Flashcards in Biochemistry (Weeks 1, 2 + 3) Deck (92):
What do the following pancreatic cells secrete?
4. PP cells
4. Pancreatic polypeptide
In what part of the β-cell is insulin made?
What is the process of insulin production?
1. Made as preprohormone (Preproinsulin)
2. Cleaved into:
- Signal peptide
3. Cleaved into:
What is the structure of insulin?
2 polypeptide chains
Linked by disulfide bonds
What can the connecting-peptide be used as an indicator of and how?
- Secreted in same vesicle as insulin
Which amino acid sequence varies greatly between species, insulin or c-peptide?
What happens if a different species' insulin is given to humans?
It is antigenic:
- Induces Ab formation against injected insulin
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
How does glucose enter the β-cell?
Via GLUT2 glucose transporter
In what range does glucokinase's Km for glucose lie?
What does a change in [Glucose] result in?
Dramatic change in glucokinase activity
What sort of release pattern does insulin have?
What does the 1st phase of insulin secretion do and how does it achieve this?
5% of insulin granules in a readily-releasable pool
What does the 2nd phase of insulin release vary with and how?
How well phase one controls blood glucose:
- Reserve pool undergoes preparation
What is the structure of the Katp?
Inward rectifier subunit (Kir):
- Regulatory subunit
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)
- Sulphonylurea drugs -> Tolbutamide/Glibenclamide
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
What happens if the Katp channels is inactive?
What mutations can cause neonatal DM?
- Activated/More Katp channels
- Insulin secreted in response to Tolbutamide
What sort of Kir6.2 + SUR1 mutations cause congenital hyperinsulinaemia? How can this be treated?
What causes familial early-onset T2DM?
Primary defect in insulin secretion
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
What mutations cause the following:
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
How do we treat MODY?
What does insulin trigger?
Amino acid uptake
Glucose uptake in:
Lipogenesis in tissue + liver
Glycogen synthesis in liver + muscle
What does insulin inhibit?
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
What causes when insulin binds to the α-subunits?
β-subunits are autophosphorylated
What happens when the β-subunits are autophosphorylated?
Activates catalytic ability:
- Insulin receptor substrates are phosphorylated
What is Leprechaunism?
- Autosomal recessive
What causes Leprechaunism and what does it result in?
Mutations in insulin receptor gene
Severe insulin resistance
Through what channel is glucose taken up into muscle and adipose tissue?
Which of the following is not associated with Leprechaunism:
- Elfin facial appearance
- Growth retardation
- Intellectual defect
- Absence of S/C fat
- Decreased muscle mass
What sort of inheritance does Rabson Mendenhall Syndrome display?
What are features of Rabson Mendenhall Syndrome?
Severe insulin resistance
Hyperglycaemia -> DKA
Hyperinsulinaemia -> fasting hypoglycaemia
Where are ketone bodies formed and in what process?
- From acetyl-CoA -> From β-oxidation
> ie. Fatty acid metabolism
Where do ketone bodies move to?
Where are ketone bodies important?
Heart muscle + renal cortex:
- As energy sources
What happens to ketone bodies in body sites where they are used for energy?
Converted back to acetyl-CoA:
- Enters TCA cycle
When does β-oxidation occur?
If no glucose available
In what situation might β-oxidation occur?
What occurs as a result of plentiful β-oxidation?
> Increased blood ketones
What happens in hyperglycaemia in DM?
High glucose excretion
> Exacerbation of ketoacidosis
Why is there normally no DKA in T2DM?
Hyperinsulinaemia inhibits hormone-sensitive lipase:
- No excess fat metabolism
What is the most diverse class of hormones? Give examples
Proteins and peptides:
What are steroid hormones derived from?
Give some examples of steroid hormones
What is the 3rd class of hormones and give some examples?
Tyrosine + tryptophan derivatives:
- Thyroid hormones
What type of receptors are hormone receptors and what family to they belong to?
G-protein coupled receptors
Receptor Tyrosine Kinase (RTK) family
What is the general structure of GPCRs?
7 transmembrane domains
Associated G-protein complex
What are the main sensors of the internal environment?
What family does the insulin receptor belong to?
What hormone receptors belong to the cytokine receptor family?
Where are steroid receptors typically located?
What factors can influence the ability to accurately measure hormone levels?
Pattern of secretion
Hormone stability (Half-life)
What do the following usually indicate:
1. Normal TSH
2. Raised TSH
3. Suppressed TSH
1. Normal thyroid
When is TSH not a reliable measure of thyroid status?
- Secondary hypothyroidism
True or false; A random cortisol measurement is highly valuable?
At what time is a cortisol measurement a good indication of HPA axis function?
How can we accurately asses HPA function formally?
Measuring what may give an indication of GH hypersecretion?
When do we measure sex hormones?
Testosterone -> 9am
Female hormones -> Depends on menstrual cycle
What cells secrete PRL and where are they located?
- Anterior pituitary
What inhibits PRL release?
What regulates PRL release?
'Short-loop' negative feedback
What stimulates ADH release from the posterior pituitary?
Reduced atrial receptor firing
How do we test for hormone excess?
How do we test for hormone deficiency?
What are some specialist tests for testing pituitary function?
Adrenal vein sampling
Petrosal sinus sampling
What causes a cortisol deficiency?
- Primary adrenal failure -> Addison's Disease
- Pituitary disease
What causes a cortisol excess?
- Pituitary origin -> Adenoma (Cushing's Disease)
- Adrenal origin
- Ectopic ACTH
- Exogenous steroids
What is the most common cause of a cortisol excess?
What is the most common cause of endogenous cortisol excess?
How do we test for cortisol deficiency?
How do we test for cortisol excess?
Dexamethasone suppression test
Which of the following is not a feature of Cushing's syndrome:
- Cushingoid facies
- Abdominal striae
- Centripetal obesity
- Distal myopathy
- Impaired glucose tolerance
- Cushing's -> Proximal myopathy
Where does Cushing's DISEASE arise from?
Adenoma (often micro-) of corticotroph cells of anterior pituitary
Are men or women more likely to suffer from Cushing's disease?
Is Cushing's disease ACTH-dependent or ACTH-independent?
What causes ACTH-independent Cushing's (syndrome)?
Bilateral macronodular adrenal hyperplasia
What can cause ectopic ACTH?
What screening tests can help identify a possible case of Cushing's?
- 1mg overnight dexamethasone suppression
(24hr urinary free-cortisol)
What is the formal diagnostic test for Cushing's syndrome?
Low dose Dexamethasone Suppression Test:
- Failure to suppress -> Cushing's Syndrome
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)
If cortisol and ACTH are raised on CRH test what is the origin of the Cushing's syndrome?
If we suspect a pituitary origin of Cushing's syndrome, how do we confirm a diagnosis?
What is the rationale behind inferior petrosal sinus sampling?
To lateralize tumour prior to surgery
What mode of inheritance is Multiple Endocrine Neoplasia 1 (MEN1) and what mutation results in the condition? How does this result in its presentation?
MEN1 gene -> 11q:
- Classic tumour suppressor
- Mutations throughout gene
Where do tumours arise in MEN1?
What mode of inheritance is Multiple Endocrine Neoplasia 2 (MEN2) and what mutation results in the condition? How does this result in its presentation?
RET gene -> 10q:
- Classic proto-oncogene
- Mutations at specific codons