Monday - Mechanism + genetics of diabetes - Pat Scott

Question 1

What does GLUT4 do?

Answer 1

allows glucose to be taken up by skeletal muscle and tissue

Question 2

What does glucose do in the pancreas

Answer 2

simulates release of insulin from beta cells

Question 3

Rare genetic diseases that cause diabetes called:

What enzymes can be effected

Answer 3

MODY (maturity onset diabetes of the young)
HNF-4alpha, 1alpha, 1beta (trascription factor for GLUT2)
glucokinase
PDX1
NeuroD1

Question 4

Mech of insulin secretion

Answer 4

Glucose –> GLUT1 or 2 –> in cell –> glucokinase –»> ATP –> inhibits K+ channel –> depolarization –> open Ca channels –> secretion of glucose

Question 5

Diabetes type 1, how do you get it?

Answer 5

Antibodies to pancreatic beta cells. get the antibodies years before the onset

Question 6

Polymorphisms associated with DM1

Answer 6

MHCII

• DQA1
• DQB1

Question 7

Development of autoimmune t cells.

Answer 7

T cells are not weeded out - can cause autoimmune ifxn if the right environmental conditions (maybe viral infection)

Question 8

Mech for DM2

Answer 8

too much nom nom
hyperglycemia
inflammation
insulin resistance
insulin insufficiency
beta cell destruction
(feedback of no insulin causes more hyperglycemia and inflammation)

Question 9

Is there a genetic risk for type 2 diabetes

Answer 9

yeah, but we don’t know what the gene is, there are a few that have weak links

Question 10

Where does the inflammation start in diabetes?

Answer 10

adipose tissue

1. grow in size because you’re fat
2. then MCP-1
3. then TNF-alpha

Question 11

What transcription factor promotes Triglyceride formation?

how is this different in diabetes

Answer 11

PPAR gamma

TNF-alpha inhibits it –> promotes fatty acid release –> lipid disregulation

Question 12

how does lipid disregulation lead to inflammation?

Insulin resistance?

Answer 12

lipids bind to TLR2,4 –> JNK –> promotes pro-inflammatory transcription factor

JNK also –> IRS inactivation –> inhibition of the insulin signaling pathway (by stopping glut4 i think)

Question 13

Insulin resistance. Does insulin still bind to the receptor?

Answer 13

yes, but the downstream signaling is not working

Question 14

Receptor liver uses to take up glucose?

is it sensitive to insulin?

Answer 14

GLUT2

nah

Question 15

Insulin resistance in liver:

two pathways that decrease glucose storage and increase production of glucose

Answer 15

insulin (which is still being made, but isn’t effective) causes decreased glycogen synthase (GS)

FOXO1 –> transcription of gluconeogenic enzymes

Question 16

so like, how do the beta cells actually die?

Answer 16

too much food –> overloads the electron transport chain –> ROS.
beta cells have low anti-oxidants so they’re real susceptible

ER stress from making so much insulin –> unfolded protein response –> IL-1beta –> initiates apoptosis!