Scott's diabetes genetics; 3.18

Question 1

What causes of DMI?

Answer 1

TCRs recognizing self-antigens of beta cells are not weeded out

Question 2

What is among the things that allow for TCRs to continue recognizing beta cells?

Answer 2

Polymorphisms in MHCII genes (HLA locus)

Question 3

When does a person with T cells that are attacking beta cells become symptomatic?

Answer 3

When roughly 80% of beta cells are destroyed

Question 4

What is the problem with when DMI patients become symptomatic?

Answer 4

By that point it is too late to reverse the disease

Question 5

What is the cause of DMII?

Answer 5

Hyperglycemia and circulating free fatty acids → secretion of Monocyte Chemotractant Protein 1 (MCP1) from adipocytes → inflammation → recruitment of macrophages → secretion of TNFa

Question 6

What are the three major affects of TNFa?

Answer 6

Promotes release of free fatty acids…rather than storage

Inhibits insulin receptor signaling

Inhibits PPAR gamma activity

Question 7

What is the effect of TNFa promoting release of free fatty acids?

Answer 7

Insulin resistance in skeletal muscle and adipocytes.(FFA → → phosphorylates/inactivates IRS-1 and inactivates Akt/PKB → Glut4 is NOT translocated)

Question 8

FFAs inhibit the IRS branch of the insulin signaling pathway. Hyperinsulinemia will cause what due to the other branch still working?

Answer 8

Increased lipid synthesis and storage (NAFA liver disease)

Question 9

What is the effect of TNFa inhibiting insulin receptor signaling?

Answer 9

Decreased glucose uptake and Hormone Sensitive Lipase (HLA) activation

Question 10

What is the effect of TNFa inhibiting PPAR gamma activity?

Answer 10

Decreased lipid uptake and adipogenesis (this seems like it should exponentiate the problem)

Question 11

Besides TNFa, what else happens as a result of the hyperglycemia/FFA induced inflammation?

Answer 11

Oxidative stress (overloaded ETC → ROS)
ER stress → unfolded protein response → initiates apoptosis

Question 12

What is the result of oxidative and ER stress?

Answer 12

Activation of TXNIP → IL-1 beta signaling → beta cell apoptosis

Question 13

What vascular changes occur with diabetes?

Answer 13

Foam cells → plaques (arteries)

Disruption of filtration barrier (podocytes in glomerular capillary)

Increased permeability → angiogenesis (pericytes in retinal capillary)

Question 14

How does diabetes cause these vascular changes?

Answer 14

ER and oxidative stress

Advanced Glycosylation End (AGE) products

Question 15

What are AGE products?

Answer 15

Non-enzymatic modification of proteins by sugar/lipids
Accumulation in vessel walls
Promotion of ROS release