Biochemistry (Weeks 1, 2 + 3) Flashcards Preview

Year 2 - Endocrinology (DP) > Biochemistry (Weeks 1, 2 + 3) > Flashcards

Flashcards in Biochemistry (Weeks 1, 2 + 3) Deck (92):
1

What do the following pancreatic cells secrete?
1. β-cells
2. α-cells
3. δ-cells
4. PP cells

1. Insulin
2. Glucagon
3. Somatostatin
4. Pancreatic polypeptide

2

In what part of the β-cell is insulin made?

RER

3

What is the process of insulin production?

1. Made as preprohormone (Preproinsulin)
2. Cleaved into:
- Proinsulin
- Signal peptide
3. Cleaved into:
- Insulin
- C-peptide

4

What is the structure of insulin?

2 polypeptide chains
Linked by disulfide bonds

5

What can the connecting-peptide be used as an indicator of and how?

Insulin secretion:
- Secreted in same vesicle as insulin

6

Which amino acid sequence varies greatly between species, insulin or c-peptide?

C-peptide

7

What happens if a different species' insulin is given to humans?

It is antigenic:
- Induces Ab formation against injected insulin

8

Put the following steps of insulin secretion in order:
- Increased glucose metabolism
- Glucose enters β-cell
- Insulin released
- ATP inhibits ATP-sensitive K+ channel (Katp)
- Increased [Ca]i
- Glucose phosphorylated by glucokinase to glucose-6-phosphate
- Increased [ATP]i
- Voltage-gates calcium channels open
- Cell depolarisation

1. Glucose enters β-cell
2. Glucose phosphorylated by glucokinase to glucose-6-phosphate
3. Increased glucose metabolism
4. Increased [ATP]i
5. ATP inhibits ATP-sensitive K+ channel (Katp)
6. Cell depolarisation
7. Voltage-gated calcium channels open
8. Increased [Ca]i
9. Insulin released

9

How does glucose enter the β-cell?

Via GLUT2 glucose transporter

10

In what range does glucokinase's Km for glucose lie?

Physiological range

11

What does a change in [Glucose] result in?

Dramatic change in glucokinase activity

12

What sort of release pattern does insulin have?

Biphasic

13

What does the 1st phase of insulin secretion do and how does it achieve this?

Prevents hyperglycaemia
5% of insulin granules in a readily-releasable pool

14

What does the 2nd phase of insulin release vary with and how?

How well phase one controls blood glucose:
- Reserve pool undergoes preparation

15

What is the structure of the Katp?

Inward rectifier subunit (Kir):
- Pore
- Kir6.2
Sulphonylurea receptor:
- Regulatory subunit
- SUR1
Octomeric structure

16

What compounds stimulated and inhibit the Katp channel and what effect does this have?

Stimulate: (ie prevents depolarisation)
- Diazoxide -> Inhibits insulin release
Inhibits: (ie causes depolarisation)
- ATP
- Sulphonylurea drugs -> Tolbutamide/Glibenclamide

17

What happens if the Katp channel is overactive? What condition does this result in?

No depolarisation -> No Calcium influx -> No insulin release:
- Profound neonatal diabetes

18

What happens if the Katp channels is inactive?

Hyperinsulinaemia

19

What mutations can cause neonatal DM?

Kir6.2 mutations:
- Activated/More Katp channels
- Insulin secreted in response to Tolbutamide

20

What sort of Kir6.2 + SUR1 mutations cause congenital hyperinsulinaemia? How can this be treated?

Trafficking/Inhibiting mutations
Diazoxide

21

What causes familial early-onset T2DM?

Primary defect in insulin secretion

22

What is MODY2 caused by and what is the pathogenesis behind it?

Glucokinase gene mutations:
- Impair activity
- Glucose sensing defect
> Increased threshold for insulin secretion

23

What mutations cause the following:
1. MODY1
2. MODY4
3. MODY6

1. HNF-4α
2. IPF1
3. NeuroD1/β2

24

What is the function of hepatocyte nuclear factor transcription factors (HNF)?

Regulate β-cell differentiation + function:
- Glycolytic flux
- Cell growth
- Glucose transport + metabolism
- GLUT2 expression
- Insulin secretion

25

How do we treat MODY?

Sulphonylureas

26

What does insulin trigger?

Amino acid uptake
DNA synthesis
Protein synthesis
Growth responses
Glucose uptake in:
- Muscle
- Adipose
Lipogenesis in tissue + liver
Glycogen synthesis in liver + muscle

27

What does insulin inhibit?

Lipolysis
Liver gluconeogenesis

28

What is the insulin receptor and what is its structure?

Dimeric tyrosine kinase:
- 2 extracellular α-subunits (for insulin binding)
- 2 transmembrane β-subunits
> Linked by disulfide bonds

29

What causes when insulin binds to the α-subunits?

β-subunits are autophosphorylated

30

What happens when the β-subunits are autophosphorylated?

Activates catalytic ability:
- Insulin receptor substrates are phosphorylated

31

What is Leprechaunism?

Donohue Syndrome:
- Autosomal recessive

32

What causes Leprechaunism and what does it result in?

Mutations in insulin receptor gene
Severe insulin resistance

33

Through what channel is glucose taken up into muscle and adipose tissue?

GLUT4

34

Which of the following is not associated with Leprechaunism:
- Elfin facial appearance
- Growth retardation
- Intellectual defect
- Absence of S/C fat
- Decreased muscle mass

Intellectual defect

35

What sort of inheritance does Rabson Mendenhall Syndrome display?

Autosomal recessive

36

What are features of Rabson Mendenhall Syndrome?

Severe insulin resistance
Hyperglycaemia -> DKA
Hyperinsulinaemia -> fasting hypoglycaemia
Developmental abnormalities
Acanthosis nigricans

37

Where are ketone bodies formed and in what process?

Liver mitochondria
- From acetyl-CoA -> From β-oxidation
> ie. Fatty acid metabolism

38

Where do ketone bodies move to?

Peripheral tissue

39

Where are ketone bodies important?

Heart muscle + renal cortex:
- As energy sources

40

What happens to ketone bodies in body sites where they are used for energy?

Converted back to acetyl-CoA:
- Enters TCA cycle

41

When does β-oxidation occur?

If no glucose available

42

In what situation might β-oxidation occur?

Starvation
DM

43

What occurs as a result of plentiful β-oxidation?

Increased acetyl-CoA
> Increased blood ketones
> Acidosis

44

What happens in hyperglycaemia in DM?

High glucose excretion
> Dehydration
> Exacerbation of ketoacidosis

45

Why is there normally no DKA in T2DM?

Hyperinsulinaemia inhibits hormone-sensitive lipase:
- No excess fat metabolism

46

What is the most diverse class of hormones? Give examples

Proteins and peptides:
- Insulin
- GH
- PRL

47

What are steroid hormones derived from?

Cholesterol

48

Give some examples of steroid hormones

Cortisol
Testosterone

49

What is the 3rd class of hormones and give some examples?

Tyrosine + tryptophan derivatives:
- Adrenaline
- Thyroid hormones
- Melatonin

50

What type of receptors are hormone receptors and what family to they belong to?

G-protein coupled receptors
Receptor Tyrosine Kinase (RTK) family

51

What is the general structure of GPCRs?

7 transmembrane domains
Associated G-protein complex

52

What are the main sensors of the internal environment?

GPCRs

53

What family does the insulin receptor belong to?

Tyrosine kinase

54

What hormone receptors belong to the cytokine receptor family?

Prolactin
GH

55

Where are steroid receptors typically located?

Intracellularly:
- Cytoplasm
- Nucleus

56

What factors can influence the ability to accurately measure hormone levels?

Pattern of secretion
Carrier proteins
Interfering agents
Hormone stability (Half-life)
Absolute concentration

57

What do the following usually indicate:
1. Normal TSH
2. Raised TSH
3. Suppressed TSH

1. Normal thyroid
2. Hypothyroid
3. Hyperthyroid

58

When is TSH not a reliable measure of thyroid status?

Pituitary dysfunction:
- Secondary hypothyroidism
- TSHoma

59

True or false; A random cortisol measurement is highly valuable?

False

60

At what time is a cortisol measurement a good indication of HPA axis function?

9am

61

How can we accurately asses HPA function formally?

Dynamic testing

62

Measuring what may give an indication of GH hypersecretion?

IGF-1

63

When do we measure sex hormones?

Testosterone -> 9am
Female hormones -> Depends on menstrual cycle

64

What cells secrete PRL and where are they located?

Lactotroph cells:
- Anterior pituitary

65

What inhibits PRL release?

Hypothalamic dopamine

66

What regulates PRL release?

'Short-loop' negative feedback

67

What stimulates ADH release from the posterior pituitary?

Hyperosmolarity
Angiotensin ii
SNS stimulation
Reduced atrial receptor firing

68

How do we test for hormone excess?

Suppression test

69

How do we test for hormone deficiency?

Stimulation test

70

What are some specialist tests for testing pituitary function?

Adrenal vein sampling
Petrosal sinus sampling

71

What causes a cortisol deficiency?

Adrenal insufficiency:
- Primary adrenal failure -> Addison's Disease
- Pituitary disease

72

What causes a cortisol excess?

Cushing's syndrome:
- Pituitary origin -> Adenoma (Cushing's Disease)
- Adrenal origin
- Ectopic ACTH
- Exogenous steroids

73

What is the most common cause of a cortisol excess?

Exogenous steroids

74

What is the most common cause of endogenous cortisol excess?

Pituitary adenoma

75

How do we test for cortisol deficiency?

SynACTHen test

76

How do we test for cortisol excess?

Dexamethasone suppression test

77

Which of the following is not a feature of Cushing's syndrome:
- Cushingoid facies
- Acne
- Hirsutism
- Abdominal striae
- Centripetal obesity
- Distal myopathy
- Osteoporosis
- Hypertension
- Impaired glucose tolerance

Distal myopathy:
- Cushing's -> Proximal myopathy

78

Where does Cushing's DISEASE arise from?

Adenoma (often micro-) of corticotroph cells of anterior pituitary

79

Are men or women more likely to suffer from Cushing's disease?

Women

80

Is Cushing's disease ACTH-dependent or ACTH-independent?

ACTH-dependent

81

What causes ACTH-independent Cushing's (syndrome)?

Adrenal adenoma/carcinoma
Bilateral macronodular adrenal hyperplasia

82

What can cause ectopic ACTH?

Malignancy:
- SCLC

83

What screening tests can help identify a possible case of Cushing's?

First line:
- 1mg overnight dexamethasone suppression
(24hr urinary free-cortisol)
(Midnight cortisol)

84

What is the formal diagnostic test for Cushing's syndrome?

Low dose Dexamethasone Suppression Test:
- Failure to suppress -> Cushing's Syndrome

85

If cortisol is not suppressed on testing, how do we distinguish between the various causes of Cushing's syndrome?

Measure ACTH levels:
- Low -> Adrenal origin
- Elevated in hundreds -> Ectopic ACTH
- Normal/Slightly high -> Cushing's disease (pituitary)

86

If cortisol and ACTH are raised on CRH test what is the origin of the Cushing's syndrome?

Pituitary

87

If we suspect a pituitary origin of Cushing's syndrome, how do we confirm a diagnosis?

Pituitary MRI

88

What is the rationale behind inferior petrosal sinus sampling?

To lateralize tumour prior to surgery

89

What mode of inheritance is Multiple Endocrine Neoplasia 1 (MEN1) and what mutation results in the condition? How does this result in its presentation?

Autosomal dominant
MEN1 gene -> 11q:
- Classic tumour suppressor
- Mutations throughout gene

90

Where do tumours arise in MEN1?

Pituitary
Parathyroid
Bronchial carcinoma
Enteropancreatic

91

What mode of inheritance is Multiple Endocrine Neoplasia 2 (MEN2) and what mutation results in the condition? How does this result in its presentation?

Autosomal dominant
RET gene -> 10q:
- Classic proto-oncogene
- Mutations at specific codons

92

Where do tumours arise in MEN2?

Nerves
Parathyroid
Thyroid C cell
Adrenal chromaffin