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C. J. Bailey, J. M. Conlon, and P. R. Flatt

ABSTRACT

Immunoreactive somatostatin and substance P were determined in extracts of alimentary tract (stomach to colon) from the following groups of adult female mice: intact control, ovariectomized, ovariectomized and treated with oestradiol (50 μg/kg per day) and/or progesterone (2 mg/kg per day) for 30 days, 19-day-pregnant, and 10-day-postpartum lactating. Ovariectomy increased the somatostatin concentration of the stomach (by 52%, P < 0·05), jejunum (by 116%, P < 0·01) and caecum (by 114%, P < 0·01). These effects were partially or totally prevented by the oestradiol and progesterone treatments, especially the oestradiol-progesterone combination, except for an increase (by 126%, P < 0·01) in gastric somatostatin after treatment with oestradiol alone. Lactation also increased gastric somatostatin (by 108%, P < 0·001), but the somatostatin concentration of other regions of the alimentary tract (jejunum to colon) was reduced (by 21–55%, P < 0·05) in pregnant and lactating mice. The concentration of substance P was increased by ovariectomy in stomach (by 69%, P < 0·01), duodenum (by 84%, P < 0·05), ileum (by 163%, P < 0·001) and caecum (by 57%, P < 0·01). This effect was partially or totally prevented by treatment with progesterone alone and by the oestradiol-progesterone combination, but not by oestradiol alone. Pregnancy and lactation increased gastric substance P by 46% (P < 0·01) and 61% (P < 0·001) respectively, but substance P concentrations in other regions of the alimentary tract were not significantly altered. The results suggest that ovarian oestrogens and progestogens are important in the maintenance of normal concentrations of somatostatin and substance P in the gastrointestinal tract of female mice.

Journal of Endocrinology (1989) 122, 645–650

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P. R. Flatt, C. J. Bailey, and K. D. Buchanan

This study examines the role of glucagon in the pathogenesis of the obese hyperglycaemic (ob/ob) syndrome in mice. Plasma C-terminal immunoreactive glucagon concentrations were measured in fed and fasted ob/ob mice at different ages between 5–40 weeks, and in 20-week-old mice after the administration of established stimulators and inhibitors of glucagon secretion. Plasma glucagon concentrations were inappropriately raised irrespective of age, nutritional status and the accompanying prominent changes in plasma glucose and insulin concentrations. Glucose suppressed plasma glucagon in the fed but not the fasted state, suggesting a dependence on the marked hyperinsulinaemia associated with feeding. Administration of 0·25 units insulin/kg to fasted mice failed to affect plasma glucagon and glucose concentrations. Increasing the dose to 100 units/kg restored the normal suppressive actions of insulin. Fasted mice showed an exaggerated glucagon response to arginine but not to the parasympathomimetic agent pilocarpine. Fed mice displayed normal plasma glucagon responses to the sympathomimetic agents noradrenaline and adrenaline. Administration of insulin antiserum or 2-deoxy-l-glucose raised plasma glucagon concentrations of fed mice. Contrary to the lack of suppression by glucose in the fasted state, heparin-induced increase in free fatty acids reduced plasma glucagon concentrations. This study demonstrates inappropriate hyperglucagonaemia and defective A-cell function in ob/ob mice. The extent of the abnormality is exacerbated by fasting and appears to result from insensitivity of the A-cell to the normal suppressive action of insulin.

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L. C. Wilkes, C. J. Bailey, M. G. Thompson, J. M. Conlon, and K. D. Buchanan

ABSTRACT

Collagenase-isolated mouse islets were incubated with gastrin-releasing peptide (GRP). At 5·6 mmol glucose/1, 10 nmol GRP/l increased the release of insulin (by 50%) and glucagon (by twofold), decreased the release of pancreatic polypeptide (by 35%), but did not significantly affect the release of somatostatin. At 16·7 mmol glucose/l, 10 nmol GRP/l increased glucagon release (by fivefold) and decreased pancreatic polypeptide release (by 46%), without significantly altering insulin and somatostatin release. GRP (200 nmol/l) did not affect insulin release by perifused mouse islets at 2·8 mmol glucose/l, but increased both first and second phase insulin release after a square wave increase in the glucose concentration to 11·1 mmol/l. At 5·6 mmol glucose/l, GRP (100 pmol/1–100 nmol/l) increased (by 50–70%) insulin release by the RINm5F clonal cell line. GRP did not affect glucose oxidation or the cyclic adenosine monophosphate content of RINm5F cells. However, the intracellular free Ca2+ concentration of RINm5F cells was rapidly and transiently increased by GRP (maximum increase of 64% about 10 s after exposure to 1 μmol GRP/l). The rise of intracellular free Ca2+ was approximately halved in the absence of extracellular Ca2+. The results suggest that GRP may contribute to the normal regulation of the endocrine pancreas. The insulin-releasing effect of GRP is mediated via increased cytosolic free Ca2+, derived both from an increased net influx of extracellular Ca2+ and from mobilization of intracellular Ca2+ stores.

Journal of Endocrinology (1990) 127, 335–340

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C. J. Bailey, L. C. Wilkes, P. R. Flatt, J. M. Conlon, and K. D. Buchanan

ABSTRACT

The effect of synthetic human growth hormone-releasing hormone(1–40) (hGHRH-40) on the function of the endocrine pancreas and on glucose homeostasis in lean and genetically obese-diabetic (ob/ob) mice and normal rats has been examined. The addition of 1 μmol hGHRH-40/1 to incubated islets from normal lean mice increased insulin release by 90 and 37% at 5·6 and 16·7 mmol glucose/l respectively. Lower concentrations of hGHRH-40 did not affect insulin release. hGHRH-40 (1 μmol/l) increased pancreatic polypeptide release by 50% at 5·6 mmol glucose/l. A range of concentrations of hGHRH-40 (1 nmol/l–1 μmol/l) reduced glucagon release by 42–73% at 5·6 mmol glucose/l, and by 38–70% at 16·7 mmol glucose/l. Somatostatin release was increased (eightfold) by 1 μmol hGHRH-40/1 at 5·6 mmol glucose/l, but at 1 nmol hGHRH-40/l somatostatin release was reduced (by > 50%). At 16·7 mmol glucose/litre 0·01–1 μmol hGHRH-40/l increased somatostatin release (three- to fourfold), but 1 nmol hGHRH-40/l produced a reduction of 50%. In vivo, administration of hGHRH-40 (50 μg/kg body weight i.p.) to fasted lean and ob/ob mice did not alter basal plasma concentrations of glucose and insulin, or the glucose and insulin responses to a concomitant i.p. glucose challenge. Intravenous injection of hGHRH-40 (20 μg/kg body weight) to anaesthetized rats increased plasma concentrations of insulin in the hepatic portal vein. A lower dose of hGHRH-40 (0·2 μg/kg) was ineffective, and neither dose of hGHRH-40 altered plasma glucose. The results indicate that hGHRH-40 exerts dose-dependent effects on the secretion of islet hormones, but this does not appear to be sufficient to produce measurable effects on plasma glucose homeostasis.

Journal of Endocrinology (1989) 123, 19–24

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C. J. Bailey, L. C. Wilkes, J. M. Conlon, P. H. Armstrong, and K. D. Buchanan

ABSTRACT

The release of insulin, glucagon, somatostatin and pancreatic polypeptide (PP) by isolated mouse pancreatic islets was determined during 30-min incubations at 5.6 and 16.7 mmol glucose/l in the absence and presence of gastric inhibitory polypeptide (GIP), vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI) at concentrations of 1–1000 nmol/l. Insulin release was enhanced (>50%) by GIP (100–1000 nmol/l) and VIP (1 μmol/l) at 5.6 mmol glucose/l, but not at 16.7 mmol glucose/l. Glucagon release was increased by GIP (100–1000 nmol/l), and by VIP and PHI (1—1000 nmol/l) at both glucose concentrations in a dose-related manner (maximum increases > tenfold). Somatostatin release was similarly increased by GIP (10–1000 nmol/l) at both glucose concentrations. Only the highest concentration (1 μmol/l of PHI tested increased somatostatin release (twofold) at 5.6 mmol glucose/l, whereas PHI and VIP (1–1000 nmol/l reduced (>37%) somatostatin release at 16.7 mmol glucose/l. PP release was increased (49–58%) by 100–1000 nmol GIP/l, but was not significantly altered by VIP, and was reduced (39–56%) by PHI. The results indicate that GIP, VIP and PHI each stimulate glucagon release in a dose-related manner, but they exert discretely different effects on other islet hormones depending upon the dose and the prevailing glucose concentration.

Journal of Endocrinology (1990) 125, 375–379

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C Stewart, N A Taylor, I C Green, K Docherty, and C J Bailey

Abstract

Insulin delivery by somatic cell gene therapy was evaluated using murine pituitary AtT20MtIns-1.4 cells. These cells have been stably transfected to release human insulin by the introduction of a recombinant plasmid bearing a human preproinsulin cDNA under the control of a zinc-sensitive metallothionein promoter. 6 × 107 AtT20MtIns-1.4 cells were implanted subcutaneously into streptozotocin-diabetic mice immunosuppressed with cyclosporin A. Release of human insulin was assessed using a specific plasma human C-peptide assay. On days 1 and 2 after implantation human C-peptide concentrations were about 0·02 pmol/ml. Consumption of zinc sulphate solution (500 mg/l) as drinking fluid for days 3–5 increased plasma human C-peptide concentrations to 0·11 ±0·01 pmol/ml (mean±s.e.m.), n=11, P<0·01, and concentrations declined when zinc was discontinued. The extent of hyperglycaemia was slightly lower (P<0·05) than in a group implanted with non-transfected AtT20 cells. The study was terminated after 9 days, and tumour-like aggregations of implanted cells were identified at autopsy. These comprised a large necrotic core with insulin-containing cells at the periphery. The study provides support for the view that somatic cell gene therapy offers a potential approach to insulin delivery in diabetes mellitus.

Journal of Endocrinology (1994) 142, 339–343

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C. A. Wilson, H. J. Herdon, L. C. Bailey, and R. N. Clayton

ABSTRACT

In the long-term castrated rat the negative feedback effect of testosterone is markedly reduced and the raised levels of plasma LH seen in the castrated animals are not suppressed by physiological concentrations of plasma testosterone. In this study we have measured pituitary gonadotrophin-releasing hormone (GnRH) receptor content as well as plasma and pituitary LH on days 1, 10 and 40 after castration and noted the effect of testosterone replacement on these parameters.

We found that the negative feedback effect of physiological concentrations of testosterone on plasma and pituitary LH, pituitary GnRH receptor content and response to exogenous GnRH was attenuated 10 and 40 days after castration. It is suggested that the lack of effect of testosterone in the long-term castrated rat is due to its inability to reduce the pituitary GnRH receptor content. On increasing testosterone to supraphysiological levels, the negative feedback effect was reinstated.

We also found that in rats 40 days after castration, physiological and subphysiological concentrations of testosterone significantly increased pituitary GnRH receptor content and this may explain the previous findings that low concentrations of testosterone can enhance the effect of GnRH and increase plasma LH levels.

J. Endocr. (1986) 108, 441–449

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P. R. Flatt, C. J. Bailey, P. Kwasowski, T. Page, and V. Marks

ABSTRACT

Gastric inhibitory polypeptide (GIP), a recognized component of the enteroinsular axis, is raised in the plasma and intestine of obese hyperglycaemic (ob/ob) mice. To evaluate the control of plasma GIP and its role in the hyperinsulinaemia of the ob/ob syndrome, GIP and insulin were determined at different ages in fed mice, and at 10–12 weeks of age after fasting/refeeding and administration of GIP, different nutrients and insulin to mice fasted for 18 h. Plasma GIP and insulin were raised in adult (10- and 20-week-old) compared with younger (3- and 5-week-old) mice, although GIP was not increased in the presence of hyperinsulinaemia at 3 weeks of age. Fasting suppressed and refeeding promptly restored plasma GIP and insulin concentrations. Administration of GIP to mimic postprandial concentrations evoked a marked but transient insulin response which was protracted in the presence of rising hyperglycaemia. Orally administered fat, glucose and amino acids raised GIP concentrations with fat having a particularly strong effect. Glucose and amino acids also evoked prominent increases of insulin, but fat produced only a small rise in insulin in the absence of increasing glucose concentrations. Consistent with glucose-potentiation, a mixture of all three nutrients greatly augmented the insulin response without further increase of plasma GIP. Glucose-induced increase in endogenous insulin and doses of exogenous insulin up to 100 units/kg did not suppress basal, fat-stimulated or glucose-stimulated GIP release. The results indicate that raised GIP concentrations make an important contribution to the hyperinsulinaemia and related metabolic abnormalities of the ob/ob syndrome.

J. Endocr. (1984) 101, 249–256

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B D Green, N Irwin, V A Gault, C J Bailey, F P M O’Harte, and P R Flatt

Glucagon-like peptide-1 (GLP-1) is a potent insulinotropic hormone proposed to play a role in both the pathophysiology and treatment of type 2 diabetes. This study has employed the GLP-1 receptor antagonist, exendin-4(9–39)amide (Ex(9–39)) to evaluate the role of endogenous GLP-1 in genetic obesity-related diabetes and related metabolic abnormalities using ob/ob and normal mice. Acute in vivo antagonistic potency of Ex(9–39) was confirmed in ob/ob mice by blockade of the insulin-releasing and anti-hyperglycaemic actions of intraperitoneal GLP-1. In longer term studies, ob/ob mice were given once daily injections of Ex(9–39) or vehicle for 11 days. Feeding activity, body weight, and both basal and glucose-stimulated insulin secretion were not significantly affected by chronic Ex(9–39) treatment. However, significantly elevated basal glucose concentrations and impaired glucose tolerance were evident at 11 days. These disturbances in glucose homeostasis were independent of changes of insulin sensitivity and reversed by discontinuation of the Ex(9–39) for 9 days. Similar treatment of normal mice did not affect any of the parameters measured. These findings illustrate the physiological extrapancreatic glucose-lowering actions of GLP-1 in ob/ob mice and suggest that the endogenous hormone plays a minor role in the metabolic abnormalities associated with obesity-related diabetes.

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A L Ferry, D M Locasto, L B Meszaros, J C Bailey, M D Jonsen, K Brodsky, C J Hoon, A Gutierrez-Hartmann, and S E Diamond

Many transcription factors are expressed as multiple isoforms with distinct effects on the regulation of gene expression, and the functional consequences of structural differences between transcription factor isoforms may allow for precise control of gene expression. The pituitary transcription factor isoforms Pit-1 and Pit-1β differentially regulate anterior pituitary hormone gene expression. Pit-1 is required for the development of and appropriate hormone expression by anterior pituitary somatotrophs and lactotrophs. Pit-1β differs structurally from Pit-1 by the splice-insertion of the 26-residue β-domain in the trans-activation domain, and it differs functionally from Pit-1 in that it represses expression of the prolactin promoter in a cell-type specific manner. In order to identify signal and promoter context requirements for repression by Pit-1β, we examined its function in the presence of physiological regulatory signals as well as wild-type and mutant Pit-1-dependent target promoters. Here, we demonstrate that Pit-1β impairs recruitment of cAMP response element-binding protein (CREB)-binding protein to the promoters that it represses. In addition, we show that repression of target promoter activity, reduction in promoter histone acetylation, and decrease of CREB-binding protein recruitment all depend on promoter context. These findings provide a mechanism for promoter-specific repression by Pit-1β.