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

Adult beagle dogs were infused intravenously with alloxan (50 mg/kg) and streptozotocin (30 mg/kg) in order to investigate sequential changes in plasma glucose, insulin, glucagon, and cortisol. These biochemical findings were correlated with ultrastructural alterations in pancreatic islets. Following infusion, the dogs became hyperglycemic by 2 hours, severely hypoglycemic by 6 to 14 hours, and permanently hyperglycemic by 24 hours. Plasma immunoreactive insulin increased sharply from 6 to 10 hours, then declined to nearly undetectable levels by 24 hours. Ultrastructurally, beta cells at 2 hours had clumped nuclear chromatin, vacuolated mitochondria, and dilated individual profiles of endoplasmic reticulum. Secretory granules appeared swollen but retained their internal cores. Degeneration of beta cells was severe after 10 hours, and plasma membranes of beta cells were disrupted by 24 hours. The cytoplasmic area of adjacent beta cells coalesced and had accumulations of membranous debris, lipofuscin, and autophagic vacuoles. Alpha and delta cells appeared to be unaffected. Plasma glucagon levels decreased markedly at 10 hours and were related reciprocally to changes in plasma insulin. Pancreatic islets in dogs with chronic (16 months) diabetes were small and composed primarily of granulated alpha and delta cells. Poorly granulated beta cells with degenerative changes were present in an occasional islet. The results of this investigation demonstrated that the combined administration of a single dose of alloxan and streptozotocin selectively destroyed the beta cells, while alpha and delta cells of the islets of Langerhans remained unaltered. Pathologic evidence of toxicity was not present in other organs. Chemically induced diabetes mellitus in dogs is a reproducible animal model that should prove useful in studies requiring repeated experimental manipulations or sampling of biologic fluids in order to evaluate the long-term effects of different routes of delivery or preparations of insulin to control the persistent hyperglycemia.
 ...
PMID:Chemically induced (streptozotocin-alloxan) diabetes mellitus in the dog. Biochemical and ultrastructural studies. 644 98

We studied aspects of perinatal rat bronchiolar Clara cell development. We found that the volume density (Vv) of glycogen areas decreased 10-fold between postnatal days 1 and 2 and that the Vv of secretory granules, rough endoplasmic reticulum (RER), and mitochondria increased markedly during the 1st postnatal wk. Compared with pups of dams allowed food ad libitum during gestation, pups from dams underfed during gestation had a higher Vv of glycogen areas for the first 2 postnatal days but a lower Vv of secretory granules and RER for the time studied (to age 7 days). Glucagon injected, in utero, into fetal rats at 21.5 days of gestation resulted in a 40% decrease in the Vv of the glycogen areas within 4 h. We conclude that 1) bronchiolar Clara cells are immature at birth and undergo marked early postnatal maturation, 2) prenatal events (maternal undernutrition) affect postnatal maturation of the Clara cells, and 3) exogenous glucagon leads to glycogen depletion in Clara cells of fetal rats of 21.5 days gestation.
 ...
PMID:Postnatal development of the bronchiolar Clara cell in rats. 647 7

Long term administration of glucagon markedly enhanced carcinoma formation in mice simultaneously treated with a chemical carcinogen, 3-methylcholanthrene (3-MCA). The number and size of squamous cell carcinomas were 3-fold greater compared to those in mice treated with MCA alone. DNA labeling and the percentage of [3H]thymidine-labeled cells were also 2- to 3-fold higher in glucagon- and MCA-treated mice than in those treated with MCA only or 5- to 6-fold higher than those in control mice. Ultrastructural studies of glucagon- and MCA-treated tumors revealed the predominance of acinar-cystoid and secretory types of tumors, with the occurrence of large and dense secretory granules (Zymogen-like granules), markedly dilated endoplasmic reticulum cisternae, and lysosomes compared to only typical squamous neoplastic cells observed in MCA-treated mice. Scanning electron microscopic observations also indicated that neoplastic cells of MCA and glucagon-treated tumors exhibited characteristic secretory features on their cell surfaces (a marked increase in blebs and microvilli). These findings demonstrate that glucagon in pharmacological doses significantly enhanced the carcinogenic process and changed the cytodifferentiation of neoplastic cells and, thus, plays an important role in controlling tumor cell biology and neoplastic transformation.
 ...
PMID:Glucagon control of carcinogenesis. 687 39

Hepatocytes, endothelial and Kupffer cells were isolated from young adult (3 month) and old (24 month) rat livers and the activities of some plasma membrane, endoplasmic reticulum, mitochondrial, lysosomal and soluble enzymes compared using biochemical and electron microscope cytochemical techniques. Age-associated changes included: a decrease in glucose-6-phosphatase activity both in hepatocytes and sinus lining cells; and increase in alkaline phosphatase in endothelial cells but a decrease in hepatocytes; reduced basal and glucagon-induced adenyl cyclase in hepatocytes and endothelial cells and an increase in the number of hepatocytes with gamma-glutamyl transferase reaction. Cytochemistry showed that heterogeneity may also be characteristic of senescence particularly with regard to hepatocyte glucose-6-phosphatase which was absent in some cells, low in many cells but high in some and gamma-glutamyl transferase which was normally lacking from hepatocytes but localised as large deposits of reaction product on the plasma membranes of occasional cells isolated from old donors.
 ...
PMID:Effects of age on rat liver enzymes. A study using isolated hepatocytes, endothelial and Kupffer cells. 706 Sep 52

Binding of halothane metabolites to rat liver histones was investigated after in vivo administration of 14C-halothane. Animals were injected with either a mixture of triiodothyronine, glucagon and heparin (TGH) to stimulate liver growth or with saline as a control. Twenty-four hours later, animals were administered 14C-halothane and maintained at 8--10 per cent O2 for 6 hours. Detergent washed nuclei from liver homogenates were subfractionated to allow quantitative measurements of 14C-halothane binding to histones. Although our studies suggest that much of the previously reported binding of halothane metabolites to major cell fractions was a result of redistribution of endoplasmic reticulum components during isolation procedures, carefully controlled experiments demonstrated that the radioactivity associated with histones could not be due to residual microsomal lipid. Of the initial 132 mumol of 14C-halothane administered, 1.1 mumol remained as nonvolatile metabolites in the liver homogenate and 25 pmol were associated with purified histones. This corresponds to approximately one halothane moiety per 15,000 histone molecules. No significant binding to liver cell RNA or DNA was observed. With this low level of histone modification and lack of convincing evidence of halothane metabolite binding to hepatic DNA or RNA, it is unlikely that significant alteration of the genome occurs after exposure to halothane.
 ...
PMID:Low-level binding of halothane metabolites to rat liver histones in vivo. 721 29

Alterations of cellular membranes under the influence of bile acids seem to be of pathophysiological importance in cholestasis. The effect of taurolithocholic acid (TLCA) and chenodeoxycholic acid (CDCA) on membrane structure and release of cellular enzymes was studied on isolated rat hepatocytes. The response of urea synthesis to glucagon was used as a parameter of membrane function. The threshold dose of TLCA, marked by rapidly increasing enzyme release, was about 100 micrometers, whereas that of CDCA was between 500 and 1,000 micrometers. Addition of albumin (1 g-%) increased the threshold dose of CDCA; this occurred for TLCA only 8 g-%. Electron-microscopical alterations of the endoplasmic reticulum and submembranous areas were found with concentrations below these threshold doses even in the presence of albumin. These alterations are interpreted as disturbance of cellular transport and energy metabolism. TLCA inhibited glucagon response of cells in concentrations below 100 micrometers. These results demonstrate an influence of the bile acids studied on structure and function of liver cell membranes, which may be of importance in the pathogenesis of cholestasis. The rough endoplasmic reticulum could be another cellular structure which is affected by these bile acids.
 ...
PMID:[Different effect of taurolithocholate and chenodeoxycholate on structure and function of isolated hepatocytes (author's transl)]. 725 40

The action of glucagon on hepatic glycogen and smooth endoplasmic reticulum (SER) was studied in samples of liver taken sequentially from anesthetized rats. The physiological state of each animal was assessed by continuously monitoring aortic blood pressure and blood lactatepyruvate ratios. High hepatic glycogen levels were established by using 10--12 hr fasted control-fed rats infused continuously with glucose. In rats receiving glucose only, hepatic glycogen levels remained above 5.0% during the 4-hr period of glucose administration. Centrilobular hepatocytes displayed an abundance of glycogen which often appeared dispersed with elements of SER between the glycogen particles. Periportal cells had dense clumps of glycogen with few vesicles of SER restricted to the periphery of the glycogen masses. The addition of glucagon to the glucose infusate caused a marked stimulation of glycogenolysis. In these rats, the hepatic glycogen level (X +/- SE) was 6.74 +/- .15% 1 hr after glucose and declined after initiation of glucagon infusion as follows: 5.86 +/- .29% (15 min), 4.89 +/- .26% (1 hr), 2.16 +/- .40% (2 hr), and 1.66 +/- .29% (3 hr). The fine structure of hepatocytes showed a dramatic response to the administration of glucagon. The glycogen regions of the cells were noticeably decreased in size and number of glycogen granules 3 hr after initiation of glucagon infusion, and SER was abundant in both periportal and centrilobular hepatocytes. The interpretation offered is that glucagon induces the formation of new SER membranes which participate in glycogen breakdown and/or glucose release from hepatocytes.
 ...
PMID:Effects of glucagon on hepatic glycogen and smooth endoplasmic reticulum. 728 65

NADPH-diaphorase activity, which has been previously reported to be associated with the enzyme nitric oxide synthase (NOS), was localized cytochemically in the pancreatic islets of normal rats. All islet cells types, i.e. insulin-, glucagon-, somatostatin- and pancreatic polypeptide-immunoreactive cells, expressed NAD-PH-diaphorase histochemical activity, whereas the exocrine tissue was almost negative. In streptozotocin-treated rats, only the surviving non-beta cells in the islet periphery were stained. Isolated beta and non-beta cells also expressed intense NADPH-diaphorase activity. By electron microscopy, the enzyme was localized primarily on membranes of the endoplasmic reticulum and nuclear envelope, as previously reported for neurons. In addition the enzyme activity was found in the cis-region of the Golgi complex. These results suggest that the four types of endocrine cells of the islets of Langerhans may contain the NOS-enzyme and thus constitutively produce nitric oxide.
 ...
PMID:Cytochemical localization of NADPH-diaphorase in the four types of pancreatic islet cell. 752 33

Hormones that elevate cytosolic Ca2+ concentrations ([Ca2+]cyt) often use Ca2+ as a messenger to activate intramitochondrial metabolic processes. However, the mitochondrial Ca2+ level also regulates the activation of the mitochondrial permeability transition (MPT), a process that involves the assembly of a high conductance proteinaceous pore across the inner and outer membrane. Studies on intact liver cells indicate that the MPT is a critical step in the cell killing induced by anoxia or respiratory inhibitors. In this study, we used freshly isolated hepatocytes to investigate to what extent the elevation of [Ca2+]cyt by vasopressin or other agonists causes Ca2+ accumulation in the mitochondria and how this treatment affects the mitochondrial susceptibility to undergo the MPT. Hepatocytes were incubated with vasopressin, glucagon, or with thapsigargin (an inhibitor of the endoplasmic reticulum Ca2+ pump) prior to permeabilization with digitonin. Mitochondrial Ca2+ accumulation was determined by following the ionomycin-induced Ca2+ release in permeabilized cells and mitochondrial swelling was studied by following cyclosporin A-sensitive light scattering changes induced by phenyl-arsenoxide and rotenone. The results indicate that agents that elevate [Ca2+]cyt cause a significant Ca2+ accumulation in the mitochondria. Excessive Ca2+ accumulation (> 10-fold increase over basal levels) was obtained with the combination of vasopressin and glucagon or with incubations containing thapsigargin. These conditions were also associated with a marked increase in rotenone-induced mitochondrial swelling. However, the more modest increase in mitochondrial Ca2+ content after treating cells with vasopressin alone did not enhance the swelling response; instead, vasopressin suppressed mitochondrial swelling compared to control incubations. Vasopressin also partly suppressed the swelling associated with thapsigargin treatment, although it did not significantly affect the Ca2+ accumulation under these conditions. This effect of vasopressin was mimicked by phorbol ester, suggesting a role for protein kinase C. The data indicate that mitochondrial Ca2+ accumulation following elevation of elevation of [Ca2+]cyt enhances the susceptibility for activation of the MPT, a response that may increase cell injury during anoxia or in response to other challenges. However, hormones also activate protective responses in the cell that suppress the MPT.
 ...
PMID:Calcium ion-dependent signalling and mitochondrial dysfunction: mitochondrial calcium uptake during hormonal stimulation in intact liver cells and its implication for the mitochondrial permeability transition. 759 32

The major rat glucocorticoid-inducible cytochrome P450 (CYP3A1) is known to be regulated at a transcriptional level by glucocorticoids and at a post-translational level by substrate-dependent stabilization. We have investigated mechanisms of substrate/ligand stabilization using primary hepatocytes, isolated liver microsomes from dexamethasone-treated rats, and purified enzymes. Treatment of hepatocytes with glucagon caused a 3-fold increase in CYP3A1 phosphorylation as well as an enhanced degradation rate of the enzyme. Specific CYP3A1 substrates or ligands, such as erythromycin, triacetyloleandomycin, and clotrimazole (CTZ) protected the enzyme from degradation in hepatocytes and inhibited in a concomitant manner (r = 0.99) glucagon-induced phosphorylation of the enzyme. In vitro experiments with purified CYP3A1 and isolated liver microsomes revealed one major site (Ser393) phosphorylated by the catalytic subunit of cAMP-dependent kinase, a reaction inhibited by ligands. Experiments in microsomes showed the presence of an endogenous cAMP-dependent kinase active on CYP3A1. Addition of exogenous cAMP-dependent kinase increased the rate of microsomal CYP3A1 phosphorylation, a reaction further stimulated by NADPH, but inhibited by CTZ. The microsomal phosphorylation caused a pronounced denaturation of cytochrome P450, as revealed spectrophotometrically, whereas CTZ protected from this reaction. Similar effects were noted when the CYP3A1-dependent 6 beta-hydroxylation of testosterone was monitored. It is suggested that the cellular CYP3A1 level is regulated to a significant extent posttranslationally by substrate-regulated cAMP-dependent phosphorylation on Ser393, followed by denaturation and degradation in the endoplasmic reticulum.
 ...
PMID:Substrate-regulated, cAMP-dependent phosphorylation, denaturation, and degradation of glucocorticoid-inducible rat liver cytochrome P450 3A1. 803 84


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>