Lecture 17 - Causes of Diabetes Flashcards
What secretes insulin?
the beta cells in the pancreas
Where does the pancreas sit?
in the abdominal cavity behind the stomach
Where are the beta cells contained within the pancreas?
In pancreatic islets which contain alpha, beta and delta cells
What cells secrete glucagon?
alpha cells
When is insulin released?
in response to high blood glucose levels
What does an increase in blood glucose lead to?
an increase of glucose uptake into the cell
What does increased glucose in the cell cause?
higher levels of ATP, which increases the ATP”ADP ratio
What does increased ATP:ADP cause?
closure of the ATP-sensitive K+ channels, which causes membrane depolarisation
What does membrane depolarisation cause?
activation of voltage gates Ca2+ channels, causing increased Ca2+ inside the cell
What does increased cytosolic Ca2+ cause?
fusion of insulin granules with the plasma membrane, causing release of insulin
What does insulin increase?
glucose uptake, glycolysis, glycogen synthesis, fatty acid/triglyceride synthesis, amino acid uptake and protein synthesis
What does insulin decrease?
glycogen breakdown, gluconeogenesis, lipolysis, proteolysis
What are the effects of insulin mediated via?
activation of insulin signalling pathways in target cells
What does insulin binding to the insulin receptor do?
activates many different signalling pathways to bring about its effects on metabolism and growth
What does insulin signalling involve?
protein phosphorylation
What does binding of insulin to the insulin receptor (IR) lead to?
auto phosphorylation of the receptor (receptor phosphorylates itself)
What do phosphorylates residues on the IR act as?
binding sites for insulin receptor substrate (IRS)
What does IR phosphorylate?
4 tyrosine residues in IRS proteins
What binds to phosphorylated residues?
The lipid kinase, phosphoinositide 3-kinase
What does the lipid kinase phosphoinositide 3-kinase do?
converts PIP2 to PIP3
What does binding of PIP3 do?
activates PKD1
What does PKD1 do?
phosphorylates and activates kinases such as PKB/Akt
What does PKB/Akt do?
diffuse through the cell and activate processes such as glucose transport and glycogen synthesis
What does insulin stimulate?
glucose transport into adipocytes and skeletal muscle
What does insulin binding to receptor on adipocytes and skeletal muscle cells do?
activates the insulin signalling pathway, leading to fusion of GLUT4 containing vesicles to the membrane
What happens when GLUT4 vesicles fuse with the membrane?
GLUT4 inserts itself into the cell surface where it can take up those glucose molecules into the cells
How does insulin repress gluconeogenesis?
by inhibiting transcription factor Fox01
Where is Fox01 synthesised?
in the cytosol
Where is Fox01 targetted?
to the nucleus
What does Fox01 do?
regulates expression of genes that mediate gluconeogenesis (PEPCK, G6Pase)
What does PKB do to Fox01?
phosphorylates it
What does phosphorylation of Fox01 do?
prevents it from entering the nucleus, leading to a loss of expression of gluconeogenic genes and hence a loss of glucose production
How does loss of insulin secretion or insulin resistance lead to hyperglycaemia?
as a result of loss of insulin stimulated uptake into target cells (skeletal muscle, adipocytes)
loss of insulin-mediated repression of gluconeogenesis (and glycogen breakdown) in the liver
What happens in type 1 diabetes?
is a chronic autoimmune disease in which destruction of beta cells results in insulin deficiency and hyperglycaemia
Who does type 1 diabetes generally occur in?
susceptible individuals, likely as a result of an environmental trigger