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)

Changes in the redox state of liver mitochondria were investigated by measuring the arterial ketone body ratio (acetoacetate/3-hydroxybutyrate: AKBR) in nine healthy volunteers (eight males and one female, mean age 38.4 +/- 5.0 years) during exercise. The correlation between the changes in AKBR and levels of various hormones controlling energy metabolism was also investigated. Subjects participated in symptom-limited exercise test using the ramping bicycle ergometer with expired gas analysis, blood pressure and 12 lead electrocardiogram monitoring. Anaerobic threshold by gas exchange parameters (ATge) was determined from the expired gas data with the v-slope method. AKBR, glucose, non-esterified fatty acid (NEFA) and lactate were measured in arterial plasma samples. Catecholamines (epinephrine, norepinephrine, dopamine), insulin, glucagon, antidiuretic hormone (ADH), growth hormone (GH), thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), human-atrial natriuretic peptide (hANP) and brain natriuretic peptide (BNP) were measured in venous plasma samples. AKBR was gradually decreased by exercise from the resting value of 1.82 +/- 0.20. AKBR reduction was potentiated after ATge to 0.93 +/- 0.18 (p < 0.01 vs rest) at peak exercise. AKBR was further decreased during recovery to the minimum value of 0.70 +/- 0.06 (p < 0.01) at 6 min in the recovery phase. AKBR then began to increase and reached 0.95 +/- 0.07 30 min after peak exercise. Epinephrine increased from 45.9 +/- 11.0 to 210 +/- 75 pg/ml (p < 0.01), norepinephrine increased from 348 +/- 52 to 1,277 +/- 111 pg/ml (p < 0.01), and dopamine increased from 13.0 +/- 1.9 to 25.0 +/- 2.5 pg/ml (p < 0.01) between rest and peak exercise, respectively. Insulin decreased from 22.0 +/- 3.5 to 14.2 +/- 2.1 pg/ml (p < 0.05). No significant change was observed in glucagon, ADH, GH, TSH, T3, T4, hANP or BNP. Glucose decreased from 124 +/- 9 to 84 +/- 8 mg/dl (p < 0.05), whereas NEFA increased from 94 +/- 10 to 190 +/- 66 mg/dl (p < 0.05). A negative correlation was observed between AKBR and lactate (r = -0.41, p < 0.001). These results indicate that hepatic adenosine triphosphate production is promoted as energy demand increases by exercise, and maximizes early in the recovery phase when hepatic energy demand is maximum due to active gluconeogenesis. The levels of catecholamines, insulin and lactate contribute to the control of liver energy metabolism.
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PMID:[Evaluation of changes in hepatic energy metabolism during exercise by ketone body ratio in humans]. 912 Jul 98

Insulin-degrading enzyme (IDE) is an evolutionarily conserved neutral thiol metalloprotease expressed in all mammalian tissues whose biological role is not well established. IDE has highly selective substrate specificity. It degrades insulin, glucagon, atrial natriuretic peptide, transforming growth factor alpha but does not act on related hormones and growth factors. The structural properties determining whether a peptide is an IDE substrate are essentially unknown. The reported cleavage sites are not consistent with simple peptide-bond recognition and it was proposed that IDE recognizes in its substrates some elements of tertiary structure. We noticed that although IDE substrates are functionally unrelated, the majority of them share a specific property, an ability to form under certain conditions amyloid fibrils. Utilizing the residue pattern recognition procedure, this study reveals a common motif in the sequences of IDE substrates, HNHHHPSH, where H is wholly or partly hydrophobic character, N is small and neutral, P is polar, and S is polar and/or small amino acid residue. It is proposed that this sequence motif predetermines a structure recognized by IDE. The identified motif appears to be essentially the same as the proposed earlier consensus sequence for amyloid-forming peptides [Turnell and Finch, J. Mol. Biol. 227 (1992) 1205-1223]. The study suggests that IDE may play a role in elimination of potentially toxic amyloidogenic peptides.
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PMID:Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme. 960 2

Excessive cerebral accumulation of the 42-residue amyloid beta-protein (Abeta) is an early and invariant step in the pathogenesis of Alzheimer's disease. Many studies have examined the cellular production of Abeta from its membrane-bound precursor, including the role of the presenilin proteins therein, but almost nothing is known about how Abeta is degraded and cleared following its secretion. We previously screened neuronal and nonneuronal cell lines for the production of proteases capable of degrading naturally secreted Abeta under biologically relevant conditions and concentrations. The major such protease identified was a metalloprotease released particularly by a microglial cell line, BV-2. We have now purified and characterized the protease and find that it is indistinguishable from insulin-degrading enzyme (IDE), a thiol metalloendopeptidase that degrades small peptides such as insulin, glucagon, and atrial natriuretic peptide. Degradation of both endogenous and synthetic Abeta at picomolar to nanomolar concentrations was completely inhibited by the competitive IDE substrate, insulin, and by two other IDE inhibitors. Immunodepletion of conditioned medium with an IDE antibody removed its Abeta-degrading activity. IDE was present in BV-2 cytosol, as expected, but was also released into the medium by intact, healthy cells. To confirm the extracellular occurrence of IDE in vivo, we identified intact IDE in human cerebrospinal fluid of both normal and Alzheimer subjects. In addition to its ability to degrade Abeta, IDE activity was unexpectedly found be associated with a time-dependent oligomerization of synthetic Abeta at physiological levels in the conditioned media of cultured cells; this process, which may be initiated by IDE-generated proteolytic fragments of Abeta, was prevented by three different IDE inhibitors. We conclude that a principal protease capable of down-regulating the levels of secreted Abeta extracellularly is IDE.
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PMID:Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. 983 16

We examined the sites of peptide hormone activation within medullary nephron segments of the house sparrow (Passer domesticus) kidney by measuring rates of hormone-induced generation of cyclic nucleotide second messenger. Thin descending limbs, thick ascending limbs, and collecting ducts had baseline activity of adenylyl cyclase that resulted in cAMP accumulation of 207 +/- 56, 147 +/- 31, and 151 +/- 41 fmol. mm-1. 30 min-1, respectively. In all segments, this activity increased 10- to 20-fold in response to forskolin. Activity of adenylyl cyclase in the thin descending limb was stimulated approximately twofold by parathyroid hormone (PTH) but not by any of the other hormones tested [arginine vasotocin (AVT), glucagon, atrial natriuretic peptide (ANP), or isoproterenol, each at 10(-6) M]. Thick ascending limb was stimulated two- to threefold by both AVT and PTH; however, glucagon and isoproterenol had no effect, and ANP stimulated neither cAMP nor cGMP accumulation. Adenylyl cyclase activity in the collecting duct was stimulated fourfold by AVT but not by the other hormones; likewise, ANP did not stimulate cGMP accumulation in this segment. These data support a tubular action of AVT and PTH in the avian renal medulla.
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PMID:Second messenger production in avian medullary nephron segments in response to peptide hormones. 1007 Jan 47

A pathological feature of Type 2 diabetes is deposits in the pancreatic islets primarily composed of amylin (islet amyloid polypeptide). Although much attention has been paid to the expression and secretion of amylin, little is known about the enzymes involved in amylin turnover. Recent reports suggest that insulin-degrading enzyme (IDE) may have specificity for amyloidogenic proteins, and therefore we sought to determine whether amylin is an IDE substrate. Amylin-degrading activity co-purified with IDE from rat muscle through several chromatographic steps. Metalloproteinase inhibitors inactivated amylin-degrading activity with a pattern consistent with the enzymatic properties of IDE, whereas inhibitors of acid and serine proteases, calpains, and the proteasome were ineffective. Amylin degradation was inhibited by insulin in a dose-dependent manner, whereas insulin degradation was inhibited by amylin. Other substrates of IDE such as atrial natriuretic peptide and glucagon also competitively inhibited amylin degradation. Radiolabeled amylin and insulin were both covalently cross-linked to a protein of 110 kDa, and the binding was competitively inhibited by either unlabeled insulin or amylin. Finally, a monoclonal anti-IDE antibody immunoprecipitated both insulin- and amylin-degrading activities. The data strongly suggest that IDE is an amylin-degrading enzyme and plays an important role in the clearance of amylin and the prevention of islet amyloid formation.
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PMID:Degradation of amylin by insulin-degrading enzyme. 1097 71

The present studies were undertaken to determine the levels of stimulatory and inhibitory guanine nucleotide regulatory proteins (Gs and Gi respectively) and their relationship with adenylyl cyclase activity in aorta from 5-day streptozotocin-induced diabetic (STZ) rats. The levels of Gi alpha-2 as determined by immunoblotting techniques using AS/7 antibody were significantly decreased by about 60% in STZ as compared to control rats, whereas the levels of Gs alpha were not altered. In addition, the stimulatory effect of cholera toxin (CT) on GTP-sensitive adenylyl cyclase was not different in STZ as compared to control rats. On the other hand, the stimulatory effects of GTPgammaS, isoproterenol, glucagon, forskolin (FSK) and sodium fluoride on adenylyl cyclase were enhanced in STZ-rats. Furthermore, GTPgammaS inhibited FSK-stimulated adenylyl cyclase activity in a concentration-dependent manner (receptor independent functions of Gi) in control rats which was almost completely abolished in STZ rats. In addition, receptor-mediated inhibition of adenylyl cyclase by angiotensin II (AII), oxotremorine and atrial natriuretic peptide (ANP) was attenuated in STZ rats. These results suggest that the decreased expression of Gi alpha, but not of Gs alpha, may be responsible for the observed altered responsiveness of adenylyl cyclase to hormonal stimulation and inhibition in STZ-rats. It may thus be suggested that the decreased Gi activity may be one of the possible mechanisms responsible for the impaired vascular functions in diabetes.
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PMID:Alterations in g-protein-linked signal transduction in vascular smooth muscle in diabetes. 1190 Mar 77

The rheological properties of plasma and blood cells are markedly influenced by the surrounding milieu: physicochemical factors, metabolism and hormones. Acid/base status, osmolality, lipid status and plasma protein pattern are well known to exert a major influence. The oxidative stress induced by increased free radicals production decreases red cell deformability. Among circulating substances, the divalent cations magnesium and zinc improve red cell deformability probably via calcium antagonistic effects. Some metabolites like lactate or ketone bodies decrease red cell deformability, although the former has apparently the opposite effect in highly trained individuals. Endothelium-derived factors such as nitric oxide (NO) and several arachidonic acid derivatives modulate both RBC and white cell mechanics. Endothelium regulates also blood rheology via the release of PAI-1 which governs plasma fibrinogen levels. However, endothelium is not the only organ involved in the regulation of blood rheology: the kidney (by releasing erythropoietin which is a major "viscoregulatory" factor), the endocrine pancreas (via the action of insulin and glucagon on red cells), the adrenal gland (norepinephrine) and the endocrine heart (atrial natriuretic peptide) are also likely to exert important effects. Recently, increasing evidence is accumulating for a role of two other endocrine tissues in the regulation of blood rheology: the adipose tissue (free fatty acids, PAI-1, IL-6, leptin) and the pituitary gland (growth hormone-somatomedin axis, including the somatomedin carrier protein IGFBP1). These organs provide a link between body composition and hemorheology, since GH and somatomedins are major regulators of the body content in fat and water while the endocrine activity of fat mass is apparently proportional to its size. These mechanisms explain to some extent why many situations, either physiological (diet, exercise) or pathological (diabetes, uremia) are associated with marked changes in blood rheology that may in turn modify micro and macrocirculatory hemodynamics and the distribution of O(2) and fuels to tissues.
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PMID:Hormones, metabolism and body composition as major determinants of blood rheology: potential pathophysiological meaning. 1208 54

The Escherichia coli outer-membrane endoprotease OmpT mainly cleaves peptide bonds between consecutive basic amino acids. The effect of adjacent residues on cleavage efficiency is currently unknown, except at positions P2 and P2'. Therefore we investigated the effects of amino acid residues upstream of the cleavage site on the ability of OmpT to cleave efficiently a fusion protein carrying human glucagon-like peptide-1 (7-37) in 4 M urea. The P1-P10 residues were replaced by Ala and each substrate was subjected to OmpT digestion. The replacement of Arg residue at P1 blocked the cleavage due to the loss of the cleavage site, and the replacement of Arg residue at P4 maximally reduced the cleavage rate. Conversely, cleavage efficiency increased on replacing Glu at P6. Substitution of the residues at P4 and P6 with several different amino acids showed that OmpT preferred basic residues at these positions, whereas acidic residues had a negative effect. This was also shown to be true with synthetic decapeptide substrates in the absence of urea. The k(cat)/ K(m) ratio increased with basic residues at P4 or P6, mainly due to a lower K(m) rather than an increase in k(cat). On the basis of these findings, we prepared a fusion protein carrying human atrial natriuretic peptide (ANP), a drug for acute congestive heart failure. OmpT released mature ANP from the E. coli-expressed fusion protein. As expected, the introduction of an Arg residue at P4 and P6 enhanced the release of ANP.
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PMID:An analysis of target preferences of Escherichia coli outer-membrane endoprotease OmpT for use in therapeutic peptide production: efficient cleavage of substrates with basic amino acids at the P4 and P6 positions. 1224 47

Dwyer has suggested that peptide receptors evolved from self-aggregating peptides so that peptide receptors should incorporate regions of high homology with the peptide ligand. If one considers self-aggregation to be a particular manifestation of molecular complementarity in general, then it is possible to extend Dwyer's hypothesis to a broader set of peptides: complementary peptides that bind to each other. In the latter case, one would expect to find homologous copies of the complementary peptide in the receptor. Thirteen peptides, 10 of which are not known to self-aggregate (amylin, ACTH, LHRH, angiotensin II, atrial natriuretic peptide, somatostatin, oxytocin, neurotensin, vasopressin, and substance P), and three that are known to self-aggregate (insulin, glucagon, and gastrin), were chosen. In addition to being self-aggregating, insulin and glucagon are also known to bind to each other, making them a mutually complementary pair. All possible combinations of the 13 peptides and the extracellular regions of their receptors were investigated using bioinformatic tools (a total of 325 combinations). Multiple, statistically significant homologies were found for insulin in the insulin receptor; insulin in the glucagon receptor; glucagon in the glucagon receptor; glucagon in the insulin receptor; and gastrin in gastrin binding protein and its receptor. Most of these homologies are in regions or sequences known to contribute to receptor binding of the respective hormone. These results suggest that the Dwyer hypothesis for receptor evolution may be generalizable beyond self-aggregating to complementary peptides. The evolution of receptors may have been driven by small molecule complementarity augmented by modular evolutionary processes that left a "molecular paleontology" that is still evident in the genome today. This "paleontology" may allow identification of peptide receptor sites.
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PMID:Molecular complementarity III. peptide complementarity as a basis for peptide receptor evolution: a bioinformatic case study of insulin, glucagon and gastrin. 1229 71

The present studies were undertaken to examine if the impaired vascular function observed in diabetes is attributed to the altered levels of G-protein. Diabetes was induced in Sprague Dawley rats by a single intraperitoneal injection of streptozotocin (STZ) (60 mg/kg body wt) and after a period of 5 days, the aorta were used for adenylyl cyclase activity determination and protein quantification. A temporal relationship between the expression of Gialpha proteins and development of diabetes was also examined on day 1, 2, 3, 4 and 5 of injection of STZ. Blood glucose levels were significantly increased from day 1 in STZ-rats as compared to their counterpart control rats and reached to about 20 mM on 3rd day and 30 mM on 5th day. The expression of Gialpha-2 and Gialpha-3 proteins as determined by immunoblotting techniques was decreased by about 70 and 50% respectively in aorta from STZ rats compared to the control rats after 5 days of treatment, whereas 40% decrease in Gialpha-2 and Gialpha-3 was observed after 3rd day of STZ injection. On the other hand, the expression of Gsalpha was unaltered in STZ rats. In addition, the stimulatory effect of cholera toxin (CT) on GTP-mediated stimulation of adenylyl cyclase was not different in STZ as compared to the control group. However, the stimulatory effects of isoproterenol, glucagon, NaF and FSK on adenylyl cyclase activity were significantly enhanced in STZ rats as compared to control rats, whereas basal adenylyl cyclase activity was significantly lower in STZ-rats as compared to control rats. In addition, GTPgammaS inhibited FSK-stimulated adenylyl cyclase activity in concentration-dependent manner (receptor-independent functions of Gialpha) in control rats which was completely attenuated in STZ-rats. In addition, receptor-mediated inhibitions of adenylyl cyclase by angiotensin II, oxotremorine, atrial natriuretic peptide (ANP99-126) and C-ANP4-23 were also attenuated (receptor-dependent functions of Gialpha) in STZ-rats. These results indicate that aorta from diabetic rats exhibit decreased levels of cAMP and decreased expression of Gialpha. The decreased expression of Gialpha may be responsible for the altered responsiveness of adenylyl cyclase to hormonal stimulation and inhibition in STZ-rats. It may thus be suggested that the impaired adenylyl cyclase-Gialpha protein signaling may be one of the possible mechanisms responsible for the impaired vascular functions in diabetes.
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PMID:Streptozotocin-induced diabetes impairs G-protein linked signal transduction in vascular smooth muscle. 1248 72


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