Preparation of highly active enterogastrone

Brown, John C.; Pederson, Raymond A.; Jorpes, Erik; Mutt, Viktor

doi:10.1139/y69-020

Cited by 170 publications

(47 citation statements)

References 3 publications

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“…The lower esophageal sphincter contracts in response to gastrin (12)(13)(14) whereas both the ileocecal (15) and choledochal sphincters (16) (25) and suggested that contaminants present in the GIH Research Unit preparation of cholecystokinin were not solely responsible for the observed response (26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

The Hormonal Regulation of Pyloric Sphincter Function

Fisher¹,

Lipshutz²,

Cohen³

1973

J. Clin. Invest.

121

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A B S T R A C T The purpose of this study was to evaluate the hormonal control of pyloric sphincter function. Studies were performed on both pyloric circular muscle, in vitro, and the human pylorus, in vivo. Full dose-response curves to gastrin I, cholecystokinin, and secretin were constructed for the pyloric muscle of the opossum studied at its length of optimal tension development, Lo. Both cholecystokinin and secretin were potent agonists on the muscle but gastrin I gave no increase in muscle tension. The combination of cholecystokinin and secretin was additive at submaximal concentrations but potentiation of the maximal responses was not observed. Gastrin I produced a surmountable, competitive-like antagonism to the effect of cholecystokinin on the pyloric muscle. The octapeptide of cholecystokinin was a more potent agonist than the whole molecule of cholecystokinin on the pyloric muscle. In man, the pyloric pressure rose significantly during intravenous infusion of either cholecystokinin or secretin. The combination of maximal doses of both hormones did not show signficant potentiation. Gastrin I did not significantly increase pyloric pressure but did antagonize the pyloric response to duodenal acidification. These studies suggest that: (a) Both secretin and cholecystokinin augment pyloric sphincter pressure while gastrin I is an antagonist inhibiting their effects. (b) The hormonal responses of pyloric sphincter circular muscle, in vitro, can be correlated with human sphincter function, in vivo.

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Section: Discussionmentioning

confidence: 99%

The Hormonal Regulation of Pyloric Sphincter Function

Fisher¹,

Lipshutz²,

Cohen³

1973

J. Clin. Invest.

121

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“…The 42 amino acid peptide GIP was isolated from a crude porcine CCK extract and shown to inhibit histamineinduced gastric acid secretion (Brown et al 1969). However, its major physiological role as a glucose-dependent stimulator of insulin secretion is now well recognized (Gault et al 2003a).…”

Section: Secretion and Actions Of Gipmentioning

confidence: 99%

Targeting β-cell cyclic 3′5′adenosine monophosphate for the development of novel drugs for treating type 2 diabetes mellitus. A review

Furman

Pyne

Flatt³

et al. 2004

Journal of Pharmacy and Pharmacology

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Cyclic 3'5'AMP is an important physiological amplifier of glucose-induced insulin secretion by the pancreatic islet -cell, where it is formed by the activity of adenylyl cyclase, especially in response to the incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). These hormones are secreted from the small intestine during and following a meal, and are important in producing a full insulin secretory response to nutrient stimuli. Cyclic AMP influences many steps involved in glucose-induced insulin secretion and may be important in regulating pancreatic islet -cell differentiation, growth and survival. Cyclic AMP (cAMP) itself is rapidly degraded in the pancreatic islet -cell by cyclic nucleotide phosphodiesterase (PDE) enzymes. This review discusses the possibility of targeting cAMP mechanisms in the treatment of type 2 diabetes mellitus, in which insulin release in response to glucose is impaired. This could be achieved by the use of GLP-1 or GIP to elevate cAMP in the pancreatic islet -cell. However, these peptides are normally rapidly degraded by dipeptidyl peptidase IV (DPP IV). Thus longer-acting analogues of GLP-1 and GIP, resistant to enzymic degradation, and orally active inhibitors of DPP IV have also been developed, and these agents were found to improve metabolic control in experimentally diabetic animals and in patients with type 2 diabetes. The use of selective inhibitors of type 3 phosphodiesterase (PDE3B), which is probably the important pancreatic islet -cell PDE isoform, would require their targeting to the islet -cell, because inhibition of PDE3B in adipocytes and hepatocytes would induce insulin resistance.

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“…The GIP receptor is expressed in various extrapancreatic sites, including adipose tissue, bone, intestine, heart, stomach and brain [20]. In relation to this, GIP has been shown to inhibit gastric acid secretion [21], attenuate glucagon-stimulated glucose production [22], decrease hepatic insulin extraction [23] stimulate glucose uptake in muscle [24] and increase both fatty acid synthesis and lipoprotein lipase activity in adipocytes [25,26]. The particularly potent stimulation of GIP secretion after high-fat feeding [27] suggests a role for GIP in fat metabolism [20].…”

Section: Introductionmentioning

confidence: 99%

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

et al. 2007

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Aims/hypothesis Ablation of gastric inhibitory polypeptide (GIP) receptor action is reported to protect against obesity and associated metabolic abnormalities. The aim of this study was to use prediabetic ob/ob mice to examine whether 60 days of chemical GIP receptor ablation with (Pro 3 )GIP is able to counter the development of genetic obesityrelated diabetes. Materials and methods Young (5-7 weeks) ob/ob mice received once daily i.p. injections of either saline vehicle or (Pro 3 )GIP (25 nmol kg −1 day −1 ) over a 60 day period. Food intake, body weight and circulating glucose and insulin were measured at frequent intervals. At 60 days, glucose tolerance, response to native GIP, postprandial responses, insulin sensitivity, HbA 1c , circulating hormones and plasma lipids were assessed. Results Body weight and food intake in (Pro 3 )GIP-treated mice did not differ from ob/ob controls. GIP receptor blockade significantly improved non-fasting glucose (p< 0.001), HbA 1c (p<0.05), glucose tolerance (p<0.001), meal tolerance (p<0.001) and insulin sensitivity (p<0.05). Remarkably, (Pro 3 )GIP treatment prevented the age-related development of diabetes, as none of these parameters differed significantly between treated ob/ob mice and normal age-matched lean controls. Circulating levels of glucagon, corticosterone, adiponectin and total cholesterol were unchanged by (Pro 3 )GIP, while levels of triacylglycerol, LDLcholesterol and resistin were decreased (p<0.05) compared with those in control ob/ob mice. Plasma and pancreatic insulin concentrations were generally lower after (Pro 3 )GIP treatment than in control ob/ob mice (p<0.01), but plasma insulin levels remained substantially raised (p<0.001) compared with those observed in lean controls. Conclusions/interpretation These data indicate that sustained GIP receptor antagonism provides an effective means of preventing the development of many of the metabolic abnormalities of obesity-driven diabetes.

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Preparation of highly active enterogastrone

Abstract: By using a 10% pure preparation of cholecystokinin–pancreozymin (CCK–PZ) a fraction was obtained which was inhibitory for H+ secretion, pepsin secretion, and motor activity in antral and fundic pouches. This material possessed no significant CCK–PZ activity or secretin-like activity.

Cited by 170 publications

References 3 publications

The Hormonal Regulation of Pyloric Sphincter Function

The Hormonal Regulation of Pyloric Sphincter Function

Targeting β-cell cyclic 3′5′adenosine monophosphate for the development of novel drugs for treating type 2 diabetes mellitus. A review

Early administration of the glucose-dependent insulinotropic polypeptide receptor antagonist (Pro3)GIP prevents the development of diabetes and related metabolic abnormalities associated with genetically inherited obesity in ob/ob mice

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