E2 - Endocrine Pancreas Flashcards
What are the exocrine functions of the pancreas?
What proportion?
Majority of pancreas; digestive enzymes produced and pushed into the main pancreatic duct secreted into the duodenum of the small intestine to break down carbohydrates, proteins and lipids in the chyme.
How are the endocrine cells/Islets of Langerhans localised in the pancreas?
What proportion of the pancreas?
- Clustered/scattered throughout the whole pancreas in small clusters of cells.
- 1-2% of total pancreatic mass but receive 10% of blood supply (well vascularised); hormones made need to travel in blood circulation to target tissue
What are the different islet cell types and their proportions?
α - glucagon (30-40%) β - insulin (50-60%) δ - somatostatin (5-10%; inhibitory) PP - pancreatic polypeptide (1-5%) ε (epsilon) - ghrelin (
What is the strutucre of insulin?
Made up of two chains:
- A-chain of 21AAs
- B-chain of 30AAs
> 2 inter-chain disulfide bonds between A- and B-chains
> 1 intra-chain disulfide bond within A-chain
Why is the half-life of insulin only 5-9 minutes?
Travels in circulation as free hormone (peptide); subject to degradation by proteases.
How many AAs is proinsulin and how does it differ in structure from the finished insulin product?
- 86AA
- Features a connecting peptide (C-peptide) between A- and B-chains 35 AAs in length; reduces to 31 AAs in length once cleaved (31, 32, 64, 65 AA cleaved)
What happens to the C-peptide once cleaved?
It is packaged along with insulin into secretory granules in a 1:1 ratio (though thought to have no biological activity)
What are the steps of insulin biosynthesis?
- Insulin gene transcribed to mRNA, mRNA translated into protein
- Preproinsulin synthesis featuring pre signal peptide, which is cleaved as preproinsulin travels through RER stack to give proinsulin
- Proinsulin transferred from RER to Golgi (processing plant) via micro-vesicles
- Golgi cleaves C-peptide as part of processing to give insulin
- Insulin then packaged into secretory granules
Which 3 enzymes are involved in C-peptide cleavage of proinsulin?
- Proconvertase 1 (PC1); cleaves at 32 - 33 (leaving 31 and 32 hanging on B-chain)
- Proconvertase 2 (PC2); cleaves at 65-66 of A-chain
- Carboxypeptidase H (CPH) removes additional 31 & 32 hanging on B-chain via degradation
- CPH also removes 64 and 65 of C-peptide to give the 31AA C-peptide
What does cleavage of the C-peptide do to the solubility of insulin?
Makes it less water-soluble; so much so that it starts to precipitate in the secretory granule
What is the net effect of insulin precipitation in the secretory granule and the ratio that it occurs?
Precipitates of a ration 2 Zn2+:6 insulins; forming densely packed crystalloid core (packing a lot of insulin in a small amount of space)
How is insulin release from the β cell?
Exocytosis; secretory granule fuses with plasma membrane and insulin expulsion occurs (requires Ca2+ influx and ATP)
Is insulin released at low blood glucose (
A basal level of insulin is secreted.
What are the events that take place in the β-cell when glucose levels > 5mmol/L?
- ) Glucose metabolised by oxidative phosphorylation pathway
- ) Ratio of ATP:ADP regulates ATP-sensitive K+ channels; glucose metabolism makes ATP from ADP phosphorylation (increased ATP, decreased ADP) thus increase ATP:ADP ratio closes ATP-sensitive K+ channel (normally open and allows K+ to leave cell in low ATP:ADP ratio/basal glucose levels)
- ) Closure of ATP-sensitive K+ channels results in build-up of +ve charge inside cell = membrane depolarisation
- ) Depolarisation results in activation of VGCC (voltage-gated calcium channels) opening; Ca2+ influx
- ) Increase in intracellular Ca2+ results in increased excocytosis and therefore insulin release
How else is insulin release regulated apart from the main OG glucose stimuli?
- AAs and fatty acids also regulate ATP:ADP ratio pathway/ATP-sensitive K+ channel
- Gut hormones (incretins) act as potentiators; presence/anticipation of food = secretion of incretins into circulation which have positive effect on insulin secretion of the β-cell to cope with imminent food intake; forming part of the enteroinsular axis
How can an earlier peak/higher level of insulin in oral glucose be explained in relation to IV glucose (which has much quicker access to the blood thus β-cells)?
- As 60% post-meal insulin secretion is due to incretins (released from gut)
- Incretins prepares body for anticipation of increase in glucose with a meal
What is glucagon’s role in potentiating insulin release?
Paracrine communication (affecting neighbouring cells without entering blood) of glucagon released from α cells, increases insulin release.
Where is somatostatin secreted and what is its effect on insulin release?
- δ-cells of Islets of Langerhans
- Inhibitory effect on insulin release (and glucagon release of α cells)
