2 Glucose Sensing

Question 1

By what mechanism do pancreatic beta-cells sense glucose?

Answer 1

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

Question 2

What are the two pools of insulin?

Answer 2

Immediately releasable pool

Reserve pool

Question 3

What receptors does Ozempic target and why?

Answer 3

GLP-1 and GIp receptors

Giving a sense of fullness

Can also target these in the brain

Question 4

What does MODY stand for?

Answer 4

Maturity-onset diabetes of the young

Question 5

What are the two types of glucose-sensing neurones?

Answer 5

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.

Question 6

What do the pancreatic islets correlate to in neurones?

Answer 6

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

Question 7

How do we know the hypothalamic “islets” are important?

Answer 7

Because they are evolutionarily conserved

Question 8

What drugs stimulate and inhibit the KATP?

Answer 8

Stimulatory = MgADP & Diazoxide

Inhibitory = sulfonylureas, glinides

Question 9

What is the structure of KATP?

Answer 9

SUR1 + Kir6.2

Question 10

What is the funciton of Kir6.2 in KATP?

Answer 10

Kir6.2 is considered the pore-forming subunit

Question 11

What are GT1-7 cells?

Answer 11

Mouse hypothalamic cell line

Question 12

What is the function of glucokinase?

Answer 12

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

Question 13

What happens in beta-cells when glucose is present?

Answer 13

Beta cell fires

Question 14

What is the difference between threshold in the brain and pancreas?

Answer 14

The brain has a lower threshold = takes lower concentrations of glucose to stimulate the neurones

Question 15

What occurs when glucokinase is activated in glucose-sensing neurones under low glucose levels?

Answer 15

Normally, there would be no cell depolarization but because glucokinase is activated the glucose there is is converted into ATP causing inhibition of KATP

Question 16

What occurs when KATP is opened in glucose-sensing neurones under high glucose levels?

Answer 16

KATP prevents depolarization of the cell so no excitability

Question 17

Why is the counterregualtory response important?

Answer 17

Body’s mechanism for counteracting hypogmlycaemia

By releasing hormones = glucagon, adrenaline, cortisol and growth hormone

Question 18

What does adrenaline do for hypoglycaemia?

Answer 18

Stimulates breakdown of glycogen to releae glucose

Reduces insulin secretion

Question 19

What was the affect of oral diazoxide on hypoglycaemia in T1D?

Answer 19

Opens KATP channels (important in the detection of hypoglycaemia)

And amplifies the CCR

Question 20

What is diazoxide?

Answer 20

KATP channel activator

Which allows more potassium to enter cells and hyperpolarizes the cell membrane

Question 21

What happens when AMPK a2 subunit is KO’d?

Answer 21

Cannot sense glucose so cell depolarizes

Question 22

What neurones need AMPK for glucose sensing?

Answer 22

AgRP (orexiogenic)

POMCP (anorexiogenic = loss of appetite)

Question 23

How does AMPK actiivty respond to hypoglycaemia?

Answer 23

Increases AMPK activity because of low ATP:ADP ratio

And increases ACC phosphorylation (by AMPK)

Question 24

What happens when VMH AMPK is downregulated under hypoglycaemic clamp?

Answer 24

Blunted CRR

Question 25

What is AICAR?

Answer 25

AMPK activator

Question 26

When AMPK is downregualted it blunts the effects of AICAR during hypoglycamia, what does this show?

Answer 26

If you try to activate AMPK with AICAR and the effects are blunted

Shows how well a2 subunit has been KO’d

Question 27

What happwns when constituitively active AMPK is injected into VMH?

Answer 27

Amplified CRR to hypoglycaemia