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).
What are the links between glucose and lipid metabolism
Glucose metabolism linked to lipogenesis.
* Pyruvate enters citric acid cycle: citrate can exit for FA
biosynthesis (role for acetyl-CoA).
* Glycolysis generates πΌ-phospho-glycerate: backbone of TAG
* Pentose phosphate pathway: generates β cofactors for FA
biosynthesis
What is HSL and futile cycling
Hormone sensitive lipase is an enzyme that sits in adipose tissue.
Its job is to take TAG and break them down into fatty acids and
glycerol.
* Insulin inhibits HSL: high insulin levels lead to inhibition of
breakdown of fat stores in adipose tissue
* During starvation, glucagon activates cAMP-dependent kinase
which activates HSL to generate fatty acids and glycerol.
* Glucocorticoids is secreted under stressful conditions and
activates HSL leading to breakdown of fat.
