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Diabetes Flashcards

1
Q

describe the normal metabolism of glucose

A

eat –> glucose in blood causes beta cells in islets of langerham of pancreas to release insulin –> insulin moves to liver, muscles + adipose tissues –> binds to insulin receptor –> allows glucose uptake by cell –> stored as energy

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2
Q

what is the main complication of T1D?

A

beta cells are damaged –> no insulin released –> impaired glucose uptake –> high glucose in blood + urine (body think it hasnt been fed/ starving itself –> increased ratio of glucagon:insulin –> increase catabolism of glycogen (glycogenolysis), fat + protein –> increase fatty acid synthesis = ketone bodies synthesis –> decrease blood pH+ dehydration

if not treated with exogenous insulin = can cause unconsciousness

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3
Q

describe the pathogenesis of T1D (immune cells)

A

1) APC (B cells, macrophages, DC) recognise beta cells as foreign, phagocytose + present antigen fragments on MHC 2 –> present to autoreactive CD4 T cells (that have escapes neg selection)
2) CD8 T cells recognise MHC 1 presenting immunogenic self antigens –> kill beta cells
3) innate + adaptive (B + T ) cells will release proinflammatory cytokines & ROS –> exacebate beta cell destruction
4) activated B cells produce autoantibodies = measured as biomarkers for diagnosing T1D

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4
Q

classifcaition of diabetes?

A

1) T1D (insulin dependant, juvenile diabetes)
- autoimmunty destruciton of insulin-producing beta cells
- 5-10%

2) T2D (insulin independant)
- insulin resistance + insulin deficiency

3) other types
- genetic defects affecting beta cell function + insulin action
- 1-2% cases

4) gestational diabetes
- insulin resistnace / decrease insulin synthesis during pregnancy
- 3-5% all pregnancies

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5
Q

T1D diagnostic criteria

A

1) fasting plasma glucose level > 7 mmol per L (126mg/dL)
2) random venous plasma glucose level of >11.1 mmol / L (200mg/dL) in patient with classic hyperglycaemic symptoms
3) plasma glucose levels >11.1mmol/L (200mg/dL) measured after glucose load (1.75g/kg)

4) glycated Hb HbAc1 > 6.5%
- when glucose levels high = glucose attaches to Hb on rbc = becomes glycated hb = reflects avg BG over lifespan of rbc containing it

5) autoantibodies- B AND T cells produce antibodies that react to self beta cell antigens
- escaped neg selection due to:
1. suboptimal presentation of beta cell antigen on MHC 2 of APC to TCR in thymus (weak interaction of beta cell antigen to MHC 2) = escape neg selection

  1. decreased thymic INS experssion = (1) reduce neg selection of autoreactive T cells
    (2) limit thymic development of beta cell specific T reg cell (FOXp3+ )
  2. mutation in PTPN33 gene = increase phosphatatse activity to TCR signalling pathway =
    (1) limit T cell gene exp
    (2) limit prod of inflammatory cytokines
    ==> reduce neg selection (dont know which T cell is auto-reactive)
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6
Q

what are the enviornemntal factors causing T1D?

A

1) infection / microbes/ gut microbiome
- Hygiene hypothesis: early child exposure to infection/microbes can increase tolerance to self antigens

2) virus infection: certain antigens can trigger local inflamation + attract other reactive lymphocytes

3) sunlight + vit D
- increase T1D in cananda + scandanavian due to lack of sunlight

4) diet:
- accelerator hypothesisis: modern diet of high sugar can put stress on beta cells

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7
Q

what is the current treatment for T1D?

A

EXOGENOUS INSULIN

1) multiple BGL measurements (>4x)
2) daily multiple-dose insulin injections to mimic pscyhologic insulin release ( ~ 4 injections per day)
3) detecting hypoglycaemia events (sudden decrease in BGL)

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8
Q

what is metabolic complication of T1D?

A

1) ketoacidosis
2) hyperglycaemia (no insulin)
3) hypoglycamia (side effect of blood sugar lowering medications)

lack of insulin release causes high glucose concentration in blood + urine –> increases glucagon: insulin ratio –> increase catabolsim of glycogen (glycogenolysis), fat, protein –> adipose tissue releases fatty acids (lipolysis) –> liver converts fatty acids into KETONE BODIES (beta oxidation) –> ketone bodies undergo beta oxidation = low pH

1) acidosis
2) acetone fruity breath

2) HYPOGLYCAEMIA:

  1. decreased bgl due to suboptimal insulin treatment
  2. if not treated can lead to loss of consciousness+ seizure (occures 1-4x per 50 patient years)
  3. treatment= quick sugar source
  4. if recurrent hypoglycameia=. results in hypoglycaemia unawareness (dont seek sugar source)
  5. assocaited w 4-10% T1D related deaths
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9
Q

describe hypoglycaemia in T1D

A

1) side effect of suboptimal insulin treatment = decreased blood glucose levels
2) treatment= sugar source
3) causes loss of consciousness / seizure (happens 1-4 times ervery 50 patient years)
4) ongoing hypoglaemica events can cause unawanreness (dont seek sugar source)
5) associated 4-10% with T1D related deaths

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10
Q

what are the microvascular complications of T1D?

A

HYPERGLYCAEMIA IS PRIMARY RISK FACTOR

  • intensive management of BGL: can have slower progression + reduced chance of microvascular complications
  • if BGL not properly managed = glucose attaches to pbody proteins, results in:
    1) retinopathy
    2) diabetic nephropathy
    3) nerve: decreased sensation in toes + fingers
    4) affects autonomic nervous system = poor blood supply

1) retinopathy
- new blood vessels form at back of the eye & burst causing vitreous hemorrhage (blood leaks around viterous humour of eye)
- >80% T1D develop retinopathy
- can lead to blindness if not proper manged

2) diabetic nephropathy
- caused by increased albumin excretion in urine
- high glucose in blood due to no insulin production = glucose sticks to Hb protein on rbc = kidney tries extra hard to eliminate glucose through urine = but since glomerulus only filters small particles , glucose binded to Hb can damage glomerula = decrease glomerular filtration rate
- may need kidney tarnsplant

LONG TERM COMPLICATIONS
3) nerve damage:
decreased sensation in fingers + toes = glove and stocking symptoms

4) autonomic nervous system issues:
- hypoglycaemia unawarness
- excessive sweating
- postural hypotension ( Low BP when stand up)
- POOR BLOOD SUPPLY

nerve damage + poor blood supply = can cause ULCERS = AMPUTATIONS

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11
Q

describe diabetic retinopathy

A
  • intensive management of BGl can slow progression + reduce incidence of microvascular complications of T1D
  • new blood vessels form at back of eye –> can burst and lead to virteous haemorrhage (blood leaks into vitreous humour of eye)
  • if not treated can lead to blindness
  • more than 80% T1D patients develop it
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12
Q

what are the long term complicartions of T1D?

A

1) nerve damage = decreased sensation in fingers and toes = glove and stocking symptoms

2) autonomic nervous system
- hypoglycaemia unawareness
- excsssiev sweating
- postural hypotension
- poor blood supply

nerve damage + poor blood supply = cause ULCERS = require AMPUTATION

3) macrovascular complicatison
- coronary heart disease
- cerebrovascular disease
- peripheral artery disease

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13
Q

what macrovascular diseases can T1D incrase the risk of ?

A

1) coronary heart disease
2) cerebrovascular disease
3) peripheral artery disease

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14
Q

acinus vs islets of langerhans

A

acinus= exocrine function = secretes products into a duct that opens into epithelium

part 1: acinar cells
- stored in ZYMOGEN GRANULES (protect pancreatic cells from destruction)

1) amylase = breaks down carb
2) lipase = breaks down lipids
3) trypsinogen = breaks down proteins

  • stimulated by Ach + CCK
    (acetylcholine + Cholecystokinin)

part 2: ductal cells

  • produce aq solution containing bicarbonate = helps neutralise acidic stomach
  • stimulated by secretion, Ach, CCK

islets of langerhans = endocrine function = secretes hormones into blood directly

1) beta cells = insulin
2) alpha cells = glucagon
3) delta cells = somatostatin
4) gamma cells (F or PP cells) = pancreatic polypeptide
5) epsilon cells= grehlin

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15
Q

whats the role of pancreas

A

releases hormones/ enzymes to digest macronutrients + maintain energy / metbaolism homeostasis

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16
Q

what abnormalities occur to pancreas + islets in T1D?

A

Endocrine compartment:

  • varibale distribution of immune infiltrating cells
  • beta cell depletion + decreased insulin expression

exocrine compartment:

  • loss of pancreatic volume
  • exocrine gland atrophy

non endocrine islet cells
- possible changes in islet vasculature & Extracelllular strucutre, still under investigation

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17
Q

what happens when there is stress/ infection ?

Or

how does polyuria, dehydrateion & polydipsisa occur?

A

stress/infection –> releases epinephrine –> stimualtes glucagon release = increases glucagon: isnulin ration –> causes liver to produce glucose (gluconeogenesis )–> increase BGL = kidney tries to remove increased blood glucose along with water + solute (osmotic diuresis)
–> results in polyuria, dehydration + poly

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18
Q

what are the stimulators and inhibitors of glucagon + insulin release

A

insulin stimulated by:

  • ^ BGL
  • ^ GLP-1, GIP
  • ^ fatty acid + amino acid in blood

inhibited by:

  • noradrenaline (stress, want ^ glucose in blood)
  • somatostatin (tries to delay nutrient absorption in GI tract)

glucagon stimualted by:

  • Adrenaline (stress)
  • CCK (favours digestion)

glucagon inhibited by:

  • insulin (to keep both levels within a range)
  • somatostatin
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19
Q

describe the insulin synthesis + secretion pathway

A

insulin synthesis:
INS transcribed on chr 11 –> signal peptide cleaves off –> A+B peptide join by disulphide bonds –> forms insulin + C peptide

when eat - glucose enters blood - glucose binds to beta cells of islets of langerhans of pancreas - moves through GLUT 1/2/3 transporters –> Glucokinase convert glucsoe –> glucose6phosphate –> change in ATP:ADP ratio inactivate ATP sensitivei K channels –> membrane depolarisation –> activates & open voltage gated Ca channels –> Ca move out, casuses insulin exocytosis

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20
Q

what is the importance of C peptide

A

used in research studies to determine beta cell function

C peptide is the 3rd peptide made after INS gene (chr 11) is transcribed–> A+B peptides are joined by disulphide bonds + C peptide
less C peptide = less insulin

1) determine those at risk of developing T1D
2) determine residual beta cell mass & fucntion in long standing T1D patients
3) determine beta cell funciton in those whove gotten pancraes/islet transplant

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21
Q

how is glucagon syntehsised

A

encoded by GCG gene on chr 2
stored in alpha cells –> stimulation by Adrenaline + CCK –> cause glucagon release

pre/pro-glucagon –> pro glucagon –> glucagon

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22
Q

what does CCK stimualte?

A

CCK stimualtes :

1) acinus cells (ACh + CCK)
- release digestive enzymes into ducts open into epithelium
- amylase = digest carb
- lipase = digest lipids
- trypsinogen = digest proteins

2) ductal cells (Ach + CCK + secretin)
- release aq soltuion of bicarbonate to neutralise stomach acid
- stimualted by ACh + CCK + Secretin

3) stimualtes glucagon release

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23
Q

how to measure glucose?

A

monitor blood glucose levels at least 4 times a day

1) take finger blood prick
glucose oxidase will convert glucose –> gluconolactone
O2 –> H2O2 = will be detected

2) electrodes are used
- electrical current = proportional to conc of blood glucose
- more current = more BGL

if BGL are:

  • above 7.8mmol/L = hyperglycemia
  • betwen 3.3-7.8 mmol/L = normal range
  • below 3.3mmol/L = hypoglycemia
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24
Q

how to measure insulin + C peptide?

A

measuring insulin:

1) to detect insulomas (insulin secreting tumours)
2) of limited use to diabetes (patients can undergo honey moon period where they are experience diabetes, but have residual insulin left )

measuring C-peptide (precursor of insulin + main target for T cells)
- present in peripheral blood of T1D onset

1) determine indivduals suceptibe to t1d
2) determine beta cell mass & function in long standing T1D patients
3) determien beta cell mass and funciton in pancreas/islet tnrasplants

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25
Q

how does diabetic ketoacidosis occur?
or
explain glucagon:insulin ratio cause & effect

A

ketoacidosis

lack of insulin –> unable to cause glucose uptake in liver, adipose, muscle cells –> unable to generate energy = body thinks its starving itself –> Adenaline (stress) + CCK stimulates glucagon release–> increases glucagon : insulin ratio –> adipose tissue releases free fatty acids (lipolysis) –> liver converts into ketone bodies (beta oxidation) , results in:

1) decreased PkA = decrease pH = ketoacidosis
2) acetone (fruity breath)

stress:
epinephrine released –> stimulates glucagon secretion: increases glucagon:insulin ratio –> contributes to increased ketone bodies

glucagon increases gluconeogenesis + glycogenolysis –> increase BGL = high glucose in blood = body would want to increase excretion via kidneys = weakens glomerulus & decreases GFR= increase glucose secretion with water + solutes (osmotic diuresis ) –> POLYURIA, DEHYDRATION, POLYDIPSIA

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26
Q

describe difference between type 1 & type 2 diabetes

A

1) t1d = hyperglycemia results from reduced/ no beta cell mass
2) t2d = hyperglycemia results from:
- down regulation of insulin receptors on liver, adipose, muscle cells
- insulin resistance
- beta cells try to overcompensate by producing more insulin since it thinks the insulin is not working = weakens beta cells –> causes beta cell dysfunction = leads to hyperglycemia
3) insulin exogenous treatment = t1d + t2d (late stages of disease)
4) t2d = preventable by lifestyle modification

27
Q

what genes confer the highest risk to t1d? describe these genes

A

HLA genes confer highest risk
- HLA genes = group of genes on chr 6, divided into 3 classes

3 genes on CLass 2 of HLA gene are invovled in susceptibily risk to T1D:

1) DQ2 > 3.6
2) DQ8 > 11.4
3) DQ2; DQ8 => 16.6 gives highest risk of T1D (highest odds ratio)

28
Q

what are the funcitons of HLA molecules?

A

1) shape the T cell repertoire during T cell development :
- determine which thymocyte is deleted + positively selected for
2) present antigens on MHC class 2- present & activate CD4 T cells in the periphery

29
Q

what are the hypothesis of why there is no central tolerance/ negative selection established in T cells?

A

1) high risk alleles of HLA genotype: can increase presentation of pro-insulin/ c-peptide to immune cells

2) Central tolernace / negative selection = process in T cell maturation in THYMUS
- eliminates T cells that bind and react to self antigens presented on MHC class 2 (HLA 2)
- usually those T cells that self-react in thymus are elimiated to estbalihs central tolerance
but. ..

in T1D: particular HLA molecules (Dq2/dq8) dont present beta cell antigens EFFCIENTLY in the thymus
1) beta cells antigens have weak interactions with HLA 2 molecule of APC = suboptimal presentation to TCR = there is no way to see which T cell will react to self = no way to eliminate those self-reactive ones
2) those TCels will escape thymus –> move into pancreas + draining lymph nodes = where there are hgih conc of beta cell antigens presented on MHC2 of APC = TCell recongises them as foreign & attacks =
causes beta cell destruction

3) makes memory T cells specific to targeting beta cell antigens

dysregulation of negative selection = generates a peripheral pool of anti-self T cells = increases avidity + affinity + likely to have a pathogenic effect

30
Q

what are the NON HLA genes involved in genetic susceptibility to T1D?

A
  • non-HLA genes confer smaller risk of T1D than HLA genes

- many non-HLA genes assocaited w immune function

31
Q

how does T cell escape negative selection?

A

HLA + NON -HLA genes:

1) HLA genes (SQ2/8):
- serotype odds ratio can change susceptibility of developing T1D
1. high risk allele of HLA genotype: can incrase presentation of PRO-INSULIN/C-PEPTIDE to immune cells

  • hypothesis:
    1. weak interaction bw beta cell antigen + HLA/MHC molecule on APC –> supotimal expression of beta cell antigens to TCR in THYMUS –> TCR are not exposed enoguh to beta cell antigens–> not able to determine which TCells are self-resctive= cant escape negative selection
    2) escape thymus –> pancreas /draining lymph nodes = where large amount of beta cell antigens are = TCells will recongise + destruct beta cell antigens
    3) produce memory T cells specific to beta cell antigens (although presence of this does not correlate with T1D- can be seen in normal ppl too)

2) NON HLA GENES:
> INS
> PTPN22

INS:
- VNTR= upstream of INS exons = has 3 classes:

class 1: predisposing allele (responsible for decreased INS expression)

class 3: protective alleles (increased INS expression)

  • increase INS expression = decreased T1D risk (class 3)
  • decrease INS expression = increased T1D risk: (class 1)
  1. reduce neg selection = allows insulin specific single positive thymocytes survive
  2. limit thymic development of beta cell specific T regulatory expression (FOXP33+ CD4 t cells)

PTPN22: phosphotase activity
- normal: when TCR binds antigen presented on MHC moelcules = signal transduciton pathway = activate TF = increase T cell gene exprression

  • C -T mutation of PTPN22 gene = increases phosphatase activity of PTPN22 = phosphorylates Lck + ZAP70 =
    1) limit TCR signalling = reduce T cell gene expression
32
Q

what are the biomarkets that distinguish T1D from T2D?

A

1) IAA ( insulin auto-antibodies )= first detected
2) GADA + IAA = most frequent in children
3) high affinity IAA + GADA = reflects progression to multiple islet autoantibodies + diabetes
4) other autoantibodies (IA-2, ZnT8) = typically appear later, indicate further progression of disease

33
Q

what 4 self antigens do pancreatic beta cells produce

A

1) insulin = prod by beta cells
2) GAD65 (glutamic acid decarboxylase) = not exclusive to pancreatic beta cells
3) IA-2 (tyrosine phosphatase like islet antigen 2) (356-760).= not exclusive to pnacreatic bet cells
4) ZNT8, zinc transporter huge role in insulin secretion + storage = highly expressed in endocrine pancreas + extra-pancreatic sites, NOT in exocrine pancreas

34
Q

what evidence supports the fact that islet autoantibodies DOES NOT mean one has T1D?

A

1) islet autoantibodies does not have cytotoxic effect on islets in vitro (mix them tog, islets still continue to make insulin normally)
2) maternal transfer of autoatnibodies into fetus= does not increase child getting T1D
3) person with X linked gammaglobuliaemia (someone who doesnt make antibodies) can still get T1D

35
Q

how are beta cell specific T cell PHENOTYPES different in healthy vs T1D ppl?

A

beta cell specific T cells in peripheral blood are RARE in T1D patients + can sometimes be found in healthy ppl.
==> DIFFERNECE IN PHENOTYPES of beta cell specific T cells bw health + T1D ppl:

healthy ppl beta cell specific T cells are:

1) naive phenotype (not activaited)
2) regulatory responses (IL-10 supressimmun response)

T1D patient:

1) memory + effector phenotype (already activated)
2) produce inflammatory cytokines (PTPN22 mutation) (IFN-g)

==> causes ongoing beta cell destruction

36
Q

what is the pathologic hallmark of t1D? + DESCRIBE INSULITIS

A

INSULITIS- where immune cells infiltrate the islets = causes beta cell loss (little insulins staining)

37
Q

DESCRIBE INSULITIS

A

insulis is pathologic hallmark of T1D: occurs when immune cells infiltrate the pancreatic islets & cause beta destruction & decrease insulin

characteristics in pancreatic tissues:

1) increased beta cell destruction
2) decrease insulin staining
3) increased glucagon
4) infiltration is NOT homogenous (diff parts of islet are infiltrated at diff rates + diff amounts)
- only 10-30% of ilsets are dmaaged at any 1 time
- small amount of islets damaged for T1D to occur
5) insulitis is lobular (some parts are more infiltrated than others)
- in insulin positive cells = insulitis can be PERI-insulitis (periphery islets) or INTRA-insulitis (within islets parenchyma)

6) there are pseudoatrophic islets with NO beta cells, but still have ALPHA + DELTA
- cells present:
- CD4 = produce inflammatory cytokines = exacebate beta cell destruction
- CD8 = recognise beta cell antigen on MHC 1= directly kill
- APC: dendritic + macrophages

38
Q

what genetic factors give people high risk for T1D?

A

1) HLA serotype: DQ2;DQ9
2) INS genes: patients homozygous for VNTR class 1 (predisposing allele)
- reduce neg selecrition of insulin specific single positive thymocytes
- limit thymic development of beta cell specific regulatory T cells (Foxp3+ cd4+ t cells)

39
Q

WHAT IS SPECIAL ABOUT PRO-INSULIN

A
  • main target for T cells
40
Q

patients with long standing T1D have:

A

1) beta cell specific CD8 T cells detected in T1D patients
- found MHC tetramers to present peptides from diff beta cell antigens: GAD65, IA-2, IGRP, IAAP

2) even up to 8 yearts after clinical diagnosis: some still showed CD8 T cell autoreactivities against islet autoantigens
- HLA class 1 tetramer w insulin derived peptide (proinsulin/c-peptide)
- HLA classs 1 tetramer w IGRP derived peptide

3) newly diagnosed T1D patients:
- had low-grade enteroVIRAL infection in islets
- viral infection + innate immune activation =
1. overexpression IFN stimualted genes
2. ^ production of IFNa in pancreas

4) hyper-expression of HLA class 1 + 2 moleculees in islets

41
Q

what does upregulation of HLA class 1 mean?

A

increase HLA class 1 expression + presentation of beta cell autoantigens

beta cells antigens present on HLA class 1 of beta cell surface

TCR recognises & binds to HLA class 1 on beta cell surface

CD8 T cells secrete PERFORIN granzyme = punch holes into beta cell membrane = induce apoptosis

+ cause Ca influx

42
Q

what are the hypothesis of why there is no central tolerance/ negative selection established in T cells?

A

1) high risk alleles of HLA genotype: can increase presentation of pro-insulin/ c-peptide to immune cells

2) Central tolernace / negative selection = process in T cell maturation in THYMUS
- eliminates T cells that bind and react to self antigens presented on MHC class 2 (HLA 2)
- usually those T cells that self-react in thymus are elimiated to estbalihs central tolerance
but. ..

in T1D: particular HLA molecules (Dq2/dq8) dont present beta cell antigens EFFCIENTLY in the thymus
1) beta cells antigens have weak interactions with HLA 2 molecule of APC = suboptimal presentation to TCR = there is no way to see which T cell will react to self = no way to eliminate those self-reactive ones
2) those TCels will escape thymus –> move into pancreas + draining lymph nodes = where there are hgih conc of beta cell antigens presented on MHC2 of APC = TCell recongises them as foreign & attacks =
causes beta cell destruction

3) makes memory T cells specific to targeting beta cell antigens

dysregulation of negative selection = generates a peripheral pool of anti-self T cells = increases avidity + affinity + likely to have a pathogenic effect

43
Q

what are the NON HLA genes involved in genetic susceptibility to T1D?

A
  • non-HLA genes confer smaller risk of T1D than HLA genes

- many non-HLA genes assocaited w immune function

44
Q

how does T cell escape negative selection?

A

HLA + NON -HLA genes:

1) HLA genes (SQ2/8):
- serotype odds ratio can change susceptibility of developing T1D
1. high risk allele of HLA genotype: can incrase presentation of PRO-INSULIN/C-PEPTIDE to immune cells

  • hypothesis:
    1. weak interaction bw beta cell antigen + HLA/MHC molecule on APC –> supotimal expression of beta cell antigens to TCR in THYMUS –> TCR are not exposed enoguh to beta cell antigens–> not able to determine which TCells are self-resctive= cant escape negative selection
    2) escape thymus –> pancreas /draining lymph nodes = where large amount of beta cell antigens are = TCells will recongise + destruct beta cell antigens
    3) produce memory T cells specific to beta cell antigens (although presence of this does not correlate with T1D- can be seen in normal ppl too)

2) NON HLA GENES:
> INS
> PTPN22

INS:
- VNTR= upstream of INS exons = has 3 classes:

class 1: predisposing allele (responsible for decreased INS expression)

class 3: protective alleles (increased INS expression)

  • increase INS expression = decreased T1D risk (class 3)
  • decrease INS expression = increased T1D risk: (class 1)
  1. reduce neg selection = allows insulin specific single positive thymocytes survive
  2. limit thymic development of beta cell specific T regulatory expression (FOXP33+ CD4 t cells)

PTPN22: phosphotase activity
- normal: when TCR binds antigen presented on MHC moelcules = signal transduciton pathway = activate TF = increase T cell gene exprression

  • C -T mutation of PTPN22 gene = increases phosphatase activity of PTPN22 = phosphorylates Lck + ZAP70 =
    1) limit TCR signalling = reduce T cell gene expression
45
Q

what are the biomarkets that distinguish T1D from T2D?

A

1) IAA ( insulin auto-antibodies )= first detected
2) GADA + IAA = most frequent in children
3) high affinity IAA + GADA = reflects progression to multiple islet autoantibodies + diabetes
4) other autoantibodies (IA-2, ZnT8) = typically appear later, indicate further progression of disease

46
Q

what 4 self antigens do pancreatic beta cells produce

A

1) insulin = prod by beta cells
2) GAD65 (glutamic acid decarboxylase) = not exclusive to pancreatic beta cells
3) IA-2 (tyrosine phosphatase like islet antigen 2) (356-760).= not exclusive to pnacreatic bet cells
4) ZNT8, zinc transporter huge role in insulin secretion + storage = highly expressed in endocrine pancreas + extra-pancreatic sites, NOT in exocrine pancreas

47
Q

what evidence supports the fact that islet autoantibodies DOES NOT mean one has T1D?

A

1) islet autoantibodies does not have cytotoxic effect on islets in vitro (mix them tog, islets still continue to make insulin normally)
2) maternal transfer of autoatnibodies into fetus= does not increase child getting T1D
3) person with X linked gammaglobuliaemia (someone who doesnt make antibodies) can still get T1D

48
Q

how are beta cell specific T cell PHENOTYPES different in healthy vs T1D ppl?

A

beta cell specific T cells in peripheral blood are RARE in T1D patients + can sometimes be found in healthy ppl.
==> DIFFERNECE IN PHENOTYPES of beta cell specific T cells bw health + T1D ppl:

healthy ppl beta cell specific T cells are:

1) naive phenotype (not activaited)
2) regulatory responses (IL-10 supressimmun response)

T1D patient:

1) memory + effector phenotype (already activated)
2) produce inflammatory cytokines (PTPN22 mutation) (IFN-g)

==> causes ongoing beta cell destruction

49
Q

what is the pathologic hallmark of t1D? + DESCRIBE INSULITIS

A

INSULITIS- where immune cells infiltrate the islets = causes beta cell loss (little insulins staining)

50
Q

DESCRIBE INSULITIS

A

insulis is pathologic hallmark of T1D: occurs when immune cells infiltrate the pancreatic islets & cause beta destruction & decrease insulin

characteristics in pancreatic tissues:

1) increased beta cell destruction
2) decrease insulin staining
3) increased glucagon
4) infiltration is NOT homogenous (diff parts of islet are infiltrated at diff rates + diff amounts)
- only 10-30% of ilsets are dmaaged at any 1 time
- small amount of islets damaged for T1D to occur
5) insulitis is lobular (some parts are more infiltrated than others)
- in insulin positive cells = insulitis can be PERI-insulitis (periphery islets) or INTRA-insulitis (within islets parenchyma)

6) there are pseudoatrophic islets with NO beta cells, but still have ALPHA + DELTA
- cells present:
- CD4 = produce inflammatory cytokines = exacebate beta cell destruction
- CD8 = recognise beta cell antigen on MHC 1= directly kill
- APC: dendritic + macrophages

51
Q

how have other potnetial biomarkers been observed ?

A
  1. transcript analysis of whole blood samples/ peripheral blood mononuclear cells
  2. responses in standardised reporter cell lines exposed to serum
  3. metabolomic analysis of serum
  4. most direct = observe presence of T cells specific to autoantigens in Beta cells
52
Q

WHAT IS SPECIAL ABOUT PRO-INSULIN

A
  • main target for T cells
53
Q

patients with long standing T1D have:

A

1) beta cell specific CD8 T cells detected in T1D patients
- found MHC tetramers to present peptides from diff beta cell antigens: GAD65, IA-2, IGRP, IAAP

2) even up to 8 yearts after clinical diagnosis: some still showed CD8 T cell autoreactivities against islet autoantigens
- HLA class 1 tetramer w insulin derived peptide (proinsulin/c-peptide)
- HLA classs 1 tetramer w IGRP derived peptide

3) newly diagnosed T1D patients:
- had low-grade enteroVIRAL infection in islets
- viral infection + innate immune activation =
1. overexpression IFN stimualted genes
2. ^ production of IFNa in pancreas

4) hyper-expression of HLA class 1 + 2 moleculees in islets

54
Q

what does upregulation of HLA class 1 mean?

A

increase HLA class 1 expression + presentation of beta cell autoantigens

beta cells antigens present on HLA class 1 of beta cell surface

TCR recognises & binds to HLA class 1 on beta cell surface

CD8 T cells secrete PERFORIN granzyme = punch holes into beta cell membrane = induce apoptosis

+ cause Ca influx

55
Q

how do CD8 T cells target beta cells

A

CD8 T cells recognise beta cell antigen presented on MHC1 of beta cell surface –> bind = intracellular signalling = secrete perforins = lyse holes in membrane of b-cell membrane –>contain serine proteases that signal apoptosis
–> release cytokines + beta cell epitopes: epitope spreading = more antibodies to be made against INS, GAD65, IA-2, ZnT8, Pro-insulin, IGRP, IAAP, ChG) = progressive insulin loss

56
Q

what are the risk factors for people developing T1D depending on:

  • First degreee relative (FDR)
  • HLA risk allele
A

low risk = no FDR + no HLA risks alleles

intermediate risk = no or 1 affected FDR + HLA risk alllele

high risk = 1 or multiple affected FDR + HLA risk alelele

very high risk = multiple affected FDR or identical twins affected + HLA risk allele

57
Q

compare the odds ratio of HLA vs NON-HLA genes

A

odds ratio of NON-HLA genes is SMALLER that HLA genes

  • INS + PTPN22 = highest odds ratio amongst NON-hla genes
58
Q

what is the relationship between no. of islet autoantibodies and risk of T1D?

A

as you increase the no. of islet antibodies produced (from CD4 T cells signalling to B cells to make antibodies) = you increase the probability of developing diabetes

59
Q

what are the risk categories of developing T1D

A

low risk:

  • single islet autoantibody (low affinity)
  • older age
  • non susceptible HLA alleles

intermediate risk

  • single islet autoantibody (high affinity)
  • proinsulin reactive IAA, middle/C terminal reactive GAD65
  • young age
  • HLA DR3/4

high risk:

  • 2 or 3 islet Abs (IA2A, Ant8A)
  • young age
  • low first phase insulin (HLA risk genotype)

very high risk:

  • 4 islet ab
  • ab to IA2b epitopes
  • higher titre
  • multiple IgG subclasses responses
  • young age @ initiation
  • impaired glucose tolerance (HLA risk genotype)
60
Q

why do we need more biomarkers for disease risks?

A

because we want to be able to identify people at risk of developing T1D, before stage 1
- having presence of single autoantibody is NOT enough to predict who has T1D (<30% of ppl w signle autoantibody progresses to clinical disease stage)

  • identify other biomarkers that will increase accuracy of predicitng who will develop T1D
61
Q

how have other potnetial biomarkers been observed ?

A
  1. transcript analysis of whole blood samples/ peripheral blood mononuclear cells
  2. responses in standardised reporter cell lines exposed to serum
  3. metabolomic analysis of serum
  4. most direct = observe presence of T cells specific to autoantigens in Beta cells
62
Q

how do we predict the development of T1D

A
  1. genetic markers
    - family history
    - HLA DR-DQ genotype
  2. T1D relevant immune markers
    - autoantibodies against insulin, GAD65, IA-2, ZnT8
  3. immune markers associated with disease progression
    - antibody affinity + epitopes
    - IVGTT = tests insulin secrtion + specifity after intravenous glucose infusion
  • OGTT = tests fasting plasma gluc levels, HbA1C, T cell immunity markers = test bodys ability to handle glucose
  1. disease development
    - for indivduals with OR wihtout family history of T1D, if they have multiple islet antibodies - they are defs gona get T1D
63
Q

what does it mean to say CLINICAL course of T1D is Heterogenous

A
  • in ppl who have multiple islet cell autoantibodies + LOW first phase insulin response= each person has DIFF RATE + DEGREE of beta cell destruction

= different amount of residual beta cell mass + function

64
Q

what are the 3 main types of clinical presentations (acute, sub-acute, asymptomatic)

A

acute:

1)

m2m (4 decks)

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