hypercatabolic state. The critically ill patient can benefit from an early metabolic support.
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PMID:Nutritional follow-up of critically ill infants receiving short term parenteral nutrition. 1088 Oct 72

Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic beta-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing beta-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate beta-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted.
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PMID:Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. 1452 86

A 68 year old Ecuadorian man was investigated for polyuria, polydipsia and weight loss of 3 kg during the previous two months. Insulin dependent diabetes mellitus was diagnosed 10 year before admission and treated with appropriate diet and insulin (35 U/d). 18 months before was diagnosed in El Ecuador of "multiple liver nodes non-suggestive of malignancy". Physical examination showed a large multinodular petrous hepatomegaly. There was no evidence of skin lesions. Results of laboratory studies included a basal plasma glucose level that ranged between 275-367 mg/dl (N=60-100), glycosylated haemoglobin of 8.9% (N<5) and a serum albumin of 2.8 gr./dl (N=3.4-4.8). At admission non-other laboratory alterations were detected. Computed tomography showed a mass on the head of the pancreas with loco-regional lymph nodes and liver metastases. Tumor markers were normal. Fine-needle aspiration cytology of the liver masses revealed the presence of liver metastases of a non-differentiated malignant tumor. A 111In-DTPAOC scintigraphy revealed the presence of somatostatin receptors in the liver metastases, also detecting the presence of multiple bone metastases in the axial and appendicular skeleton. Plasma glucagon level was 678 pg/ml (N<250). A diagnosis of metastatic glucagonoma was established and therapy with streptozocin, 5-FU, insulin and synthetic somatostatin analogs was initiated. Three months after the therapy initiation the patient was symptom free. Some weeks after the patient suffered from left hip pain, and a control 111In-DTPA scintigraphy showed progression of his bone metastases. In conclusion, glucagonoma must be suspected in all diabetic patients with metastatic liver, even in absence of necrotic migratory erythema. In these circumstances, plasmatic glucagon level and somatostatin receptors scintigraphy will be a useful tool for establishing the final diagnosis.
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PMID:[Diabetes mellitus and pancreatic tumor]. 1471 49

This report describes an enhancement of the signal intensities of proteins and peptides in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS). When alpha-cyano-4-hydroxycinnamic acid (CHCA) premixed with human transferrin (Tf) was used as a matrix, the signal intensity of insulin was amplified to more than ten times that of the respective control in CHCA without Tf. The detection limit of insulin was 0.39 fmol on-probe in the presence of Tf, while it was 6.3 fmol in the absence of Tf. The signal intensity of insulin was also enhanced when the CHCA matrix was premixed with proteins other than Tf (80 kDa), such as horse ferritin (20 kDa), bovine serum albumin (BSA, 66 kDa), or human immunoglobulin G (150 kDa). The optimum spectrum of insulin was obtained when the added amount of protein was in the range 0.26-0.62 pmol, regardless of the molecular weight of the added protein. Tf and BSA outperformed the other tested proteins, as determined by improvements in the resulting spectra. When the mass spectra of several peptides and proteins were recorded in the presence of Tf or BSA, the signal intensities of large peptides such as glucagon were enhanced, though those of smaller peptides were not enhanced. In addition, the signal enhancement achieved with Tf and BSA was more pronounced for the proteins, including cytochrome C, than for the large peptides. This enhancement effect could be applied to improve the sensitivity of MALDI-TOFMS to large peptides and proteins.
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PMID:Improved sensitivity for insulin in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry by premixing alpha-cyano-4-hydroxycinnamic acid matrix with transferrin. 1515 Aug 41

Peptide hormones exert unique actions via specific G protein-coupled receptors; however, the therapeutic potential of regulatory peptides is frequently compromised by rapid enzymatic inactivation and clearance from the circulation. In contrast, recombinant or covalent coupling of smaller peptides to serum albumin represents an emerging strategy for extending the circulating t(1/2) of the target peptide. However, whether larger peptide-albumin derivatives will exhibit the full spectrum of biological activities encompassed by the native peptide remains to be demonstrated. We report that Albugon, a human glucagon-like peptide (GLP)-1-albumin recombinant protein, activates GLP-1 receptor (GLP-1R)-dependent cAMP formation in BHK-GLP-1R cells, albeit with a reduced half-maximal concentration (EC(50)) (0.2 vs. 20 nmol/l) relative to the GLP-1R agonist exendin-4. Albugon decreased glycemic excursion and stimulated insulin secretion in wild-type but not GLP-1R(-/-) mice and reduced food intake after both intracerebroventricular and intraperitoneal administration. Moreover, intraperitoneal injection of Albugon inhibited gastric emptying and activated c-FOS expression in the area postrema, the nucleus of the solitary tract, the central nucleus of the amygdala, the parabrachial, and the paraventricular nuclei. These findings illustrate that peripheral administration of a larger peptide-albumin recombinant protein mimics GLP-1R-dependent activation of central and peripheral pathways regulating energy intake and glucose homeostasis in vivo.
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PMID:A recombinant human glucagon-like peptide (GLP)-1-albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor-dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. 1533 66

A series of analogs of GLP-1(7-36) amide containing a Nepsilon-(2-[2-[2-(3-maleimidopropylamido)ethoxy]ethoxy]acetyl)lysine has been synthesized and the resulting derivatives were bioconjugated to Cys34 of human serum albumin (HSA). The GLP-1-HSA bioconjugates were analyzed in vitro to assess the stabilizing effect of bioconjugation in the presence of DPP-IV as well as GLP-1 receptor binding and activation. Compound 9 (CJC-1131) having the point of attachment to albumin at the C-terminal of GLP-1 and a D-alanine substitution at position 8 was identified as having the best combination of stability and bioactivity.
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PMID:Identification of CJC-1131-albumin bioconjugate as a stable and bioactive GLP-1(7-36) analog. 1535 60

Heterologous protein production late in Saccharomyces cerevisiae fermentations is often desirable because it may help avoid the unintentional selection of more rapidly growing, non-protein-expressing cells or allow for the expression of toxic proteins. Here, we describe the use of the MET25 promoter for the production of human serum albumin (HSA) and HSA-fusion proteins in S. cerevisiae. In media lacking methionine, the MET25 promoter yielded high expression levels of HSA and HSA fused to human glucagon, human growth hormone, human interferon alpha, and human interleukin-2. More importantly, we have shown that this system can be used to delay heterologous protein production until late log phase of the growth of the culture and does not require the addition of an exogenous inducer.
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PMID:Heterologous protein production from the inducible MET25 promoter in Saccharomyces cerevisiae. 1580 8

We have previously demonstrated the ability of electric fields to dissociate ascorbate and catecholamines and shown that the electric field generated by cell membranes is sufficient to produce dissociation of these complexes up to 8 nm from the cell membrane. We show here that this process is applicable to a wide range of biological complexes including small molecules (norepinephrine-morphine sulfate), protein-protein complexes (insulin-glucagon), and small molecule-protein complexes (epinephrine-bovine serum albumin). The extrapolation of the slope of the electric field dependence to zero electric field can be used to estimate the log of the dissociation constant (K(D)) of a complex and, by multiplying the log(K(D)) by -2.303RT, the association energy (E) of the complex. The slope of the electric field dependence is inversely related to the molecular radii, with the best fit of the slope related to E*(1/r1 + 1/r2), where r is the estimated radius of each molecule in the complementary pair. This indicates that the binding site of the pair is shielded by the remaining parts of the molecules, and the larger the molecule the greater the shielding. When the slope of the electric field dependence goes to 0 as r goes to infinity and 1/r goes to 0, the molecular shielding constant is 7.04 x 10(-8) cm2/V. Very large complexes will be minimally affected by the electric field due to molecular shielding and reduced electric field as their radius restricts approach to the membrane. Large protein receptors will deflect the membrane electric field and allow agonist binding.
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PMID:Molecular shielding of electric field complex dissociation. 1629 72

Ghrelin affects not only growth hormone secretion but also nutrient utilization and metabolic hormone secretion in humans and experimental animals. The effects of ghrelin on plasma metabolic hormone and metabolite levels in domestic herbivores remain unclear despite the fact that the physiological characteristics of nutrient digestion and absorption imply specific responses to ghrelin. Therefore, the effects of ghrelin on plasma glucose, pancreatic hormones and cortisol concentrations were investigated in Holstein dairy cattle in various physiological states. Ghrelin (0.3 nmol/kg) or placebo (2% bovine serum albumin in saline) was intravenously injected in pre-ruminant calves (pre-rumen function), adult non-lactating (functional rumen) and lactating cows (functional rumen and lactation), and plasma glucose, insulin, glucagon and cortisol concentrations were then determined. Ghrelin injection increased plasma glucose concentrations in adult cows, especially in lactating cows. No hyperglycemic response was observed in pre-ruminant calves. A transient rise of insulin and glucagon levels was distinctively found in lactating cows in response to the ghrelin administration. Ghrelin injection decreased the insulin level in pre-ruminant calves. Ghrelin increased cortisol secretion independently of the physiological state. The results of the present study suggest that the effects of ghrelin on plasma glucose and pancreatic hormone levels may reflect differences in the physiological states of dairy cattle.
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PMID:Effects of ghrelin injection on plasma concentrations of glucose, pancreatic hormones and cortisol in Holstein dairy cattle. 1632 22


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