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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
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

Year 2 - Endocrinology (DP) (15 decks)

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