GI hormones.pdf

• Introduction to the endocrinology of the GI tract: neurogenic components, endocrine components and regulatory mechanisms. Enteroendocrine cells, hormone families, hormones of the GI tract and their neuro-endocrine control.

• GI hormones: Gastrin / CCK family: gastrin, CCK; Secretin family: secretin, VIP, GIP, GLP; PP family: PPY, peptide YY, NPY; Other GI hormones: neurotensin, galanin, GRP, motilin, TRH, CGRH, SS, enkephalins, endorphins, SP.

• Neuroendocrine control of food intake

• Pathologies associated with GI hormones

GI Hormones 11 10

VIP

Introduction

GI Hormones and “story lines”

serosa

muscle, circular layer

submucosal plexus (synapses)

submucosa

muscularis mucosae

mucosa

oral

end

aboral

end

GI tract

lumen

muscle, longuitudinal layer

myenteric plexus (synapses)

• The GI tract

• GI Hormones

• Leptin and food Intake

• Pathologies

Introduction

Stimulus

Brush border

Exocytosis

Paracrine

Endocrine

Intrinsic reflex

Extrinsic reflex

Satiety

Overview of the GI tract: neurogenic and endocrine

components, and regulatory mechanisms S

E

Stimulus

Brush border

Exocytosis

Paracrine

Endocrine

Intrinsic reflex

Extrinsic reflex

Satiety

• The GI tract

• GI Hormones


• Pathologies

Introduction

afferent / efferent

commu-nication

pathways

might be neuro-

genic and / or

endocrine

pathways negative feedback

Integrator ( )

PS S

pre

post

Ach Ne

ANS


components, and regulatory mechanisms S

E

• The GI tract

• GI Hormones


• Pathologies

Introduction


components, and regulatory mechanisms

intrinsic

i / o • intrinsic vs extrinsic

• inputs vs outputs

• neuronal vs endocrine

• vago - vagal reflexes

• endocrine reflexes

• Neuroendo-crine reflexes

extrinsic

input /

output

sensory receptors (mech / chem)

synapsis or neuro-musc-junction

intrinsic exocrine gland of GI syst

S

E

• The GI tract

• GI Hormones


• Pathologies

Introduction



esophagusfunds, HCl, pepsine, mucus

antrum, hormone

gall bladder, bile salts

liver, metabolism

pancreas

enzymes

hormones

smallintestine

HCl, pepsine, mucus

gastrin, histamine, Ach

PPY

insulin

glucagon

somatostatin

stomach

gastrin

duodenumsecretin

CCK, GIP

glicentinmoti-

lin

gall bladder, bile salts

liver, metabolism

S

E

• The GI tract

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Introduction



Ach

Ach

muscle, gland,endocrine cell

NE

PS+

S -

NEGastrin

CCK

Ach

gastric muscleoxyntic cell

Ach

NE

NE

Secretin

agonists+

antago-nists --

Ach

Ach LES

AchCCK

Gastrin Secretin

(+) ( - )

Ach pylorus

Ach

Gastrin

(+) ( - )

CCKSecretin

EnteroendocrineCells

HClOxyntic cell

Ach, atropineHistamine

cimetidine

Gastrin

proglumide

Ca

commonintermediate

cAMP Ca

Enz

AchSecretin CCK

Ca

common

intermediate

cAMP

Ca

HCO3

Pancreaticcell

S

E

• The GI tract

• GI Hormones


• Pathologies

Gastrointestinal Hormones

GI hormones are clustered into families having

similar / overlaping functions S

E

• The GI tract

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• Pathologies


S

E

Hormones Physiological effects Gastrin Secretin

CCK

GIP SS VIP

GRP

Bulbogastrone Urogastrone Enteroglucagon

Villikinin Enkephalins

Neurotensin Motilin Histamine

Prostagalndins

GI hormones are clustered into families having

similar / overlaping functions

• The GI tract

• GI Hormones


• Pathologies


examples of articles from Time magazine

on the importance of GI hormones S

E

• The GI tract

• GI Hormones


• Pathologies

Gastrin / CCK family

The gastrin / CCK family has a major role in

gastric / duodenal interactions S

E

CCK 33

G34

• The GI tract

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E

• The GI tract

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• Pathologies




E

• The GI tract

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E

Bombesin

Cephalicphase

centralstimuli

G cell

Ach

vagal nuclei

oxynticcell HCl

SS

+

++

--

--

+

+

+

+

• The GI tract

• GI Hormones


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E

vago-vagalreflex

gastric distension

G cell oxyntic cell HCl

Gastricphase

localreflex

vago-vagalreflex

BombesinAch

peptidesand aa

+

+

+

+

+ +

+

+

+

• The GI tract

• GI Hormones


• Pathologies




E

• gastrin, stimulate gastric acid secretion. Its release from G antral cells (open cells) is induced by aromatic aa, small peptides, and Ca in the GI tract. SS release from neighboring D cells in response to acidification is a major inhibitor of gastrine

• CCK (5 aa), inhibits gastric emptying, pancreatic enzyme secretion, gallblader emptying, induced satiation, and memory enhancement. Its release is induced by fat and proteins in the GI tract. GRP and Bombesin also stimulate CCK release. Stimulation of PKA and PKC pathways result in increase CCK mRNA

• the two CCK receptors (A in gut and B in brain) share 48 % homology at the aa level

• the oxyntic gastrin receptor is identical to the CCK-B one and both are coupled to PLC

• glucocorticoids transiently stimulate increases in CCK-A receptor mRNA stability with- out affecting transcription

• The GI tract

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• Pathologies

S

E



gastric / duodenal interactions

• The GI tract

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E

• The GI tract

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E

• The GI tract

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• Pathologies

Secretin / VIP family

The secretin / VIP family also has a major

role in gastric / duodenal interactions S

E

Secretin

Glucagon

GIP

VIP

• The GI tract

• GI Hormones


• Pathologies


The secretin / VIP family include secretin,

the VIP, GIP and GLP hormones S

E

• secretin, stimulate pancreatic bicarbonate / enzyme and hepatic bile secretion, and LES relaxation. Its release is induced by acid, bile, FA, and peptides GI

• VIP, stimulates LES and gastric receptive relaxation, descending relaxation of intestine, water / electrolyte secretion from colon, biliary / pancreatic secretion, and promotes lipolysis. VIP gene expression is regulated by cAMP, PKC, and Ca. Outside the GI is modulated by E2, cortisol T3/T4, retinoic acid and IGF I

• GIP, stimulates insulin and inhibits acid secretion. Its release is induced by Glu, Prot, aa, and FA in GI tract

• GLP has insulinotropic effects and inhibits gastric motility. Its release is induced by Glu and aa in GI tract

• the VIP / PACAP receptor has homology with secretin, GLP-1, PTH, GHRH, and calcitonin glycoprotein receptors

• VIP-1 receptor is found in gut and VIP-2 receptor in brain. VIP, cAMP, IP3, PKC, Ca

• VIP and NO colocalize in the myenteric plexus of the gut. Both are inhibitory in GI tract

• secretin receptor couples to stimulation of AC, Ca, & PLC

• The GI tract

• GI Hormones


• Pathologies




E

VIP

VIP

Secretin

Glucagon

GIP

• The GI tract

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E

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E

How GLP-1

might work? +

_


Gut Sensations (recent news about GLP-1). Recent studies have helped to define the proteins that transform the arrival of sugars on the tongue into a sensation of sweetness. Two studies suggest that the same pathway functions in the intestinal tract. Jang et al. found that the sugar-sensitive G protein-coupled receptor (T1R2/T1R3) and the G protein subunit gustducin could be detected in enteroendocrine cells--specifically, the L cells, which secrete the appetite-regulating glucagon-like peptide (GLP-1) of the human duodenum. Application of glucose to human L cells resulted in GLP-1 release, which was blocked by an antagonist of T1R3. In mice, gustducin was also present in L cells, and delivering glucose directly into the duodenums (to bypass the tongue) of normal mice and of gustducin-deficient mice showed that GLP-1 secretion was absent in the latter group of animals and that the temporal pattern of insulin secretion was altered. Margolskee et al. connect glucose absorption to glucose sensing via the T1R2/T1R3 pathway. Normal mice, unlike those deficient in gustducin or T1R3, showed an increase in sodium-glucose cotransporter 1 (SGLT1) mRNA and protein and in glucose uptake when fed a high-carbohydrate diet or a low-carb diet containing artificial sweeteners.

Proc. Natl. Acad. Sci. U.S.A. 104, 15069; 15075 (2007).


http://www.economist.com/science/displaystory.cfm?story_id=11785235 Hormones influence how sensitive taste buds are to sugar (2008).

That sweetness is pleasant is no coincidence. Sweet food is at a premium in the wild because the sugars it contains provide valuable calories. But even with sugar there can be too

much of a good thing, so it would be no surprise if the body were able to regulate the perception of sweetness as its nutritional needs vary. According to two studies presented to the International Symposium on Olfaction and Taste, held in San Francisco this week, that is exactly what happens.

The studies, one on mice and one on people, have identified two hormones that seem to fine-tune perception of sweetness, and thus regulate intake of sugar independently of previously known

mechanism of satiation that is located in brain. The mouse study was done by Steven Munger, a neurobiologist at the University of

Maryland, and his colleagues. They picked a hormone called glucagon-like peptide-1 (GLP-1) that is

made by intestinal cells in response to sugar and fat. This hormone is already known to act in the pancreas and the brain, where it helps, respectively, to regulate blood-sugar levels and the feeling

of satiation that tells you when to stop eating. Dr Munger, though, found that both GLP-1 and the receptor molecule that picks it up and thus allows it to act are found in taste buds too. To investigate GLP-1's role in taste, the team used a strain of mice that were

genetically engineered to lack GLP-1 receptors. They found that such animals are much less sensitive to sweetness than their un-engineered confr鑽es. Indeed, the mutants were no more

interested in a dilute sugar solution (or, indeed, a solution of artificial sweetener) than they were in plain water—though they did respond to concentrated solutions of sweetness. The "wild-type" mice, by contrast, drank significantly more of the sweet solution than they did of the water, even

when the sweet solution was dilute. Moreover, the effect was limited to sweetness. The animals' responses to the other four fundamentals of taste—bitterness, sourness, saltiness and

"umami" (the flavour of monosodium glutamate)—were unaffected. That suggests, though it does not yet prove, that there is feedback from the gut to regulate the desirability of eating sweet food.


http://www.economist.com/science/displaystory.cfm?story_id=11785235 Hormones influence how sensitive taste buds are to sugar (2008).

The human study was done by Yuzo Ninomiya, a neuroscientist at Kyushu University, in

Japan. He and his colleagues looked at leptin, another hormone that is known to regulate appetite and metabolism. Leptin levels are also known to fluctuate naturally over a 24-hour period, being lowest in the morning and highest at night, at least in people who eat three

meals a day.

In their experiments, Dr Ninomiya and his colleagues found that their volunteers were more sensitive to sweetness when their leptin levels were low. As the level of the hormone increased over the course of a day, the threshold for detecting sweetness rose. And when the

researchers shifted the pattern of leptin production by changing the number of meals their volunteers ate, the volunteers' sensitivity to sweetness shifted as well, suggesting that it was

the hormone rather than merely the time of day that was causing the effect. As in the case of the mice, the humans did not show any changes in their sensitivity to other tastes. However, individuals who had lower leptin levels, and thus more sweet-taste sensitivity before a meal,

experienced sharper increases in blood-sugar levels when they had eaten.

Whether either of these results cast light on the perpetual search for pain-free ways of cutting calorie-intake in the modern world of abundant sweetness is not yet clear. But they may, at least, explain why so many people like lashings of sugar on their breakfast cereal.

• The GI tract

• GI Hormones


• Pathologies




E

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• Pathologies

PP family and others

The PP family include PPY, peptide YY and

NPY S

E

NPY

PYY

PP

• The GI tract

• GI Hormones


• Pathologies


Others neuropeptides include neurotensin,

galanin, GRP, motilin, TRH, CGRH, SS, enkaphline, endothelin, substance P

S

E

Somatostatinoma

with typical

electro- dense

granules

A duodenal

endocrine tumor

showing dense

immunoreactivity for

somatostatin

somatostatin

ocreotide

lanotride

• The GI tract

• GI Hormones


• Pathologies


The PP family include PPY, peptide YY and

NPY, others include neurotensin, galanin, GRP, motilin, TRH, CGRH, SS, enk, end, SP

S

E

• PPY, inhibits pancreatic excretion. Its release is induced by fat in the GI tract

• PYY, inhibits acid and pepsine secretion from stomach, water and chloride from jejunum, slows small intestine transit time, inhibits pancreatic exocrine secretion and colonic motor activity. Its release is induced by Prot, FA bile acids and aa in GI tract

• NPY, inhibits gastric and small intestinal motility and secretion. Centrally is a potent enhancer of food intake. It acts through a 7 transmembrane domain receptor ne-gatively coupled to AC and is associated to Ca mobilization

• At least 5 receptor types (Y1, Y2, Y3, Y4, Y5) have been reported

• neurotensin, inhibits gastric / pancreatic secretion, and stimulates colonic motility. Its release is induced by fat

• galanin, inhibits gastric emptying, slows colonic transit time, and increase food intake in the CNS through a G-protein. Its release is induced by intestinal distention

• GRP, stimulates gastrin release from antrum, contracts LES. Its release is induced by cholinergic stimulation

• motilin, regulates motor complexes, contracts gall bladder, relea pepsinogen. Its release is induced by acidification of duodenum and gastric contraction

• TRH, release by pancreas / stomach, inhibits gastric acid, amylase, lipase, mucosal cholesterol synthesis

• CGRH, induced vasodilation in respone to glucose

• SS, inhibits peptide hormone, fluid / electrolyte secretion

• The GI tract

• GI Hormones


• Pathologies

Control of GI function by hormones /

metabolites S

E


• The GI tract

• GI Hormones


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Some hormones involved in the

neuroendocrine control of food intake S

E

Leptin

Insulin

CCK

NPY

Leptin and food intake

• The GI tract

• GI Hormones


• Pathologies


Leptin, an adipocyte hormone, inhibits

food intake & promote energy expenditure S

E

No

Leptin

No

Leptin-R

• The GI tract

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S

E Leptin, an adipocyte hormone, inhibits

food intake & promote energy expenditure

decrease energy intake

and Increase energy

expenditure

• The GI tract

• GI Hormones


• Pathologies


S

E Leptin, an adipocyte hormone, inhibits

food intake & promote energy expenditure

• The GI tract

• GI Hormones


• Pathologies


Some endocrine pathologies involved in

disfunction of the GI system S

E

• The GI tract

• GI Hormones


• Pathologies



disfunction of the GI system S

E

• The GI tract

• GI Hormones


• Pathologies


S

E

acute diarrhea bowel resection

malabsorption

celiac disease pancreatitis


disfunction of the GI system

GI hormones.pdf

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