Lecture 17: Causes of Diabetes Flashcards
What is insulin secreted by?
Beta cells in the pancreas
What regulates insulin secretion?
Blood glucose levels
How is insulin secreted from beta cells?
- An increase in glucose uptake and metabolism leads to an increase in ATP:ADP
- This leads to a closure of ATP sensitive K channels and membrane depolarisation
- This leads to an opening of voltage gated calcium channels
- The increase in cytosolic calcium promotes secretion of insulin via exocytosis of insulin granules
What is the insulin signalling pathway?
- binding of insulin to the insulin receptor leads to receptor auto phosphorylation
- Phosphorylated residues on the insulin receptor acts as binding sites for insulin receptor substrate proteins
- Insulin receptor phosphorylates 4 tyrosine residues in insulin receptor substarte proteins
- The lipid kinase, phosphoinositide 3-kinase binds to phosphorylated residues on IRS proteins, and then converts PIP2 to PIP3
- Binding to PIP3 activates PDK1, which then phosphorylates and activates kinases such as PKB/Akt
- Activated PKB/Akt can then diffuse through the cell and activate processes such as glucose transport and glycogen synthesis
What are the mechanisms that inhibit the insulin signalling pathway?
- Protein tyrosine phosphatse 1B (PTP1B) dephosphorylates the insulin receptor leading to a loss of IRS binding
- Phosphatase and tensin homologue (PTEN) dephosphorylayes PIP3 back to PIP2
- IRS proteins are inactivated by phosphorylation of serine residues by PKC, which prevents IR from phosphorylating tyrosine residues on IRS
How does insulin stimulates glucose transport into adipocytes and skeletal muscle?
- The glucose transporter GLUT4 is contained inside the cell in storage vesicles
- The protein AS160 acts to retain these vesicles in the cell
- Actiavted PKB phosphorylates AS160 and inactivates it
- This allows GLUT4 vesicles to fuse with the plasma membrane, leading to increased levels of the glucose transporter at the surface
What is gluconeogenesis?
process by which the liver produces glucose from non-carbohydrate sources, such as amino acids and glycerol.
Where does gluconeogenesis take place?
Liver
How is gluconeogenesis inhibited?
- insulin signalling leads to activation of PKB
- PKB phosphorylates Fox01
- Phosphorylation of Fox01, 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?
- Loss of insulin stimulated glucose uptake into target cells.
- Loss of insulin mediated repression of gluconeogenesis in the liver
What are the autoantibodies against beta cell antigens?
- Glutamic acid decarboxylase - 65 (GAD 65)
- Insulin
- Inslet antigen 2 (IA2)
- Zinc transporter 8 (ZnT8)
What is the auto immune destruction of beta cells?
In type 1 diabetes, an effector T cell recognizes peptides from a beta cell specific protein and kills the beta cell
What causes beta cell destruction in type 2 diabetes?
Beta cells respond to prevailing insulin resistance by synthesising more insulin. This puts endoplasmic reticulum under stress so can no longer fold and process new insulin. Activates unfolded protein response (UPR). Eventually results in apoptosis and beta cell death
How does TNFa contribute to insulin resistance?
- induces expression of PTP1B, which can dephosphorylate the insulin receptor
- activates JNK (Jun-N-terminal kinase), which causes serine phosphorylation and inactivation of IRS proteins
How do adipocytes contribute to insulin resistance?
Adipose tissue from lean individuals secrete anti-inflammatory and insulin-sensitising adipokines such as adiponectin
