Molecular Basis of T2DM Flashcards
Type 2 Diabetes develops when…
insulin secretory capacity cannot compensate for obesity related insulin resistance
What part of the body accounts for the most glucose uptake
Skeletal muscle
What are the cardinal abnormalities of T2DM?
Decreased glucose uptake in skeletal muscle
Increased glucose production by liver
Dysfunctional adipose tissue with increased lipolysis
Defective insulin secretion from pancreatic beta cell
How does insulin actually decrease blood glucose levels (general answer)
Increases the number of GLUT4 transporters on the cell surface that uptake glucose
What is the chain of reaction from insulin binding to its receptor and GLUT4 transporters released on cell surface?
Insulin (tyrosine kinase) activates AKT (protein kinase B) –> translocation of GLUT4 to cell surface
What is the central kinase in insulin signaling for glucose uptake?
AKT (Protein Kinase B)
How does exercise help lower glucose levels?
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
What is the central kinase in exercise signaling for glucose uptake?
AMPK (recognizes low AMP levels after exercise)
In the liver after a meal, insulin normally turns OFF gluconeogenesis via which transcription factor?
FOXO1
makes sense because you do not need to make glucose when you have just eaten
In the liver after a meal, insulin normally turns ON lipogenesis via which transcription factor?
SREBP1c
makes sense because you want to store the glucose as fat for energy
In T2DM patient in regards to the liver, what does it mean that insulin resistance is selective ?
There is persistent lipogenesis (insulin turns on SREBP1) yet a failure to suppress gluconeogenesis (insulin does NOT turn off FOXO1)
FACT: Type 2 Diabetes is marked by a fatty liver
Yep
In adipose cells after a meal, insulin normally increases lipid synthesis via what transcription factor?
SREBP1c (just like in liver)
In adipose cells after a meal, insulin uptakes fat via what?
LPL
In fed state (i.e after a meal), how does insulin repress lipolysis (fat breakdown and FFA release?)
inhibits HSL activity (HSL normally breaks down fats to FFAs to be used in tissues)
What goes wrong in the adipose tissue in T2DM?
Even in the presence of insulin there is lipolysis and FFA release
FACT: Type 2 Diabetes is marked by elevated serum FFA
Yep
Explain the Ectopic Lipid Deposition model for insulin resistance
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
What are TZDs and how do they work?
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
Why is the clinical use of TZD low?
concerns over side effects (fluid retention and decreased bone mass) and adverse events (bladder cancer, heart attacks, maybe)
What is the adipose tissue distribution risk factor hypothesis underlying T2DM?
SQ fat (pear shape) may be protective while visceral fat (apple shape) leads to insulin resistance
Does increase in BMI increase risk for T2DM?
Yep
What’s the big deal about white fat vs. brown/beige fat?
White fat stores energy while brown/beige fat burns energy by using UCP1 to uncouple mitochondrial respiration and generate heat
Explain B-cell function and failure in T2DM
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)
What are the three ways the beta cells apoptose in T2DM?
ER stress
Oxidative stress
Inflammation
Monogenic diabetes is uncommon
Yep
