Human metabolism lecture 1

Question 1

Insulin

Answer 1

• A chain = 21aa, B chain - 30aa linked by 2 disulphide

- Preproinsulin → proinsulin

Question 2

Metabolic effects of insulin

Answer 2

• Fed state hormone
• Obese subjects secrete ↑
• T2D lose control over [glucose]
• Major anabolic hormone, stimulates uptake of nutrients

Question 3

Effects of insulin on carbohydrate metabolism

Answer 3

• Effects:
  1. uptake of glucose in muscle + incorp into glycogen (GLUT4, GS, PDH)
  2. Inhibits hepatic production of glucose from glycogen breakdown + gluconeogenesis (stim of GS, inhib of glycogen phosphorylase + gluconeogenic E)

Question 4

Effects on fat metabolism

Answer 4

1. Stimulates synthesis of FA from glucose
2. Uptake of TAG into adipose + inhibition of mobilisation of stored fat from adipose (stimulates extracellular lipoprotein lipases, inhibition of ATGL + HSL)

Question 5

GS in muscle

Answer 5

• GS (active) → GS-P (inactive)
• Phosph at many sites by PKA, AMPK or GSK3
• 3a,b,c,4,5 = GSK3
• Insulin inhibits GSK3

Question 6

Insulin receptor

Answer 6

• Tetrameric
• Insulin binds → relieves inhibition of tyrosine kinase activity → substrate recruited to IR → IRS1 is phosph + binds PI3K which catalyses PIP2 → PIP3 → PKB recruited + phosph
• Phosph GSK3 at Ser21

Question 7

GLUT4 in muscle + adipose

Answer 7

• W/o insulin, 5% of GLUT4 = at cell surface

- Insulin promotes GLUT4 from GSV to cell surface by phosph 2 Rab GTPases (Rab13 in muscle)

Question 8

PDH in muscle

Answer 8

• PDH-P (inactive)
• Activated by ↑ ratio of AcCoA : CoASH, NADH:NAD + ATP:ADP
• Different isofordms
• PDK4 phosph + inactivates PDH
• Transcription of PDK4 = controlled by FOXO1, insulin → proteolysis + exclusion of FOXO1 → PDK4 x have TF → active PDH

Question 9

HSL + adipose triacylglycerol lipase

Answer 9

• TAG = surrounded by 100s of lipid droplet proteins
• e.g. = perilipin (barrier btw lipase + substrate)
• CGI-58 = activator for ATGL
• FAB4 binds FA + transports from lipid droplet to plasma membrane
• Adrenaline → PKA stimulated → perilipin fragments barrier, HSL recruited to surface of lipid droplet → CGI-58 binds ATGL → hydrolysis of TAG, FAB4 binds FA
• Insulin ↓ cAMP, lipolysis inhibited

Question 10

Transcriptional effects of insulin on hepatic gluconeogenic E

Answer 10

1. FOXO1
   - insulin → PKB → Phosph FOXO1 → nuclear exclusion + degradation → x stimulate expression for G6Pase or PEPCK
2. Creb
   - insulin → ↑ AKT which phosph Sik2
   - SIK2 phosph CBP + Crtc2 → Crtc2 degraded → inhibits transcription of gluconeogenic E
3. PGC-1a
   - Inhibits recruitment to gluconeogenic E

Question 11

Transcriptional effects of insulin on lipogenic gluconeogenic E

Answer 11

• Insulin stimulates transcription of FA synthesis
• All have TF SREBP which binds SRE
• insulin ↑ SREBP-1c by ↑ its transcription and activation via RIP
• RIP = when ER has ↓ cholesterol, SREBP2 moves from ER to Golgi by COPII, activated by Site1/2 protease → active TF, when ↑ cholesterol retained in ER
• Insulin phosph SREBP1c, has ↑ affinity for SCAP, moves to Golgi + activated
• Akt Phosphor + inactivates TSC1/2