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Management of GI and Endocrine Conditions > Lecture 17 - Causes of Diabetes > Flashcards

Lecture 17 - Causes of Diabetes Flashcards

1
Q

What secretes insulin?

A

the beta cells in the pancreas

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2
Q

Where does the pancreas sit?

A

in the abdominal cavity behind the stomach

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3
Q

Where are the beta cells contained within the pancreas?

A

In pancreatic islets which contain alpha, beta and delta cells

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4
Q

What cells secrete glucagon?

A

alpha cells

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5
Q

When is insulin released?

A

in response to high blood glucose levels

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6
Q

What does an increase in blood glucose lead to?

A

an increase of glucose uptake into the cell

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7
Q

What does increased glucose in the cell cause?

A

higher levels of ATP, which increases the ATP”ADP ratio

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8
Q

What does increased ATP:ADP cause?

A

closure of the ATP-sensitive K+ channels, which causes membrane depolarisation

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9
Q

What does membrane depolarisation cause?

A

activation of voltage gates Ca2+ channels, causing increased Ca2+ inside the cell

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10
Q

What does increased cytosolic Ca2+ cause?

A

fusion of insulin granules with the plasma membrane, causing release of insulin

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11
Q

What does insulin increase?

A

glucose uptake, glycolysis, glycogen synthesis, fatty acid/triglyceride synthesis, amino acid uptake and protein synthesis

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12
Q

What does insulin decrease?

A

glycogen breakdown, gluconeogenesis, lipolysis, proteolysis

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13
Q

What are the effects of insulin mediated via?

A

activation of insulin signalling pathways in target cells

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14
Q

What does insulin binding to the insulin receptor do?

A

activates many different signalling pathways to bring about its effects on metabolism and growth

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15
Q

What does insulin signalling involve?

A

protein phosphorylation

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16
Q

What does binding of insulin to the insulin receptor (IR) lead to?

A

auto phosphorylation of the receptor (receptor phosphorylates itself)

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17
Q

What do phosphorylates residues on the IR act as?

A

binding sites for insulin receptor substrate (IRS)

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18
Q

What does IR phosphorylate?

A

4 tyrosine residues in IRS proteins

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19
Q

What binds to phosphorylated residues?

A

The lipid kinase, phosphoinositide 3-kinase

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20
Q

What does the lipid kinase phosphoinositide 3-kinase do?

A

converts PIP2 to PIP3

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21
Q

What does binding of PIP3 do?

A

activates PKD1

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22
Q

What does PKD1 do?

A

phosphorylates and activates kinases such as PKB/Akt

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23
Q

What does PKB/Akt do?

A

diffuse through the cell and activate processes such as glucose transport and glycogen synthesis

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24
Q

What does insulin stimulate?

A

glucose transport into adipocytes and skeletal muscle

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25
Q

What does insulin binding to receptor on adipocytes and skeletal muscle cells do?

A

activates the insulin signalling pathway, leading to fusion of GLUT4 containing vesicles to the membrane

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26
Q

What happens when GLUT4 vesicles fuse with the membrane?

A

GLUT4 inserts itself into the cell surface where it can take up those glucose molecules into the cells

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27
Q

How does insulin repress gluconeogenesis?

A

by inhibiting transcription factor Fox01

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28
Q

Where is Fox01 synthesised?

A

in the cytosol

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29
Q

Where is Fox01 targetted?

A

to the nucleus

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30
Q

What does Fox01 do?

A

regulates expression of genes that mediate gluconeogenesis (PEPCK, G6Pase)

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31
Q

What does PKB do to Fox01?

A

phosphorylates it

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32
Q

What does phosphorylation of Fox01 do?

A

prevents it from entering the nucleus, leading to a loss of expression of gluconeogenic genes and hence a loss of glucose production

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33
Q

How does loss of insulin secretion or insulin resistance lead to hyperglycaemia?

A

as a result of loss of insulin stimulated uptake into target cells (skeletal muscle, adipocytes)

loss of insulin-mediated repression of gluconeogenesis (and glycogen breakdown) in the liver

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34
Q

What happens in type 1 diabetes?

A

is a chronic autoimmune disease in which destruction of beta cells results in insulin deficiency and hyperglycaemia

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35
Q

Who does type 1 diabetes generally occur in?

A

susceptible individuals, likely as a result of an environmental trigger

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36
Q

What has been identified as a cause of type 1 diabetes?

A

susceptibility genes and possible triggers (e.g. enteroviruses)

37
Q

How much higher is the risk of T1D for first degree relatives of someone with the disease?

A

~15 times higher

38
Q

What is the HLA region?

A

a critical susceptibility locus for T1D

39
Q

What does the HLA region contain?

A

genes that encode components of major histocompatibility complex and is a key component of the immune system

40
Q

How many people with the HLA gene variant develop T1D?

A

only 5%

41
Q

Where is the HLA gene region?

A

chromosome 6

42
Q

What do the HLA genes have strongest known association with?

A

T1D

43
Q

What is a significant risk factor for development of T1D?

A

presence of autoantibodies against beta cell antigens

44
Q

Examples of autoantibodies?

A

glutamic acid decarboxylate 65 (GAD-65)

insulin

ICA512

ZnT8 (zinc transporter 8)

45
Q

How many people test positive for these antibodies? And how many of those develop T1D?

A

3-5% of general population test positive and only 20% of those develop T1D

46
Q

What does the presence of 2 antibodies do?

A

increases risk of developing T1D within next 10 years to 75%

47
Q

Why is it difficult to identify precipitating events for T1D?

A

these might occur many years before onset of symptoms

several precipitating events might be involved

48
Q

What have been implicated as a possible precipitating event?

A

Enteroviruses such as coxsackie virus

49
Q

Why is the coxsackie virus thought to be a precipitating factor?

A

striking similarity between the 2C protein of the coxsackie virus and GAD65 suggests molecular mimicry might be involved in aetiology of T1D

leading to beta cell destruction

50
Q

When do clinical onset (symptoms) of T1D typically occur?

A

until you have lost ~90% of beta cell mass, there is no way back from this

51
Q

Why is it important to identify before clinical onset?

A

to identify people at risk and intervene before they have lost so much of their beta cell mass

52
Q

Treatment of type 1 diabetes?

A

insulin injections for the rest of their life

careful monitoring of diet and regular blood tests to check glucose levels

53
Q

What are high blood glucose levels as a result of in type 2 diabetes?

A

insulin resistance of target tissues

insufficient production/secretion of insulin (beta cell dysfunction)

54
Q

What is one of the first things to develop in T2D?

A

insulin resistance - the cells in the body no longer respond to insulin as they should

55
Q

Why is there not really a change in blood glucose levels as insulin resistance begins?

A

the beta cells secrete more insulin to overcome the resistance and keep blood glucose levels normal

56
Q

What happens after a while of producing excess insulin?

A

there is too much stress on the beta cells and they become dysfunctional and die

57
Q

What is the amount of insulin secreted by beta cells established by?

A

the prevailing insulin sensitivity

58
Q

What happens when the body is in an insulin sensitive state?

A

beta cells secrete a low amount of insulin

59
Q

What happens when the body goes into a insulin resistant state?

A

the beta cells sense this and respond by secreting more insulin

this gives insulin resistance but normal blood glucose levels

60
Q

Strong link between insulin resistance and…?

A

obesity

61
Q

What does protein tyrosine phosphatase 1B (PTPB1) do?

A

dephosphorylates the insulin receptor, leading to a loss of insulin receptor substrate binding

62
Q

What does PTEN (phosphatase and tensin homologue) do?

A

dephosphorylates PIP3 back to PIP2, switches off insulin signalling

63
Q

What does PKC do?

A

serine phosphorylates IRS proteins and when it serine phosphorylates IRS proteins, this prevents the insulin receptor from activating tyrosine phosphorylation on IRS proteins

64
Q

What is a consequence of obesity?

A

the amount of triglycerols exceeds the storage capacity of adipose cells and as a result fat starts to accumulate in other tissues such as liver and muscle

65
Q

What does excess fat lead to?

A

increased levels of the intracellular lipid signalling intermediates diaglycerol (DAG) and ceramide (a component of sphingolipids) in the cytoplasms of cells

66
Q

What are DAG and ceramide formed from?

A

fatty acids

67
Q

What does ceramide do?

A

inactivates PKB

68
Q

What does diaglycerol do?

A

key second messenger leading to the activation of PKC

69
Q

What is adiponectin?

A

is secreted from adipocytes and promotes insulin sensitivity

70
Q

What does adiponectin do?

A

binds to adiponectin receptor on target cells, and activates ceramidase, which converts ceramide into sphingosine

71
Q

What does sphingosine do?

A

reduces levels of ceramide inside of the cells (interferes with PKB)

72
Q

What happens to adiponectin secretion in obesity?

A

it is decreased, which contributes to insulin resistance

73
Q

What does decreased conversion of ceramide do?

A

ceramide accumulates inside the cells and interferes with insulin signalling to increase insulin resistance

74
Q

What is obesity?

A

a pro-inflammatory condition in which hypertrophied adipocytes and adipose resident immune cells both contribute to increased circulating levels of pro-inflammatory cytokines

75
Q

What does adipose tissue in lean individuals secrete?

A

anti-inflammatory and insulin sensitising adipokines such as adiponectin

76
Q

What is released in obesity?

A

pro-inflammatory cytokines such as TNF alpha (tumour necrosis factor alpha)

77
Q

What does TNF alpha have?

A

different effects that contribute to insulin resistance

78
Q

What does TNF alpha increase?

A

expression of PTP1B, which can dephosphorylate the insulin receptor, preventing IRS binding

79
Q

What does TNF alpha activate?

A

JNK (Jun-N-terminal kinase, which causes serine phosphorlyation and inactivation of IRS proteins

80
Q

What is thought to contribute to type 2 diabetes

A

loss of beta cell mass and loss of insulin secretory capacity

81
Q

What is dysregulation of insulin secretion linked to?

A

accumulation of fat in pancreas

82
Q

What % of beta cell mass decrease after 5 years diagnosis of T2D?

A

25% decrease

83
Q

What % of beta cell mass decrease after >15 years diagnosis of T2D?

A

50%

84
Q

What happens when beta cells synthesise more insulin?

A

the endoplasmic reticulum is put under stress and can no longer fold and process new insulin

85
Q

What happens when the endoplasmic reticulum is put under stress?

A

activates unfolded protein response (UPR)

86
Q

What does unfolded protein response result in?

A

apoptosis and beta cell death

87
Q

What is type 2 classed as?

A

a complex polygenic disorder (caused by a combination of genetic and lifestyle factors)

88
Q

What have GWAS studies identified that happen more freqently in type 2 diabetes?

A

many gene polymorphisms (SNPs) (>75 risk genetic loci have been indentified

Management of GI and Endocrine Conditions (24 decks)

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