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

Biochemistry (Weeks 1, 2 + 3) Flashcards

1
Q

What do the following pancreatic cells secrete?

  1. β-cells
  2. α-cells
  3. δ-cells
  4. PP cells
A
  1. Insulin
  2. Glucagon
  3. Somatostatin
  4. Pancreatic polypeptide
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2
Q

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

A

RER

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3
Q

What is the process of insulin production?

A
  1. Made as preprohormone (Preproinsulin)
  2. Cleaved into:
    • Proinsulin
    • Signal peptide
  3. Cleaved into:
    • Insulin
    • C-peptide
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4
Q

What is the structure of insulin?

A

2 polypeptide chains

Linked by disulfide bonds

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5
Q

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

A

Insulin secretion:

- Secreted in same vesicle as insulin

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6
Q

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

A

C-peptide

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7
Q

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

A

It is antigenic:

- Induces Ab formation against injected insulin

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8
Q

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
A
  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
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9
Q

How does glucose enter the β-cell?

A

Via GLUT2 glucose transporter

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10
Q

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

A

Physiological range

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11
Q

What does a change in [Glucose] result in?

A

Dramatic change in glucokinase activity

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12
Q

What sort of release pattern does insulin have?

A

Biphasic

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13
Q

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

A

Prevents hyperglycaemia

5% of insulin granules in a readily-releasable pool

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14
Q

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

A

How well phase one controls blood glucose:

- Reserve pool undergoes preparation

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15
Q

What is the structure of the Katp?

A 
Inward rectifier subunit (Kir):
     - Pore
     - Kir6.2
Sulphonylurea receptor:
     - Regulatory subunit
     - SUR1
Octomeric structure
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16
Q

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

A

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

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17
Q

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

A

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

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18
Q

What happens if the Katp channels is inactive?

A

Hyperinsulinaemia

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19
Q

What mutations can cause neonatal DM?

A

Kir6.2 mutations:

 - Activated/More Katp channels
 - Insulin secreted in response to Tolbutamide
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20
Q

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

A

Trafficking/Inhibiting mutations

Diazoxide

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21
Q

What causes familial early-onset T2DM?

A

Primary defect in insulin secretion

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22
Q

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

A

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

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23
Q

What mutations cause the following:

  1. MODY1
  2. MODY4
  3. MODY6
A
  1. HNF-4α
  2. IPF1
  3. NeuroD1/β2
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24
Q

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

A

Regulate β-cell differentiation + function:

 - Glycolytic flux
 - Cell growth
 - Glucose transport + metabolism
 - GLUT2 expression
 - Insulin secretion
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25
Q

How do we treat MODY?

A

Sulphonylureas

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26
Q

What does insulin trigger?

A 
Amino acid uptake
DNA synthesis
Protein synthesis
Growth responses
Glucose uptake in:
     - Muscle
     - Adipose
Lipogenesis in tissue + liver
Glycogen synthesis in liver + muscle
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27
Q

What does insulin inhibit?

A

Lipolysis

Liver gluconeogenesis

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28
Q

What is the insulin receptor and what is its structure?

A

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

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29
Q

What causes when insulin binds to the α-subunits?

A

β-subunits are autophosphorylated

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30
Q

What happens when the β-subunits are autophosphorylated?

A

Activates catalytic ability:

- Insulin receptor substrates are phosphorylated

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31
Q

What is Leprechaunism?

A

Donohue Syndrome:

- Autosomal recessive

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32
Q

What causes Leprechaunism and what does it result in?

A

Mutations in insulin receptor gene

Severe insulin resistance

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33
Q

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

A

GLUT4

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34
Q

Which of the following is not associated with Leprechaunism:

 - Elfin facial appearance
 - Growth retardation
 - Intellectual defect
 - Absence of S/C fat
 - Decreased muscle mass
A

Intellectual defect

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35
Q

What sort of inheritance does Rabson Mendenhall Syndrome display?

A

Autosomal recessive

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36
Q

What are features of Rabson Mendenhall Syndrome?

A 
Severe insulin resistance
Hyperglycaemia -> DKA
Hyperinsulinaemia -> fasting hypoglycaemia
Developmental abnormalities
Acanthosis nigricans
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37
Q

Where are ketone bodies formed and in what process?

A

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

38
Q

Where do ketone bodies move to?

A

Peripheral tissue

39
Q

Where are ketone bodies important?

A

Heart muscle + renal cortex:

- As energy sources

40
Q

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

A

Converted back to acetyl-CoA:

- Enters TCA cycle

41
Q

When does β-oxidation occur?

A

If no glucose available

42
Q

In what situation might β-oxidation occur?

A

Starvation

DM

43
Q

What occurs as a result of plentiful β-oxidation?

A

Increased acetyl-CoA
> Increased blood ketones
> Acidosis

44
Q

What happens in hyperglycaemia in DM?

A

High glucose excretion
> Dehydration
> Exacerbation of ketoacidosis

45
Q

Why is there normally no DKA in T2DM?

A

Hyperinsulinaemia inhibits hormone-sensitive lipase:

- No excess fat metabolism

46
Q

What is the most diverse class of hormones? Give examples

A

Proteins and peptides:

 - Insulin
 - GH
 - PRL
47
Q

What are steroid hormones derived from?

A

Cholesterol

48
Q

Give some examples of steroid hormones

A

Cortisol

Testosterone

49
Q

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

A

Tyrosine + tryptophan derivatives:

 - Adrenaline
 - Thyroid hormones
 - Melatonin
50
Q

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

A

G-protein coupled receptors

Receptor Tyrosine Kinase (RTK) family

51
Q

What is the general structure of GPCRs?

A

7 transmembrane domains

Associated G-protein complex

52
Q

What are the main sensors of the internal environment?

A

GPCRs

53
Q

What family does the insulin receptor belong to?

A

Tyrosine kinase

54
Q

What hormone receptors belong to the cytokine receptor family?

A

Prolactin

GH

55
Q

Where are steroid receptors typically located?

A

Intracellularly:

 - Cytoplasm
 - Nucleus
56
Q

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

A 
Pattern of secretion
Carrier proteins
Interfering agents
Hormone stability (Half-life)
Absolute concentration
57
Q

What do the following usually indicate:

  1. Normal TSH
  2. Raised TSH
  3. Suppressed TSH
A
  1. Normal thyroid
  2. Hypothyroid
  3. Hyperthyroid
58
Q

When is TSH not a reliable measure of thyroid status?

A

Pituitary dysfunction:

 - Secondary hypothyroidism
 - TSHoma
59
Q

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

A

False

60
Q

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

A

9am

61
Q

How can we accurately asses HPA function formally?

A

Dynamic testing

62
Q

Measuring what may give an indication of GH hypersecretion?

A

IGF-1

63
Q

When do we measure sex hormones?

A

Testosterone -> 9am

Female hormones -> Depends on menstrual cycle

64
Q

What cells secrete PRL and where are they located?

A

Lactotroph cells:

- Anterior pituitary

65
Q

What inhibits PRL release?

A

Hypothalamic dopamine

66
Q

What regulates PRL release?

A

‘Short-loop’ negative feedback

67
Q

What stimulates ADH release from the posterior pituitary?

A

Hyperosmolarity
Angiotensin ii
SNS stimulation
Reduced atrial receptor firing

68
Q

How do we test for hormone excess?

A

Suppression test

69
Q

How do we test for hormone deficiency?

A

Stimulation test

70
Q

What are some specialist tests for testing pituitary function?

A

Adrenal vein sampling

Petrosal sinus sampling

71
Q

What causes a cortisol deficiency?

A

Adrenal insufficiency:

 - Primary adrenal failure -> Addison's Disease
 - Pituitary disease
72
Q

What causes a cortisol excess?

A

Cushing’s syndrome:

 - Pituitary origin -> Adenoma (Cushing's Disease)
 - Adrenal origin
 - Ectopic ACTH
 - Exogenous steroids
73
Q

What is the most common cause of a cortisol excess?

A

Exogenous steroids

74
Q

What is the most common cause of endogenous cortisol excess?

A

Pituitary adenoma

75
Q

How do we test for cortisol deficiency?

A

SynACTHen test

76
Q

How do we test for cortisol excess?

A

Dexamethasone suppression test

77
Q

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
A

Distal myopathy:

- Cushing’s -> Proximal myopathy

78
Q

Where does Cushing’s DISEASE arise from?

A

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

79
Q

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

A

Women

80
Q

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

A

ACTH-dependent

81
Q

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

A

Adrenal adenoma/carcinoma

Bilateral macronodular adrenal hyperplasia

82
Q

What can cause ectopic ACTH?

A

Malignancy:

- SCLC

83
Q

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

A

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

84
Q

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

A

Low dose Dexamethasone Suppression Test:

- Failure to suppress -> Cushing’s Syndrome

85
Q

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

A

Measure ACTH levels:

 - Low -> Adrenal origin
 - Elevated in hundreds -> Ectopic ACTH
 - Normal/Slightly high -> Cushing's disease (pituitary)
86
Q

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

A

Pituitary

87
Q

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

A

Pituitary MRI

88
Q

What is the rationale behind inferior petrosal sinus sampling?

A

To lateralize tumour prior to surgery

89
Q

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

A

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

90
Q

Where do tumours arise in MEN1?

A

Pituitary
Parathyroid
Bronchial carcinoma
Enteropancreatic

91
Q

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

A

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

92
Q

Where do tumours arise in MEN2?

A

Nerves
Parathyroid
Thyroid C cell
Adrenal chromaffin

Year 2 - Endocrinology (DP) (15 decks)

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