Endocrine Pancreas Flashcards
True or false: Pancreas develops as an outgrowth of the gut tube, and is closely associated with the development of the GB
TRUE
Which cells in the pancreas are exocrine ? What proportion of the pancreas do these make up ? endocrine ?
EXOCRINE: Pancreatic acini (produce pancreatic amylase, proteases, lipases, bicarbonate)- 98%
ENDOCRINE: Islets of Langerhan (produce hormones)- Less then 2%
Identify the main cells types making up the islets of Langerhand.
- A cells (AKA alpha cells, produce glucagon)
- B cells (AKA beta cells, produce insulin)
- D cells (produce somatostatin)
- F cells (produce pancreatic polypeptide)
Describe chemical structure of Insulin.
Two peptides linked by 2 disulphide bonds
Identify the main functions of the endocrine pancreas.
1) Control of blood glucose in absorptive and post-absorptive states (through insulin and glucagon)
2) Stimulate/inhibit digestive enzymes and HCO3- secretion in GI tract (pancreatic peptide and somatostatin)
Describe the anatomy of the Islets of Langerhan. Explain the significance of this.
- A cells are found in the periphery
- B cells are found in the center
- D cells juxtaposed between the two
- F cells randomly located, mostly in periphery
- Blood supply comes into the center of the islet, and then flows from the center to through the cells to the periphery
Significance: if insulin is released from B cells, it has to pass by alpha cell on way to systemic circulation
Describe the process of synthesis and processing of insulin.
-mRNA released from nucleus into cytosol, where it gets bound by ribosomes which are associated with RER
-Translation of mRNA begins, by translating codon sequences into AAs (start at amino terminal)
-Part of the peptide that is synthesised is a signal sequence (sequence of AAs that is recognised by docking proteins which
dock this part of the protein to the membrane and insert it through lipid bilayer into lumen of the ER), i.e. when the protein is made, it is secreted into the ER through this docking sequence
-Once amino terminal is translocated into the ER by the ribosome as it is
synthesising, the signal peptide is cleaved off and the protein starts to be folded up as it is being synthesized, in specific confirmation of lowest energy
-This is pro-insulin, single polypeptide made up of A chain (C terminal half) and B chain (amino terminal half), and C peptide which connects A and B chains
-In this pro insulin form, number of disulphides groups, of which six will form three disulphide bonds. Two of those bonds will be between A and B chain, and one will be within the A chain (still in the ER)
-Pro insulin is packaged up and sent to Golgi, which combines pro insulin with proteases called converting enzymes which cleave C peptide. Mature insulin (containing two peptide chains held together by disulphide bonds) along with the C peptide (and about 5% of pro-insulin) end up in secretory vesicle
-To help increase concentration of insulin inside secretory vesicles, vesicles take up zinc, which coordinates with insulin and forms precipitate. This allows very high concentrations of insulin inside these vesicle, and prevents an osmotic effect from being set up (because precipitated out)
Identify the main factors regulating insulin release.
The main one is INCREASED BLOOD GLUCOSE (which is influenced by absorption of food from the GI tract). Without this, there will be no increase in insulin release. If this is present, stimulates insulin release from beta cells, and other factors can further stimulate insulin release (ONLY if increased blood glucose):
- FAs and AAs increase metabolism
- Incretins (GI hormones) including GIP, GLP-1, CCK, released from GI tract when higher concentrations of carbs enter GI tract
- Neuronal innervations to pancreas (PSNS and beta adrenergic stimulation)
Other factors can suppress insulin release:
- Alpha adrenergic stimulation
- Autocrine (insulin) and paracrine (somatostatin, glucagon) signaling systems
Describe mechanisms of insulin release from pancreatic beta cell.
1) Glucose enters the cell via GLUT2 transporter which mediates facilitated diffusion of glucose into the cell
2) Increased glucose influx sitmulates glucose metabolism, leading to increase in intracellular, ATP, or in ATP/ADP. This is because:
- When glucose enters the cell, it is phosphorylated by glucokinase into glucose-6-phosphate, which is a substrate for metabolism
- Through glycolysis, glucose-6-P is converted to pyruvate, producing ATP in the process
- Trough the citric acid cycle, Pyruvate is converted to Acetyl coA, generating ATP in the process
3) Increased ATP and/or ATP/ADP inhibits ATP-sensitive K+ channel
4) Inhibition of K+ channel causes Vm to become more positive (depolarisation)
5) Depolarisation activates a voltage-gated Calcium channel in plasma membrane
6) Activation of this Calcium channel promotes Calcium influx, and thus increases Calcium which also evokes Calcium-induced Calcium release (by binding to Ryanodin receptor on ER)
7) Elevated intracellular Calcium leads to exocytosis and release into the blood of insulin contained within the secretory granules
Explain how incretins, glucagon, somatostatin, the PSNS, alpha adrenergic agonists and beta adrenergic agonists affect insulin release (on a molecular level).
STIMULATE INSULIN RELEASE
-CCK (incretin) and ACh (e.g. in PSNS stimulation) bind to G protein coupled muscarinic receptor, which (through G protein) activate PLPC, which cleaves PIP2 into IP3 and DAG. IP3 increases Calcium release from intracellular stores, and DAG activates PKC which causes phosphorylation (and activation) of
a number of proteins involved in exocytotic mechanism
-Glucagon, GIP (incretin), beta adrenergic agonists
bind to G protein coupled receptor, which activates G protein, which subsequently activates Adenylate Cyclase. AC then converts ATP into cAMP which activates PKA which phosphorylates proteins of the
exocytotic matrix and augments insulin release
INHIBIT INSULIN RELEASE
-Somatostatin and alpha adrenergic agonists suppress insulin release by working through inhibitory G-coupled protein. Inhibit adenylate cyclase and suppress PKA activation.
Identify the main physiological actions of Insulin.
1) Increased protein synthesis (turnover of proteins in cells is normal, but insulin increases anabolic effect) (in most tissues), leading to growth and maintenance of tissues
2) Increased glycogenesis (using glucose coming into liver, muscle), leading to increased glucose transport into cells (muscle/adipose tissue normally impermeable to glucose, but insulin binds to receptor and causes recruitment of GLUT4 receptors), leading to decreased blood glucose
3) Increased lipogenesis (synthesis of TAGs from FAs and glycerol) (in liver and adipose tissue)
Does insulin stimulate glucose uptake across membrane in the liver ? Why or why not ?
Insulin does not stimulate glucose uptake across membrane in liver, liver always permeable to glucose irrespective of insulin concentration
Identify factors regulating Glucagon release.
The main one is DECREASED BLOOD GLUCOSE (which is influenced by absorption of food from the GI tract).
Factors which stimulate glucagon release include (but REQUIRE absence of insulin/amylin):
- GI tract hormones
- Certain AAs
- Parasympathetic stimulation (ACh)
- Beat adrenergic stimulation (Adr)
- Alpha adrenergic stimulation (NorA)
Factors which suppress glucagon release include:
- Insulin
- Somatostatin
How does insulin inhibit glucagon release ?
Normally, insulin released from beta cells, and blood flow passes alpha cells, so insulin inhibits glucagon release.
IF insulin is not present in the blood passing the alpha cells, glucagon is not suppressed and can be released
Identify the main physiological actions of Glucagon.
1) Decreased lipogenesis and increased lipolysis, leading to increased free FAs and glycerol (not actually due to increased glucagon but thanks to reduced insulin)
2) Increased glycogenolysis (glycogen into glucose 6 P which is then dephosphorylated) leading to increased blood glucose
3) Increased gluconeogenesis (along with cortisol) (partly using glycerol produced as a result of increased lipolysis)
(through cAMP, glucagon phosphorylates enzymes to stimulate gluconeogenesis) leading to increased blood glucose
