Pathophysiology

Question 1

high insulin sensitivity

Answer 1

lean
normal glucose tolerance and good glucose control
low blood glucose and FFA

Question 2

Low insulin sensitivity

Answer 2

IR
impaired glucose tolerance and poor glucose control
high blood glucose and high FFA
T2D

Question 3

insulin sensitive

Answer 3

• increase gluocse uptake
• decrease glucose output
• Decrease blood glucose
• decrease lipolysis
• decrease blood FFA

Question 4

insulin resistance

Answer 4

• decrease gluocse uptake
• increase glucose output
• increase blood glucose
• increase lipolysis
• increase blood FFA

Question 5

Adipose tissue

Answer 5

Enlarged adipocytes
* Inflammation
* Insulin resistance

Question 6

muscle

Answer 6

Insulin resistance – glucose intolerance

Question 7

liver

Answer 7

Insulin resistance – elevated glucose output
* Fatty liver and damage

Question 8

Obesity and adipocytes

Answer 8

Hypertrophic adipocytes (hypoxia, dysfunction) send stress signal
* Pro-inflammatory macrophages infiltrate adipose tissue
Cause insulin resistance in the adipose tissue =
↓ ability of insulin to inhibit lipolysis and stimulate glucose uptake

Question 9

inflammation

Answer 9

• macrophage infiltration
• pro-inflammatory molecules called cytokines are secreted into the blood
• chronic low grade inflammation
• development of insulin resistance

Question 10

Lipolysis is ___ related to
adipocyte size

Answer 10

directly
increase Lipolysis in obesity leads to ectopic fat deposition

linear relationship

Question 11

Fat depots

Answer 11

ectopic - in organ
visceral- in the abdominal cavity but outside organs
Subcutaneous
(superficial and deep)
outside the abdominal
cavity

Question 12

How do excess exposure to FFA and
inflammatory cytokines lead to skeletal
muscle and liver insulin resistance?

Answer 12

2 theories
lipotoxicity
inflammation

Question 13

Lipotoxicity

Answer 13

Oversupply of FFA leads to accumulation of “toxic”
lipid intermediates which impair insulin signaling

Oversupply of FFA coupled with insufficient mitochondrial oxidation
leads to build up of fatty acyl-coA and toxic fatty acid byproducts that
impair insulin signaling in the muscle

draw it out

Question 14

Lipotoxicity in the Liver

Answer 14

Lipid intermediates accumulation in liver
impairs insulin signaling (insulin resistance).
* Same mechanism as muscle but:
↓ ability of insulin to inhibit liver glucose
production
* Ectopic fat accumulation =
Damage to hepatocytes causes release of
liver enzymes.

Question 15

Inflammation

Answer 15

Oversupply of inflammatory molecules directly
impairs insulin signaling
How do excess exposure to FFA and
inflammatory cytokines lead to skeletal
muscle and liver insulin resistance?

Question 16

Cytokines released from inflamed
adipose tissue cause insulin resistance

Answer 16

NF-α infusion in
humans reduces glucose
infusion rate during
hyperinsulinemic-
euglycemic clamp (i.e.,
caused muscle insulin
resistance).

Higher rate of glucose infusion
= higher insulin sensitivity
Lower rate of glucose infusion
= lower insulin sensitivity

Question 17

Why is hyperglycemia a problem?

Answer 17

Chronic high blood glucose is associated
with vascular complications leading to long-
term tissue damage, dysfunction, and
failure of various organs including eyes,
kidneys, nerves, heart.
* Due to formation of advanced glycation end
products (AGE) and reactive oxygen
species (ROS).

Question 18

AGEs and ROS

Answer 18

draw it out slide 21