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1.
J Diabetes Res ; 2015: 385395, 2015.
Article in English | MEDLINE | ID: mdl-26236746

ABSTRACT

Reduced beta cell mass in pancreatic islets (PI) of Goto-Kakizaki (GK) rats is frequently observed in this diabetic model, but knowledge on delta cells is scarce. Aiming to compare delta cell physiology/pathology of GK to Wistar rats, we found that delta cell number increased over time as did somatostatin mRNA and delta cells distribution in PI is different in GK rats. Subtle changes in 6-week-old GK rats were found. With maturation and aging of GK rats, disturbed cytoarchitecture occurred with irregular beta cells accompanied by delta cell hyperplasia and loss of pancreatic polypeptide (PPY) positivity. Unlike the constant glucose-stimulation index for insulin PI release in Wistar rats, this index declined with GK age, whereas for somatostatin it increased with age. A decrease of GK rat PPY serum levels was found. GK rat body weight decreased with increasing hyperglycemia. Somatostatin analog octreotide completely blocked insulin secretion, impaired proliferation at low autocrine insulin, and decreased PPY secretion and mitochondrial DNA in INS-1E cells. In conclusion, in GK rats PI, significant local delta cell hyperplasia and suspected paracrine effect of somatostatin diminish beta cell viability and contribute to the deterioration of beta cell mass. Altered PPY-secreting cells distribution amends another component of GK PI's pathophysiology.


Subject(s)
Aging , Diabetes Mellitus, Type 2/pathology , Insulin Resistance , Somatostatin-Secreting Cells/pathology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/metabolism , Gene Expression Regulation, Developmental , Hyperplasia , Immunohistochemistry , Insulin/metabolism , Insulin Antagonists/pharmacology , Insulin Secretion , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/pathology , Octreotide/pharmacology , Pancreatic Polypeptide/antagonists & inhibitors , Pancreatic Polypeptide/genetics , Pancreatic Polypeptide/metabolism , RNA, Messenger/metabolism , Rats, Inbred Strains , Rats, Wistar , Somatostatin/antagonists & inhibitors , Somatostatin/genetics , Somatostatin/metabolism , Somatostatin-Secreting Cells/drug effects , Somatostatin-Secreting Cells/metabolism
2.
J Clin Endocrinol Metab ; 89(2): 581-4, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14764765

ABSTRACT

A patient with a large prolactinoma developed a metastatic islet cell tumor secreting pancreatic polypeptide. Dopamine agonist drugs reduced the prolactin levels to normal, caused a 7-fold decrease in the pancreatic polypeptide levels, and inhibited the liver metastases. Elevated chromogranin A levels also normalized on the higher doses of bromocriptine. Dopamine receptors are found in many endocrine tissues, and the expression of dopamine-2 receptor on endocrine tumors establishes the potential for response to dopamine agonist treatment. The relatively benign risk profile of dopaminergic agents makes further testing of these drugs to treat neuroendocrine tumors a worthwhile endeavor.


Subject(s)
Adenoma, Islet Cell/drug therapy , Adenoma, Islet Cell/metabolism , Bromocriptine/therapeutic use , Dopamine Agonists/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Polypeptide/antagonists & inhibitors , Adenoma, Islet Cell/diagnosis , Bromocriptine/administration & dosage , Chromogranin A , Chromogranins/blood , Dopamine Agonists/administration & dosage , Dose-Response Relationship, Drug , Female , Humans , Liver Neoplasms/diagnosis , Liver Neoplasms/secondary , Neoplasms, Multiple Primary/metabolism , Pancreatic Neoplasms/diagnosis , Pancreatic Neoplasms/pathology , Prolactinoma/diagnosis , Prolactinoma/drug therapy
3.
Regul Pept ; 82(1-3): 91-102, 1999 Jun 30.
Article in English | MEDLINE | ID: mdl-10458651

ABSTRACT

Sites sensitive to human and rat pancreatic polypeptides (hPP and rPP) accounted for more than 30% of the specific binding of [125I](Leu31,Pro34) human peptide YY (LP-PYY) in particulates from rabbit kidney cortex, and about 10% of the specific binding in membranes from rabbit hypothalamus. The binding of [125I]hPP or [125I]rPP showed a high-affinity displacement with either hPP, rPP, LP-PYY, neuropeptide Y or peptide YY (Ki below 50 pM for all), while being quite insensitive to Y2-selective ligands. The PP binding had a high sensitivity to alkali cations and inhibitors of phospholipase C, very similar to that of LP-PYY binding 'masked' by excess cold hPP. However, as different from the Y1-like LP-PYY binding, but similar to the binding of the Y2-selective ligand [125I]human peptide YY(3-36) (hPYY(3-36)), the PP binding showed a low sensitivity to guanosine polyphosphates. The PP binding was much more sensitive to N5-substituted amiloride inhibitors of Na+ transport than the binding of LP-PYY, or that of hPYY(3-36). The inhibition of PP binding by N5-substituted amilorides was not enhanced by guanine nucleotides or by phospholipase C blockers. However, pairing of N5-substituted amilorides disproportionately increased the inhibition of hPP binding. Thus, in rabbit kidney or hypothalamus, the high-affinity PP-responding sites share some of the basic properties of the Y1 and Y2 sites, but are distinguished from both by a high sensitivity to compounds affecting sodium transport. These PP/NPY receptors could associate with membrane structures involved in the control of ion balance and osmotic responses.


Subject(s)
Brain/metabolism , Kidney Cortex/metabolism , Neuropeptide Y/metabolism , Pancreatic Polypeptide/metabolism , Receptors, Neuropeptide/metabolism , Amiloride/pharmacology , Amino Acid Sequence , Animals , Binding, Competitive , Bridged-Ring Compounds/pharmacology , Cations, Monovalent/metabolism , Cations, Monovalent/pharmacology , Enzyme Inhibitors/pharmacology , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , Humans , Hypothalamus/metabolism , Iodine Radioisotopes , Ion Transport/drug effects , Male , Molecular Sequence Data , Norbornanes , Pancreatic Polypeptide/antagonists & inhibitors , Peptide YY/antagonists & inhibitors , Peptide YY/metabolism , Phosphodiesterase Inhibitors/pharmacology , Quinacrine/pharmacology , Rabbits , Rats , Sequence Alignment , Sodium/metabolism , Thiocarbamates , Thiones/pharmacology , Type C Phospholipases/antagonists & inhibitors
4.
Life Sci ; 62(6): 525-32, 1998.
Article in English | MEDLINE | ID: mdl-9464464

ABSTRACT

Neuropeptide Y (NPY) potentiates the contractile response of the rat caudal artery to adrenergic nerve stimulation in-vitro. The NPY Y1 selective antagonist BIBP3226 ((R)-N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)methyl]-argininami de), inhibited the vascular effects of NPY in rat caudal artery preparations in-vitro (IC50 =126 nM). BIBP3226 also inhibited the effects of the selective Y1 agonist [Leu31,Pro34]NPY and completely abolished the effects of avian pancreatic polypeptide that was shown to be capable of potentiating neurogenic vasoconstriction in this preparation. These effects were reversible and are most likely mediated by the Y1 receptor subtype since we failed to observe any functional evidence of a Y2 receptor subtype in rat caudal artery. The caudal artery provides a useful functional assay for pharmacological analysis of NPY and NPY antagonists.


Subject(s)
Arginine/analogs & derivatives , Neuropeptide Y/antagonists & inhibitors , Pancreatic Polypeptide/antagonists & inhibitors , Receptors, Neuropeptide Y/antagonists & inhibitors , Vasoconstriction/drug effects , Animals , Arginine/pharmacology , In Vitro Techniques , Male , Rats , Rats, Sprague-Dawley , Sympathetic Nervous System/physiology
5.
Biophys J ; 69(2): 340-55, 1995 Aug.
Article in English | MEDLINE | ID: mdl-8527647

ABSTRACT

We describe a computer algorithm to predict native structures of proteins and peptides from their primary sequences, their known native radii of gyration, and their known disulfide bonding patterns, starting from random conformations. Proteins are represented as simplified real-space main chains with single-bead side chains. Nonlocal interactions are taken from structural database-derived statistical potentials, as in an earlier treatment. Local interactions are taken from simulations of (phi, psi) energy surfaces for each amino acid generated using the Biosym Discover program. Conformational searching is done by a genetic algorithm-based method. Reasonable structures are obtained for melittin (a 26-mer), avian pancreatic polypeptide inhibitor (a 36-mer), crambin (a 46-mer), apamin (an 18-mer), tachyplesin (a 17-mer), C-peptide of ribonuclease A (a 13-mer), and four different designed helical peptides. A hydrogen bond interaction was tested and found to be generally unnecessary for helical peptides, but it helps fold some sheet regions in these structures. For the few longer chains we tested, the method appears not to converge. In those cases, it appears to recover native-like secondary structures, but gets incorrect tertiary folds.


Subject(s)
Algorithms , Antimicrobial Cationic Peptides , Models, Genetic , Peptides/chemistry , Peptides/genetics , Proteins/chemistry , Proteins/genetics , Amino Acid Sequence , Apamin/chemistry , Apamin/genetics , Bacterial Proteins , Biophysical Phenomena , Biophysics , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/genetics , Melitten/chemistry , Melitten/genetics , Models, Molecular , Molecular Sequence Data , Molecular Structure , Pancreatic Polypeptide/antagonists & inhibitors , Peptides, Cyclic/chemistry , Peptides, Cyclic/genetics , Plant Proteins/chemistry , Plant Proteins/genetics , Protein Structure, Secondary , Ribonucleases/chemistry , Ribonucleases/genetics , Ubiquitins/chemistry , Ubiquitins/genetics , Zinc Fingers/genetics
6.
Surgery ; 115(6): 713-7, 1994 Jun.
Article in English | MEDLINE | ID: mdl-8197564

ABSTRACT

BACKGROUND: The purpose of the present study was to determine whether vasoactive intestinal polypeptide (VIP) is released from the tumor cells of VIPoma and if so then to attempt to show how its release is regulated by cultured human VIPoma cells. METHODS: A resected specimen of a pancreatic tumor from a patient with watery diarrhea, hypokalemia, and achrohydria syndrome was examined. The dissociated cells were obtained by collagenase digestion of the tumor tissue and were cultured in vitro. RESULTS: The extraction of tumor cells disclosed that the cells contained VIP and pancreatic polypeptide (PP). Neither insulin, glucagon, somatostatin nor pancreastatin was detected. Immunohistochemically, 40% to 60% of the cells in the tumor stained positively for VIP and 1% to 5% stained positively for PP. The dissociated cells became reaggregated in the culture (50 to 300 microns) and could be maintained in vitro. Incubation experiments revealed a simultaneous in vitro release of VIP and PP with a significant increase by either carbachol or phorbol myristate acetate but not by theophylline or caerulein. Atropine completely abolished the stimulatory effects of carbachol on VIP and PP release. Octreotide (somatostatin analogue [SMS 201-995]) significantly inhibited the carbachol and phorbol myristate acetate-stimulated VIP and PP release. CONCLUSIONS: These findings show the in vitro release of VIP and PP from the VIPoma cells and also provide evidence for the direct inhibitory effect of somatostatin analogue on both the VIP and PP release from the tumor cells.


Subject(s)
Octreotide/pharmacology , Pancreatic Neoplasms/metabolism , Pancreatic Polypeptide/metabolism , Vasoactive Intestinal Peptide/metabolism , Vipoma/metabolism , Adult , Atropine/pharmacology , Carbachol/pharmacology , Ceruletide/pharmacology , Dose-Response Relationship, Drug , Female , Humans , Immunohistochemistry , Microscopy, Phase-Contrast , Pancreatic Polypeptide/antagonists & inhibitors , Tetradecanoylphorbol Acetate/pharmacology , Theophylline/pharmacology , Tumor Cells, Cultured , Vasoactive Intestinal Peptide/antagonists & inhibitors
8.
Pancreas ; 2(3): 320-5, 1987.
Article in English | MEDLINE | ID: mdl-3628230

ABSTRACT

Dogs with chronic pancreatic fistulae were given 0.5 ml of nonimmune rabbit serum or antibody S5, an antibody raised against the C-terminal pancreatic polypeptide (PP) hexapeptide. A 3-h infusion of secretin (125 ng/kg/h) and CCK8 (50 ng/kg/h) was started 30 min after injecting serum. Exogenous BPP (400 pmol/kg/h) was administered during the middle secretin/CCK hour. In a second protocol, 30 min after injecting nonimmune serum or PP-anti-serum, the animals were fed 15 g/kg cooked ground beef. Pretreatment with S5 enhanced secretin/CCK-induced bicarbonate outputs; protein outputs did not differ. Exogenous BPP inhibited pancreatic secretion, even in S5-treated animals. Meal-induced pancreatic secretion was not altered by S5 pretreatment. Significant increments in PP were measured by radioimmunoassay during administration of secretin/CCK and during BPP infusion. Anti-PP pretreatment abolished the former and significantly decreased, but did not abolish, the latter. The meal evoked significant postprandial increments in PP which were essentially abolished following S5 pretreatment. A physiological role for PP cannot be proved or refuted because antiserum pretreatment failed to block the effects of exogenous hormone. The latter must be established before excluding a peptide's physiological role based on negative in vivo immunoneutralization data.


Subject(s)
Pancreas/metabolism , Pancreatic Polypeptide/antagonists & inhibitors , Animals , Bicarbonates/metabolism , Dogs , Eating , Pancreas/drug effects , Pancreatic Polypeptide/immunology , Proteins/metabolism , Secretin/pharmacology , Sincalide/pharmacology , Time Factors
9.
Digestion ; 23(2): 119-24, 1982.
Article in English | MEDLINE | ID: mdl-6124471

ABSTRACT

A dose-response study of the effect of 0.1-5.0 micrograms kg-1 h-1 somatostatin was performed on food-induced rise of pancreatic polypeptide and insulin in 4 dogs. There was a dose-dependent suppression of the release of pancreatic polypeptide and insulin with an ED50 of approximately 0.65 and 0.8 microgram kg-1 h-1, respectively, during the first 45-min period. In the second 45-min period, high doses of somatostatin failed to suppress insulin concentrations whereas, the serum concentrations of pancreatic polypeptide were reduced by a similar degree as in the first 45 min. The differing effects of somatostatin on food-stimulated serum concentrations of insulin and pancreatic polypeptide indicate that somatostatin does not represent a uniform suppressor of pancreatic hormones.


Subject(s)
Insulin/metabolism , Pancreatic Polypeptide/metabolism , Somatostatin/pharmacology , Animals , Dogs , Dose-Response Relationship, Drug , Food , Insulin Antagonists , Insulin Secretion , Pancreatic Polypeptide/antagonists & inhibitors , Time Factors
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