Insulin production, secretion and action Flashcards
What do all the cells of pancreatic islets secrete?
Beta - insulin
Alpha - glucagon
Delta - somatostatin
PP - pancreatic polypeptide
How is insulin synthesized?
In the RER of pancreatic beta cells as preproinsuln where it is then cleaved to insulin releasing C peptide
What is the name of the ultrafast insulin?
Lispro
When is lispro used?
Within 15 mins of a meal
What is the name of the ultra long acting insulin?
Glargine - peakless prolonged action
When is glargine used?
As a single bedtime use
How does glucose enter beta cells?
Via GLUT2 receptors
What happens when glucose enters the pancreatic cells?
It is phosphorlyates by glucokinase to glucose-6-phosphate
What is the Km for glucokinase?
Around 5mmol/L
How many ATP are produced per glucose molecule?
36
What is the action of ATP in the secretion of insulin?
Inhibits kATP which leads to depolarisation of the cell membrane
What occurs when the cell membrane of beta islet cells depolarises?
Opening of voltage gated calcium channels which leads to fusion of clacium with secretory vesicles releasing insulin
When will beta cells release insulin?
In blood glucose levels over 5 mM
Why is the release of insulin biphasic?
Only 5% of insulin granules are readily avaliable for release to prevent all the stores of insulin being depeted
What is the action of sulphonylurea?
Mimics the action of ATP to depolarise beta cells
What are the 2 subunits of the kATP channel?
An inward rectifier subunit - Kir6
A sulphonylurea receptor which is regulatory - SUR1
What is the action of diazoxide?
Stimulates kATP receptors inihibiting insulin secretion
What does a mutation in Kir6.2 lead to?
Neonatal diabetes due to an increase in kATP receptors
What is MODY?
Monogenic diabetes with a genetic defect in beta cell function usually in the function of gluokinase or the development of the cell
What is MODY2?
Glucokinase activity impaired leading to a glucose sensing defect where the blood glucose threshold for insulin secretion is too high
What is MODY 1 and 3?
Mutation in HNF transcription factors which play a key role in pancreatic foetal development and neogenesis
Why is it important to distinguish between MODY and type 1 DM?
MODY can be treated with sulphonylurea (tablets) instead of insulin (injections)
What will insulin turn on biologically?
Amino acid uptake in muscle DNA and protein synthesis Growth response Glucose uptake in muscle and adipose tissue Liogenesis in adipose tissue and liver Glycogen synthesis in liver and muscle
What will insulin turn off biologically?
Lipolysis
Gluconegenesis in liver
What class of receptor is the insulin receptor?
Receptor tyrosine kinase
What will binding of insulin to its receptor cause?
Insulin will bind to the alpha subunit and cause the beta subunits to dimerise and to autophosphorylate thus activating the catalytic activity of the receptor
What pathway will regulate the metabolic pathway?
PKB pathway
What pathway will regulate the gene expression properties of insulin?
Ras
MAP kinase pathway
What is leprechaunism?
Rare autosomal recessive genetic disease resultin in severe insulin resistance due to mutations in the gene for the insulin receptor
What developmental abnormalities are present in leprechaunism?
Elfin facial appearance
Growth retardation
Absence of subcutis fat, decreased muscle mass
What is rabson mendenahll syndrome?
A rare autosomal recessive genetic disease that results in severe insulin resistance, hyperglycaemia and compensatory hyperinsuliemia
What wil rabdon mendenhall syndrome present with?
Developmental abnormalities
Acanthosis nigricans
Fasting hypoglycaemia
DKA
What are the symptoms of DKA?
Vomiting
Dehydration
Increased HR
Distinctive pear drop smell on breath
Where are ketone bodies formed?
In the liver mitochrondria from acetyl-CoA from beta oxidation of fats
What are ketone bodies needed for?
Energy metabolism for heart muscle and renal cortex where they are converted back to acetyl co-A to enter the TCA cycle
How does DKA come about?
There is a lack of glucose and therefore a lack of oxaloacetate and therefore oxaloacetate is used for gluconeogenesis
When glucose is not avaliable, fatty acida are oxidised but this produces excess acetyl-coA
Excess acetyl coA is converted to ketone bodies and the accumulation leads to acidosis
