Diabetes Flashcards
Type one initiation?
Up regulation of IFN alpha
Which stimulates cytotoxic Tcells
Up regulation of MHC class 1 enables cytotoxic T cells to attack
TCell attack
Beta cells become available due to apoptosis and the antigens are then displayed to the autoimmune system which creates antibodies
CD8 cytotoxic T cells
Attack the beta cells and bind the cell receptors causing apoptosis as the fasl bind the gas on the B cell
CD4
Present the Antigen receptor on the surface causing the B cell to release cytokines such as TNF alpha which induces apoptosis on other beta cells
Autoimmune diseases
Generally occur when an issue with the Tcell suppression cells, auto reactive cells
Process of increasing autoantibodies
Increased production of IFN before MHC1 increases as well then CD8 binds eating the beta cells before the antigen from the beta cells are transported
Can be extended when CD8 binds and destroys periforin and the process repeats
Time of diagnosis in T1
8years
Type 2
Insulin sensing and signalling
Glucose induced secretion
Glut1 allows glucose into the cell and glucokinase causes its metabolism releasing ATP to close the k channel and sends PDX1 to the nucleus to increase production of insulin and calcium channel opens causing the release of insulin from its capsules
Incretin and glucose induced secretion
GLP1 released when glucose is sensed in the gut and binds the receptor on the B cell increasing camp levels and then PKA and epac2 converge on the exocytosis path increasing insulin secretion
Glucose kinase mutation
Loss of metabolism as glucose cannot be metabolised
Kcnd11 abbc8
Loss of function mutations in the k channel so it cannot be closed
PDX1 mutation
Lethal so no cases present as no insulin at all can be transcribed as its a TF for islet cell or birth
Insulin receptor
TRK docking to IRS1 which activates pi3 kinase which the catalysed the phosphorylation of pip2 converting it to pip3 which activates akt which catalysed phosphorylation of key proteins such as glycogen synthase
Non receptor mutation
The serine is phosphorylated on IRS as opposed to the tyrosine
CDKAL1
TCF7L2
Risk alleles associated with low and high birth weight both leading to potential t2
Type 1
Destruction of beta cells
Genetic susceptibility
ROS
At least six main pathways contribute to them
Islet cells have worst chance as they have low number of antioxidants in them
Increased glucose
Means more production of acetyl co enzyme A and oxaloacetate which cause increased oxidative phosphorylation increasing ROS
Islets at risk
Due to low levels of sod 12
Adipocytes
Lean state stores fat as triglycerides
Excess calories leads to metabolic overload and enlargement
Further intake causes hyper trophy and they release cytokines (mcp1) which recruits macrophages
Adipose inflammation pathway
Macrophage attracts by mcp1 which secretes TNF causing chronic inflammation and the excess free fatty acids inhibit glucose uptake
Ketoacidosis
T1
Fatty acids converted into ketones
Glycation metabolism
Glycation and protein damage
Glyceradehyde autoxidation
Hydrogen peroxide and alpha ketoaldehydes
Treatment for type 1
Insulin therapy
Transplantation
Prevention of autoimmunity
T1 insulin treatment
Injects insulin at continuous basal level
Autoimmunity treatment t1
Immune supresives e.g methotrexate
Anti inflammatory e.g aspirin or NSAIDs
T cell inhibitors e.g sirolimus
Best would be a cd8 inhibitor
Transplants t1
Pancreas to people who need new kidneys
Islets to achieve normoglycemia
Type 2 therapies
Sensitisers
Secretagogues
Glucosidase inhibitors
Glucosidase inhibitors
Acarbose inhibits production of glucose from oligosaccharides
Side effects are standard
Insulin sensitisers
Rosiglitizone activate ppar increasing transcription of insulin sensitive genes but have been taken of market
Metformin ampk agonist increasing sensitivity and reducing hepatic glucose production
Secretagogues
Meglitidines inhibit k channels so it stays shut
Byetta GLP1 agonists
DPP4 inhibitors prolong the activation of of beta cells
SGLT inhibitors
Located in the kidneys
Dapagliflozin causes excess glucose to be eliminated n the urine
