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 pH DODENAL LUMEN < 4.5 BICARBONATE ENDOCRINE CELLS OF MUCOSA SOMATO- STATIN GLUCAGON PANCREAS

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 SOMATO- STATIN GASTRIN MUCOSAL CELL GASTRIN HCl ENTERO- CHROMAFFIN CELL PARIETAL CELL HISTAMINE

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 PROTEIN SOMATOSTATIN CCK CELL CCK GALL BLADDER PANCREATIC ACINI BILE RELEASE 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 STOMACH ACID PROTEIN FAT CHOLINERGIC STIMULATION 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) Stimulates release of Gastrin

Other Peptides Substance P Enkephalins Neurotransmitter Stimulates Contraction of Smooth Muscle Enkephalins 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