Molecular Basis of T2DM

Question 1

Type 2 Diabetes develops when…

Answer 1

insulin secretory capacity cannot compensate for obesity related insulin resistance

Question 2

What part of the body accounts for the most glucose uptake

Answer 2

Skeletal muscle

Question 3

What are the cardinal abnormalities of T2DM?

Answer 3

Decreased glucose uptake in skeletal muscle
Increased glucose production by liver
Dysfunctional adipose tissue with increased lipolysis
Defective insulin secretion from pancreatic beta cell

Question 4

How does insulin actually decrease blood glucose levels (general answer)

Answer 4

Increases the number of GLUT4 transporters on the cell surface that uptake glucose

Question 5

What is the chain of reaction from insulin binding to its receptor and GLUT4 transporters released on cell surface?

Answer 5

Insulin (tyrosine kinase) activates AKT (protein kinase B) –> translocation of GLUT4 to cell surface

Question 6

What is the central kinase in insulin signaling for glucose uptake?

Answer 6

AKT (Protein Kinase B)

Question 7

How does exercise help lower glucose levels?

Answer 7

Helps transport DIFFERENT GLUT4 transporters to surface

For T2DM in whom the insulin pathway does not function properly, exercise can help decrease blood glucose levels

Question 8

What is the central kinase in exercise signaling for glucose uptake?

Answer 8

AMPK (recognizes low AMP levels after exercise)

Question 9

In the liver after a meal, insulin normally turns OFF gluconeogenesis via which transcription factor?

Answer 9

FOXO1

makes sense because you do not need to make glucose when you have just eaten

Question 10

In the liver after a meal, insulin normally turns ON lipogenesis via which transcription factor?

Answer 10

SREBP1c

makes sense because you want to store the glucose as fat for energy

Question 11

In T2DM patient in regards to the liver, what does it mean that insulin resistance is selective ?

Answer 11

There is persistent lipogenesis (insulin turns on SREBP1) yet a failure to suppress gluconeogenesis (insulin does NOT turn off FOXO1)

Question 12

FACT: Type 2 Diabetes is marked by a fatty liver

Answer 12

Yep

Question 13

In adipose cells after a meal, insulin normally increases lipid synthesis via what transcription factor?

Answer 13

SREBP1c (just like in liver)

Question 14

In adipose cells after a meal, insulin uptakes fat via what?

Answer 14

LPL

Question 15

In fed state (i.e after a meal), how does insulin repress lipolysis (fat breakdown and FFA release?)

Answer 15

inhibits HSL activity (HSL normally breaks down fats to FFAs to be used in tissues)

Question 16

What goes wrong in the adipose tissue in T2DM?

Answer 16

Even in the presence of insulin there is lipolysis and FFA release

Question 17

FACT: Type 2 Diabetes is marked by elevated serum FFA

Answer 17

Yep

Question 18

Explain the Ectopic Lipid Deposition model for insulin resistance

Answer 18

underlying insulin resistance is the fact that too many FFAs get released from adipose and fatty acids from calorie intake go to the liver and muscle, causing dysfunction

best current model for how obesity specifically leads to diabetes/insulin resistance

Question 19

What are TZDs and how do they work?

Answer 19

drug that treats diabetes by increasing insulin sensitivity

turn on PPAR-gamma (a transcription factor needed to make a fat cell) –> this makes a “healthier fat” (less inflamed, more expandable) –> results in less fat deposition in other organs

Question 20

Why is the clinical use of TZD low?

Answer 20

concerns over side effects (fluid retention and decreased bone mass) and adverse events (bladder cancer, heart attacks, maybe)

Question 21

What is the adipose tissue distribution risk factor hypothesis underlying T2DM?

Answer 21

SQ fat (pear shape) may be protective while visceral fat (apple shape) leads to insulin resistance

Question 22

Does increase in BMI increase risk for T2DM?

Answer 22

Yep

Question 23

What’s the big deal about white fat vs. brown/beige fat?

Answer 23

White fat stores energy while brown/beige fat burns energy by using UCP1 to uncouple mitochondrial respiration and generate heat

Question 24

Explain B-cell function and failure in T2DM

Answer 24

B-cells take up glucose constitutively by GLUT1, resulting in insulin release

In T2DM, B cell failure is caused by chronic glucolipotoxicity (there too much glucose and fat and it hyper-stimulates and exhausts the beta cell)

Question 25

What are the three ways the beta cells apoptose in T2DM?

Answer 25

ER stress
Oxidative stress
Inflammation

Question 26

Monogenic diabetes is uncommon

Answer 26

Yep