Biochemistry Flashcards
What cells are found within exocrine tissue?
Acinar cells
What type of cells make up pancreatic islets?
Alpha (10-20%), beta (60-80%), gamma (~5%), PP-cells (less than 1%)
What do B cells secrete?
Insulin
What do a cells secrete?
Glucagon
What do gamma cells secrete?
Somatostatin
What do PP cells secrete?
Pancreatic polypeptide
Where is insulin synthesized within B cells, and as what?
RER as larger single chain preprohormone- preproinsulin
What links the polypeptide chains in insulin?
Disulphide bonds
What is a byproduct of preproinsulin cleavage?
Connecting (C) peptide
What will form against injected non-human insulin when given over a prolonged period of time?
Antibodies
How does glucose enter B cells, and what happens after this initially?
Through GLUT2 glucose transporter, phosphorylated by glucokinase
What does increased glucose metabolism in B cells lead to?
An increase in intracellular ATP concentration
What does ATP inhibit in B cells, and what does this lead to?
ATP-sensitive K+ channel K(ATP)- leads to depolarization of the cell membrane
What does depolarization of the B cell membrane result in?
Opening of voltage gated Ca2+ channels
What does an increase in internal Ca2+ concentration in B cells cause?
Fusion of secretory vesicles with the cell membrane and insulin release
In what wave pattern is insulin released?
Biphasic
Why are there 2 phases of insulin release?
5% insulin granules are immediately available as a RRP-readily releasable pool. Reserve pool undergoes reactions to become mobilized and available
What two proteins does the Katp channel consist of?
Inward rectifier subunit (Kir)-pore subunit: Kir6.1, and sulphonylurea receptor - regulatory subunit- SUR1
What structure does a Katp channel have?
Octomeric
What class of drugs inhibit Katp?
Sulphonylurea class- e.g. tolbutamide, glibenclamide
What oxide stimulates Katp inhibiting insulin secretion?
Diazoxide
What can mutations in Kir6.x and SUR1 cause?
Kir6.x mutations can lead to neonatal diabetes: activated or increased Katp, B cells secreting insulin in response to tolbutamide. Some Kir6.x/SUR1 mutations lead to congenital hyperinsulinism: trafficking or inhibiting mutations, diazoxide can help inhibit insulin secretion
What is Maturity onset diabetes of the young (MODY)?
Monogenic diabetes with genetic defect in B cell function. Familial form of early-onset type II dm, primary defects in insulin secretion. Mutations in several genes cause this
What do HNF transcription factors do?
Play key role in pancreas foetal development and neogenesis. Also regulate B cell differentiation and function-glycolytic flux, expression of GLUT2 transporters, cell growth, insulin secretion, glucose transport + metabolism
What allows you to differentiate MODY from T1DM allowing treatment with sulphonylurea rather than insulin?
Robust genetic screening
Where do proteins get phosphorylated on their chain?
Any hydroxyl group
What does phosphorylation do in terms of charge to a protein?
Large negative charge
What is the insulin receptor?
Dimeric tyrosine kinase
What is the structure of tyrosine kinase?
Two extracellular alpha sub-units with insulin binding domains, two transmembrane beta subunits, linked by disulphide bonds
What does binding of insulin to the alpha subunits of tyrosine kinase cause?
The beta subunits phosphorylate themselves (autophosphorylation), thus activates catalytic activity of receptor
What do insulin receptor substrates do when phosphorylated?
Activate the RAS/MAPK pathway and gene expression, and PI3K, PKB and glycogen synthesis,
What does PKB do in insulin signaling?
Stimulates GLUT4 translocation
What are the biological effects of insulin?
aa uptake by muscle, DNA/protein synthesis, growth responses, glucose uptake in muscle/adipose tissue, lipogenesis in adipose/liver, glycogen synthesis liver/muscle, gene expression, lipolysis, gluconeogenesis in liver
What is leprechaunism (Donohue syndrome)
Rare autosomal recessive, mutations in gene for insulin receptor, severe insulin resistance, elfin facial appearance, growth retardation, absence of subcut fat, decreased muscle mass, caused by defects in insulin binding or receptor signalling
What is Rabson Mendenhall syndrome?
Rare autosomal recessive, severe insulin resistance, hyperglycaemia, compensatory hyperinsulinaemia, developmental abnorms, acanthosis nigricans, fasting hypoglycaemia, DKA- mutations in insulin receptor reduce sensitivity
Where are ketone bodies formed?
Formed in liver mitochondria
What are ketone bodies derived from?
Acetyl-CoA from B oxidation
What are ketone bodies important for?
Energy metabolism for heart muscle and renal cortex-converted back to acetyl-CoA, which enters TCA cycle
How does accumulation of ketone bodies causing acidosis occur?
Oxaloacetate consumed for gluconeogenesis, when glucose not available fatty acids oxidized, excess acetyl-CoA converted to ketone bodies, blood levels increase. Leads to accumulation
What does high glucose excretion cause, and what does this exacerbate?
Dehydration, exacerbates acidosis caused by accumulation of ketones
What does acidosis caused by ketone bodies exacerbated by dehydration result in?
Coma > death
What type of DM is associated with DKA?
Type 1-
How does DKA arise in a T1DM patient when their insulin is not injected?
Cells fail to receive enough glucose, switch to fat breakdown
Why does DKA not normally occur in T2DM?
High concentrations of insulin in T2DM inhibits lipase, no excessive breakdown of fat resources occurs
What are standard baseline tests in endocrine disease?
TSH, fT4, LH, FSH, Testosterone, GH, IGF-1, PRL
What follows sodium around the body?
Water
What is sodium controlled by?
Mineralcorticoid activity
What does mineralocorticoid activity refer to?
Sodium retention in exchange for potassium and/or hydrogen ions
What steroids have mineralocorticoid activity?
Aldosterone (main one), other steroids e.g. cortisol
Where is ADH released from?
Posterior pituitary
What is ADH released in response to?
Osmotic and non-osmotic stimuli
Does concentrated urine have a high or low osmolality?
High urine osmolality
What can a low sodium concentration be caused by in terms of water and sodium?
Too much water/too little sodium
What can a high sodium concentration be caused by in terms of water and sodium?
Too little water/too much sodium
How can too much water cause a decrease in sodium concentration?
Decreased excretion e.g SIAD, increased intake -compulsive water drinking
How can too little sodium cause a decrease in sodium concentration?
Increased sodium loss- kidneys (e.g. Addisons), Gut, Skin. Decreased sodium intake-rare
How can too little water cause an increase in sodium concentration?
Increased water loss-DI (problem with ADH secretion/action). Decreased water intake-e.g. young, elderly (insensible water loss continues)
How can too much sodium cause an increase in sodium concentration?
Rare- may not be suspected. Some IV medications given as sodium salt, near-drowning in sea, infants given high salt feeds
How does Addison’s cause low sodium?
Adrenal insufficiency>can’t make enough steroids>decreased mineralocorticoid activity>can’t retain sodium in kidneys>loses sodium (and water from ECF), decreased ECF volume causes dehydration
In Addison’s what are the symptoms of dizziness caused by?
Reflect hypotension from decreased ECF
Why does excess pigmentation occur in Addisons?
Excess ACTH from pituitary, ACTH contains MSH sequence, ACTH degraded by proteases exposing MSH
What is SIAD?
Syndrome of inappropriate antidiuresis
What are some non-osmotic stimuli of ADH release?
Hypovolaemia/hypotension, pain, nausea/vomiting
When is too much water usually noticed?
When U&E done and [Na] is low
How is a diagnosis of water excess as the mechanism for low sodium usually made?
Often by exclusion-once adrenal insufficiency etc ruled out
Why can’t ADH be secreted by the posterior pituitary in DI?
Disruption of pituitary or pituitary stalk
Why does DI lead to too little water?
No ADH to act on kidneys to reabsorb water, lots of water lost in urine. High sodium reflects deficit. Can be corrected with exogenous ADH to replace it
Why will a patients volume status be unremarkable even in water retention?
Retained water is distributed all over body compartments (ICF and ECF)
If hypovolaemia is present when sodium is low, what does this mean?
There is a water deficit, but an even bigger sodium deficit
What is the problem biochemically with hypovolaemia in hyponatraemia?
Too little sodium (as water follows sodium)
What clinical signs is hypervolaemia often seen as?
Oedema
How can you tell if a high or low [Na] is serious?
If [Na] is low (155mmol/l), then serious. If patient has symptoms e.g. altered consciousness, confusion nausea in context or abnormal [Na], then serious. If [Na] fallen or risen sharply to level, then possibly serious
When does pseudohyponatraemia occur?
When serum concentration of sodium is normal, but reported low due to hyperlipidaemia or hyperproteinaemia
