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Transcript
Hormones of the Gut Beginning of Endocrinology • Bayliss and Starling--1902 – Acidification of denervated duodenum or jejunum stimulated pancreatic exocrine secretion. – Injected extract of jejunal mucosa also stimulated pancreatic exocrine secretion. – Postulated a humoral regulatory factor they called “Secretin.” – Secretin finally isolated in 1961. Gut Regulatory Peptides • Gut Nervous System • Endocrine cells of mucosa – Basal secretory granules • Gut Peptides may be – Hormones • Travel to different organ through blood stream. – Paracrine – Neurosecretory • Neurotransmitters Secretin • 29 amino acid peptide • Related to: glucagon, GIP, VIP, PHI, PHM (Secretin family) • Action: – Stimulates Bicarbonate and Water Secretion by Pancreas Secretin Control pH DUODENAL LUMEN > 4.5 BICARBONATE pH DODENAL LUMEN < 4.5 ENDOCRINE CELLS OF MUCOSA SECRETIN PANCREAS SOMATOSTATIN Gastrin • 1905, Edkins discovered that an extract of gastric mucosa stimulated acid secretion that he called Gastrin. • 1960s, Gregory isolated and sequenced Gastrin. • 3 biologically active forms: – “Big” = 34 amino acids – ‘Little” = 17 amino acids – “Mini” = 14 amino acids Gastrin (Cont.) • Structurally similar to Cholecystokinin: – Gastrin-Cholecystokinin Family. • Found in endocrine cells of gastric antrum. • Also identified in CNS. • Stimulated by proteins and amino acids in gastric lumen. – Carbohydrates and Fats in effective. • Somatostatin inhibits Gastrin release Gastrin Action • Stimulates Acid Secretion by Gastric Mucosa – May be due to stimulation of histamine release by neighboring cells (paracrine) • Stimulates growth of parietal cells of the Gastric Mucosa • Stimulates Mucosal blood flow • Stimulates Pepsin Release Gastrin Control HIGH PROTEIN MEAL VAGUS (X) GRP SOMATOSTATIN GASTRIN MUCOSAL CELL GASTRIN ENTEROCHROMAFFIN HISTAMINE CELL HCl PARIETAL CELL Cholecystokinin (CCK) • 1928: Fat in small intestine stimulates the gall bladder to contract--cholecystokinin. • 1940s: Extract of duodenal mucosa stimulates pancreas to secrete enzymes-pancreozymin. • 1964-8: Purification of a single substance that stimulated both contraction of the gall bladder and pancreatic enzyme secretion--settled on one name: cholecystokinin (CCK). Cholecystokinin • Polypeptide found in different forms including: 58, 39, 33, & 8 amino acids. • 8 amino acid form has full biological potency. • Carboxy terminal 8 amino acids identical in all forms. • Larger forms may be prohormones. • Preprocholecystokinin found: 115 amino acids. Cholecystokinin • Located in duodenal and proximal jejunal mucosa. • Also found in CNS. • Secretion stimulated by the presence of intraduodenal protein or fat. • May be a low molecular weight CCK-releasing factor. • Release is inhibited by somatostatin. CCK Actions • Stimulates contraction of gall bladder, forcing bile into the duodenum. • Stimulates pancreatic enzyme secretion. • Trophic effects on pancreatic acini. • Causes sphincter of Oddi to relax. • Induces satiety. CCK Control FAT SOMATOSTATIN PROTEIN CCK CELL CCK GALL BLADDER BILE RELEASE PANCREATIC ACINI ENZYMES Somatostatin • 14 & 28 amino acid forms. • Found in hypothalamus, throughout CNS and Gut (including pancreas) • Major inhibitory peptide of Gut. Inhibits secretion of – insulin – – – – – – glucagon CCK secretin gastrin VIP somatostatin (autocrine) Somatostatin Control PROTEIN CHOLINERGIC STIMULATION FAT STOMACH ACID SOMATOSTATIN CELLS SOMATOSTATIN Other Peptides • Vasoactive Intestinal Peptide (VIP) – Neurotransmitter/neuroendocrine – Relax esophageal and anal sphincter – Increases blood flow in the gut – Causes penile erection • Gastrin-Releasing Peptide (GRP) – Neurotransmitter/neuroendocrine – Stimulates release of Gastrin Other Peptides • Substance P – Neurotransmitter – Stimulates Contraction of Smooth Muscle • Enkephalins – Neurotransmitter – Inhibits gut motility, antagonizes action of Substance P Ghrelin • Produced by the stomach when stomach is empty. • Stimulates appetite • Reduces metabolic rate Peptide YY • Produced by intestine in response to being distended. • Inhibits appetite. • Increases metabolism. Incretins • • • • • Glucagon Like Peptide-1 (GLP-1) Produced by digestive tract. Acts to give feeling of satiety Inhibits gastric emptying Inhibits glucose absorption from the gut • Increases insulin secretion • Increases pancreatic β-cell mass GLP-1