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Biomedical subjects

R E Chance

Publications and source records attributed to R E Chance.

At least 37 records · Page 2Linked to original sources
PubMed1992

Altering the association properties of insulin by amino acid replacement.

The importance of ProB28 and LysB29 on the self-association of insulin was established by systematically truncating the C terminus of the B chain. The relationship between structure and association was further explored by making numerous amino acid replacements at B28 and B29. Association was studied by circular dichroism, size-exclusion chromatography and ultracentrifugation. Our results show that the location of a prolyl residue at B28 is critical for high-affinity self-association. Removal of ProB28 in a series of C-terminal truncated insulins, or amino acid replacement of ProB28, greatly reduced association. The largest disruption to association was achieved by replacing LysB29 with Pro and varying the amino acid at B28. Several of the analogs were predominantly monomers in solutions up to 3 mg/ml. These amino acid substitutions decreased association by primarily disrupting the formation of dimers. Such amino acid substitutions also substantially reduced the Zn-induced insulin hexamer formation. The formation of monomeric insulins through amino acid replacements was accompanied by conformational changes that may be the cause for decreased association. It is demonstrated that self-association of insulin can be drastically altered by substitution of one or two key amino acids.

Amino Acid Sequence↗
PubMed1992

The effect of pancreatic polypeptide on glucose disposal after surgical alterations of the pancreas.

Surgical alterations of the pancreas result in anatomic changes that can affect postoperative glucose metabolism. Pancreas transplantation results in reduction of beta-cell mass, systemic release of insulin, and denervation. The authors hypothesized that such alterations affect peripheral glucose disposal to induce an "insensitivity" to endogenously (systemically) released insulin. Additionally, they hypothesized that surgically induced deficiency of the postprandial hormone, pancreatic polypeptide, might contribute to altered glucose disposal. The authors studied two surgical models in dogs known to be devoid of pancreatic polypeptide--70% proximal pancreatectomy (PPx) and PPx plus distal pancreas autotransplantation (PAT/B). Oral glucose challenge and euglycemic hyperinsulinemic clamp studies were performed before and after a 16-day "pulsed" infusion of pancreatic polypeptide. Both surgical procedures resulted in elevations in the integrated glucose response after oral glucose, which was not affected by pancreatic polypeptide infusion. Euglycemic clamp studies showed decreased hepatic glucose output (Ra) and overall glucose disposal (Rd) in the fasted state for both surgical groups. The transplant animals demonstrated significant decreases in Rd during the hyperinsulinemic challenge (3.2 +/- 0.01 versus 5.7 +/- 0.01 mg/kg/minute at 60 to 120 minutes for PAT/B versus control). After 16 days of pancreatic polypeptide infusion, however, basal Ra, as well as basal and 60- to 120-minute Rd values, were returned to control values in the transplant group. The authors conclude that pancreas transplantation results in altered glucose disposal, possibly due to an altered effectiveness of systemically released insulin. They conclude that pancreatic polypeptide is an important modulator of peripheral insulin action. Therefore, the role of pancreatic polypeptide must be taken into account when evaluating postoperative glucose metabolism in canine models of pancreas transplantation.

Animals↗
PubMed1991

Structural requirements of pancreatic polypeptide receptor binding.

Pancreatic polypeptide (PP) receptors have been identified and characterized on the basolateral membranes (BLM) of canine intestinal mucosa. The present study was designed to ascertain the structural requirements of the PP molecule for binding to its receptor. A radioreceptor assay using purified BLM was employed to elucidate receptors specific to PPs of various mammalian species and to modified bovine PP (bPP) fragments. Receptor cross-reactivities (CR) to various PPs and bPP fragments were established. Results show that percent receptor CR by PPs of various species was as follows: bPP (100%) greater than human PP (68%) greater than porcine PP (50%) greater than canine PP (45%) greater than ovine PP (36%) greater than rat PP (3%). The fragments bPP-(1-15), bPP-(1-17), bPP-(1-26), bPP-(16-23), bPP-(18-30), bPP-(24-36), bPP-(27-35), and bPP-(31-36) at 500 nM did not significantly displace tracer from receptor (less than 0.1% CR). Des-COOH-terminal tyrosinamide [bPP-(1-35)] produced less than 0.1% CR. Oxidation of bPP methionine-30 residue to methionine sulfoxide decreased displacement to 67%. Modification of native amidated tyrosinamide to the free acid abolished receptor binding, whereas esterification to the methyl ester of COOH-terminal tyrosine restored binding to 60%. Additionally, percent CR decreased progressively as amino acid residues were deleted from the NH2-terminal region. We conclude that the molecular homologue of PP primary structure is necessary for full receptor binding. Both the NH2- and COOH-terminal residues are required for recognition, and the COOH-terminal tyrosinamide must be intact for PP binding to its receptor.

Amino Acid Sequence↗
PubMed1990

Purification and analysis of the major components of chum salmon protamine contained in insulin formulations using high-performance liquid chromatography.

A simple high-performance liquid chromatographic method has been developed for the rapid purification and analysis of protamine components contained in insulin formulations. Only a single step is needed to separate peptides whose compositions, sizes, and unusual isoelectric points (pI 13.8) are nearly identical. The method involves their isocratic separation on a reversed-phase column using a pH 2 phosphate buffer and a low acetonitrile content as an eluant. The purified chum salmon components were analyzed by amino acid analysis, solid-phase amino acid sequencing, carboxypeptidase B digests, insulin complexation analysis, and a mass spectrophotometric procedure which gives an accurate mass of the intact peptides. This HPLC purification technique may also be applicable to protamines and other highly basic peptides isolated from other sources.

Amino Acid Sequence↗
PubMed1988

Reversal of abnormal glucose production after pancreatic resection by pancreatic polypeptide administration in man.

Pancreatic polypeptide (PP) deficiency has been associated with impaired hepatic sensitivity to insulin and pancreatogenic diabetes in chronic pancreatitis. Since pancreatic resection might also result in PP deficiency, hepatic responses to insulin infusion (0.25 mU/kg/min) were determined by the euglycemic glucose clamp technique in 10 patients who had previously undergone pancreatic resection for trauma and in eight healthy control subjects. Six resection patients (RES-PP) demonstrated deficient PP levels, with a mean increase of plasma immunoreactive PP of 20 +/- 7 pg/ml above basal rate after a test meal compared with 232 +/- 82 pg/ml in control subjects (p less than 0.01) and 353 +/- 133 pg/ml in four other patients undergoing resection with normal levels of immunoreactive PP (RES + PP) (p less than 0.03). Three identical insulin infusion studies were performed in each subject, the second of which was performed during the final 2 hours of an 8-hour infusion of bovine PP (2.0 pmol/kg/min). Whereas hepatic glucose production (HGP) in control subjects fell 74% +/- 4% from a basal rate of 2.0 +/- 0.1 mg/kg/min to a 60- to 120-minute value of 0.5 +/- 0.1 mg/kg/min during insulin infusion, HGP was suppressed only 58% +/- 5% in RES-PP subjects, from 1.9 +/- 0.1 to 0.8 +/- 0.1 mg/kg/min (p less than 0.05 vs controls). Intravenous infusion of PP corrected the hepatic resistance to insulin seen in the PP-deficient group. During PP infusion, HGP was suppressed 74% +/- 5% in RES-PP subjects, from 2.1 +/- 0.2 to 0.5 +/- 0.1 mg/kg/min (p less than 0.04 compared with initial study). PP infusion produced no significant change in glucose metabolism in control and RES + PP subjects. Overall glucose disposal rates were not altered by PP infusion in any group. These findings support a role of PP as a glucoregulatory hormone and suggest that PP deficiency may serve as a reversible pathophysiologic factor in the abnormal glucose metabolism seen after pancreatic resection.

Adult↗
PubMed1986

Reversal of abnormal glucose metabolism in chronic pancreatitis by administration of pancreatic polypeptide.

Chronic pancreatitis, induced in dogs by pancreatic duct ligation, is associated with glucose intolerance due to insulin deficiency, reduced hepatic sensitivity to insulin, and a marked deficiency of pancreatic polypeptide. Treatment with a 14 day continuous subcutaneous infusion of pancreatic polypeptide resulted in improved oral glucose tolerance and improved hepatic glucose responses to insulin in dogs with chronic pancreatitis. No effect of continuous subcutaneous infusion of pancreatic polypeptide was seen in the control dogs. The time course of the effect of continuous subcutaneous infusion on the hepatic response to insulin was relatively immediate, whereas the effects on improvement in oral glucose tolerance were prolonged. We conclude that pancreatic polypeptide may function physiologically to enhance the hepatic glucose response to insulin and that alterations in glucose metabolism seen in chronic pancreatitis may be due, in part, to a deficiency in pancreatic polypeptide. Since treatment with continuous subcutaneous infusion of pancreatic polypeptide restored the hepatic response to insulin and oral glucose tolerance to more normal levels in our animal model, administration of pancreatic polypeptide may play a therapeutic role in the treatment of certain forms of pancreatogenic diabetes.

Animals↗
PubMed1984

Isolation and characterization of a genetic variant of bovine proinsulin.

A genetic variant of bovine proinsulin has been isolated using preparative reverse-phase HPLC. The new proinsulin (bovine proinsulin II) differs from the known proinsulin (bovine proinsulin I) by a single amino acid residue at position C-48 in the connecting peptide. The amino acid replacement is a leucine substitution for proline. The two proinsulins were found in a ratio of approximately 9:1, proinsulin I: proinsulin II. No chemical or biological differences were observed for the two proinsulins other than their different elution times on reverse-phase HPLC.

Amino Acid Sequence↗
PubMed1984

Pancreatic polypeptide from rat pancreas.

Pancreatic polypeptide (PP) has been isolated from rat pancreas by gel filtration, ion exchange chromatography, and high performance liquid chromatography. The isolation was monitored with a RIA, using antibody to the carboxyl-terminal hexapeptide of bovine PP. Rat PP contains 36 amino acids and is similar in composition to PP from other mammalian sources. The single methionine residue in the peptide appears to oxidize easily to the sulfoxide, thereby giving rise to two immunoactive peaks on high performance liquid chromatography. Reduction to the native peptide can be accomplished with mercaptoethanol. The PP content of rat pancreas is about 2 mg/kg. The amino acid sequence of rat PP is Ala-Pro-Leu-Glu-Pro-Met-Tyr-Pro-Gly-Asp- Tyr-Ala-Thr-His-Glu-Gln-Arg-Ala-Gln-Tyr-Glu-Thr-Gln-Leu-Arg-Arg-Tyr-Ile- Asn-Thr-Leu-Thr-Arg-Pro-Arg-Tyr-NH2. This sequence preserves characteristics necessary for stabilization of the compact globular conformation found in avian PP.

Amino Acid Sequence↗
PubMed1983

Crystallization of bovine pancreatic polypeptide.

Bovine pancreatic polypeptide, a 36-residue polypeptide hormone, was successfully crystallized for the first time. During purification by extensive dialysis against distilled water a surprisingly insoluble form of the peptide was obtained which led to its crystallization as orthorhombic needles up to 2 mm in length.

Amino Acid Sequence↗
PubMed1983

Distribution, pathways and reactions to drug treatment of nerves with neuropeptide Y- and pancreatic polypeptide-like immunoreactivity in the guinea-pig digestive tract.

Pancreatic polypeptide-like immunoreactivity (PPLI) has been localized in nerves of the guinea-pig stomach and intestine with the use of antibodies raised against avian, bovine and human pancreatic polypeptide (PP), the C-terminal hexapeptide of mammalian PP, and against the related peptide, NPY. Each of the antibodies revealed the same population of neurones. Reactive cell bodies were found in both myenteric (5% of all neurones) and submucous ganglia (26% of all neurones) of the small intestine, and varicose processes were observed in the myenteric plexus, circular muscle, mucosa and around arterioles. The nerves were unaffected by bilateral subdiaphragmatic truncal vagotomy, but the staining of the periarterial nerves disappeared after treatment of animals with reserpine or 6-hydroxydopamine and was also absent after mesenteric nerves had been cut and allowed to degenerate. Vascular nerves showing immunoreactivity for dopamine beta-hydroxylase and PPLI had the same distribution. It is concluded that PPLI is located in periarterial noradrenergic nerves. However, other noradrenergic nerves in the intestine do not show PPLI, and PPLI also occurs in nerves that are not noradrenergic. Analysis of changes in the distribution of terminals after microsurgical lesions of pathways in the small intestine showed that processes of myenteric PP-nerve cells provide terminals in the underlying circular muscle and in myenteric ganglia up to about 2 mm more anal. Submucous PP-cell bodies provide terminals to the mucosa.

Animals↗
PubMed1981

Effect of pancreatic polypeptide and its C-terminal hexapeptide on meal and secretin induced pancreatic secretion in dogs.

1. Gastric acid and pancreatic bicarbonate and protein secretion as well as immunoreactive serum gastrin and pancreatic polypeptide concentrations in response to a meal and secretin have been measured before and after infusion of bovine pancreatic polypeptide or its C-terminal hexapeptide. 2. Liver extract meal kept in the stomach at pH 5.5 (by intragastric titration) produced a marked increase in gastric acid and pancreatic protein secretion accompanied by a rise in serum gastrin and pancreatic polypeptide levels. Exogenous bovine pancreatic polypeptide caused little change in gastric secretion and serum gastrin but resulted in a profound suppression of pancreatic secretion. 3. Ordinary feeding a liver meal produced a marked increase in pancreatic bicarbonate and protein secretion that was dose-dependently inhibited by bovine pancreatic polypeptide or its C-terminal hexapeptide, the degree of inhibition being closely correlated with the increments in plasma pancreatic polypeptide. 4. Bovine pancreatic polypeptide and its C-terminal hexapeptide also inhibited secretin and caerulein-induced pancreatic secretion in a dose-dependent manner. 5. This study shows that bovine pancreatic polypeptide inhibits pancreatic secretion at least in part by acting directly on the exocrine pancreas and that its biological activity resides in its C-terminal hexapeptide fragment.

Animals↗
PubMed1980

Glucagon-, glicentin-, and pancreatic polypeptide-like immunoreativities in rectal carcinoids and related colorectal cells.

Three nonargentaffin rectal carcinoids have been investigated immunohistochemically. In one case most tumor cells reacted with antiglucagon sera as well as with antiglicentin, antibovine pancreatic polypeptide (BPP), and antihuman pancreatic polypeptide (HPP) sera; they were identified ultrastructurally as L cells. Another case showed glucagon-, glicentin-, and BPP-immunoreactive cells but lacked HPP immunoreactivity. In the third case glucagon- and glicentin-immunoreactive cells were well represented, while PP immunoreactivities were scarce. Parallel investigations of human rectal and sigmoid mucosa showed numerous cells reacting with glucagon, glicentin, and BPP antisera, most of which lacked HPP immunoreactivity. Cells reacting with glucagon and glicentin antisera, while lacking PP immunoreactivities, were also found. Thus, both tumor and nontumor cells produce glucagonlike immunoreactive (GLI) peptides--one of which may be glicentin or a related molecule--as well as PP-related sequences, although differing histochemically and ultrastructurally from glucagon or PP cells of the human pancreas. It is concluded that nonargentaffin rectal carcinoids are histogenetically linked to nonargentaffin endocrine cells of the human rectum.

Adult↗
PubMed1978

On the preparation and characterization of standard materials for natural human proinsulin and C-peptide.

The preparation and characterization of intact native human proinsulin and C-peptide to serve as reference standards in immunologic and biologic assays is described. The major difficulty encountered in the preparation of human proinsulin from crystalline human insulin is the rather low yield (0.08 per cent), which may be due to postmortem autolysis in the pancreatic specimens. Under such circumstances, minor degrees of contamination of batches by fresh pancreases from other species, such as cows or pigs, may be magnified considerably. Such contamination can be readily detected with various currently available proinsulin- or C-peptide-specific antisera. Autolysis before or during preparation may also affect the yields and quality of human C-peptide preparations. Some of these C-peptide by-products are described, along with methods for their purification and characterization.

Amino Acids↗
PubMed1978

Regional pancreatic concentration and in-vitro secretion of canine pancreatic polypeptide, insulin, and glucagon.

The regional concentrations and in-vitro secretions of canine pancreatic polypeptide (cPP), insulin, and glucagon were studied. CPP is found predominantly in the uncinate process of the dog pancreas, whereas insulin and, more markedly, glucagon predominate in the body and tail of the pancreas. In-vitro secretion studies of pancreatic pieces indicate that dibutyryl cyclic AMP (dcAMP) alone can stimulate cPP release whereas glucose and arginine alone have no effect. Arginine, but not glucose, potentiates this stimulant effect of dcAMP. These studies suggest that the cAMP generating system may play a role in regulation of cPP secretion.

Animals↗
PubMed1978

A pancreatic-polypeptide-producing tumour associated with the WDHA syndrome.

A case with the clinical appearance of WDHA syndrome is described in which serum concentrations of the newly recognized hormonal principle pancreatic polypeptide (PP) were highly elevated, while plasma levels of vasoactive intestinal peptide were within the normal range. The symptoms of the patient seem to be derived from the high levels of circulating PP, as illustrated by an improvement after resection of liver metastases accompanied by a marked decrease of serum PP concentration. Streptozotocin treatment was without effect upon the watery diarrhoea, and PP levels also remained unchanged during medical treatment. The appearance of a PP-secreting tumour leading to a clinical WDHA syndrome widens the spectrum of hormone assays that have to be performed in these patients.

Adult↗
PubMed1977

Ultrastructural and immunohistochemical demonstration of pancreatic polypeptide-containing F-cells in the stomach and pancreas of Tupaia belangeri.

The gastro-entero-pancreatic (GEP) system in Tupaia belangeri contains a specific cell which reacts with antisera to pancreatic polypeptide (PP). The cells are scattered between exocrine pancreatic cells and also found in the pancreatic islets. Furthermore, they are also located in the fundic glands and to a very small extent in the corpus mucosa and in the glands of the upper duodenum. The cell reacting with antisera against PP is identified as the F-cell which has a specific ultrastructure especially with respect to its secretion. The present identification of the F-cell as the PP-cell in pancreas and stomach is discussed with respect to its possible functional implications.

Animals↗
PubMed1977

The identification of the F-cell in the dog pancreas as the pancreatic polypeptide producing cell.

The endocrine cells of the processus uncinatus in the dog pancreas were investigated with special reference to the formerly known F-cell. The F-cell was detected frequently in the periphery of pancreatic islets as well as among exocrine tissue. In both localizations the F-cell shows similar ultrastructural features. Membrane-bound irregularly shaped secretory granules of variable electron density were seen. The cell possesses all features of an endocrine polypeptide secreting cell. Using the immunofluorescence and immunoperoxidase technique in the uncinate processus of the dog, we could reveal that the anti-sera against bovine pancreatic polypeptide (BPP) reacts with the cell which is localized at the same sites as the F-cell. We therefore conclude that the pancreatic F-cell is identical to the pancreatic polypeptide-producing cell. The other endocrine cell types of the dog pancreas are glucagon-producing A-cells, insulin-producing B-cells, and somatostatin-producing D-cells, as well as serotonin-producing EC-cells which are regularly present in the dog pancreatic islets and also scattered among exocrine tissue and the duct epithelial cells.

Animals↗