10.1 - Endocrine Pancreas Flashcards
what is the pancreas
- Both endocrine and exocrine (heterocrine)
- Located in abdomen behind stomach
- Secrete insulin and glucagon (endocrine) to control metabolism
- Grows embrologically as outgrowth of the foregut
What is the exocrine function of the pancreas
- Most of pancreas is exocrine tissue
- Exocrine acinar cells arranged in clusters (acini)
- Secrete pancreatic juice (acidic) into pancreatic duct
- Contains digestive enzymes and bicarbonate ions
- Bicarbonate ions buffer gastric acid released from the stomach creating appropriate pH for digestive enzyme function
Exocrine secretions from pancreas, produced by and primary signal?
secretin stimulates bicarbonate ions to be released from Ductal cells
CCK stimulates digestive enzymes to be released form acinar cells
what are the digestive enzymes associated with the pancreas
proteases - trypsin + chymotrypsin
* Stored and secreted as inactive pro-enzymes (trypsinogen and chymotrypsinogen)
* acinar cells also secrete a protein called trypsin inhibitor
* enteropeptidases in the intestinal mucosa activate trypsinogen by cleaving it to form trypson. Trypsin also cleaves both trypsinogen and chymotrypsinogen.
pancreatic lipase
Digests triglycerides
pancreatic amylase
Digests starch to glucose
Note: this will be covered in GI in Sem 3
Islets of langerhans
endocrine function of pancreas
Spherical structures
Only about 1% of pancreas
major types of cell in islets
β cells secrete insulin
α cells secrete glucagon
δ cells secrete somastostatin
minor types
PP cells secrete PP
ε cells secrete ghrelin
G cells secrete Gastin
Effects of insulin and glucagon
Both are peptide hormones (water soluble) and have a short half life
insulin
dominates in the fed state and acts to lower plasma glucose
receptor is tyrosine kinase
stimulates glucose oxidation, glycogen synthesis, fat synthesis and protein synthesis
anabolic (promotes storage)
acts on liver, adipose and skeletal muscle to promote storage
glucagon
Dominates in the fasted state and acts to raise plasma glucose
receptor is GPCR
stimulates glycogenolysis, gluconeogenesis and ketogenesis
catabolic (breaking down)
Acts on liver and adipose to promote catabolism
glucagon has no effect on skeletal muscle since muscle lacks glucagon receptors
What are the receptors for insulin and glucagon
insulin = tyrosine kinase
glucagon = GPCR
insulin structure and storage
structure
51 amino acid peptide hormone
made of 2 chains (the A and B chains)
the A + B chains are held together by 2 disulphide bonds
There’s a third intra-chain disulphide bond in the A chain
the disulphide bonds are formed between cysteine residues
produced by pancreatic β cells
storage
monomer is active form
stored as a hexamer held together by a zinc ion co-ordinated by histidines
hexamer is highly stable
hexamer serves to keep insulin protected, yet readily available
how is insulin made
DNA in β cell → mRNA
Transcription
mRNA → preproinsulin
Translation. Preproinsulin is preprohormone. The chain is directed into the ER limen by a singal sequence of amino acids.
preproinsulin → proinsulin
Signal peptide cleavage. Proinsulin is a prohormone. Enzymes in the ER remove the signal sequence, creating an inactive prohormone.
proinsulin → insulin + C-peptide
Proteolytic processing. Prohormone passes from the ER through the Golgi apparatus. Secretory vesicles containing enzymes and prohormone bud off the Golgi. The enzymes chop the prohormone into one or more active peptides plus additional peptide fragments.
The secretory vesicle fuses with plasma membrane (need calcium ions) and releases its contents by exocytosis into the extracellular space. The hormones move into the circulation for transport to its target.
What is proinsulin
- It is a prohormone (ie a precursor for insulin).
- Consists of C-peptide and insulin (chains A + B)
- Residues are trimmed off by carboxypeptidase H to form insulin and C-peptide
What is C-peptide and why is it a clinical marker
- A peptide fragment released from proinsulin → insulin
- Thought to have a physiological role as a hormone (a lack of C-peptide is related to some clinical issues eg retinopathy)
- Artificial insulin consists only of A + B chain
- Therefore, any C peptide present would have been produced endogenously by patient
- Shows a person’s ability to produce insulin
How is insulin released from pancreatic β cells
- High levels of glucose enter pancreatic β cell via GLUT2 transporter
- This means more glucose is inside cells, which is used for metabolic processes, such as glycolysis
- This causes an increase in ATP
- Increased ATP levels inside cell inhibit the Katp channel (transport K+ to outside of cells)
- This leads to a build up of K+ ions inside cell, and therefore build up of positive charge
- This causes depolarisation
- Voltage gated calcium channel opens, allowing Ca2+ to enter cell
- Ca2+ triggers binding of vesicles (filled with insulin) to the plasma membrane
- Insulin and C-peptide is released by exocytosis
What happens to β cell at rest
- At rest, there are normal or lower levels of glucose in blood
- Some of this glucose enters the β cell via the GLUT2 transporter
- There isn’t much glucose, so metabolism slows
- Less ATP produced
- Therefore Katp channel is open
- K+ is able to leave cell, so positive charges don’t build up
- Voltage gated calcium channels are not stimulated as cell is at resting membrane potential
- Insulin filled vesicles remain in the cell
Stimulators of insulin release
- Increased plasma glucose
- Increased amino acids
- Plasma free fatty acids
hormones
* Gastroinhibitory peptide (GIP)
* Gastrin
* Glucagon
* Secretin
* Cholecystokinin (CKK)
* Adrenaline (at β cell receptor)
*
Parasympathetic nervous system
inhibitors of insulin release
- decreased plasma glucose
- decreased plasma amino acids
- decreased free fatty acids
hormones
* Somatostatin
* Leptin
* Adrenaline (at α cell receptor)
Sympathetic nervous system
