Flashcards in Scott's diabetes genetics; 3.18 Deck (15):
What causes of DMI?
TCRs recognizing self-antigens of beta cells are not weeded out
What is among the things that allow for TCRs to continue recognizing beta cells?
Polymorphisms in MHCII genes (HLA locus)
When does a person with T cells that are attacking beta cells become symptomatic?
When roughly 80% of beta cells are destroyed
What is the problem with when DMI patients become symptomatic?
By that point it is too late to reverse the disease
What is the cause of DMII?
Hyperglycemia and circulating free fatty acids → secretion of Monocyte Chemotractant Protein 1 (MCP1) from adipocytes → inflammation → recruitment of macrophages → secretion of TNFa
What are the three major affects of TNFa?
Promotes release of free fatty acids...rather than storage
Inhibits insulin receptor signaling
Inhibits PPAR gamma activity
What is the effect of TNFa promoting release of free fatty acids?
Insulin resistance in skeletal muscle and adipocytes.(FFA → → phosphorylates/inactivates IRS-1 and inactivates Akt/PKB → Glut4 is NOT translocated)
FFAs inhibit the IRS branch of the insulin signaling pathway. Hyperinsulinemia will cause what due to the other branch still working?
Increased lipid synthesis and storage (NAFA liver disease)
What is the effect of TNFa inhibiting insulin receptor signaling?
Decreased glucose uptake and Hormone Sensitive Lipase (HLA) activation
What is the effect of TNFa inhibiting PPAR gamma activity?
Decreased lipid uptake and adipogenesis (this seems like it should exponentiate the problem)
Besides TNFa, what else happens as a result of the hyperglycemia/FFA induced inflammation?
Oxidative stress (overloaded ETC → ROS)
ER stress → unfolded protein response → initiates apoptosis
What is the result of oxidative and ER stress?
Activation of TXNIP → IL-1 beta signaling → beta cell apoptosis
What vascular changes occur with diabetes?
Foam cells → plaques (arteries)
Disruption of filtration barrier (podocytes in glomerular capillary)
Increased permeability → angiogenesis (pericytes in retinal capillary)
How does diabetes cause these vascular changes?
ER and oxidative stress
Advanced Glycosylation End (AGE) products