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Biomedical subjects

M Ghiglione

Publications and source records attributed to M Ghiglione.

At least 19 recordsLinked to original sources
PubMed1994

Effect of lithium on plasma glucose, insulin and glucagon in normal and streptozotocin-diabetic rats: role of glucagon in the hyperglycaemic response.

1. Lithium salts, used in the treatment of affective disorders, may have adverse effects on glucose tolerance in man, and suppress glucose-stimulated insulin secretion in rats. 2. To study the interaction of these effects with pre-existing diabetes mellitus, plasma glucose and insulin responses to lithium chloride were measured in male Wistar rats made diabetic with intraperitoneal streptozotocin, and in normal controls. 3. In both normal and diabetic anaesthetized rats, intravenous lithium (4 mEq kg-1) caused a rise in plasma glucose. In absolute terms, the rise was greater in diabetic (5.2 mmol l-1) than in normal rats (2.3 mmol l-1). 4. Plasma insulin concentrations were reduced by lithium in normal rats, but the low insulin concentrations measured in the diabetic rats were not significantly changed. 5. After intravenous glucose (0.5 g kg-1), lithium-treated diabetic rats showed a second rise in plasma glucose at 60-90 min without any insulin response, while normal rats showed typically reduced insulin responses and initial glucose disappearance rates. 6. Intravenous glucose reduced plasma glucagon concentrations to a greater extent in normal than in diabetic rats, but lithium induced an equal rise in plasma glucagon in both groups, with a time-course similar to that of the hyperglycaemic effect. 7. The hyperglycaemic action of lithium is greater in the hypoinsulinaemic diabetic rats and appears to involve a stimulation of glucagon secretion in both normal and diabetic animals.

Animals↗
PubMed1991

Effect of pertussis pretreatment on plasma glucose and insulin responses to lithium in rats.

1. Administration of lithium to rats causes a rise in plasma glucose and suppresses glucose-stimulated insulin secretion. These effects are blocked by the alpha 2-adrenoceptor antagonist, yohimbine. 2. Pretreatment of rats with Bordetella pertussis toxin resulted in a reversal of the usual plasma glucose and insulin responses to intravenously administered lithium (4 mEq kg-1). There was a slow fall in plasma glucose, while plasma insulin rose to 267 +/- 42% (+/- s.e.mean) of control values at 30 min. The effect of lithium on glucose-stimulated insulin secretion was also reversed; there was a marked increase in the insulin response which contrasted with the suppression seen in normal controls. 3. In perifused islets of Langerhans isolated from pertussis pretreated rats, the previously described inhibition by lithium of the second phase of glucose-stimulated insulin secretion from normal islets was almost completely abolished. 4. The results are consistent with the hypothesis that these effects of lithium are mediated by the influence of catecholamines on the islets. When the inhibitory effect of alpha 2-adrenoceptors is abolished by pertussis treatment, which blocks the action of the inhibitory guanine nucleotide-binding protein Gi, effects of beta-adrenoceptor stimulation predominate, leading to an increased secretion of insulin.

Animals↗
PubMed1988

Distribution of a novel pituitary protein (7B2) in mammalian gastrointestinal tract and pancreas.

The distribution of a novel pituitary protein (7B2) was determined in the gastrointestinal tract and pancreas of four mammalian species (man, pig, guinea pig, and rat) by a specific radioimmunoassay. The highest concentrations of cross-reacting immunoreactive 7B2 (IR-7B2) were observed in the pancreas and the proximal gut (antrum or duodenum). While the intestinal concentrations varied widely among species, pancreatic IR-7B2 concentrations appeared to be similar in all four species. In the rat, pancreatic islets were found to contain high concentrations of IR-7B2 (5.73 +/- 0.14 fmol/islet, mean +/- SEM). Neonatal capsaicin treatment and enteric nerve section did not affect the concentrations of IR-7B2 in the rat intestine. Layer separation of human gut showed that IR-7B2 is mainly (71 +/- 8%) present in the epithelial fraction. Chromatographic analysis of intestinal and pancreatic extracts from the four species on Sephadex G-100 showed the presence of two immunoreactive peaks at Kav 0.3 and 0.6, but there were both inter- and intraspecies variations in the proportions of the larger and smaller molecular forms.

Animals↗
PubMed1987

Acute and short term effects of intestinal alpha-glucosidase inhibition on gut hormone responses in man.

The effect of 50-, 100-, 200-, and 400-mg oral doses of acarbose, a competitive inhibitor of intestinal alpha-glucosidases, on the postprandial release of gut and pancreatic hormones after a 2.2 MJ carbohydrate-rich mixed test meal was determined in five normal subjects according to a double-blind, Latin-square protocol. All the doses of acarbose tested slowed the postprandial plasma glucose rise, without evidence of dose dependency, while maximal inhibition of integrated insulin and gastric inhibitory polypeptide responses to 31 +/- 8% and 28 +/- 7% of control values, respectively, was obtained at the 400-mg dose. The enteroglucagon response was increased to a maximum of 905 +/- 262% of control at the 200-mg dose, and total motilin responses were slightly but not significantly elevated. After one week of regular acarbose administration at 100 mg three times daily, the effects of the 100-mg dose on insulin and enteroglucagon responses were slightly enhanced, and there was no evidence of intestinal adaptation in the form of diminished postprandial endocrine responses. The observed effects are attributed to impairment of carbohydrate digestion in the upper small intestine and suggest that the optimal ratio of desired to unwanted effects is obtained at low doses of acarbose.

Acarbose↗
PubMed1986

Long-term effects of intestinal alpha-glucosidase inhibition on postprandial glucose, pancreatic and gut hormone responses and fasting serum lipids in diabetics on sulphonylureas.

Seventeen non-insulin-dependent diabetics poorly controlled by diet and sulphonylurea drugs took part in a long-term (20-52 weeks) trial of the effect of an alpha-glucosidase inhibitor (acarbose 100 mg thrice daily) on postprandial glycaemic and gastro-entero-pancreatic hormone responses. Patients were assessed before, during, and after the trial period with identical 2.2 MJ mixed test meals plus placebo or acarbose 100 mg, and sulphonylurea therapy was continued throughout. Acarbose administration reduced the integrated postprandial plasma responses of glucose to 58 +/- 10% (mean +/- SEM, p less than 0.001), insulin to 61 +/- 10% (p less than 0.01) and gastric inhibitory polypeptide to 45 +/- 8% (p less than 0.001) of control values, increased the enteroglucagon response to 152 +/- 26% (p less than 0.001) of control and slightly prolonged the postprandial release of motilin. Recorded glycosuria was significantly (p less than 0.01) reduced throughout the treatment period. The effects of acarbose on postprandial glycaemic and endocrine responses remained approximately constant throughout the trial period, and responses returned to pre-treatment values within 2 days of stopping treatment.

Acarbose↗
PubMed1986

Effects of decapeptide of mammalian bombesin and neuromedin B on pancreatic exocrine secretion in the rat.

The effects on pancreatic exocrine secretion of intravenous bolus injections of decapeptide of mammalian bombesin (also called neuromedin C) and neuromedin B, recently isolated mammalian bombesin-like peptides, have been studied and compared with those of amphibian bombesin in anaesthetized rats. Decapeptide of mammalian bombesin and neuromedin B stimulated the volume output from the pancreas with the same potency as that with which they stimulated protein output, as did amphibian bombesin. The maximal peak rates of volume and protein secretion observed in the 5- to 10-min period after the injection of 3 X 10(-10) mol/kg decapeptide of mammalian bombesin were 24.5 +/- 1.2 microliters/5 min and 8.5 +/- 0.5 mg bovine serum albumin equivalents per 5 min (mean +/- SEM, n = 5). These rates were equivalent to those produced by the same dose of amphibian bombesin, but the duration of responses to decapeptide of mammalian bombesin were shorter than those of equimolar doses of amphibian bombesin. The relative potencies of decapeptide of mammalian bombesin and neuromedin B, calculated from the doses producing 50% of maximum effect on total responses, were, respectively, 100 and 0.5% of that of amphibian bombesin. The results suggest that decapeptide of mammalian bombesin, and possibly neuromedin B, could play a regulatory role in the control of exocrine pancreatic secretion.

Animals↗
PubMed1985

Molecular forms of glucagon-like peptides in man.

Molecular forms of the glucagon-like peptides (GLP) encoded by the human preproglucagon gene were analysed by chromatography combined with specific radioimmunoassays to the synthetic peptides. Whereas extracts of human pancreas and a glucagonoma contained a large proglucagon cleavage product possessing both GLP-1 and GLP-2 immunoreactivities, extracts of human intestine contained products corresponding to free GLP-1 and a small amount of chromatographically distinct GLP-2 immunoreactivity. It is concluded that post-translational processing of proglucagon differs in pancreas and intestine, so that the C-terminal portion of the molecule is cleaved to liberate free GLP-1 in the intestine. Further processing or degradation results in loss especially of GLP-2 immunoreactivity.

Chromatography, High Pressure Liquid↗
PubMed1985

Glucagon-like peptide-1 does not have a role in hepatic carbohydrate metabolism.

Glucagon-like peptide-1 does not have specific, high-affinity receptors on rat liver membranes, does not displace glucagon from glucagon receptors on these membranes and does not stimulate the production of cyclic AMP by isolated rat hepatocytes. In the presence of glucagon, high concentrations of glucagon-like peptide-1 do not significantly alter the production of cyclic AMP. Thus, glucagon-like peptide-1 appears unlikely to have a direct action on hepatic carbohydrate metabolism.

Animals↗
PubMed1985

Plasma glucagon-immunoreactive components in early life in dogs.

High plasma concentrations of C-terminal immunoreactive glucagon (IRG) have been found during early life in several mammalian species. We have analyzed the plasma IRG of 12 h to 60 day-old dogs in terms of the 4 peaks (IRG greater than 20,000, IRG9000, IRG3500 and IRG2000) obtained by gel filtration on Bio-Gel P-30. Significant changes with age and in response to administered agents were confined to IRG9000 and IRG3500. IRG9000 was 9-fold higher in 12-36 h old dogs than in adults (108 +/- 24 pg/ml pancreatic glucagon equivalents v. 12 +/- 3 pg/ml, mean +/- SEM) and showed a decline to 2-fold higher (27 +/- 5 pg/ml) at 31-60 days. IRG3500 was higher than in the adult only during the first 36 h of life (36 +/- 5 pg/ml v. 15 +/- 3 pg/ml). Arginine infusion (0.5 g/kg over 15 min) caused an increase in plasma levels of both IRG9000 and IRG3500 in the newborn, whereas in adult dogs only IRG3500 was increased. Insulin injection (0.2 U/kg intravenously) causing a marked hypoglycemia had no significant effect on the plasma level of any IRG component in newborn dogs. Dihydrosomatostatin infusion (10 micrograms/kg bolus +/- 90 micrograms/kg over 30 min) caused a decrease in both IRG9000 and IRG3500. The increased basal level and secretory response to arginine of IRG9000 in newborn dogs may reflect an immaturity of the A cells, whereby more of this component, which may represent a precursor of pancreatic glucagon, is secreted than in the adult. The immature A cells also appear to have an impaired secretory response to hypoglycemia.

Aging↗
PubMed1985

Pentagastrin-stimulated gastric acid output and plasma enteroglucagon in acarbose-treated rats.

Although the purified porcine enteroglucagons glicentin and oxyntomodulin inhibit pentagastrin-stimulated gastrin acid secretion when given parenterally to rats, it is not known whether the postprandial rise in endogenous enteroglucagons is capable of exerting a similar effect. We have used the alpha-glucosidase inhibitor acarbose in combination with a sucrose- and starch-rich semisynthetic diet over 8 days to bring about a mean increase of 89 pmol/l in the fasting plasma enteroglucagon concentration in rats, without significantly affecting plasma gastrin concentrations. There was no significant suppression of pentagastrin-stimulated gastric acid secretion in the acarbose-treated rats, suggesting that endogenous enteroglucagons do not act as physiological inhibitors of gastric acid secretion.

Acarbose↗
PubMed1985

Molecular forms of glucagon-like peptide-1 in human pancreas and glucagonomas.

The structure of human preproglucagon, as deduced from nucleotide sequencing of the preproglucagon gene, contains two glucagon-like peptides (GLP-1 and GLP-2) in the portion C-terminal to glucagon. A rabbit antiserum was raised against synthetic GLP-1-(1-19) which had 20% cross-reactivity with synthetic GLP-1 and des-Gly37-GLP-1 amide, two possible forms of the GLP-1 whole molecule, but no significant cross-reactivity with glucagon or other pancreatic peptides. Immunocytochemistry revealed that the distribution of GLP-1-(1-19) immunoreactivity followed that of glucagon-like immunoreactivity in the normal human pancreas and in two human glucagon-secreting pancreatic tumors. Chromatography of human pancreas extracts on Sephadex G-50 gave peaks of cross-reactivity at Kav values of 0.06-0.16, 0.34-0.39, 0.54-0.58 (the elution position of synthetic GLP-1), and 0.64-0.70. The concentration of immunoreactivity in the Kav 0.54-0.58 peak measured by RIA using GLP-1 or des-Gly37-GLP-1 amide as standard was 94 +/- 7 pmol/g (mean +/- SEM), while the total pancreatic glucagon content was 4.8 +/- 0.8 nmol/g. One extract of a human glucagon-secreting pancreatic tumor contained a prominent peak of GLP-1-(1-19) peptide cross-reactivity with properties identical to those of GLP-1 or des-Gly37-GLP-1 amide on gel filtration and reverse phase high pressure liquid chromatography, but another tumor contained a preponderance of cross-reactive forms of greater molecular size. Pretreatment plasma from three patients with radiological and biochemical evidence of glucagon-secreting tumors contained a peak of cross-reactivity with the chromatographic properties of intact GLP-1. The low concentrations of intact GLP-1 in normal pancreas compared with pancreatic glucagon concentrations suggest that the majority of the proglucagon is cleaved in a manner that does not produce GLP-1, as defined by its delimiting pairs of basic amino acid residues.

Adenoma, Islet Cell↗
PubMed1984

How glucagon-like is glucagon-like peptide-1?

Although glucagon-like peptide-1 has the appearance of a glucagon-homologue that may be co-secreted with glucagon, synthetic glucagon-like peptide-1-(1-37) does not significantly affect plasma glucose and insulin concentrations when administered at high doses (100 and 400 micrograms) to cortisone-pretreated rabbits. This synthetic preparation thus lacks the primary metabolic effect of glucagon at the doses tested. An intra- or extra-pancreatic role of glucagon-like peptide-1 has yet to be discovered.

Amino Acid Sequence↗
PubMed1983

The stimulus-secretion coupling of glucose-induced insulin release. LIII. Calcium-dependency of the cyclic AMP response to nutrient secretagogues.

Above a threshold value in excess of 5.6 mM, D-glucose increases the amount of cyclic AMP measured by radioimmunoassay in pancreatic rat islets and their surrounding incubation medium. As judged from the cyclic AMP content of islets exposed to isobutylmethylxanthine (1.0 mM), the glucose-induced increment in the rate of cyclic AMP generation represents a rapid and sustained phenomenon. The stimulant action of glucose on cyclic AMP accumulation is mimicked by L-leucine, and L-glutamine, these amino acids acting synergistically of one another. Trifluoperazine slightly decreases but fails to abolish the effect of glucose. In the absence of extracellular Ca2+, however, the cyclic AMP response to D-glucose, L-leucine and/or L-glutamine is severely impaired. These findings are compatible with the view that an increase in the generation rate of cyclic AMP participates in the process of nutrient-stimulated insulin release. This increase could be secondary to the nutrient-induced accumulation of Ca2+ in the islet cells leading to activation of adenylate cyclase by calmodulin.

1-Methyl-3-isobutylxanthine↗
PubMed1982

PHI stimulates intestinal fluid secretion.

Regulatory peptides are likely to have a role in the control of net intestinal fluid transport. PHI is a peptide recently isolated from porcine duodenum which has been shown to have sequence homologies with other peptides of the glucagon-secretin family. We have studied the effect of intravenous infusion of synthetic PHI on net intestinal fluid transport in the rat small intestine. During PHI infection net absorption was reduced in the duodenum and jejunum and net secretion was observed in the ileum. Thus synthetic PHI appears to be capable of strongly stimulating intestinal secretion in the rat.

Animals↗
PubMed1982

Renal metabolism of gut glucagon-like immunoreactivity.

To examine the role of the kidney in the catabolism of gut glucagon-like immunoreactivity (GLI), we compared the plasma GLI responses of normal and nephrectomized dogs given intraduodenal glucose loads and studied the clearance of gut GLI by the isolated perfused rat kidney. Both basal and postload plasma samples were analyzed with a glucagon C-terminal specific antibody and a GLI-reacting N-terminal antibody. The GLI response was taken to be the difference between the increments seen with these two antibodies after glucose loading. Although glucose-induced GLI increments could not be detected in untreated plasma from nephrectomized dogs, chromatographed plasma revealed a significant rise in GLI-fraction II (7000--12000 daltons) in both nephrectomized and normal dogs (732 +/- 200 and 586 +/- 111 pg/ml, respectively). We also found that crystalline glucagon was cleared by the isolated closed-circuit perfused rat kidney, but gut-GLI either as crude extract or as peak I (7000--12000 daltons) was not. Our data suggest that the kidney may not play an important role in gut-GLI catabolism.

Animals↗
PubMed1979

Chromatographic pattern of gut glucagon-like immunoreactivity (GLI) in plasma before and during glucose absorption.

In this work we have studied the chromatographic pattern on Bio-Gel P-30 columns of the glucagon-like immunoreactivity (GLI) present in unextracted plasma from normal dogs in the basal state and after intraduodenal administration of glucose. Basal plasma GLI, measured by R-8 antiserum, was distributed in four distinct fractions, whose approximate molecular weights were: greater than 30000 delta (Fraction I), 10000 delta (Fraction II), 3500 delta (Fraction III) and 2000 delta (Fraction IV). Fraction I accounted for the highest percent of total immunoreactivity. The increase in plasma GLI during glucose absorption was due to a significant increase of Fraction II, which may well correspond to tissue GLI Peak I, while no significant changes were evident in the other three fractions. The fact that tissue Peak I (or plasma Fraction II) ssems to be the factor secreted during glucose absorption puts the material/s of this molecular size in the first place for further investigation.

Animals↗