The normal endocrine pancreas Flashcards
What are the 2 main functions of the pancreas
Exocrine (acinar cells):
accessory digestive, flows
through ducts. Exocrine glands
include mammary glands, tear
glands, salivary glands.
* Endocrine (islets of Langerhans): ductless, secretes hormones
directly into blood.
Describe organisation of the pancreas
Anatomical position: lies deep
in stomach, tail close to spleen,
and head is encircled by
duodenum.
* Lobules: 80% of mass. Acinar
cells secrete enzymes and fluid.
* Ducts: 4% of mass. Intercalated
ducts join to form pancreatic
duct. This fuses with common
bile duct before emptying in
duodenum.
* Islets of Langerhans: 2% of mass.
o Sympathetic adrenergic input: splanchnic nerve (from
coeliac plexus).
o Parasympathetic cholinergic input: vagus nerve.
Describe insulin
Synthesised in pancreatic π½ cells.
* Single chain precursor: preproinsulin (green part is preinsulin).
* Removal of signal peptide: proinsulin (everything apart from
green part). Made in endoplasmic reticulum, packaged in Golgi
network, then secreted.
* Proinsulin has 3 domains
o N-terminal B chain.
o C-terminal A chain.
o Middle C-peptide (lost when insulin formed).
* 3 disulphide links.
* Cleaved by prohormone convertases 1 and 3 releases C-peptide.
* Insulin itself is B and A chain stuck together by disulphide bonds.
Describe glucagon
29 AA peptide hormone.
* GLP-1 and GLP-2 are structurally similar to glucagon (as If
glucagon was cloned 3 times).
* Synthesised from preproglucagon.
* Processed by prohormone convertases 1 and 2.
* Differential processing in πΌ cells vs L-cells.
* πΆ cells: release glucagon.
* L cells: release GLP-1 GLP-2 and oxyntomodulin (glucagon + IP-1
(tail portion)).
What are the other pancreatic hormones
Somatostatin: paracrine role (suppresses insulin and glucagon).
* Pancreatic polypeptide:
secreted after eating and
suppresses appetite.
* Islet amyloid
polypeptide (IAPP or
amylin): appears to
suppress insulin
secretion.
How does insulins secretion occur
[1] Extracellular glucose enters π½ cells through GLUT-2
(constitutive glucose transporter).
* [2] Once inside π½ cells, it is glycolyzed (metabolised to form ATP).
[3] β ATP:ADP ratio.
* [4] β ATP is sensed by
ATP-sensitive πΎ
+
channels. In response,
these close, causing
depolarisation of
membrane and voltagegated πΆπ
2+ channels
open.
* [5] πΆπ
2+ binds to
storage granules to
cause insulin release.
Describe the endocrine vs paracrine pancreas
Endocrine SST is mainly released from gastric D cells:
o Inhibition of gastric acid secretion.
o Inhibition of gastric emptying.
o β small bowel contractions.
* Pancreatic SST is likely to play paracrine role:
o Inhibition of pancreatic exocrine secretion.
o Inhibition of pancreatic endocrine secretion (insulin,
glucagon, ghrelin etc.)
Describe carbohydrate metabolism and insulin
Carbohydrate metabolism and insulin
* β blood [glucose] stimulates release of insulin.
o Facilitates entry of glucose to tissues: especially liver,
muscle, adipose.
o Stimulates liver to store glucose in form of glycogen
(glucose β tonicity of water, so enters via osmosis
causing osmolysis. Therefore, store as glycogen instead).
Describe glucose disposal
- Glucose disposal (glucose being taken out of blood or peripheral
tissue)
* Glucose disposal: rate of uptake into peripheral tissue.
* Insulin mediated: skeletal muscle and adipose tissue.
* Non-insulin mediated: CNS and other tissues.
* Liver can take up glucose or release glucose.
Describe how insulin facilitates glucose uptake
- Insulin facilitates glucose uptake
* Facilitated diffusion
* Hexose transporters: GLUT4 (major transporter in muscles,
adipose).
o Absence of insulin: GLUT4 stored in cytoplasmic
vesicles.
Action of insulin: fusion of vesicles and insertion of
glucose transporters in plasma membrane.
Describe hexose transporters
Large integral membrane proteins.
* All similar structures:
o 12 membrane-spanning regions.
o Cytoplasmic C-terminal tail.
o Cytoplasmic N-terminal tail.
o Glycosylated on 1 of extracellular loops.
How does insulin stimulate hepatic glycogen storage
Activates hexokinase: phosphorylates glucose, trapping it in cells.
* Activates enzymes directly involved in glycogen synthesis:
phosphofructokinase and glycogen synthase.
* Inhibits activity of glucose-6-phosphatase: converts glucose-6-
phosphate back to glucose.
* Net effect: insulin tells liver to store as much glucose as possible
for later use.
Describe glucose in the fed and fasting state
- Fed state
* Insulin is secreted.
* Inhibits glycogen breakdown and gluconeogenesis.
* β glucose uptake and muscle as fat: 85% of intramuscular glucose
disposal. - Fasting state
* Glucagon is secreted.
* Glycogen breakdown (liver) and gluconeogenesis (kidney).
* Glucose is diverted to supply brain .
Describe glycogen metabolism
- Glycogen synthase (GS) and glycogen phosphorylase (GP)
* Both enzymes can be converted between active and less active
forms using a system of protein kinases.
* PKA phosphorylates and activates PKB, which activates GP.
* PKA phosphorylates and inactivates GS, which prevents cycling of
glucose-1-P.
* PKA leads to glycogen breakdown. - Glycogen synthase/glycogen phosphorylase coordination
* Insulin: phosphatases activate glycogen synthase and inhibits
glycogen phosphorylase by dephosphorylation. This causes system
to manufacture glycogen.
* Glucagon: kinases activate glycogen phosphorylase and inhibit
glycogen synthase by phosphorylation. This causes system to
break down glycogen.
Glucagon switches on glycogen phosphorylase
* Glycogen activates AC:
o β cAMP
o β cAMP-dependent kinase (PKA)
o Activates phosphorylase kinase.
o Activates GP (glycogen phosphorylase).
* Glycogen phosphorylase b (GPb) is converted to glycogen
phosphorylase a (GPa).
Glucagon switches off glycogen synthetase (GS)
* Glucagon acts via cAMP to switch on GPa which inhibits
phosphatase, which switches off glycogen synthetase as
dephosphorylation is inhibited.
* Glucagon can also switch on cAMP-dependent kinase, which can
phosphorylate GS to its inactive form.
Insulin switches on glycogen synthetase (GS)
* Insulin switches on phosphatase to dephosphorylate GS to
activate it.
* Insulin inhibits cAMP-independent kinase so that it cannot
phosphorylate GS to its inactive form.
Describe lipid metabolism
- Lipid metabolism and insulin
* Metabolic pathways for utilisation of fats and carbohydrates are
deeply and intricately intertwined.
- 2 important effects of insulin:
o Promotes synthesis of fatty acids in liver.
o Inhibits breakdown of fat in adipose tissue. - Therefore, insulin has a fat-building effect.
- Lipid metabolism
* Insulin (anabolic): β net TAG synthesis
o Activates acetyl-CoA carboxylase
o Inactivates hormone-sensitive lipase HSL).
* Glucagon (catabolic): stimulates net breakdown of TAG stores
(spares glucose)
o Inactivates acetyl-CoA carboxylase.
o Activates hormone-sensitive lipase (HSL).
