Trigger 1: Insulin secretion Flashcards
Normal blood glucose
4-7mmol/l
When is blood glucose highest
after food
factors that affect BG
-exercise -food -illness -stress
Insulin
- released from the B-cells in the islets of langerhans - increases uptake of glucose lowering blood sugar - stimulate glycogensis - inhibits glycolysis (Glycogen synthesis in skeletal muscle and liver and Increased lipogenesis and inhibition of gluconeogenesis in liver)
Glucagon
-released from alpha cells - increases blood glucose - inhibition of glycolysis and glycogenesis (i.e. decreases glycogen production) -stimulates glucoseneogenesis and glycogenolysis
receptor for glucagon is a
GPCR found on liver, increases cAMP and PKA
Beta cells
Insulin- decrease BG
Alpha cells
Glucagon- increase BG
When BG is high
1) beta cells stimulated to release insulin into blood 2) body cells and liver take up more glucose- stored as glycogen in liver 3) BG declines to a set point. Stimulus for insulin release diminished
When BG is low
1) Alpha cells stimulated to release glucagon 2) glucagon causes liver to break glycogen down and releases glucose into the blood 3) glucose level rises
How many GLUT transporters
14 main
GLUT 1
o Found in most cells. o Does not require insulin stimulation. o Facilitated diffusion of glucose o Works with GLUT3 to allow glucose across BBB
GLUT 2
o Transports glucose when BGL is high o Metabolic trigger to coordinate insulin secretion o LIVER and B cells
GLUT 3
o Brain o Higher affinity for glucose than other GLUTs
GLUT 4
o Liver, muscle and adipose tissues o Activated by Insulin signalling pathway o GLUT4 vesicles fuse with the plasma membrane and allows glucose to enter the cell
GLUT 5
o Intestinal tissue, kidney and spermatozoa o Fructose transporter
Which GLUT is activated during the insulin signalling pathway
GLUT 4
which GLUT signals for B cells to release insulin
GLUT2
action of glucagon
Increase BG - causes glycogen to break down in liver via glucagon receptors to increase cAMP and PKA - inhibits glycolyis and glycogenesis -stimulates glucoseneogenesis - prevent glycolysis
insulin acts on
muscle, adipose and liver
response to insulin has how many phases
2
phase 1 of insulin release
initially rapid but transient bursts of insulin secretion. Probably due to the release of insulin from granules that directly adjacent to CM
phase 2 of insulin release
If BGL remains high, then rise in insulin secretion is sustained due to the release of both stored and newly synthesises insulin
Outline the molecular signalling cascade by which insulin promotes glucose uptake in adipose tissue
1) Insulin binds to receptor and causes dimerization and auto phosphorylation of tyrosine residues 2) Binding and phosphorylation of adaptor protein e.g. IRS 3) Activation of P13K, which phosphorylates PIP2 to PIPs 4) Phosphorylation of AKt 5) Causes GLUT4 vesicle to translocate to the cell membrane 6) Allows uptake of glucose from the blood stream by facilitated diffusion
Activates PKb/AKT (insulin signalling pathway) causes
• GLUT4 translocation to the plasma membrane/glucose uptake in adipocytes and skeletal muscle • Glycogen synthesis in skeletal muscle and liver • Increased lipogenesis and inhibition of gluconeogenesis in liver
2 types of stimulated insulin release
(1) Nutrient stimulated release (e.g. amino acids and fatty acids) (2) Neuronal stimulation of insulin secretion
Nutrient stimulated release (e.g. amino acids and fatty acids)
• GLUT2 has a lower affinity for glucose than GLUT4
- ATP ( produced due to detection of insulin/ amino acids) causes B cell K+ channels to close
- Leading to membrane depolarisation (becomes more negative)
- Causing Ca2+ gates to open
- Ca2+ influx
- Release of insulin granules
(2) Neuronal stimulation of insulin secretion
• Sympathetic- Prevents insulin secretion: o Inhibits cAMP, so PKA not activated • Parasympathetic- stimulates insulin secretion by stimulating Ach
Sympathetic
Prevents insulin secretion: o Inhibits cAMP, so PKA not activated
Parasympathetic
stimulates insulin secretion by stimulating Ach
How are B cell specialised for insulin secretion? (5)
1) GLUCOKINASE
2) GLUT2 has a low affinity for glucose
3) Islets are highly vascularised to release insulin into the bloodstream
4) Number of B cells are tightly regulated
6) Highly differentiated- many unique TFs
Glucokinase
is also known as hexokinase IV and catalyses the conversion of glucose to glucose 6 phosphate
glucokinase is a key componenet of
glucose sensing machinery- - Sets the threshold for glucose stimulated insulin secretion
characteristics of glucokinase
(1) Low affinity for glucose (S0.5 8-10mM) (2) Lack of inhibition by substrate
signalling pathway within Bcells
Glut2 senses high conc of glucose 1) Glucose is converted to glucose-6-p by glucokinase 2) G-6-P is converted to F-6-P 3) to pyruvate 4) to acetyl-CoA 5) to cholesterol, fatty acids etc
processing of insulin within beta cells
insulin is synthesises as a preproinsulin in the ribosome of the RER. Preproinsulin is then cleaved to proinsulin, which is transported to the Golgi apparatus where is it packaged into secretory granules located close to the cell membrane
proinsulin is cleaved into
proinsulin is cleaved into equimolar amount son insulin and C peptide in the secure granules
what is insulin packaged into
secretory granules
where are secretory granules located
close to the membrane to allow rapid release
processing of insulin within beta cells (easy)
1) preproinsuline is cleaved to proinsulin
2) proinsulin is cleaved to insulin and c-peptide in equal amounts
this is why C-peptide is a marker of insulin
Insulin secretion from B cells
1) unactivated b cell will have open K+ channels
2) when GLUT2 senses a high enough BP, it opens and allows the influx of glucose
3) glucose is converetd to glucose 6 phosphate by glucokinase
4) glucokinase is further metabolised to produce ATP
5) ATP causes K+ channels to close
6) this depolarises the membrane (becomes more negative)
7) stimulates the influx of calcium
8) calcium causes insuli secretry granules to fuse withteh cell membrane
