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PATH30003- Frontiers in Human Disease > Lecture 22-Type 1 Diabetes > Flashcards

Lecture 22-Type 1 Diabetes Flashcards

1
Q

insulin was the first hormone to be?

A

cloned and produced recombinantly for therapeutic use

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2
Q

insulin is made by

A

pancreatic islets

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3
Q

3 types of cells in islets and function

A

beta cells- insulin
alpha cells- glucagon
gamma cells- somatostatin

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4
Q

what part of proinsulin is cleaved?

A

C peptide- detected in blood

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5
Q

A and B chain of proinsulin bond through

A

disulfide bonds

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6
Q

C-peptide

A

detected in blood

- loss of C peptide, diagnosis for Type 1 diabetes

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7
Q

4 classifications of diabetes

A
  • T1D- immune mediated beta cell destruction (5-10%)
  • T2D- insulin resistance and insulin deficiency (90-95%)
  • other specific types (genetic factors affecting beta cell function or insulin action) (1-2%)
  • gestational diabetes (in pregnancy, 3-5%)
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8
Q

diabetes prevalence

A
  • 2014-
  • 8.5% adults over 18
  • 140,000 cases of T1D in australia, more commonly diagnosed in children
  • average 7 new cases/day Aus
  • cost $570m- insulin injection and long term complications
  • rising prevalence of T1D; 3-5% per year
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9
Q

are islet autoantibodies involved in pathology?

A

no, even though they mark the presence

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10
Q

islet autoantibodies and diagnosis of T1D

A

autoAbs precede diagnosis (95% newly diagnosed children have Ab)

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11
Q

what do islet autoAbs mark? (2)

A
  • mark the presence of autoimmune beta cell destruction

- evidence of disease specific b cell response

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12
Q

what do islet cell autoAbs recognise?

A

a composite of islet antigens

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13
Q

where are islet autoAbs found?

A

in serum not in the islets

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14
Q

what can islet autoAbs be used to study?

A
  • study natural history of disease
  • identify individuals at risk (before diagnosis appearance)
  • select high risk individuals for immune intervention and diagnosis
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15
Q

less number of islet autoAbs in children=

A

less probability of getting disease

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16
Q

what happens in presymptomatic T1D?

A
  • env trigger
  • development of autoAbs to islet Ags
  • beta cell sensitivity to injury
  • loss of first phase insulin response
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17
Q

what happens in symptomatic t1D?

A

glucose intolerance

absence of C-peptide

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18
Q

difference between stage 1 and 2 of natural history of T1D?

A

stage 1- normoglycemia

stage 2- dysglycemia

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19
Q

how many susceptibility loci for T1D identified so far?

A

~53

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20
Q

genes and diabetes

A

different combinations of genes increase risk for T1D

  • many genes have immune cell function
  • reveal new cellular pathways to be investigated for potential drug targets
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21
Q

risk of T1D with twin

A

65% chance if you have identical twin with T1D

-risk of diabetes in autoAb positive twin is 89%

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22
Q

proposed triggers of T1D

A

-infectious microbes/gut microbiome
-virus infection
-sunlight and vitD
-diet
controversial- independent studies have not consistently replicated findings

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23
Q

type 1 IFN and T1D

A

increased IFNalpha detected in T1D pancreas

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24
Q

what is IFN

A

potent activator of immune system

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25
Q

what triggers IFN production?

A

viral infection and innate immune activation

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26
Q

mice model of T1D

A

NOD mice

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27
Q

IFN stimulated genes in islets of NOD mice- expression

A

overexpressed

28
Q

where do samples for study of T1D come from?

A

pancreatic organ donors with diabetes

tissue from living donors

29
Q

definition of insulitis

A

lymphocytic infiltration targeting islets of langerhans

30
Q

two forms of insulitis

A

peri- immune cells are around outside of islet

intra- immune cells in centre of islet

31
Q

insulitis is often lobular- meaning

A

there is pathology in some lobes of pancreas and normal in other lobes
- feature of human disease that we dont see in mouse models

32
Q

insulitis mainly affects

A

insulin positive islets

33
Q

insulitis always accompanied by

A

pseudoatrophic islets devoid of beta cells

34
Q

3 criteria for insulitis

A

1- fraction of infiltrated islets low (<10% islets)
2-should be lesions in >3 islets
3- >15 leucocyte common antigen (CD45)+cells/islet

35
Q

what T cells are found within and around the islets in T1D pancreas?

A

CD4+, CD8+, CD68+

36
Q

can you have insulin positive cells in pancreas even after diagnosis? implication?

A

yes- CD3+ T cells in diabetic individual 58 years after diagnosis
- if we dampen the anti-beta cell immune response, we can promote proliferation of these remaining beta cells so patient can make their own insulin

37
Q

unmet clinical need for insulin injections

A

multiple injections per day

  • but no currently approved therapies address underlying cause of disease
  • approach that targets immune system is desirable
38
Q

immune therapies for T1D

A

many tested in trials

  • shown to slow progression of disease in trials
  • but not in real treatment yet
  • need new modulating therapy that can be used for large number of patients
39
Q

T cells found in human islets are?

A

Beta cell antigen specific

- recognise proteins produced by beta cells

40
Q

how do autoreactive T cells in T1D develop?

A
  • T cells escapes the negative selection in thymus,–>naive islet reactive T cells–>reach circulation (peripheral blood)
  • pancreatic lymph node (activation and expansion of T cells)
  • back to peripheral blood
  • into pancreas (T cells gain effector function and expand, produce cytokines and cytotoxic molecules)
  • go back to peripheral blood (detect cells in blood) or lymph node where there is upregulation of activation markers
41
Q

tetramer staining for?

A

to detect autoantigen-specific T cells in islets

- complex of 4MHC molecules together

42
Q

catching T cells at the scene of the crime meaning

A
  • isolating islets from T1D organ donors
  • culture islets in presence of cytokines that promote growth of T cells
  • many of the CD4 T cells recognised peptide in the islets and in peripheral blood
  • also T cells that recognise B chain and A chain
43
Q

main difference between human and mouse T1D

A

mouse- large proportion of islets affected and lots of immune cells
humans- not generally

44
Q

NOD mouse model of autoimmune diabetes

A
  • high risk HLA (env and genetic disposition)
  • insulitis
  • gradual increase of insulitis
  • 4 months- diabetes development
45
Q

immune modulation…

A

delays disease progression

46
Q

immune suppression…

A

stops disease

47
Q

how to CD8+T cells interact with beta cells?

A

T cell receptor (CD8+T cells) interact with peptide/MHCI on the beta cell
-autoreactive CD8+ T cells recognise and kill beta cells

48
Q

upregulation of MHC class I correlates with?

A

number of CD8+ T cells in the islets

49
Q

what is upregulated in T1D in humans?

A

HLA expression

50
Q

what is upregulation of HLA mediated by?

A

by cytokine or IFN-gamma which signals through the JAK-STAT pathway

51
Q

stat1 correlates with?

A

increase in HLA

52
Q

how do we know stat1 is important for disease?

A

Stat1 KO mice dont develop disease- protected from autoimmune diabetes
- therefore target JAK/STAT pathway in T1D

53
Q

JAKs are direct activators of ?

A

STAT proteins downstream of cytokines

54
Q

JAK inhibitors in clinical use

A

few approved and used in clinics

safety- reactivation of varicella zoster virus (can be prevented with vaccination)

55
Q

STAT1 inhibitors in clinic?

A

not yet

56
Q

what do JAK inhibitors do?

A

reduce the interaction between beta cells and T cells

- but need to keep administering to keep glucose levels down in newly diagnosed diabetes

57
Q

cadaveric islet allograft

A

isolated from organ donors

58
Q

future transplants of beta cells

A

using stem cells- unlimited supply

OR from other animals

59
Q

when is T1D diagnosed in terms of beta cells?

A

when there is almost no beta cells remaining in pancreas

- therefore need a source of new beta cells

60
Q

autograft (pancreatitis)

A

disease of exocrine

-remove pancreas, isoalte islets, reinfuse the islets so we dont have pancreatitis and T1D

61
Q

how does islet transplantation occur?

A
  • pancreas from organ donor
  • islets isolated in lab
  • sufficient quantity
  • reinfused into portable circulation, go into liver, lodge in capillaries of liver
  • sense glucose in the blood and secrete insulin into blood stream like normal pancreas
62
Q

what is hypoglycemic unawareness? implications?

A

brain doesnt tell the patient that their blood sugar is low- can slip into coma

  • need someone with them all the time
  • excellent candidates for transplantation- life changing experience
63
Q

4 main limitations to islet allotransplantation

A
  • lack of sufficient donor pancreases (1-3 donors required per recipient)
  • immunosuppression required
  • eventual loss of graft function
  • islet isolation is a process that is highly damaging to islets
64
Q

examples of islet isolation being a process that is highly damaging to the islets

A
  • long cold ischemia (pancreas sitting in ice from donor to lab)
  • mechanical and enzymatic digestion
  • disruption of ECM and BM (cells damaged)
  • upregulation of hypoxia response genes (no blood supply)
  • therefore putting back population of unhealthy cells into bloodstream
65
Q

alternative sources of beta cells

A
  • expansion/transdifferentiation (of glucagon cells to insulin producing cells)
  • ESCs (need to ensure enough blood supply, otherwise wont survive)
  • iPSCs
  • adult stem cells
  • xenotransplantation (using genetic modification in transgenic pigs_
66
Q

future clinical trials focus

A
  • immune suppression (repurpose drugs for T1D)
  • regulatory T cells (grow in vitro, made antigen specific)
  • antigen specific therapies (good for safety and due to lack of permanent remission with non-specific agents BUT difficult to tolerize memory T cells developed from primary immune response to the disease for proinsulin antigen)
  • beta cell replacement (stem cells, xenotransplantation

PATH30003- Frontiers in Human Disease (20 decks)

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