Molecular Basis of DM Flashcards
What maintains fasting glucose levels?
Glucose output by liver via gluconeogenesis and glycogenolysis
Cardinal abnormalities in T2DM? (4)
Decreased glucose uptake by skeletal muscle
Increased glucose output by liver
Dysfunctional adipose with increased lipolysis
Defective insulin secretion
What is normal insulin mechanism in skeletal muscle?
Insulin binds receptor–>kinase cascade–>AKT phosphorylates GLUT4 containing vesicles–>GLUT4 on membrane surface
Where is defect in skeletal muscle insulin resistance?
Downstream of insulin receptor and upstream of GLUT4 translocation
What is the effect of exercise in skeletal muscle?
Increased AMP–>AMPK stimulates glucose uptake via phosphorylation of exercise-responsive GLUT4 vesicles
Does exercise increase glucose uptake in insulin resistance?
Yes, it still does.
What is normal insulin mechanism in liver? What are primary end results?
Insulin binding leads to activated AKT–>
Phosphorylation of FOXO1 leads to reduced gluconeogenesis
Phosphorylation of SREBP1c increases lipogenesis
Reduced gluconeogenesis; increased lipogenesis
How is insulin resistance in the liver “selective”?
Insulin is unable to suppress gluconeogenesis, but it still persists up-regulating lipogenesis
What happens to liver in T2DM?
Fatty liver due to lipogenesis and inability to suppress hepatic glucose production
How does insulin normally function in adipocytes? Lipid and glucose effects?
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
How does obesity affect adipose tissue?
Adipose becomes dysfunctional and inflamed leading to release of FFA and adipokines
What are the effects of sedentary lifestyle?
Reduced muscle/liver glycogen depletion–>glucose is more channeled towards lipogenesis–>ectopic lipid deposition (IMCL)
What are cumulative effects of ectopic lipids and inflammation?
Skeletal muscle and liver insulin resistance
What drugs target fat to improve insulin sensitivity? What is their mechanism? What are their Effects
TZDs are agonists for PPARgamma
PPARgamma leads to increased GLUT4 transcription
Effects: Weight gain, bladder cancer, hepatocellular injury BUT lower FFAs, less adipose inflammation
What does Brown fat have to do with diabetes?
Something to do with uncoupled mitochondrial respiration via UCP1–>burn energy and are good fat
What does fat distribution have to do with diabetes?
Visceral fat is associated with increased insulin resistance
Subcutaneous fat may be okay…
Why are men more likely than women to get T2DM? Why are asian populations more susceptible?
Fat distribution…more visceral fat
What is mechanism of ß-cell insulin release
Glucose enters via GLUT1/2–>glycolysis generates ATP–>ATP-depedent K channel opens–>V-gated Ca channel opens–>insulin vesicle exocytosis
What prompts ß-cell proliferation/adaptation? (4)
Insulin/IGF signaling
Incretin signaling
Prolactin signaling (pregnancy)
Leptin signaling (obesity)
Adaptations to Insulin resistance
ß-cell hypertrophy and hyperplasia
ß-cell failure causes (4)
Glucotoxicity
ER Stress
Oxidative stress: ROS and mitochondrial
Inflammation
Monogenic Diabetes Pathways (2)
Insulin resistance
Defective insulin secretion
GWAS Identified SNPS in Diabetes
Highest OR: TCF7L2 (novel)
PPARG, IRS1
ß-cell factors KCNJ/HFN1A
