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)

Two groups, each composed of 20 women, who used depomedroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) injectable contraceptives were investigated for changes in 75-g OGTT and in the fasting and two-hour post oral glucose load (2-hours) levels of serum insulin, growth hormone, glucagon, cortisol and blood pyruvate. Samples were taken before and 3, 6 and 12 months after use of injectables. DMPA and NET-EN caused significant changes in mean blood glucose and pyruvate and in mean serum insulin, growth hormone and glucagon, but not in mean fasting cortisol. Changes with NET-EN started after 3 months, became maximal after 6 months and reverted to normal after 12 months of use, due to more frequent administration during the first 6 months of use (every 60 +/- 5 days) and to more spacing of the injections (every 84 +/- 5 days) after that. Changes with DMPA started after 3 months, and increased with the duration of use to become maximal after 12 months. Maximal changes were similar with DMPA and NET-EN and consisted of: a significant increase in fasting blood glucose and pyruvate and serum insulin; a significant increase in 2-hour blood glucose and pyruvate, serum insulin, growth hormone and glucagon. Although significant changes in blood glucose levels occurred with both DMPA and NET-EN, yet they did not reach the lower cut-off levels for impaired glucose tolerance in any user. With the same spacing of injections, i.e. every 84 +/- 5 days for NET-EN and every 90 +/- 5 days for DMPA, the effects on various parameters studied were less with NET-EN.
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PMID:Effect of long-acting progestagen-only injectable contraceptives on carbohydrate metabolism and its hormonal profile. 183 54

Phosphorylation of the beta-adrenergic receptor (beta AR) is closely associated with homologous desensitization of the beta-adrenergic receptor-coupled adenylate cyclase system. Homologous desensitization and receptor phosphorylation also occur in cell mutants which are deficient in their cAMP-dependent protein kinase (kin- mutant of S49 lymphoma cells). beta AR phosphorylation is mediated by a cAMP-independent protein kinase which phosphorylates the receptor only when it is occupied by a beta-agonist. During the time course of desensitization the beta AR kinase (beta ARK) activity is translocated from a cytoplasmic to a plasma membrane location. beta ARK translocation can also be effected by prostaglandin E1 (PGE1) suggesting that this beta ARK may represent a more general enzyme capable of phosphorylating other adenylate cyclase-coupled receptors. Thus, beta ARK may play a key role in the process of homologous desensitization of adenylate cyclase coupled receptors. Extracellular hormones interact with specific receptors at the outer surface of the plasma membrane and thus initiate a cellular response. One of the best studied transmembrane signalling systems known to be coupled to the occupancy of cell surface receptors is adenylate cyclase. The adenylate cyclase system is composed of various components all of which have been purified to homogeneity (Shorr et al., 1982; Homcy et al., 1983; Benovic et al., 1984; Codina et al., 1984; Northup et al., 1980; Sternweis et al., 1981; Bokoch et al., 1984; Pfeuffer et al., 1985). Initially, agonist binding to the receptor promotes coupling of the occupied receptor to one of the guanine nucleotide binding regulatory proteins. These proteins are members of a family of heterotrimeric proteins consisting of alpha, beta and gamma subunits. Stimulatory receptors like the beta-adrenergic (Cerione et al., 1984) or glucagon (Iyengar et al., 1979) receptors couple to the stimulatory regulatory protein Ns (or Gs) whereas inhibitory receptors like the alpha 2-adrenergic (Jacobs et al., 1976) or M2-muscarinic (Harden et al., 1982) receptors couple to the inhibitory regulatory protein Ni (or Gi). Prolonged exposure to agonist hormones, either stimulatory or inhibitory, results in an attenuation of the response to the hormonal activation, a phenomenon called tachyphylaxis or desensitization (Harden, 1983; Sibley and Lefkowitz, 1985; Sharma et al., 1975). One of the best studied models for desensitization is the beta-adrenergic receptor-coupled adenylate cyclase system. In this system two different forms of desensitization have been characterized.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The beta-adrenergic receptor kinase: role in homologous desensitization in S49 lymphoma cells. 284 12

We investigated cardiovascular and metabolic responses in 23 healthy pregnant volunteers in their third trimester prior to, during, and after a 15-minute period of treadmill exercise. The energy utilization of this exercise was 2.33 MET with an oxygen consumption under 0.5 L/minute. Exercise induced a significant increase in maternal heart rate and a shortening of the R time intervals; both returned to baseline by 30 minutes of recovery. This light exercise also induced a significant increase in glucagon, norepinephrine, and epinephrine concentrations, all of which were transitory and reversed within 30 minutes of the recovery period. No change in glucose or cortisol concentration resulted from this exercise. We conclude that light exercise of brief duration elicits appropriate and transitory cardiovascular and metabolic responses in normal pregnancy.
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PMID:I. Maternal cardiovascular and metabolic responses in normal pregnancy. 701 63

Insulin-like growth factor binding protein-1 (IGFBP-1) serum levels are increased by glucocorticoids and glucagon, and are decreased by insulin; these effects seem to reflect changes in hepatic IGFBP-1 expression. Human HEP G2 hepatoma cells respond to cAMP or insulin with stimulation or inhibition of IGFBP-1 expression, respectively; however, dexamethasone alone does not stimulate IGFBP-1 expression. Studies presented here show that in the presence of cAMP and theophylline, nontransfected HEP G2 cells respond to further addition of dexamethasone with a approximately 70% rise in IGFBP-1 mRNA levels, and HEP G2 cells transfected with IGFBP-1 promoter constructs respond to further addition of dexamethasone with a approximately 70% rise in IGFBP-1 protein levels and a approximately 9-fold rise in IGFBP-1 promoter activity. The stimulatory effect of dexamethasone and cAMP, conferred to the IGFBP-1 promoter between 357 and 103 base pairs 5' to the mRNA cap site, is inhibited by insulin. Thus, the cis elements necessary to confer multihormonal regulation of IGFBP-1 expression appear to reside in a short stretch of DNA just upstream from the IGFBP-1 transcription start site.
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PMID:Dexamethasone stimulates expression of insulin-like growth factor binding protein-1 in HEP G2 human hepatoma cells. 768 15

In hepatocytes, insulin-like growth factor-binding protein-1 (IGFBP-1) levels are increased by glucocorticoids and by agents that raise intracellular cAMP levels such as glucagon, theophylline, forskolin, and cAMP analogues. In contrast, insulin lowers IGFBP-1 levels, an effect dominant over the glucocorticoid and cAMP effects. Previous studies showed that dibutyryl cAMP (Bt2cAMP) and theophylline increase IGFBP-1 promoter activity in HEP G2 human hepatoma cells and that insulin abolishes this increase. In studies reported here, HEP G2 cells were used to further evaluate the role of cAMP in stimulating IGFBP-1 expression. Initial studies found that either 0.5 or 5.0 mM Bt2cAMP alone, or the combination of 0.5 mM Bt2cAMP and 2 mM theophylline, increased IGFBP-1 protein levels, mRNA levels, and promoter activity, but that the addition of theophylline to Bt2cAMP was required to give a approximately 5-fold increase in promoter activity. Deletion mutations of the IGFBP-1 promoter were used to show that much of the effect of Bt2cAMP and theophylline was conferred by the region between 269 and 246 base pairs (bp) 5' of the IGFBP-1 mRNA cap site. DNase I protection assays showed that HEP G2 nuclear extract footprinted the region from 273 to 249 bp 5' of the cap site; this region, designated P2, has a central CGTCA motif common to cAMP-responsive elements (CREs). Mutating the CGTCA motif in the 1205-bp IGFBP-1 promoter construct to TAGCA led to a 51% decrease in the ability of Bt2cAMP and theophylline to stimulate IGFBP-1 promoter activity above control levels. In addition, cotransfection of the catalytic subunit of cAMP-dependent protein kinase A (PKA) with the native 1205-bp IGFBP-1 promoter construct stimulated IGFBP-1 promoter activity 3.9-fold, but the TAGCA mutation decreased by 73% the ability of PKA to stimulate IGFBP-1 promoter activity above control levels. Mutating the CGTCA motif to TAGCA also blocked the ability of both crude HEP G2 nuclear extract and recombinant CRE-binding protein to bind to the P2 element. These data suggest that the P2 element is a CRE that confers at least part of the stimulatory effect of cAMP on the human IGFBP-1 promoter.
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PMID:Identification of a promoter element which participates in cAMP-stimulated expression of human insulin-like growth factor-binding protein-1. 768 58

The aim of the study was to investigate the effect of aging on cytoprotective properties of prostaglandins. Hepatocytes were obtained by collagenase perfusion of livers of young (4-6 mo) and old (24-28 mo) male Wistar rats. Cells were incubated for 1.5 h in Krebs-Ringer-bicarbonate buffer containing glucose and 3H-leucine in the presence of galactosamine (2.5-100 mM), PGE1, or two prostacyclin analogues: 9 beta-methylcarbacyclin and TRK-100. Cell damage was assessed by decrease in the rate of protein synthesis measured as 3H-leucine incorporation into acid precipitable material, and by increase in lactate dehydrogenase release into the medium. Hepatocytes from old rats were more susceptible to suppression of protein synthesis by GalN than cells of young ones. Preincubation of cells for 15 min with 9MC (41-560 nM) or PGE1 (10-100 nM), but not with TRK-100, before adding 10 mM GalN, led to a partial recovery of protein synthesis in both age groups. GalN increased LDH release and decreased ATP/ADP ratio to a similar extent in hepatocytes of young and old rats; both parameters were not altered by preincubation of cells with PGs. PGE1 and 9MC, but not TRK-100, elevated cyclic AMP content in hepatocytes of young but not old rats. Glucagon and forskolin similarly increased cyclic AMP content in cells of both young and old animals. These in vitro results suggest that PGE1 and some prostacyclin analogues might protect hepatocytes of both young and old rats from chemical damage, and stress the necessity for further research on cyto- and hepato-protection in the elderly.
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PMID:Prostaglandin cytoprotection of galactosamine-incubated hepatocytes isolated from young and old rats. 803 Aug 38

Expression of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting step in hepatic gluconeogenesis, is primarily regulated at the level of gene transcription. Insulin and phorbol esters inhibit basal PEPCK transcription and antagonize the induction of PEPCK gene expression by glucocorticoids and glucagon (or its second messenger cAMP). Insulin activates a signaling cascade involving Ras --> Raf --> p42/p44 mitogen-activated protein (MAP) kinase kinase (MEK) --> p42/p44 MAP kinase (ERK 1 and 2). Recent reports suggest that activation of this Ras/MAP kinase pathway is critical for the effects of insulin on mitogenesis and c-fos transcription but is not required for insulin action on metabolic processes such as glycogen synthesis, lipogenesis, and Glut-4-mediated glucose transport. We have used three distinct approaches to examine the role of the Ras/MAP kinase pathway in the regulation of PEPCK transcription by insulin in H4IIE-derived liver cells: (i) chemical inhibition of Ras farnesylation, (ii) infection of cells with an adenovirus vector encoding a dominant-negative mutant of Ras, and (iii) use of a chemical inhibitor of MEK. Although each of these methods blocks insulin activation of MAP kinase, none alters insulin antagonism of cAMP- and glucocorticoid-stimulated PEPCK transcription. Although phorbol esters activate MAP kinase and mimic the effects of insulin on PEPCK gene transcription, inhibition of MEK has no effect on phorbol ester inhibition of PEPCK gene transcription. Using the structurally and mechanistically distinct phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors, wortmannin and LY 294002, we provide further evidence supporting a role for PI 3-kinase activation in the regulation of PEPCK gene transcription by insulin. We conclude that neither insulin nor phorbol ester regulation of PEPCK gene transcription requires activation of the Ras/MAP kinase pathway and that insulin signaling to the PEPCK promoter is dependent on PI 3-kinase activation.
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PMID:Insulin regulation of phosphoenolpyruvate carboxykinase gene expression does not require activation of the Ras/mitogen-activated protein kinase signaling pathway. 856 35

Surgical resection has been the standard approach for primary and metastatic liver tumors. Long-term survival, however, is limited because of recurrence or hepatic decompensation. Failure of chemotherapeutic regimens or liver transplantation (OLT) to prevent recurrence has resulted in the need for multimodality therapies. We report our experience with preoperative hepatic arterial chemoembolization (CET) followed by OLT in highly select patients. Over a 33-month period, 23 of 41 patients (56%) referred with primary (n = 16) or metastatic neuroendocrine (n = 7) liver tumors met eligibility requirements. Despite mild, self-limited chemical hepatitis, CET was well tolerated in all but three elderly patients who succumbed to liver failure. Four of five patients ultimately received OLT. Three are alive and free of disease at a mean followup of 17 months, one died of recurrent hepatocellular carcinoma, and one (NET) remains well at 33 months with elevated glucagon levels but no measurable disease. All NET patients are alive with resolution of hormonal symptoms. Four of five noncirrhotic patients died of disease, and one has progressive tumor growth. Although OLT following CET achieves superior survival, its application is limited to a minority of patients with such tumors. Careful pretreatment staging and patient selection combined with caution in the use of CET in elderly cirrhotic patients is critical to the success of such therapies.
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PMID:Intrahepatic arterial chemoembolization for hepatocellular carcinoma and metastatic neuroendocrine tumors in the era of liver transplantation. 875 63

We present genetic and biochemical evidence that PAX6 is a key regulator of pancreatic islet hormone gene transcription and is required for normal islet development. In embryos homozygous for a mutant allele of the Pax6 gene, Small eye (Sey(Neu)), the numbers of all four types of endocrine cells in the pancreas are decreased significantly, and islet morphology is abnormal. In the remaining islet cells, hormone production, particularly glucagon production, is markedly reduced because of decreased gene transcription. These effects appear to result from a lack of PAX6 protein in the mutant embryos. Biochemical studies identify wild-type PAX6 protein as the transcription factor that binds to a common element in the glucagon, insulin, and somatostatin promoters, and show that PAX6 transactivates the glucagon and insulin promoters.
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PMID:Genetic analysis reveals that PAX6 is required for normal transcription of pancreatic hormone genes and islet development. 922 16

Transcription of the phosphoenolpyruvate carboxykinase (PEPCK) gene is induced by glucagon, acting through cAMP and protein kinase A, and this induction is inhibited by insulin. Conflicting reports have suggested that insulin inhibits induction by cAMP by activating the Ras/mitogen-activated protein kinase (MAPK) pathway or by activating the phosphatidylinositol 3-kinase (PI3-kinase), but not MAPK, pathway. Insulin activated PI3-kinase phosphorylates lipids that activate protein kinase B (PKB) and Ca2+/diacylglycerol-insensitive forms of protein kinase C (PKC). We have assessed the roles of these pathways in insulin inhibition of cAMP/PKA-induced transcription of PEPCK by using dominant negative and dominant active forms of regulatory enzymes in the Ras/MAPK and PKB pathways and chemical inhibitors of PKC isoforms. Three independently acting inhibitory enzymes of the Ras/MAPK pathway, blocking SOS, Ras, and MAPK, had no effect upon insulin inhibition. However, dominant active Ras prevented induction of PEPCK and also stimulated transcription mediated by Elk, a MAPK target. Insulin did not stimulate Elk-mediated transcription, indicating that insulin did not functionally activate the Ras/MAPK pathway. Inhibitors of PI3-kinase, LY294002 and wortmannin, abolished insulin inhibition of PEPCK gene transcription. However, inhibitors of PKC and mutated forms of PKB, both of which are known downstream targets of PI3-kinase, had no effect upon insulin inhibition. Dominant negative forms of PKB did not interfere with insulin inhibition and a dominant active form of PKB did not prevent induction by PKA. Phorbol ester-mediated inhibition of PEPCK transcription was blocked by bisindole maleimide and by staurosporine, but insulin-mediated inhibition was unaffected. Thus, insulin inhibition of PKA-induced PEPCK expression does not require MAPK activation but does require activation of PI3-kinase, although this signal is not transmitted through the PKB or PKC pathways.
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PMID:Assessment of the roles of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase B, and protein kinase C in insulin inhibition of cAMP-induced phosphoenolpyruvate carboxykinase gene transcription. 966 48


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