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MBB334 - Biochemical Basis of Human Disease > Watson - Diabetes > Flashcards

Watson - Diabetes Flashcards

1
Q

How was the 1st disease model of diabetes created?

A
  • studied lipid metabolism and suspected pancreas played a role → removed pancreas of dogs and saw exhibited symptoms of diabetes
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2
Q

What is insulin?

A
  • polypeptide hormone that controls circulating levels of glucose
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3
Q

Where is insulin synthesised?

A
  • in pancreatic β cells as preproinsulin
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4
Q

How is insulin cleaved?

A
  • proteolytically cleaved to gen 2 chains joined by disulphide bonds
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5
Q

What is the structure of insulin?

A
  • 110 res

- chain A and B

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6
Q

What is the corresponding opposing hormone to insulin?

A
  • glucagon
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7
Q

What cells release glucagon?

A
  • pancreatic alpha cells
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8
Q

What are the characteristics of TID?

A
  • typically adolescent onset, “juvenile diabetes”
  • cachexia
  • absolute req for insulin
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9
Q

What are the characteristics of TIID?

A
  • typically mature onset
  • may not req insulin
  • can be mod by diet/exercise
  • not always due to obesity, big genetic component
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10
Q

What are the key tissues involved in glucose homeostasis?

A
  • pancreas
  • liver
  • muscle
  • adipose
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11
Q

What is the typical glucose blood level?

A
  • 5mmol/L

- 2 hrs after meal can increase to 8mmol/L (then decreases again)

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12
Q

How do endocrine tissues release hormones?

A
  • release them into circulation by diffusion
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13
Q

What are the components of pancreatic beta cells?

A
  • Kir 6.2 = ATP-gated inwardly rectifying K+ channel
  • L-type Ca2+ channel = voltage dependent
  • GLUT2 glucose transporter
  • Hexokinase IV (glucokinase)
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14
Q

What happens when glucose enters beta cells, and what is the role of ATP?

A
  • enters via GLUT-2 (inefficient glucose transporter)
  • phos by hexokinase IV
  • G-6-P metabolised by mt, alt levels ATP in cell
  • can’t leave as charged
  • ATP and other oxidative metabolites act as sensor for circulating glucose levels
  • increased ATP closes K+ transporter, causing -ve shift in cell pot
  • voltage shift activates Ca2+ channel –> Ca2+ influx
    Ca2+ influx drives membrane fusion of secretory granules and release of insulin
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15
Q

What kind of receptor is the insulin receptor and where is it present?

A
  • RTK

- present on basically all cell types

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16
Q

What happens when insulin binds its receptor?

A
  • receptor phosphorylated –> activating S/T kinases
  • leads to phos of series of insulin receptor substrates (IRS-1 to IRS-4)
  • phos of IRS-1/2 activates phosphoinositol pathway –> activates PI3K, which activates PDK1
  • then phos and activation of Akt (prot kinase B)
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17
Q

What is the role of Akt, (ie. why is it the main mediator of insulin)?

A
  • Akt signalling drives cytoskeleton rearrangements that lead to insertion/activation of high affinity transporter GLUT-4 –> increases uptake of glucose 20x
  • increased uptake by skeletal muscle and adipocytes decreases blood levels quite rapidly –> these tissues act as reservoir for excess glucose, eg. after meal, v important
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18
Q

What are the effects of insulin in the liver?

A
  • downreg gluconeogenesis
  • upreg glycogenesis (if excess glucose want to store it)
  • downreg glycogenolysis
  • upreg lipogenesis (makes fats as LT store of energy)
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19
Q

What are the effects of insulin in adipocytes?

A
  • increased glucose transport
  • increased lipogenesis (fat prod)
  • decreased lipolysis (fat breakdown)
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20
Q

What are the effects of insulin in the pancreas?

A
  • decreased glucagon levels

- increased β cell growth

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21
Q

What are the effects of insulin in skeletal muscle?

A
  • increased glucose transport (take up glucose from blood)

- increased glycogenesis (glycogen made as store of energy)

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22
Q

What is glycogenesis and why is it needed?

A
  • synthesis of polymer of glucose

- way of storing glucose as branching polymer

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23
Q

What is glycogenolysis?

A
  • opp process to glycogenesis

- breakdown of glycogen in liver to release glucose when levels too low

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24
Q

When is lipogenesis needed and what is it?

A
  • in times of glucose sufficiency
  • acetyl-CoA used to synthesise FAs
  • FAs esterified w/ glycerol to form triglycerides
  • some tissues can use FA, eg. adipocytes, liver, but not brain
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25
Q

What is lipolysis?

A
  • opp process to lipogenesis

- breakdown of triglycerides to prod FFA, in periods of glucose depletion

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26
Q

What is glucagon?

A
  • 29 AA peptide hormone w/ opp actions to insulin
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27
Q

What effects does glucagon have?

A
  • increases gluconeogenesis and glycogenolysis

- decreases lipogenesis

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28
Q

What is the cause of TID?

A
  • problem in thymus, where T cells dev, so recognise self as non self cells, so destroy β cells
  • ‘starvation in presence of plenty’
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29
Q

How do insulin and blood glucose levels change t/o lifetime of diabetic?

A
  • DIAG*
  • early stages characterised by increasing blood glucose levels and often asymptomatic
  • insulin levels become abnormally high as pancreas responds to glucose
  • later insulin levels progressively fall as β cell mass and productivity fall off –> hyperglycaemia
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30
Q

What causes TIID, ie. the initial event?

A
  • not responding to signal –> insulin sensitivity, then loss of insulin prod/beta cells
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31
Q

What is the pathogenesis of TIID?

A
  • initial event is loss of response to insulin signalling –> ie. ‘insulin resistance’
  • glucose remains high –> driving increased insulin prod by β cells
  • initially increased insulin prod maintains normal glucose levels
  • β cell mass and productivity fall away and insulin levels progressively fall until glucose levels uncontrolled
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32
Q

When do TIID patients req exogenous insulin?

A
  • typically after 7-8 yrs
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33
Q

When is TIID usually diagnosed?

A
  • after insulin production has fallen sufficiently that blood glucose levels give rise to symptoms of hyperglycemia
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34
Q

What glucose levels would a pre-diabetic have?

A
  • > 7 mmol/L (fasting) and >11 mmol/L (random)
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35
Q

What are glucose meters and how do they work?

A
  • engineered forms of glucose oxidase coupled to test strip
  • FAD-glucose deHase used –> metabolises glucose
  • chemical e- acceptors contained in electrode re-ox FAD
  • gen electrical current
  • damages small blood vessels (capillaries, capillary wall integrity and neuropathy, proteins become brown)
36
Q

What is the aim of glucose meters, and why are they not ideal in this respect?

A
  • mimic natural control

- would be better if monitoring constantly

37
Q

What is the pathogenesis of TIID on adipose tissue?

A
  • lipolysis not inhib by insulin (as not sensitive to insulin)
  • so increase in FFA into circulation, as breaking down fats
38
Q

What is the pathogenesis of TIID on the liver?

A
  • processes FFA to increase triglycerides
  • increases lipid in blood in form of LDL/HDL (can lead to atherosclerosis, hence its assoc w/ TIID)
  • gluconeogenesis can be active even w/ high circulating glucose concs (liver thinks shortage of glucose)
39
Q

Which type(s) of diabetes cause hyperglycemia?

A
  • both
40
Q

What are the effects of hyperglycemia?

A
  • polyuria (= excess urine)
  • neuropathy (= damage to nerves) –> esp in periphery
  • macrovascular damage (big vessels)
  • microvascular damage (small vessels)
  • infection
41
Q

What happens in the kidney during hyperglycemia?

A
  • above renal threshold (11mmol/L glucose) not enough active transport to take all glucose back in
  • so overwhelms transport system and start passing glucose into urine
  • so filtrate contains glucose, exerts osmotic pressure, so reduced water absorption = increased vol of urine and thirst
  • then damage to glomerulus, damages kidney, can fail, prots secreted, attacks tubule lining, inflam, glucose itself is irritant and renal failure
42
Q

What is glucosuria?

A
  • glucose in urine
43
Q

What are the microvascular complications assoc w/ diabetes?

A
  • high glucose toxic to endothelial cells lining capillaries
  • induces expression of fibrinogenic GFs (means prod more ec matrix)
  • -> PDGF (platelet derived GF)
  • -> TGFβ (transforming GF β)
  • increased dep of matrix in basement membrane (much more drastic effects in kidneys than capillaries, but still issue)
  • thickening of vascular wall and loss of elasticity in vessel (can’t stretch in response to BP)
  • loss of circulation (due to narrowing of vessel), mainly in periphery and ischemia
44
Q

What are the macrovascular complications assoc w/ diabetes?

A
  • pathological effects of high glucose concs increase permeability of endothelial cell lining of arteries
  • liver now prod lots of LDL, so lots in circulation, can enter underneath vessel due to increased permeability, so deposition of lipids in supportive layers of vessels = atheroma (plaque)
  • restricted blood flow can lead to coronary artery disease → approx 2x increase risk
45
Q

What are the results of hyperglycemia leading to infection in diabetes?

A
  • high levels of tissue glucose provide good habitat for MOs
  • reduced microvascular function changes nature of normal inflam response (so infection can go unnoticed) –> reduced diffusion of normal inflam mediators and reduced migration of immune cells
  • peripheral neuropathy can reduce awareness of damage (can get out of control more quickly, amputation etc.)
46
Q

What role does β cell depletion play in the pathogenesis of TIID?

A
  • glucotoxicity = persistent high levels glucose cause apoptosis and loss of β cells
  • FA = high levels circulating FA assoc w/ glucose insensitivity
47
Q

What role does amyloid play in the pathogenesis of TIID?

A
  • β cells in advanced TIID show presence of abnormal prot aggregates, lead to LoF and cell death
  • -> aggregates formed from normal cellular prot, IAPP (islet amyloid polypeptide)
  • -> IAPP co-expressed w/ insulin, shares common promoter regulatory motifs
  • -> excess levels of insulin prod in early stages might be driving prod of amyloid, which is ultimately killing β cells
48
Q

What is the concordance in both types of diabetes?

A
  • TID MZ concordance = 30%

- TIID MZ concordance = 40-100%

49
Q

What genes has TID been assoc w/?

A
  • HLA, DR3 and DR4
50
Q

How is genetic and env basis of TIID diff?

A
  • stronger genetic basis, but also dep more on env
51
Q

Why is TIID becoming more common?

A
  • due to western affluent lifestyle and dietary habitats
52
Q

What did a study on Pima indians show about TIID

A
  • when migrated and changed lifestyle had greatly increased incidence of TIID, despite genetic background being the same
  • therefore dep on env
53
Q

What genes are involved in TIID?

A
  • Calpain 10 = protease, assoc w/ insulin release from pancreas cells
  • Glucokinase = hexokinase IV, glucose sensing
  • Glucose transporter, GLUT-2 –> transports glucose into cell, gene variants may disrupt glucose reg
54
Q

When do the genes involved in TIID diabetes become important?

A
  • when lifestyle puts them at risk
55
Q

What interventions are there for TIID

A
  • Sulfonylureas
  • Metformin
  • insulin
56
Q

How does sulfonylureas work as an intervention for TIID?

A
  • targets SUR1 subunit of ATP gated K+ channel, blocking K+ transport
  • triggers Ca2+ influx and increased insulin secretion
57
Q

How does metformin work as an intervention for TIID?

A
  • mech unclear, but main target organ is liver
  • passes unmetabolised through body
  • alt membrane fluidity
  • increases insulin receptor signalling sensitivity, reduces gluconeogenesis in liver and increases GLUT-4 activation and improves glucose transport
  • can be good at start of disease as increases insulin sensitivity, so easier to control glucose levels
58
Q

What do those w/ TID req for survival?

A
  • exogenous insulin
59
Q

Why is TID described as ‘starvation in the midst of plenty’?

A
  • insulin essential for uptake and utilisation of glucose

- but complete destruction of pancreatic beta cells –> no insulin prod and glucose not utilised

60
Q

How does a TID patient typically present?

A
  • wasting of muscles and other tissues
  • polyuria = excessive urine
  • glycosuria = excess glucose in urine
  • polydipsia = excessive thirst
61
Q

How is TID an eg. of an organ specific autoimmunity?

A
  • no. of diff high affinity autoantibodies against beta cell prots are detected in patients
  • can be detected in children from 9 mo
  • detection usually forecasts dev of TID in adolescence
  • evidence for presence of islet specific CD4 T helper cells (somatic hypermutation –> T cells stim autoreactive B cell dev)
  • patients exhibit ‘insulinitis’ even before symptoms evident (infiltration of lymphocytes in pancreas)
  • beta cells silently destroyed and insulin prod fades
  • diagnosis only when symptoms appear
62
Q

What high affinity auto Abs against beta cell prots are detected in TID patients?

A
  • glutamic acid decarboxylase (GAD)
  • insulin (IAA)
  • Zn transporter 8 (ZnT8)
  • insulin assoc antigen 2 (IA-2)
63
Q

What can the genetics of TID tell us?

A
  • understanding risk factors can lead to general insight into pathogenesis of other autoimmunities, screening for those at increased risk and suggestions of ways to intervene in early stages
64
Q

What did initial case/control studies of TID involve?

A
  • early studies focussed on HLA region –> assoc was strong enough to prove
  • limits of tech, serotyping of HLA, SB of gDNA, compare alleles in 100-200 indivs w/ and w/o TID
65
Q

What is the problem w/ case/control studies in TID?

A
  • lacks power as no.s limited, genetic diversity between pops dilutes effect of risk alleles, often results not reproducible
66
Q

How much of the TID risk do HLA alleles account for?

A
  • 40-50%
67
Q

Which class of HLA alleles are involved w/ disease?

A
  • no. of specific HLA class II alleles are known to be assoc w/ increased risk of disease
  • recently high res linkage studies have also estab assoc w/ HLA class I alleles
68
Q

Why might HLA alleles be involved w/ TID?

A
  • viral infection and IR to them play signif part in triggering autoimmunity to islets
69
Q

What are the advantages of the NOD mouse as a model in TID?

A
  • well characterised phenotype and genetics
  • no. inbred strains
  • reduced genetic variability - enables powerful genetic analysis
  • easy to breed large no.s
70
Q

What is a NOD mouse?

A
  • non obese diabetic mouse
  • spontaneously dev TID in 90% females
  • mirrors human disease: insulinitis, autoantibodies, progressive loss of beta cells
71
Q

How was assoc of genes w/ TID confirmed in NOD mice, and what was discovered?

A
  • hypothesis = risk loci identified are likely to be reflected in humans
  • by crossing to other mouse strains was poss to identify genetic loci that determined susceptibility to TID
  • initially assoc of HLA region was confirmed (MHC in mice)
  • other loci of lesser effect rapidly identified –> approx 20, inc Idd-1, -2, -3, -4, -5, -18
72
Q

What is Idd-1?

A
  • MHC region gene
73
Q

What is Idd-2, and its role in TID?

A
  • insulin gene
  • VNTR (= short stretches of DNA that are repeated in tandem)
  • diff alleles w/ differing no. of repeats, some alleles protective, some increase risk, reduced exp of insulin assoc w/ increased risk (risk alleles assoc w/ reduced exp have been demonstrated in thymus)
74
Q

What is Idd-3, and its role in TID?

A
  • IL-2 gene
  • IL-2 is key reg cytokine for T cells, necessary for gen and survival of TREGs (suppressive T cells)
  • studies suggest NOD Idd-3 mice possess less effective TREG pops
75
Q

What is Idd-4, and its role in TID?

A
  • IFN viral response gene
  • locus assoc w/ aberrant overexp of IFN response to viral infection, implications for role of viral infection in triggering in TID?
76
Q

What is Idd-5, and its role in TID?

A
  • CTLA-4 gene
  • CTLA-4 is key reg of T cell antigen response, TCR activation req MHC and co-receptors, some co-receptors +vely drive T cell response, others exert -ve effect, CTLA-4 acts to dampen TCR response
77
Q

What is Idd-18, and its role in TID?

A
  • PTPN22 gene
  • PTPN22 is a tyr phosphatase, exp mainly in lymphocytes, important in shutting down tyr kinase pathways activated by antigen binding in B/T cells
78
Q

How have many NOD risk loci been confirmed?

A
  • in human genetic analyses

- can do GWAS, physical maps of SNPs, fine mapping, linkage studies, sequencing, identification of gene mutations

79
Q

What is CTL-4 a signif risk factor for?

A
  • no. of human autoimmune conditions

- inc TID, autoimmune thyroid disease, rheumatoid arthritis

80
Q

What is PTPN22 a signif risk factor for?

A
  • TID and autoimmune thyroid disease
81
Q

Is there evidence for role of viral infection in TID?

A
  • evidence is dev for role of IFN antiviral response gene in human TID
  • also identified protective alleles, so evidence accum
82
Q

In theory how could islet transplantations be carried out for TID?

A
  • beta cells cultivated artificially and transplanted into patients
  • 1° beta cells or SC derived
  • infused into liver
  • beta cells able to sense blood glucose and respond approp
  • better glucose control than exogenous insulin
  • still experimental only
83
Q

What problems are there w/ islet transplantations?

A
  • still autoimmune, beta cells destroyed again over time
84
Q

Why is the use of immunosuppressants not a viable option for treating TID?

A
  • dangerous side effects w/ LT use, infection, tumour dev → we need the adaptive IS
85
Q

Could artificial induction of tolerance be used to treat TID?

A
  • introd high doses of antigen in absence of ‘danger signals’
  • no 2nd signals of infection
  • results in anergy (= absence of normal immune response) in antigen specific T cells
  • experiments ongoing in animal studies
  • promising results w/ insulin as antigen
  • no data in humans
86
Q

If dev of autoreactive T/B cells in repertoire is cause of autoimmune disease (and TID), is there a way of starting over?

A
  • in lymphoma patients lymphopoietic SC harvested from bone marrow
  • reintrod after intense chemo (completely eradicates IS) to try and reestab IS
  • diversity of B/T cells unaffected and full repertoire dev again
  • MIST is intl trial assessing LT benefits of SC transplants in MS (disease driven by autoreactive T cells)
  • patients w/ MS shown remarkable degree of remission following transplants –> immune repertoire appears to have been reset, pot a new and effective treatment
87
Q

What are the problems if reset the adaptive immune repertoire as a treatment for TID?

A
  • will autoreactivity reappear?
  • high risk of infection during treatment period, pot fatal if transplant doesn’t take
  • in case of TID insulin treatment exists (there is an alt), can this approach be justified?

MBB334 - Biochemical Basis of Human Disease (7 decks)

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