The Endocrine Pancreas Flashcards
How does glucose get into cells?
Sodium-glucose cotransporters (SGLTs):
Rely on secondary active transport
SGLT1: glucose absorption from gut
SGLT1, SGLT2: glucose reabsorption from kidney (PCT)
What is the family of glucose transporters (GLUTs) made up of?
Family of glucose transporters (GLUTs)
GLUT 1 (brain, erythrocytes) – high affinity for glucose: constant uptake of glucose at 2-6 mM
GLUT 2 (liver, kidney, pancreas, gut) – low affinity: glucose equilibrates across membrane
Glucose-dependent insulin release in pancreas
GLUT 3 (brain) – high affinity
GLUT 4 (muscle and adipose tissue) – medium affinity. Insulin recruits transporters
Insulin-dependent uptake of glucose into cells
What are the islets of Langerhans and the hormones secreted from them?
Islets of Langerhans. Clusters of endocrine cells surrounded by exocrine pancreas
Several cell types:
α-cells (A cells): glucagon
β-cells (B cells): insulin
δ-cells: somatostatin
Somatostatin from the pancreas does not have any systemic effect, it is a powerful inhibitor of the alpha and beta cells secretion of glucagon and insulin (a local paracrine effect)
How is insulin synthesised?
Original transcript: pre-pro insulin
Signal sequence removed: proinsulin (in rough endoplasmic reticulum)
Transfer to Golgi apparatus
Peptidases break off the C peptide leaving an A and B chain linked by disulphide bonds
One mole of C-peptide is secreted for each mole of insulin
C peptide is a handy marker for insulin production
How is insulin released into the circulation?
Pancreas supplied by branches of the coeliac, superior mesenteric, and splenic arteries.
The venous drainage of the pancreas is into the portal system.
Half of the secreted insulin is metabolized by the liver in it’s first pass (when it binds to the receptors) ; the remainder is diluted in the peripheral circulation
C-peptide is more accurate index of insulin secretion in peripheral circulation (not metabolized by liver)
What are the factors regulating insulin secretion?
Sympathetic stimulation via alpha adrenergic inhibits insulin secretion while parasympathetic via muscarinic stimulates it
Glucagon secretion increases insulin secretion
Incretin hormones increase insulin secretion as plasma glucose rises which also stimulates insulin secretion
Somatostatin inhibits insulin secretion from delta-cells
What are the factors regulating glucagon secretion?
As plasma glucose rises alpha cells’ secretion of glucagon is inhibited
Amino acids stimulate glucagon secretion; arginine is a potent stimulator of both insulin and glucagon
It is present as a result of protein digestion that stimulates glucagon as a result of food uptake to balance out the insulin secreted
Sympathetic outflow via beta adrenergic nerves stimulates glucagon secretion
Parasympathetic nervous system also stimulates glucagon secretion
Somatostatin also inhibits glucagon secretion as it does with insulin
How do beta cells sense rise in glucose?
No glucose receptor
GLUT2 / Glucokinase can be thought of as the sensor
Effector is rise in ATP due to glucose oxidation
Extracellular glucose rises so more glucose enter the beta cell via the GLUT-2 transporter
The glucose is converted to G6P by glucokinase
G6P goes into glycolysis and further to full oxidative phosphorylation in the Krebs cycle producing ATP
On the beta-cell membrane, there is an ATP-sensitive K+ channel, the K+/ATP channel.
It is closed by ATP when it binds to it
The net effect is that this reduces the outward potassium current
This will lead to depolarisation of the beta cell (the extent depends on how many channels are closed (the next steps are the same as nervous system)
The depolarisation causes voltage-sensitive Ca2+ channels to open so calcium can then flow into the cells leading to a rise in calcium triggers a biochemical cascade
The biochemical cascade results in the exocytosis of insulin-rich secretory granules
How do different chemicals affects the beta cell?
The way some chemicals promote insulin secretion is essentially anything that can enter the cell and get metabolised to generate ATP leads to an increase in insulin secretion
Ach via muscarinic receptors initiates an increase in intracellular calcium via the phospholipase C pathway
Adrenergic stimulation inhibits via adenylate cyclase (G-protein coupled receptors) generate cAMP which activates PKA which potentiates the mobilisation of insulin secretory granules in response to the rise in calcium
GLP-1 (an incretin) has the opposite effect and stimulates adenylate cyclase
What is the insulin receptor like?
The insulin receptor is a member of the tyrosine kinase superfamily
Insulin binds to its receptor (1), which, in turn, starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5), and fatty acid synthesis (6)
Insulin binding to its receptor:
Activates cascade of protein phosphorylation, which stimulates or inhibit specific metabolic enzymes by modulating enzyme phosphorylation
Modulates activity of metabolic enzymes by regulating gene transcription
What happens after insulin binds to its receptor?
The insulin receptor is a tetrameric protein with two alpha subunits on the surface where insulin binds and the beta subunits that span the membrane and protrude onto the intracellular side
These are associated with a set of proteins called insulin receptor substrate proteins that are responsible for transducing some of the receptor action
Some actions are via modulation of transcription
The more immediate effects are via activation of membrane phospholipids
For example one of these results in the phosphorylation of membrane phospholipids; mainly phosphatidylinositol triphosphate which activates multiple downstream enzymes
So we know insulin promotes lipogenesis
The key starter for lipogenesis is acetyl CoA carboxylase (ACC)
This enzyme is under inhibitory control via protein kinase A
PKA depends on cAMP
Insulin binds to receptor activating PI3K activating PD1K activating PKB activating PDE38 (a phosphodiesterase) reducing cAMP therefore reducing PKA activity and indirectly stimulating ACC (thus promoting synthesis of malonyl CoA)
What is the glucagon receptor like?
Its receptor is a member of the G-protein coupled receptor superfamily
Most of its actions are mediated via adenylate cyclase and production of cAMP which in turn activates PKA (to phosphorylate many substrates)
How is diabetes mellitus classifies?
Type 1: absolute insulin deficiency (due to destruction of insulin-producing pancreatic beta cells)
Type 2: variable combination of insulin resistance and insulin insufficiency
What is the importance of glycaemic control?
Reduce macro- and microvascular complications
Glycosylated Hb (A1C) levels are good indicator of glycaemic control
Less than 6.5% is good
Every 1% fall in A1C results in 20-30% relative risk reduction in microvascular complications
But …
Glycaemic control is hard.
What is the incretin effect and how is it used?
You give an oral glucose load (50g) and track plasma glucose every 5 mins for 3 ours
Plasma glucose would rise a little
At the same time you would measure insulin which you see peaking then decreasing mirroring glucose
The second phase is when you infuse glucose and track insulin
Adjust your glucose infusion rate so that you achieve the same pattern of glucose as you would from the first phase diagram
The difference is the change in plasma glucose is not due to glucose absorption via the gut rather the direct infusion of glucose
Then measure the insulin
What you see is that the insulin is much lower when the glucose is infused as opposed to it being absorbed via the oral route- this is the incretin effect
So we conclude that some factor is triggered when glucose is absorbed via the GI tract that increases insulin- these are now known as the incretin hormones
The first to be identified was GIP and subsequently was GLP-1
Evidence for its impairment in T2DM
Major target for new drug development
