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ERS > ERS39 Biochemical Basis Of Diabetes Mellitus I > Flashcards

ERS39 Biochemical Basis Of Diabetes Mellitus I Flashcards

1
Q

Insulin

A
  • Peptide hormone
  • Regulates “nutrient/fuel” status of body
  • Interact with insulin receptor on membrane
  • Disruption of insulin biosynthesis —> wide spectrum of metabolic impairments
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2
Q

Physiological actions of Insulin

A

Take good care of fuel resources of human body

Liver:

  • ↑ Glucose uptake but NOT utilisation, ***↓ Gluconeogenesis
  • ↑ Glycogenesis, ↓ Glycogenolysis
  • ↑ Lipogenesis (Fatty acid)

Muscle:

  • ↑ Glucose uptake + utilisation
  • ↑ Glycogenesis

Adipose tissue:

  • ↑ Glucose uptake + utilisation
  • ↓ Lipolysis (TAG synthesis)
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3
Q

Biosynthesis of Insulin

A

Insulin gene
—> mRNA
—> **Pre-proinsulin (nascent: synthesised in rER)
—> Signal peptide cleavage + Disulphide bond formation (enable folding into right shape) (Post-translational modification: mature in rER)
—> **Proinsulin (Golgi)
—> C-peptide cleavage (Golgi)
—> ***Mature insulin
—> Insulin + C-peptide packaged into secretory vesicles in β cells
—> Secretion

Pre-proinsulin (nascent polypeptide in rER):
- Signal peptide (important for vectorial transport of polypeptide into rER lumen) + B chain + C chain + A chain

Proinsulin:

  • B chain + C chain + A chain
  • Disulfide bond formation (2 Inter between A/B chains, 1 Intra within A chain)

Mature insulin:
- B chain + A chain

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4
Q

Type 1 DM Pathogenesis

A

Genetic predisposition + Environmental trigger
—> **Islet cell-directed Ab + **T cell-mediated β cell injury + **Cytokines + **Macrophages
—> ↓ in β cell mass
—> ↓ ability of insulin secretion
—> ↓ beyond a certain point
—> Metabolic disorders (carbohydrates, protein, lipid)
—> Type 1 DM

Features:

  • ***↓ in β cell mass
  • Presence of insulitis (***infiltration of lymphocytic cells) —> chronic inflammation —> ↓ in β cell mass
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5
Q

Genetic correlation with Type 1 DM

A

MHC Haplotype (a group of MHC genes inherited together at the same time)

  1. Susceptibility haplotypes / alleles (occurrence in T1D patients higher than normal population)
    - e.g. B62, SC31, DR4
  2. Neutral haplotypes (occurrence in T1D patients not significantly different than normal population)
  3. Protective haplotypes (occurrence in T1D patients lower than normal population)
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6
Q

MHC/HLA genes

A

ALL MHC/HLA genes located on ***Chromosome 6 (MHC/HLA locus)
—> Code for MHC class I / II
—> MHC transmembrane protein (α + β chain)
—> possess peptide-binding cleft (for host protein, foreign pathogens etc.)

MHC genes are highly polymorphic:
i.e. many different α / β gene alleles (different version of same gene)
—> code for different respective α / β chains
e.g. β gene allele 1
—> specific a.a. sequence
—> a different polypeptide
—> usually a change in ***Peptide binding region of MHC molecule
—> determine whether a peptide can bind + how tight the binding is

N.B.: Certain alleles of MHC genes occur more frequently in Type 1 DM

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7
Q

Significance of forming a peptide:MHC complex

A
  1. Direct peripheral T cell response
    - Activation of CD4 mediated / CD8 mediated responses
    - T cell receptor: MHC binding site + Peptide binding site
    —> T cell cannot function with only binding of peptide alone
    —> must have MHC to bind to it as well
    —> ∴ stability of MHC/peptide complex very important (how tightly peptide bind to MHC protein)
    —> determine interaction with TCR (i.e. T cell response)

Rmb: T cell is restricted to recognise **peptide antigen bound to **self-MHC molecules

  1. Shaping T cell repertoire (∵ not all T cell receptor isoforms are function / beneficial to individual)
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8
Q
  1. Direct peripheral T cell response:

Antigen presentation by MHC-I and MHC-II molecules

A 
MHC class I:
Cytosolic pathway (for cytosolic proteins, self-protein, proteins from intracellular bacteria / virus)
—> recognised by CD8+ CTL
MHC class II:
Endocytic pathway (for exogenous proteins, extracellular microbes, antigens)
—> recognised by CD4+ helper cell
Basic overall process:
Antigen uptake
—> Antigen processing
—> MHC biosynthesis
—> Peptide-MHC complex formation within ER
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9
Q
  1. Shaping T cell repertoire:

Maturation of T cells in Thymus

A

Positive / Negative selection of T cells

Positive selection (要bind到self-MHC + foreign peptide):
- Double-positive immature Thymus T cell (CD4+ and CD8+) are screened for their ability to recognise **foreign peptides when presented to TCR by **self-MHC
—> T cell has opportunity to test several consecutive α chain rearrangements
—> recognise peptide bound to MHC class I molecules
—> programmed to express CD8 co-receptors (single positive) (vice versa)

  • T cells with TCRs having ***moderate affinity for self-MHC are allowed to further develop
  • Failure to recognise peptide-MHC complex on Thymic epithelial cells
    —> Apoptotic cell death
    —> ***Ensures mature T cells can recognise antigens in context of self-MHC molecules
  • Mediated by ***Thymic cortical epithelial cells

Negative selection (唔可以bind self peptide):
- T cells with receptors that recognise **self peptides:self MHC complex **too well will be destroyed
(if affinity very high —> that means peptide is self peptide)
—> eliminating potentially self-reactive cells
- Mediated by ***Dendritic cells, Macrophages

Overall:
Immature T cell
—> Positive selection (Thymus cortex)
—> MHC-restricted T cells (CD4+ / CD8+)
—> Negative selection (Thymus medulla)
—> Non-self T cells (some Autoreactive cells maybe in disguise)
—> migrate to periphery
—> Normally Autoreactive T cells can be kept silent by Anergic mechanisms
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10
Q

Treg cells

A

Treg cells:
1. Inhibit Th cell
2. Also undergo selection in Thymus (i.e. affected by actual MHC protein an individual possess)
—> Overall: can inhibit Autoreactive Th CD4+ cells

(However, rmb Treg may also be autoreactive)

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11
Q

Possible roles of MHC molecules in predisposing to Type 1 DM

A
  1. Certain variants of MHC-II molecules (on an individual)
    —> lead to ***faulty negative selection of T cells
    —> generation of too many Autoreactive T cells
  2. Certain MHC molecules through their effects on Treg cells (?)
    —> may ***compromise Anergic mechanisms (normally Autoreactive T cells can still be kept silent by Anergic mechanisms by Treg cells)
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12
Q

Summary of Negative selection

A

Above affinity threshold (i.e. if affinity very high)
—> meaning TCR can recognise self-peptide
—> TCR deletion

Below affinity threshold
—> TCR released to periphery
—> TCR close to affinity threshold for MHC:peptide complex is liable to act as autoreactive T cells
—> TCR well below affinity threshold will be non-self T cells (but cannot be too low otherwise cannot recognise foreign antigens)

Therefore:
MHC polymorphism
—> determines binding affinity
—> determines outcome of T cells (deletion / released to periphery)
—> determine whether autoreactive T cells will arise

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13
Q

Environmental factors causing β cells death

A
  1. Molecular mimicry model (Viral infection)
    Environmental factors (Pathogens)
    —> Infected pancreatic β cells
    —> express viral peptides (    very similar to self peptide derived from β cells)
MHC class I display of viral peptide on ***infected β cells
—> activation of ***autoreactive CD8+ T cells
—> β cells elimination

MHC class II display of viral peptide on **APC
—> activation of **autoreactive CD4+ T cells (Th2 subtype)
—> activation of B cells
—> ***Ab against Islet cells
—> β cells elimination

  1. Other environmental stimuli (diet, trauma)
    Toxic food substances, drugs, trauma
    —> damaged β cells
    —> release of β cells proteins (Autoantigens)
    —> β cell Autoantigens acquired, processed, presented by APC on MHC-II
    —> activation of **autoreactive CD4+ T cells (Th1 subtype)
    —> secretion of **    IL-1, TNFα, IFNγ / activation of ***autoreactive CD8+ T cells
    —> β cell killing

***記住: 本身已經有Autoreactive T cell, 再加上Environmental trigger
—> autoimmune destruction of β cells

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14
Q

Other genetics factor contributing to selection of T cells

A
  1. ***Proinsulin gene
  2. PTPN22 (protein phosphotyrosine-specific phosphatase)
  3. AIRE (autoimmune regulator, a transcription factor regulating expression of peripheral self-antigens: Tissue-restricted antigens (TRA) in ***thymic epithelial cells)

—> all involve expression of genes (i.e. antigens) in Thymus
—> affect selection of T cells

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15
Q
  1. Proinsulin gene
A

Promoter region: containing a region known as Variable number of tandem repeats (VNTR)
—> VNTR varies among individuals
—> affect ***expression of insulin gene in Thymus (for T cell selection)

(Proinsulin is expressed in Thymus (apart from β cells) —> serve as self-antigen for selection of T cells)

Class I VNTR:

  • 26-63 repeats —> Susceptibility gene —> Predispose to autoimmune destruction of β cells
  • much expressed in β cells but ***less expressed in Thymus —> insulin gene less expressed (訓練唔到T cell) —> cannot eliminate autoreactive T cells

Class III VNTR:

  • 140-200 repeats —> Protective gene
  • much expressed in β cells + also much expressed in Thymus
Overall:
Within Thymus (medullary epithelial cells)
—> Class III VNTR —> Insulin expression —> Normal selection of T cells + Treg cells
—> ***Class I VNTR —> ***Insulin under-expression —> ***Faulty selection of T cells + Treg cells
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16
Q

***Other genetic factors affecting Insulin secretion

A
  1. Glucokinase
    - high Km, high rate enzyme —> serve as **threshold to determine [glucose] level in cell
    - MODY2: gene mutation **    inactivating Glucokinase (responsible for phosphorylating glucose to G6P before glycolysis) —> ***cannot undergo glycolysis
  2. Mutations of transcription factors
    - controlling expression of proteins involved in **TCA cycle, glucose transport, insulin expression
    —> respiration cannot function properly
    —> **    problem with ATP production in response to high glucose
    - MODY3: HNF-1α
    - MODY1: HNF-4α
    - MODY5: HNF-1β
  3. Maternally Inherited Diabetes with Deafness (MIDD)
    - **mutation of mitochondrial genome
    —> **    problem with ATP production
  4. Permanent Neonatal DM (PNDM)
    - **permanent activation of ATP-sensitive K channel
    —> permanent hyperpolarisation of membrane
    —> **    no insulin secretion
17
Q

Opposing actions of Insulin / Glucagon

A

Insulin:

  • ↑ Glycogenesis
  • ↓ Glycogenolysis
  • ↑ Glycolysis
  • ↓ Gluconeogenesis

Glucagon:

  • ↓ Glycogenesis
  • ↑ Glycogenolysis
  • ↓ Glycolysis
  • ↑ Gluconeogenesis
18
Q

Regulation of glucose metabolism by Insulin

A

Diet / De novo synthesis of glucose
—> Glucose in circulation
—> **Insulin dependent (or independent) uptake into cells
—> **Insulin stimulated Glycolysis, Glycogenesis etc.

Type 1 DM:
—> not enough insulin secretion
—> cannot uptake + utilise glucose
—> ***Hyperglycaemia

19
Q

***Regulation of a.a. metabolism by Insulin

A

Insulin:
- ↓ Proteolysis (tissue protein —X—> a.a. —X—> glucose)

Glucagon:
- ↑ Proteolysis (tissue protein —> a.a. —> glucose) (only during starvation)

Type 1 DM:
—> not enough insulin secretion
—> nothing to oppose Glucagon
—> ***Tissue proteins continuously broken down into a.a. (irrespective of need)
—> ***Weight loss
20
Q

***Regulation of fatty acid metabolism by Insulin

A

TAG in adipocytes
—> Lipolysis by Hormone Sensitive Lipase (Inhibited by Insulin, **Stimulated by Glucagon, Ephinephrine)
—> Fatty acids in circulation
—> Fatty acids in cells
—> Fatty acids in mitochondria (Inhibited by Malonyl CoA)
—> β oxidation in mitochondria
—> **Ketone bodies

Insulin effects:

  1. Inhibits Lipolysis
  2. Promotes conversion of Acetyl CoA —> Malonyl CoA —> in turn ***inhibit transport of fatty acids into mitochondria
Type 1 DM:
—> not enough insulin secretion
—> nothing to oppose Glucagon
—> continuous ***break down of fat + no inhibition of ***β oxidation (irrespective of need)
—> production of Ketone bodies
—> ***Diabetic ketoacidosis
21
Q

***Diabetic Ketoacidosis in Type 1 DM (NOT usually occur in Type 2)

A

Insulin deficiency

  1. ↑ Hepatic glucose output (Over-production of glucose)
    —> Hyperglycaemia
    —> ↓ reabsorption of water in Kidney / Osmotic diuresis
    —> Polyuria
    —> Dehydration
  2. ↓ Non-oxidative glucose metabolism in skeletal muscle (Under-utilisation of glucose)
    —> Hyperglycaemia
    —> Polyuria
    —> Dehydration
3. ↑ Lipolysis
—> ↑ Fatty acid oxidation
—> ↑ Ketone body production
—> Too much ketone body to be metabolised by mitochondria (in TCA cycle) (Production > Metabolism)
—> Ketoacidosis

***Dehydration + Ketoacidosis —> Diabetic ketoacidosis

***Type 2 DM —> Insulin amount sufficient to suppress ketone body generation

ERS (41 decks)

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