2 Glucose Sensing Flashcards
By what mechanism do pancreatic beta-cells sense glucose?
Glucose is transported in to the b-cells via GLUT1/2
It then produces increase in ATP via mitochondria
This increase in ATP inhibits the K_ATP channel so K+ stops leaving
Depolarization occurs causing Ca2+ release into the cell which causes release of insulin
What are the two pools of insulin?
Immediately releasable pool
Reserve pool
What receptors does Ozempic target and why?
GLP-1 and GIp receptors
Giving a sense of fullness
Can also target these in the brain
What does MODY stand for?
Maturity-onset diabetes of the young
What causes MODY?
Single gene mutation = lead to impaired insulin secretion
Causes non-insulin-dependent hyperglycemia
What are the two types of glucose-sensing neurones?
GI (glucose-inhibited) neurons decrease their activity when glucose levels rise
While GE (glucose-excited) neurons increase their activity in response to higher glucose levels
GI neurons are most active when blood sugar is low, signaling the body to take actions to raise glucose levels, while GE neurons signal when blood sugar is high, potentially triggering mechanisms to lower it.
What do the pancreatic islets correlate to in neurones?
Glucose-excited neurone triggers mechanism to lower blood glucose = like beta-cell releasing insulin
Glucose-inhibited neurone triggers mechanism to increase blood glucose = like alpha-cell releasing glucagon
How do we know the hypothalamic “islets” are important?
Because they are evolutionarily conserved
What drugs stimulate and inhibit the KATP?
Stimulatory = MgADP & Diazoxide
Inhibitory = sulfonylureas, glinides
What is the structure of KATP?
SUR1 + Kir6.2
What is the funciton of Kir6.2 in KATP?
Kir6.2 is the pore-forming subunit
What are GT1-7 cells?
Mouse hypothalamic cell line
Why do SUR2A and Kir6.1 not fire in GT1-7 (mouse hypothalamic) cells ?
Because different subtypes = present in different cell types
What happens in beta-cells when glucose is present?
Beta cell fires
What is the difference between threshold in the brain and pancreas?
The brain has a lower threshold = takes lower concentrations of glucose to stimulate the neurones
What is the function of glucokinase?
Acts as a “glucose sensor” in the body, primarily in the pancreatic beta cells, by detecting blood glucose levels and triggering the appropriate insulin secretion response
It phosphorylates glucose, the first step in glucose metabolism
What factors control neuronal activity in GT1-7 cells?
Pancreatic glucokinase
AMPKa2
SUR-1 KATP channel
What occurs when glucokinase is activated in glucose-sensing neurones under high glucose levels?
Normally, there would be no cell depolarization but because glucokinase is activated the glucose there is is converted into ATP causing inhibition of KATP
Inhibition of KATP allows depolarization to occur in BETA cells
What occurs when KATP is opened in glucose-sensing neurones under low glucose levels?
KATP open = prevents depolarization of the cell because K+ can still leave cells and keep it hyperpolarized so no excitability
Why is the counterregualtory response important?
Body’s mechanism for counteracting hypogmlycaemia
By releasing hormones = glucagon, adrenaline, cortisol and growth hormone
What does adrenaline do for hypoglycaemia?
Stimulates breakdown of glycogen to releae glucose
Reduces insulin secretion
What was the affect of oral diazoxide on hypoglycaemia in T1D?
Opens KATP channels (important in the detection of hypoglycaemia)
And amplifies the CCR
What is diazoxide?
KATP channel activator
Which allows more potassium to enter cells and hyperpolarizes the cell membrane
What happens when AMPK a2 subunit is KO’d?
Cannot sense glucose so cell depolarizes
Which neurones need AMPK for glucose sensing?
AgRP (orexiogenic)
POMCP (anorexiogenic = loss of appetite)
How does AMPK activity respond to hypoglycaemia?
Increases AMPK activity because of low ATP:ADP ratio
And increases ACC phosphorylation (by AMPK)
What happens when VMH AMPK is downregulated under hypoglycaemic clamp?
Blunted CRR
What is AICAR?
AMPK activator
When AMPK is downregualted it blunts the effects of AICAR during hypoglycamia, what does this show?
If you try to activate AMPK with AICAR and the effects are blunted
Shows how well a2 subunit has been KO’d
What happens when constituitively active AMPK is injected into VMH?
Amplified CRR to hypoglycaemia
