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PATH30003- Frontiers in Human Disease > Lecture 12- Type 2 diabetes > Flashcards

Lecture 12- Type 2 diabetes Flashcards

1
Q

type 2 diabetes definition

A
  • metabolic disorder characterised by chronic hyperglycemia
  • relative lack of insulin action/response (insulin resistance), insulin production or both
  • leads to impaired glucose metabolism
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2
Q

3 ways to diagnose diabetes

A
  1. glycated haemoglobin test (HbA1c test)
  2. oral glucose tolerance test (oral GTT)
  3. impaired fasting blood glucose levels
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3
Q

HbA1c test

A

glycated haemoglobin test

  • measures how much glucose is bound to Hb in RBCs
  • diabetes >6.5%
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4
Q

oral glucose tolerance test (oral GTT)

A

consumption of 75g of anhydrous glucose, test plasma glucose 2 hrs later
-11.1mmol/L- diabetes

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5
Q

impaired fasting blood glucose levels

A

plasma glucose>7.0mmol/L following 8 hr fast

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6
Q

type 1 diabetes

A

autoimmune disease, immune mediated Beta cell destruction

- insulin deficiency, 5-10%

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7
Q

type 2 diabetes

A

insulin resistance and insulin deficiency, 90-95%

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8
Q

gestational diabetes

A

insulin resistance and relative insulin deficiency in pregnancy
- 3-5% of all pregnancies

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9
Q

genetic defects affecting Beta cell function

A

1-2% of cases

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10
Q

glucose homeostasis

A

balance of glucose intake/production and uptake/storage/usage

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11
Q

when high blood glucose

A

gets stored in liver and muscle (as glycogen) and fat/WAT

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12
Q

when low blood glucose

A

glucose released from stores- liver, muscle, WAT

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13
Q

where is insulin produced?

A

produced and secreted by Beta cells of pancreatic islets

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14
Q

beta cells of pancreatic islets

A

75-80% of the islet cells

produce and secrete insulin

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15
Q

glucagon

A

alpha cells in pancreatic islets

- raises blood glucose level (acts opposite to insulin)

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16
Q

somatostatin

A

gamma cells

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17
Q

insulin synthesis pathway

A
  1. genes encoding for insulin transcribed to mRNA in nucleus
  2. Pre-proinsulin synthesised (in beta cell), excision of signal peptide, formation of disulphide bonds in ER (b/w A and B chain)
  3. Transport of proinsulin to Golgi apparatus, cleaved by pro-hormone convertase
  4. Formation of separate C-peptide and mature biologically active insulin (A and B chain)
  5. Insulin stored in storage granules , secretion of insulin granules by exocytosis when calcium influx
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18
Q

Insulin secretion pathway

A
  1. glucose enters beta cells (via GLUT2 transporter)
  2. glycolysis (breakdown of glucose) increases ATP:ADP ratio, increase energy supply to beta cells
  3. Closes ATP-sensitive K channels (K cant go outside of beta cell now)
  4. increase K in cells, makes cell more positively charged, depolarisation of cells
  5. Opens voltage dependent Ca channels, influx of calcium, promotes exocytosis of insulin granules form storage granules
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19
Q

glycogen synthesis

A

convert glucose into glycogen

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20
Q

glycogenolysis

A

break down of glycogen

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21
Q

gluconeogenesis

A

production of glucose from fat

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22
Q

lipogenesis

A

convert/synthesise glucose into fat

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23
Q

Normal glucose levels- liver

A
  • increased glycogen synthesis
  • decreased glycogenolysis
  • decreased gluconeogenesis
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24
Q

normal glucose levels- muscle

A
  • increased glucose uptake

- increased glycogen synthesis

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25
Q

normal glucose levels- WAT/fat

A
  • increased glucose uptake

- increased lipogenesis

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26
Q

vagus nerve

A

parasympathetic control of digestive tract e.g. liver

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27
Q

high glucose levels- pancreas

A

decrease beta cell function

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28
Q

normal glucose levels- brain

A

decrease appetite

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29
Q

high glucose levels- liver

A
  • decreased glycogen synthesis

- increased gluconeogenesis

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30
Q

high glucose levels- muscle

A
  • decreased glucose uptake

- decrease glycogen storage

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31
Q

high glucose levels- WAT/fat

A
  • decrease fat/TG storage
  • increased lipolysis
  • increase FFA in blood
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32
Q

lipolysis

A

breakdown of fats and other lipids by hydrolysis to release FAs

33
Q

high glucose levels- insulin

A
  • lots produced but not used by liver, muscle, WAT or brain
34
Q

high glucose levels- brain

A

increased appetite

35
Q

GLUT4 vesicle

A

used in glucose uptake by fat, muscle

36
Q

Akt

A

responsible for increasing glycogen synthesis

- Akt activates FOXO and GLUT4 vesicle

37
Q

FOXO

A

decreases gluconeogenesis in liver

38
Q

PI3K

A

activates Akt–>FOXO and GLUT4 vesicle

39
Q

how does insulin lead to changes in glucose production in organs and tissues?

A

insulin receptor (IR) binds to IRS (insulin receptor substrate)–>PI3K–>Akt–>

  1. GLUT4 vesicle- increase glucose uptake
  2. increased glycogen synthesis
  3. FOXO- decrease gluconeogenesis
40
Q

chronic inflammation

A

triggers recruitment of immune cells–>increase pro inflammatory cytokine levels (IL-1, IL-18, TNF) in affected tissues (muscle, liver, islets, adipose tissue)
- islets (resident macrophages become activated, increased immune T and B cells)

41
Q

anti- inflammatory drugs

A

TNF, IL-1 blockers- beneficial for T2D- clinical trial

42
Q

ER stress

A

chronic overnutrition and increased FA (due to adiposity)–>accumulation of unfolded/misfolded proteins in ER lumen –>ER stress

43
Q

ER

A

central organelle in which trans-membrane and secretory proteins are synthesised and folded

44
Q

unfolded protein response- UPR

A

mitigate ER stress

  • reduces protein synthesis through (PERK/ATF4)
  • increase ER molecular chaperones through (ATF6)
  • Activation of ER-associated degradation proteins through (IRE1/XBP1)
  • CHOP- apoptosis
45
Q

PERK/ATF4

A

reduces translation, protein synthesis to reduce ER stress

46
Q

ATF6

A

increases ER molecular chaperones

47
Q

IRE1/XBP1

A

activates ER-associated degradation proteins (ERAD)

48
Q

CHOP

A

apoptosis of unfolded/misfolded proteins in ER

49
Q

BiP/GRP78

A

ER chaperones

50
Q

therapeutic potential for ER stress

A

chemical chaperones to reduce ER stress- clinical trial

51
Q

risk factors for T2D

A

lifestyle, age, genetics, history of gestational diabetes

52
Q

hallmarks of T2D

A

insulin resistance
hyperinsulinemia
hyperglycemia

53
Q

acute complications of T2D

A

hyperglycemic hyperosomlar state (HHS)

- high blood glucose levels–>high osmolarity–>extreme dehydration (dry skin, drowsy)

54
Q

chronic complications of T2D

A

micro- diabetic retinopathy/nephropathy/neuropathy

macro- stroke, heart disase, peripheral vascular disease

55
Q

key principle in treatment of T2D

A

control blood glucose levels

56
Q

3 key components of T2D treatment

A
  1. lifestyle modification
  2. oral glucose-lowering therapy
  3. insulin therapy
57
Q

lifestyle modification

A

diet- healthy eating

exercise- reduce weight to improve insulin sensitivity and glucose uptake

58
Q

oral glucose lowering therapy

A

metformin

  • safe, cheap, first line oral treatment (mono/combo therapy)
  • activates AMP-activated kinase (AMPK)
59
Q

metformin

A

activates AMP-activated kinase (AMPK)

  • liver- suppresses gluconeogenesis and lipogenesis
  • skeletal muscle- increases insulin sensitivity and glucose uptake
  • side effects- liver disease and GIT issues (diarrhoea)
60
Q

lipogenesis

A

formation of fat

61
Q

metformin- liver

A

suppresses gluconeogensis and lipogenesis

62
Q

metformin- skeletal muscle

A

increases insulin sensitivity and glucose uptake

63
Q

metformin side effects

A

liver disease and GIT issues

64
Q

incretin hormones

A

stimulate insulin production and trigger insulin release in response to meals

65
Q

GLP-1

A

gut derived glucagon peptide 1

- rapidly degraded by DPP-4

66
Q

function of GLP-1

A

activates GLP-1R–>decrease blood glucose levels and improve glycemic control

67
Q

DPP-4

A

degrades GLP-1 within minutes

68
Q

GLP-1R action on brain

A

decrease appetite

69
Q

GLP-1R action on stomach

A

decrease gastric emptying

70
Q

GLP-1R action on pancreas

A
  • increase insulin secretion/synthesis
  • decrease glucagon secretion
  • increase beta cell proliferation
  • decrease beta cell apoptosis
71
Q

GLP-1R agonists/ DPP-4 inhibitors

A

act on GLP-1R and DPP

72
Q

GLP-1R agonist

A

Exenatide

  • inject subcutaneously
  • side effects- hypoglycemia (act directly on beta cells)
73
Q

DPP-4 inhibitor

A

Gliptin

  • Tablets, reduce GLP-1 degradation
  • side effects- sinusitis, nausea, allergic issues
74
Q

sulfonylureas

A

safe, cheap, second generation

e.g. glimepiride, glipizide, glyburide

75
Q

function of sulfonylureas

A
  • inhibit opening of ATP-sensitive K channels (no K goes out)
  • increase Ca influx–>depolarisation
  • increase insulin release from beta cells in pancreas

side effects– hypoglycemia, weight gain

76
Q

acarbose

A

alpha glucosidase inhibitor

- cheap, effective

77
Q

function of acarbose

A

lowers blood glucose, prevent T2D

  • reduces rate of digestion of carbs in intestine–>less glucose is absorbed
  • side effects- flatulence, diarrhoea
78
Q

alpha glucosidase

A

intestinal enzyme that breaks down carbs into glucose

79
Q

future therapies

A

prevention- public health policies, lifestyle modification

basic science- further understanding for causes of diabetes

PATH30003- Frontiers in Human Disease (20 decks)

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