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Phase 2 3. Endocrinology > Insulin and glucagon action > Flashcards

Insulin and glucagon action Flashcards

1
Q

How is CHO stored and transported?

A

Stored as glycogen

Transported as glucose

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2
Q

What are the normal glucose concentrations?

A

Fasted = 4-5mM

After meal = 8-12mM

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3
Q

How is CHO regulated?

A

By insulin and glucagon

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4
Q

List the actions of insulin

A

> Stimulates glycogen production in liver and muscle
Stimulates glucose uptake in muscle and adipose via GLUT 4
Stimulates synthesis of FA/TAG from glucose

> Inhibits glycogen breakdown
Inhibits gluconeogenesis in the liver

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5
Q

What is the action of glucagon

A

> Stimulates gluconeogenesis and glycogen breakdown

No direct effect on muscle or adipose as they have no glucagon receptors

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6
Q

How is glycogen synthesised and stored?

A

Synthesised from glucose
> Stored in liver for blood glucose maintenance
> Stored in muscle for local energy production (only used by muscle itself

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7
Q

How is glycogen metabolised in the liver in the fed state?

A

Glycogen synthase and glucokinase activated
Glucose-6-phosphatase and glycogen phosphorylase inhibited

Very little glucose goes through glycolysis

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8
Q

How is glycogen metabolised in the muscle in the fed state?

A

No G6Pase present in the muscle
Hexokinase and glycogen synthase is activated
Glycogen phosphorylase is inhibited

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9
Q

How is glycogen metabolised in the liver in the fasted state?

A

There is decreased glucokinase and glycogen synthase activity
Activation of glycogen phosphorylase and G6Pase
Glycogen is broken down into glucose
Glucose is transported back into the bloodstream via GLUT 2 (down conc. gradient)

> Same effect with (nor)adrenaline
- Will always counteract insulin -> far more potent stimulus

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10
Q

How is glycogen metabolised in the muscle in the fasted state?

A

No effect of glucagon as no glucagon receptors are present
Only (nor)adrenaline
Muscle glycogen is broken down

If depleted -> fatigue; have to switch to FA substrate

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11
Q

What is gluconeogenesis?

A

The synthesis of glucose from a noncarbohydrate (nonhexose) source

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12
Q

What are the substrates in gluconeogenesis?

A

Lactate
Pyruvate
Glycerol
Certain amino acids

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13
Q

Where does gluconeogenesis occur?

A

Mainly in the liver
The kidneys can contribute in prolonged starvation
(Essentially a reversal of glycolysis)

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14
Q

What reactions are irreversible in liver glycolysis

A

The reactions requiring the following enzymes:

  • glucokinase (GK)
  • phosphofructokinase (PFK)
  • pyruvate kinase (PK)

All involve ATP

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15
Q

How is glucokinase bypassed?

A

By glucose 6-phosphatase (G6Pase)

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16
Q

How is PFK bypassed?

A

By fructose 1,6-bisphosphatase (F16bPase)

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17
Q

How is pyruvate kinase bypassed?

A 
By two enzymes:
Pyruvate carboxylase (PCOX)
Phosphoenolpyruvate carboxykinase (PEPCK)
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18
Q

Which hormones regulate gluconeogenesis?

A

Glucagon
Adrenaline
Insulin
Steroid hormones

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19
Q

How do hormones regulate gluconeogenesis?

A

The effect is at the level of gene expression, so more or less enzyme is synthesised

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20
Q

How does glucagon, adrenaline and glucocorticoids affect gluconeogenesis?

A

Decreases glucokinase activity

Increases G6Pase and PEPCK activity -> stimulate glycogenolysis

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21
Q

How does insulin affect gluconeogenesis?

A

Increases glucokinase activity

Decreases G6Pase and PEPCK activity -> prevents liver from raising plasma glucose (inhibits gluconeogenesis)

22
Q

What are the principle actions of insulin in the liver?

A

Increases glycogen synthesis -> rapid effects, NOT at the level of gene expression

Increases fatty acid synthesis -> slightly slower

Inhibits gluconeogenesis (PEPCK and G6Pase) -> level of gene expression

23
Q

What are the principle actions of insulin in the muscle?

A

Increases glucose transport (GLUT4) -> almost instantaneous

Increases glycogen synthesis -> very rapid

24
Q

What are the principle actions of insulin in the adipose tissue?

A 
Increases glucose transport (GLUT4)
Suppresses lipolysis
Increases fatty acid synthesis
Increases AA transport and protein synthesis in many tissues
Has specific effects on some genes
25
Q

Describe the qualities of TAG

A

The most fuel-efficient energy store

- Very energy dense and don’t need the same tight packing as glycogen

26
Q

What is synthesised from glucose in adipocytes?

A

Lipids - both G-3-P and fatty acids

27
Q

How does insulin contribute to TAG synthesis?

A

Stimulates enzymes involved in TAG synthesis

  • Lipoprotein lipase (LPL)
  • GLUT4
  • Acetyl CoA carboxylase
28
Q

What is lipolysis?

A

TAG breakdown

29
Q

What is adrenaline’s effect on adipose tissue?

A

Stimulates hormone-sensitive lipase to breakdown TAG

Adrenaline -> cAMP -> PKA -> HSA

30
Q

How does insulin inhibit lipolysis?

A

Inhibits stimulation of HSL by adrenaline

  • this occurs indirectly
  • insulin binds to insulin receptor -> PKB/Akt -> inhibits cAMP
31
Q

What happens during post prandial metabolism?

A

> Insulin inhibits adipose lipolysis
This causes a reduction in FA concentration in plasma
Muscle switches to oxidation of glucose for fuel
Insulin stimulates uptake of glucose by adipose and skeletal muscle (GLUT 4)
Glucose is used to make glycogen (in muscles and liver), and TAG (in adipose tissue)

NB: Effects in liver are not GLUT 4 mediated, but dependent on glucokinase
No effect on brain glucose usage (same in fed/fasted state)

32
Q

Describe T1DM

A

Autoimmune destruction of beta cells

Therapy through insulin injection/pumps to maintain blood glucose

33
Q

Describe T2DM

A

Later onset, but getting earlier
Insulin resistant: no longer as sensitive to endogenous insulin
Associated with obesity

34
Q

How does T2DM progress?

A

Years of insulin hypersecretion (because of resistance)

Eventually results in beta cell failure

35
Q

What are the different hypoglycaemic drugs available

A 
Sulphonylureas
Biguanides
Thiazolidinediones
Incretin mimics & DPP-4 inhibitors
SGLT2 inhibitors
36
Q

How do sulphonylureas work?

A

Inhibit ATP-sensitive K+ channels

37
Q

Name the sulphonylureas used clinically

A 
Glibenclamide
Gliclazide
Glimepiride
Tolbutamide
Glipizide
38
Q

Name the biguanides used clinically

A

Metformin

39
Q

Explain the mechanism of action of metformin

A

Mimics insulin by inhibiting hepatic gluconeogenesis
Mechanism of action uncertain but all involve inhibition of liver mitochondrial function
- Acts as a weak poison to inhibit mitochondrial ATP synthesis
- Stimulates body to stop gluconeogenesis due to perceived lack of energy

40
Q

Name the thiazolidinediones used clinically

A

Pioglitazone still used

Troglitazone and rosiglitazone was withdrawn (latter caused small increased risk in CVD)

41
Q

Describe the mechanism of action of pioglitazone

A

ligand for peroxisome proliferator-activated receptor-g (PPARg), a transcription factor, stimulating expression of genes involved in triglyceride storage

Stops inappropriate deposition of lipid in non-adipose tissues (which leads to insulin resistance) -> improves insulin sensitivity

42
Q

What is the incretin effect?

A

Observation that if you inject someone with glucose or get them to ingest the same amount of glucose you get different insulin secretion

More insulin is released when glucose is ingested orally

This process is dependent on incretins - gut hormones that sensitise beta cells to stimulate more insulin release

43
Q

What are incretins?

A

Gut hormones that potentiate insulin secretion

44
Q

Name the incretins

A

Glucagon-like peptide-1 (GLP-1)

Gastric inhibitory peptide (GIP)

45
Q

How are incretins inactivated?

A

Rapidly inactivated by the enzyme dipeptidyl peptidase-4 (DDP-4)

46
Q

Name incretin mimetics

A

Exanatide

Liraglutide

47
Q

Describe the mechanism of action of incretin mimetics

A 
Mimin incretins (GLP-1)
Engineered for slower breakdown - not cleaved by DDP-4
Injected - improve endogenous insulin secretion
48
Q

Name DPP-4 inhibitors

A

Sidagliptin

Vildagliptin

49
Q

Describe the mechanism of action of DPP-4 inhibitors

A

Inhibit DPP-4 enzyme that breaks down endogenous incretins
Increase endogenous incretin-mediated increase in insulin secretion

Oral drug

50
Q

Name the SGLT2 inhibitors

A

Canagliflozin
Dapagliflozin
Empagliflozin

51
Q

Describe the mechanism of action of SGLT2 inhibitors

A

Inhibit renal re-uptake of glucose from filtrate by SGLT2
Reduce hyperglycaemis by increased loss of glucose through urine (NB: makes patients more prone to UTIs)

Marked effect on weight loss and blood pressure
Trials suggest reduces cardiovascular mortality and hospitalisation due to cardiovascular events

Phase 2 3. Endocrinology (25 decks)

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