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bioc2005 - metabolism > 2 - Glucose Sensing and Fed/Fasted Liver Carbohydrate Metabolism > Flashcards

2 - Glucose Sensing and Fed/Fasted Liver Carbohydrate Metabolism Flashcards

1
Q

What are the four primary responses to high blood glucose levels?

A

1 - Glucose sensing and consequent signalling in the liver and pancreas.
2 - Glycogenesis stimulation/glycogenolysis inhibition.
3 - Glycolysis stimulation/glycogenesis stimulation.
4 - Fatty acid oxidation inhibition/synthesis stimulation.

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2
Q

What tissues or cells are glucose-sensitive?

A

Pancreatic Islet of Langerhans cells, hepatocytes, some brain neurons.

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3
Q

Why are liver cells somewhat glucose sensitive?

A

To allow fast response before insulin signalling begins.

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4
Q

Where is GLUT2 found? And how does this relate to its Km?

A

GLUT2 is found in glucose sensitive cells such as in the pancreas, liver and brain. As such they have a high Km to ensure that the uptake of glucose continues to vary at high concentrations without plateauing.

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5
Q

Where is GLUT4 found? And how does this relate to its Km?

A

GLUT4 is found in the muscle and adipose tissues. These are not glucose sensitive so the transporter has a low Km for strong binding of glucose at physiological concentrations, but no variation across this range.

It is also insulin sensitive to allow for regulation.

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6
Q

Where is GLUT3 found? And how does this relate to its Km and insulin sensitivity?

A

GLUT3 transporters are found in the non-glucose sensitive areas of the brain. It has the lowest Km in order to take up glucose preferentially to sate the brain’s energy needs with no variation across physiological ranges.

GLUT3 is not insulin sensitive as the brain must have a constant glucose supply.

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7
Q

What is K_0.5?

A

The equivalent of Km used for proteins that do not obey M-M kinetics due to cooperativity.

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8
Q

What is HkIV?

A

Hexokinase IV - AKA glucokinase. It is found in the glucose sensitive tissues.

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9
Q

Describe and explain the K_0.5 of glucokinase compared to other hexokinases.

A

Glucokinase - 8mM
HkI, II and III - 1mM

Higher K_0.5 of glucokinase allows for greater glucose sensitivity by glycolysis product sensing as the hexokinases are rate-limiting in glycolysis when [glucose] is not limiting.

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10
Q

What shape are the glucose affinity curves for HkI, II and III.

A

Rectangular hyperbola.

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11
Q

What shape is the glucose affinity curve for glucokinase?

A

Sigmoidal, with an inflection point of 3.9mM.

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12
Q

What is the physiological range of blood glucose in healthy adults?

A

4.5 - 10mM

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13
Q

What form of cooperative binding does glucokinase show?

A

The mnemonic model.

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14
Q

What rules out the possibility of the concerted and sequential cooperativity?

A

All hexokinases are monomeric.

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15
Q

Describe the cooperativity model used by glucokinase.

A

The mnemonic model relies on the continuous homotropic allosteric effect of glucose over time, which shifts the enzyme into the relaxed state.

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16
Q

What is Mature Onset Diabetes of the Young (MODY2)?

A

A form of diabetes caused by heterozygous mutation of the glucokinase gene. Various identified mutations affect the substrate binding, thermostability and cooperativity with varying stability.

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17
Q

What sort of inheritance pattern does MODY2 show?

A

Autosomal dominant.

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18
Q

What are the symptoms of MODY2 and how can it be treated?

A

Reduced glucose sensitivity due to lack of glucokinase, so reduced insulin response.

Can be treated with insulin injections.

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19
Q

What is Neo-natal Diabetes Mellitus?

A

When an individual is homozygous for the glucokinase mutation. Consequently this is far more serious.

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20
Q

What pancreatic cells are responsible for glucose sensing and insulin release?

A

Beta cells in the Islets of Langerhans.

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21
Q

Briefly describe the mechanism of pancreatic glucose sensing and insulin release.

A

1 - Glucose is taken up through GLUT2, phosphorylated by glucokinase and entered into glycolysis.
2 - The increased [ATP] and decreased [Mg-ADP] act to close K+ transporters causing membrane depolarisation.
3 - Depolarisation opens L-type voltage gated Ca channels leading to an inrush.
4 - Calcium ions bind to insulin vesicles causing exocytosis.

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22
Q

What are incretins?

A

Small hormones released from the small intestine when glucose is ingested that begin to stimulate pancreatic insulin release before blood glucose spikes.

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23
Q

Name one incretin.

A

GLP1

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24
Q

Describe the mechanism of an incretin.

A

GLP1 increases sensitivity of K+ transporters to inhibitory ATP and decreases sensitivity to MgADP which acts to keep it open.

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25
Q

When the K+ transporter closes in pancreatic glucose sensing on which side is the buildup of K+?

A

Inside the cell, leading to a more positive membrane potential.

26
Q

Define membrane potential.

A

The difference in charge between the interior and exterior of the cell (Q-int - Q-ext).

27
Q

What is the typical resting membrane potential for most cells?

A

-70mV

28
Q

Where is GLUT2 expressed in the highest concentrations?

A

The liver, as unlike the pancreas this is one of the primary sites of glucose metabolism.

29
Q

What two proteins are primarily responsible for liver glucose sensing?

A

Glucokinase and GLUT2.

30
Q

Describe the three-point regulation of liver glucokinase.

A

Activation by glucose due to high Km and mnemonic allostery.
Activation by fructose 1-P due to GKRP inhibition.
Inhibition by nuclear sequestration by Glucokinase Regulatory Protein (GKRP).

31
Q

What enzyme is regulated for control of liver glycogen synthesis?

A

Glycogen synthase.

32
Q

What enzyme is regulated for control of liver glycogenolysis?

A

Glycogen phosphorylase.

33
Q

What structural features do glycogen synthase and glycogen phosphorylase share?

A

Both are dimers with phosphorylation sites.

34
Q

What protein is responsible for ensuring that glycogenesis and glycogenolysis never occur simultaneously?

A

PP1 - Phosphoprotein Phosphatase 1

35
Q

When glycogen phosphorylase is phosphorylated it is…

A

Active.

36
Q

What is responsible for phosphorylating glycogen phosphorylase?

A

Phosphorylase kinase, which itself is phosphoactivated by PKA triggered by glucagon signalling.

37
Q

Describe the regulation of glycogen phosphorylase.

A 
\+ AMP
\+ Phosphorylase Kinase/PKA/Glucagon
- ATP
- Glucose or glucose 6-P
- PP1 (dephosphorylation)
38
Q

Describe the interactions between PP1 and glycogen phosphorylase.

A

Bound to ACTIVE glycogen phosphorylase by its glycogen binding domain. When glycogen phosphorylase is inhibited it dissociates and dephosphorylates glycogen phosphorylase and phosphorylase kinase compounding deactivation.

39
Q

What is the ratio of PP1 to glycogen phosphorylase, and why is this significant?

A

10x less PP1, meaning that almost all the glycogen phosphorylase present must be deactivated before PP1 can dissociate to activate fed state metabolism.

40
Q

What does PP1 do to glycogen synthase?

A

Dephosphoactivates it when it is already in the relaxed state due to G6P binding.

41
Q

When glycogen synthase is phosphorylated it is…

A

Inhibited.

42
Q

Describe the regulation of glycogen synthase.

A

+ Glucose/G6P (T to R)

+ PP1 (dephosphoactivation of R state only)

43
Q

Describe the regulation of phosphorylase kinase.

A

+ Glucagon (phosphoactivation)

  • Insulin
  • PP1 (dephosphodeactivation)
44
Q

What do pyruvate carboxylase and PEPCK do in relation to liver carbohydrate metabolism?

A

The first step of gluconeogenesis - convert pyruvate to phosphoenol pyruvate.

45
Q

How is pyruvate carboxylase regulated in response to fed/fasting states?

A

It isn’t.

46
Q

How is PEPCK regulated regulated in response to fed/fasting states?

A

Insulin causes a decrease in its transcription and mRNA stability.

47
Q

Describe the action and regulation of glucose phosphatase.

A

The final enzyme in gluconeogenesis, producing glucose from G6P.

Insulin decreases its expression.

48
Q

Describe the action and regulation of pyruvate kinase.

A

The final enzyme in glycolysis, producing pyruvate from phosphoenolpyruvate.

\+ AMP
\+ Fructose 1,6 bisP (feedforward activation)
- ATP
- Alanine (glucose-alanine cycle)
- Glucagon (via PKA phosphorylation)
49
Q

What is the primary point of regulation in glycolysis and glycogenesis?

A

The PFK1-FBPase-1 complex.

50
Q

Describe the PFK1-FBPase-1 complex.

A

Phosphofructokinase-1 and Fructose bisphosphatase-1 are a catalytic domains of a single multifunctional enzyme that catalyse opposite reactions in the glycolytic/gluconeogenic pathway.

51
Q

Describe the action and regulation of FBPase-1.

A

Fructose bisphosphatase-1 is a gluconeogenic enzyme that dephosphorylates fructose 1,6 bis-P to fructose 6-P.

  • F 2,6 bisP
  • Insulin (via F 2,6 bisP)
    + Glucagon (via F 2,6 bisP)
52
Q

Describe the action and regulation of PFK-1.

A

Phosphofructokinase 1 is a glycolytic enzyme that phosphorylates fructose 6-P to fructose 1,6 bis-P.

\+ F 2,6 bisP
\+ Insulin (via F 2,6 bisP)
\+ AMP
- ATP
- Citrate (CAC Saturation/ß-ox)
- Glucagon (via F 2,6 bisP)
53
Q

Describe the action of the PFK-2/FBPase-2 complex.

A

Phosphofructokinase-2 and Fructose bisphosphatase-2 are a catalytic domains of a single multifunctional enzyme that catalyse opposite reaction.

PFK-2 produces fructose 2,6 bisP from fructose 6-P, removing it from the glycolytic/gluconeogenic pathways. FBPase does the opposite.

54
Q

Describe the regulation of the PFK-2/FBPase-2 complex.

A

PKA phosphorylates the complex, activating FBPase-2 and inactivating PFK-2, hence reducing the concentration of glycolysis stimulating Fructose 2,6 bis-P.

PKA is activated by glucagon and inhibited by insulin.

55
Q

When PFK-2/FBPase-2 is phosphorylated…

A

FBPase is active and PFK-2 is inactive.

56
Q

When PFK-2/FBPase-2 is dephosphorylated…

A

PFK-2 is active and FBPase-2 is inactive.

57
Q

Which three enzymes are regulated to control the Citric Acid Cycle?

A

Citrate Synthase, Isocitrate Dehydrogenase, a-Ketoglutarate Dehydrogenase.

58
Q

What is the Citric Acid Cycle (CAC) also known as?

A

The Tricarboxylic Acid Cycle (TCA).

59
Q

Describe the action and regulation of Citrate Synthase.

A

Produces citrate from oxaloacetate and Acetyl CoA.

  • ATP
  • Citrate
60
Q

Describe the regulation of hepatic isocitrate dehydrogenase.

A
  • ATP
  • NADH
    + NAD
    + ADP
61
Q

Describe the regulation of hepatic a-ketoglutarate dehydrogenase.

A
  • ATP
  • NADH
  • Succinyl CoA (Product inhibition)
62
Q

What effect does high [fructose] have on glycolysis rate? Give the mechanism for this.

A

Increases glycolysis by inhibiting GKRP.

bioc2005 - metabolism (8 decks)

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