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MBBS II ERS > L40 - Biochemical basis of Diabetes Mellitus II > Flashcards

L40 - Biochemical basis of Diabetes Mellitus II Flashcards

1
Q

Describe how overnutrition can lead to diabetes?

A 
Overnutrition 
> obesity 
> Insulin resistance + impaired glucose tolerance >> increase stress on beta cells
> Beta cell dysfunction 
> Hyperglycaemia 
> diabetes
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2
Q

Explain the relationship between Abdominal fat and lipolytic rate?

A

Higher abdominal fat:

  • Increase pro-lipolytic b-adrenergic receptors
  • Increase Insulin resistance
  • Increase 11β-HSD1 = Increase Cortisol

> > > fatter = higher lipolytic rate

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3
Q

Describe the intracellular effects of PRO-Lipolytic β-adrenergic receptors on lipolytic rate at adipose tissue?

A

Increase expression of pro-lipotypic B- receptors:

  • Increase cAMP formation: activate PKA:
    1) PKA phosphorylate Hormone sensitive lipase (HSL): break DAG into FA
    2) Disintegrate protective protein coat of Perilipin on surface of lipid droplet&raquo_space; more HSL action

> > increase lipolysis

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4
Q

Describe the intracellular effects of ANTI-Lipolytic adrenergic receptors receptors on lipolytic rate at adipose tissue?

A
  1. Catecholamines activate α-Adrenergic receptor > Gαi inhibit cAMP production**
  2. Insulin receptor:
    a) Activate IRS > P13K/PKB pathway to degrade cAMP

b) Inhibit desnutrin (HSL) > less DAG converted to FA
c) IRS > PP1 pathway to preserve perilipin protein coat on lipid droplet

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5
Q

Summarize all the altered adipocyte metabolism pathways caused by obesity?

A

1) Increase expression of pro-lipolytic B-adrenergic receptors&raquo_space; Increase basal rate of lipolysis
2) Increase leptin-stimulated lipolysis
3) Decrease expression of IRS-1 = decrease insulin sensitivity (less anti-lipolysis)
4) expression of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)&raquo_space; more cortisol
5) Activate Denustrin (HSL)

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6
Q

Describe the normal function of IRS-1 in insulin receptors in adipocyte (Careful: not asking about skeletal muscle)

A

1) Activate IRS > P13K/PKB pathway to degrade cAMP
2) IRS > PP1 pathway to preserve perilipin protein coat on lipid droplet

> > decrease lipolysis rate/ Anti-lipolysis

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7
Q

Describe how obeisity/ overnutrition/ lack of exercise can lead to increased TAG in liver and skeletal muscles?

A

Dysregulation of lipolysis

> > Fatty acid transported into liver and muscles

> > Fatty acyl CoA not transported into mitochondria for B-oxidation to make ATP (no exercise)

> > Fatty acyl CoA converted to DAG and TAG:

  • VLDL-TAG in liver
  • Intramyocellular TAG in skeletal muscle
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8
Q

Compare the functions of IRS-1 in Insulin receptors based on which part is phosphorylated?

A

1) Phos. at tyrosine residues&raquo_space; normal downstream signalling
2) Phos. at serine, threonine residues&raquo_space; no signalling&raquo_space; IRS incapacitated

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9
Q

Describe how increased abundance of DAG (due to dysregulation) in adipocyte can directly*** cause insulin inhibition?

A

DAG
> Activation of Novel Protein Kincase C***

> Phosphorylate serine/threonine residue of IRS

> Disable IRS, no downstream signalling

> Selective inhibition of insulin receptor: Increase pro-lipolytic receptors, no inhibition on HSL, more cortisol…etc

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10
Q

Describe how increased abundance of Fatty acid can INDIRECTLY cause insulin resistance? not asking about DAG and PKC

A

Increase FA

> > Activate PPARα/δ (peroxisome proliferator activated receptor)

> > Increase B-oxidation pathway activity

> > Increase NADH, FADH, Acetyl-CoA

> > Saturation of respiratory electron transport chain in mitochondria

> > Produce ROS to activate protein kinases

> > IRS phosphorylation = insulin resistance

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11
Q

Describe the effects of IRS on glycogenolysis, glycogenesis and glucose transport?

A

IRS&raquo_space; P13K/PDK pathway:

(Recruit P13K (lipid kinase)&raquo_space; Make Ptdlns 3,4,5-triphosphate&raquo_space; Recruit PDK to plasma membrane)

a) Activate GLUT4 translocation = more glucose transport
b) Activate AKT kinase:
i) Inhibit glycogenolysis
ii) Activate glycogenesis

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12
Q

Explain how Fatty acid can increase VLDL secretion?

A

Fatty acid cause insulin resistance (direct pathway via novel PKC + indirect pathway via PPARα/δ and ROS)

> > Remove insulin inhibition on conversion from TAG to VLDL-TAG (VLDL1)/ VLDL packaging

> > Untimely export of VLDL from liver

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13
Q

Summarize the effects of insulin resistance on liver glucose control?

A

1) PI3K/PDK/AKT kinase pathway affected&raquo_space; Persistent gluconeogenesis and glycogenolysis + impaired glycogenesis
2) Increase De novo lipid synthesis and untimely VLDL packaging&raquo_space; Increases VLDL1 secretion

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14
Q

Summarize the effects of elevated VLDL in serum on other lipoproteins?

A

1) More VLDL transfer Triglycerides to HDL&raquo_space; Increase HDL degradation, impair reverse cholesterol transport
2) More VLDL converted to LDL to Dense LDL&raquo_space; Harmful, highly Atherogenic

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15
Q

Explain how physical exercise can lead to increase FA utilization (instead of converted to TAG in liver and muscles)?

A
  • Increase exercise = more ATP used = more AMP
  • AMP activates AMP-activated kinase&raquo_space; Inactivation of Acetyl CoA carboxylase
  • Less A-coA made into Malonyl CoA&raquo_space; less inhibition of transporting Fatty acyl CoA into mitochondria for B-oxidation
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16
Q

What is the normal function of malonyl CoA in lipid metabolism?

A

Inhibit the translocation of Fatty acyl CoA into mitochondria for B-oxidation

17
Q

Explain how physical exercise can improve glucose metabolism in muscles?

A

Exercise: more ATP used, converted to AMP, activate AMP-Kinase (AMPK)
1) AMPK-independent: GLUT 4 translocation to plasma membrane&raquo_space; increase glucose transport into skeletal muscle

2) AMPK- dependent: increase FA utilization&raquo_space; reduce inhibitory phosphorylation of insulin receptor&raquo_space; restore insulin sensitivity

18
Q

Describe the triple action of Thiazolidinediones (TZD, e.g. rosiglitazone, pioglitazone)?

A

bind to activate PPARγ (= transcription factor for β-oxidation enzymes) in adipose tissue and muscle:

1) Increase FA uptake in adipocyte
2) Suppress Anti-inflammatory reaction (NF-kB) that cause insulin resistance by PPARγ complex
3) Differentiation of pre-adipocyte: more insulin-sensitive

19
Q

MoA of Biguanides?

A

insulin sensitizers, e.g. metformin

act on liver to activate AMP-protein kinase:
Inactivation of Acetyl CoA carboxylase = less malonyl CoA = more Fatty acyl CoA transport into mitochondria
» better FA utilization

20
Q

MoA of DDP-4 inhibitors?

A

inhibit breakdown of incretins&raquo_space; increase stimulation on pancreas for insulin secretion

MBBS II ERS (37 decks)

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