Molecular Basis of DM

Question 1

What maintains fasting glucose levels?

Answer 1

Glucose output by liver via gluconeogenesis and glycogenolysis

Question 2

Cardinal abnormalities in T2DM? (4)

Answer 2

Decreased glucose uptake by skeletal muscle
Increased glucose output by liver
Dysfunctional adipose with increased lipolysis
Defective insulin secretion

Question 3

What is normal insulin mechanism in skeletal muscle?

Answer 3

Insulin binds receptor–>kinase cascade–>AKT phosphorylates GLUT4 containing vesicles–>GLUT4 on membrane surface

Question 4

Where is defect in skeletal muscle insulin resistance?

Answer 4

Downstream of insulin receptor and upstream of GLUT4 translocation

Question 5

What is the effect of exercise in skeletal muscle?

Answer 5

Increased AMP–>AMPK stimulates glucose uptake via phosphorylation of exercise-responsive GLUT4 vesicles

Question 6

Does exercise increase glucose uptake in insulin resistance?

Answer 6

Yes, it still does.

Question 7

What is normal insulin mechanism in liver? What are primary end results?

Answer 7

Insulin binding leads to activated AKT–>
Phosphorylation of FOXO1 leads to reduced gluconeogenesis
Phosphorylation of SREBP1c increases lipogenesis

Reduced gluconeogenesis; increased lipogenesis

Question 8

How is insulin resistance in the liver “selective”?

Answer 8

Insulin is unable to suppress gluconeogenesis, but it still persists up-regulating lipogenesis

Question 9

What happens to liver in T2DM?

Answer 9

Fatty liver due to lipogenesis and inability to suppress hepatic glucose production

Question 10

How does insulin normally function in adipocytes? Lipid and glucose effects?

Answer 10

Lipogenesis via AKT phosphorylation of SREBP1c

Increased lipid uptake via AKT phosphorylation of LPL; decreased lipolysis via HSL (hormone-sensitive lipase)

Increased glucose uptake via GLUT4 translocation

Question 11

How does obesity affect adipose tissue?

Answer 11

Adipose becomes dysfunctional and inflamed leading to release of FFA and adipokines

Question 12

What are the effects of sedentary lifestyle?

Answer 12

Reduced muscle/liver glycogen depletion–>glucose is more channeled towards lipogenesis–>ectopic lipid deposition (IMCL)

Question 13

What are cumulative effects of ectopic lipids and inflammation?

Answer 13

Skeletal muscle and liver insulin resistance

Question 14

What drugs target fat to improve insulin sensitivity? What is their mechanism? What are their Effects

Answer 14

TZDs are agonists for PPARgamma

PPARgamma leads to increased GLUT4 transcription

Effects: Weight gain, bladder cancer, hepatocellular injury BUT lower FFAs, less adipose inflammation

Question 15

What does Brown fat have to do with diabetes?

Answer 15

Something to do with uncoupled mitochondrial respiration via UCP1–>burn energy and are good fat

Question 16

What does fat distribution have to do with diabetes?

Answer 16

Visceral fat is associated with increased insulin resistance

Subcutaneous fat may be okay…

Question 17

Why are men more likely than women to get T2DM? Why are asian populations more susceptible?

Answer 17

Fat distribution…more visceral fat

Question 18

What is mechanism of ß-cell insulin release

Answer 18

Glucose enters via GLUT1/2–>glycolysis generates ATP–>ATP-depedent K channel opens–>V-gated Ca channel opens–>insulin vesicle exocytosis

Question 19

What prompts ß-cell proliferation/adaptation? (4)

Answer 19

Insulin/IGF signaling
Incretin signaling
Prolactin signaling (pregnancy)
Leptin signaling (obesity)

Question 20

Adaptations to Insulin resistance

Answer 20

ß-cell hypertrophy and hyperplasia

Question 21

ß-cell failure causes (4)

Answer 21

Glucotoxicity

ER Stress
Oxidative stress: ROS and mitochondrial
Inflammation

Question 22

Monogenic Diabetes Pathways (2)

Answer 22

Insulin resistance

Defective insulin secretion

Question 23

GWAS Identified SNPS in Diabetes

Answer 23

Highest OR: TCF7L2 (novel)
PPARG, IRS1
ß-cell factors KCNJ/HFN1A