Molecular Basis of T2D

Question 1

Which type of diabetes has a greater genetic contribution?

Answer 1

Type 2

Question 2

What are the 2 stages of T2D?

Answer 2

1. Insulin resistance
   - serum glucose may be normal, but insulin levels are elevated and sensitivity is beginning to decrease
   - Increased risk for CVD
2. Hyperglycemia
   - Early stages of disease, beta cells break down

Question 3

Explain counter regulation

Answer 3

After insulin does its job, and serum glucose levels decrease, glucagon is released to promote glucose production

Question 4

What do insulin levels do to galactose?

Answer 4

Insulin increases the volume of distribution of galactose

Question 5

What is the rate limiting step in glucose metab?

Answer 5

Insulin-regulated transport across the plasma membrane

Question 6

Describe the process of inc transporters on membrane

Answer 6

1. Insulin binds its receptor and promotes translocation of GLUT4 (fat and muscle cells) onto the cell surface
2. Contraction of skeletal muscle (ie exercise) promotes increased numbers of GLUT4 receptors on the cell surface and also increases cell’s sensitivity to insulin

Chronic exercisers have inc total amt of available GLUT4

1 &2 are regulated by two dif pathways

Question 7

Define insulin insensitivity

Answer 7

Inability to stim glucose uptake by body tissues AND inability of insulin to suppress hepatic output of glucose

Question 8

What tissue is responsible for most of the insulin dependent glucose disposal?

Answer 8

Muscle

Question 9

What is the cause of elevated fasting glucose levels in T2D?

Answer 9

Increased hepatic output

Question 10

What 2 things can cause hyperglycemia following a meal in T2D?

Answer 10

1. Inability of insulin to stimulate glucose uptake

2. Inability of insulin to shut down hepatic glucose production

Question 11

What is the euglycemic insulin/glucose clamp?

Answer 11

Gold standard for measuring insulin resistance: Infuse insulin at a constant rate and infuse glucose at a rate that will achieve a stable serum glucose level. The rate of glucose utilization is then equal to the rate of glucose infusion. If you are insulin resistant, less glucose is needed to maintain a predetermined serum glucose level

Question 12

Describe the time frame for sources of glucose after a fast

Answer 12

After about 4 hours, glucose levels dec
Glycogen is responsible for the rise in glucose levels until about hour 10. After that, they begin to decline. Gluconeogenesis takes over and peaks at 2 days and continues to maintain a constant level

Question 13

What is the major determinant of fasting blood glucose?

Answer 13

Glucose output from the liver

Question 14

What level should glucose uptake be by the muscle during fasting?

Answer 14

0

Question 15

What does insulin stimulate in fat cells?

Answer 15

Uptake of fatty acids and their storage

Question 16

What happens in insulin resistant fat cells?

Answer 16

Fat cells can’t take up glucose, can’t maintain TGs and the rate of FA release into the blood increases.

Question 17

What happens to glucagon levels after a normal meal in normal people and in T2D?

Answer 17

• Normal: crash

- T2D: do not decrease/go up after a meal

Question 18

What is responsible for the greatest morbidity and mortality in diabetics?

Answer 18

CVD

Question 19

What determines the rate of TG synthesis in the liver?

Answer 19

FAs in the blood. So since fat is insulin insensitive and they thus release more FAs, then more TGs are made by the liver. In addition, after a meal, there are FAs from that meal, which the liver also makes into TGs. This leads to increased CV risk and for a fatty liver

Question 20

What is insulin’s role in stimulating the production of new FAs/TGs?

Answer 20

Insulin actually stimulates the synthesis of new FAs/TGs by the liver…

Question 21

There is a disconnect here…if insulin stimulates the synthesis of new FAs by the liver…but the liver is resistant to the actions of insulin (in terms of glucose), then why is there increased FA synthesis in insulin resistant people?

Answer 21

Insulin resistance is SELECTIVE
-The liver is resistant to the inhibitory effects of insulin on glucose output, but maintains sensitivity to the actions of insulin on lipids (ie it produces more lipids for the reasons stated in other answers)

Question 22

Explain how selective insulin resistance fits in to pre-diabetes

Answer 22

• Explains why people with hyperinsulinemia (pre diabetes) are at inc risk for CV events, even in absence of hyperglycemia
• In pre-diabetes, insulin remains selectively able to regulate blood glucose (to an extent), but perhaps it is not able to control the liver’s production of fatty acids

Question 23

Predisposition to T2 diabetes is related to…

Answer 23

Amt of fat you have and the distribution of body fat [apple (upperbody/truncal obesity) vs pear(gynoid obesity)]

Question 24

Is BMI a good indicator of adiposity?

Answer 24

NO! Doesn’t take muscle into account, and diabetes is a disease of the fat cell

Question 25

How does obesity (increased fat cell mass) lead to insulin resistance in liver and muscle?

Answer 25

2 Theories…

1. High plasma FA concentration predicts insulin resistance and increased intracellular TG is associated with insulin resistance
   - Get insulin resistance when storage of fat mechanism fails and fat goes to other organs
2. Inflammation: over-nutrition causes an increase in fat mass–this activates the innate immune system leading to insulin resistance. Fat cells of obese people are filled with macrophages…no one knows why.