L6 Flashcards
Which subunit of the insulin receptor does insulin bind to?
A. alpha
b. beta
A. alpha
True or False: The alpha subunit of the insulin receptor has tyrosine kinase activity and receptor autophosphorylation
False - beta subunit
In the insulin receptor, phosphorylation of insulin receptor substrate (IRS) proteins leads to activation of PI3K/MAPk, as well as ___trafficking
GLUT-4
____: the principal effector of the PI3K pathway
AKT
True or False: In the insulin receptor, the cytoplasmic protein CBL is the DIRECT phosphorylation target
True
True or False: Skeletal muscle glucose uptake is increased in T2DM
False - skeletal muscle glucose uptake is REDUCED in T2DM
Impaired insulin receptor signaling is a result of: ____ cytokines, which is mediated by activation of _____ receptors
intracellular; TLR
Impaired insulin receptor signaling is a result of: ____ cytokines, which is mediated by ____ (such as: TNF-a)
extracellular; adipokines
Excessive oxidation of free fatty acids is just one mechanism of skeletal muscle insulin resistance. Which two locations do FFA’s come from?
1) Visceral adipose tissue
2) Intracellular lipid storage
True or False: Mitochondrial dysfunction and modulation of gene transcription are mechanisms of skeletal muscle insulin resistance
True
What two sources can activate TLR’s?
A. Bacterial products in plasma (e.g LPS)
B. Antibiotics
C. Cytokines
D. Systemic FFA’s
A/D
True or False: Obesity alters intestinal bacterial composition
True
True or False: Leaky gut does NOT allow entry into systemic circulation
False - leaky gut ALLOWS entry into systemic circulation
Activation of TLR leads to intracellular production of ___ (leads to inflammatory gene expression) and ___
NF-kB; MAPK
TLR activation generates intracellular cytokines, such as _____
TNF-a
TLR activation leads to interruption of insulin receptor signaling via: phosphorylation of ____
IRS (insulin receptor substrate)
True or False: Systemic fatty acids activate TLR (e.g TLR4)
True
Binding of FA to TLR4 leads to activation of ____, which activates NF-kB and MAPK.
A. TNF
B. IL-6
C. proIL-1B
D. MD2
E. MyD88
E. MyD88
True or False: Activation of NF-kB leads to activation of TNF, IL-6, proIL-1B, and proIL-18
True
True or False: Bacterial products (LPS) lead to activation of TLR, which leads to production of cytokines and inhibition of insulin signaling
True
____ KO mice are protected from diet induced obesity (DIO)
A. TLR4
B. MyD88
C. NF-kB
D. MAPK
B. MyD88
Activation of TLR leads to activation of ___ kinases
A. glutamate
B. glycine
C. serine
D. tryptophan
E. tyrosine
C. serine
Phosphorylation of serine residues INHIBITS function of insulin receptor and prevents ___ kinase from phosphorylating IRS proteins
A. glutamate
B. glycine
C. serine
D. tryptophan
E. tyrosine
E. tyrosine
How does TNF-alpha (extracellularcytokine) affect tyrosine kinase activity?
Decrease it
- Thereby: block fx of insulin receptor
True or False: Visceral adipose tissue has a low lipolytic activity
False - it has a HIGH lipolytic activity
Insulin resistance ____ lipid accumulation in adipocytes
A. limits
B. exceeds
A. limits
True or Fales: excess storage capacity of adipocytes (obesity) leads to increased in lipid storage in other organs (e.g - liver, skeletal m., pancreatic islets)
True
There is a higher density of which type of receptor, in visceral adipose tissue, that contributes to its higher lipolytic activity?
High density of adrenergic receptors (B2 on adipocytes is activated by NE/EPI)
True or False: In visceral adipose tissue, the isoform of lipase IS effectively inhibited by insulin
False - it is NOT
Visceral adipose tissue has high ___ activity
A. HSD11B2
B. HSD11B1
C. CYP21
What is the effect?
B. HSD11B1 (converts cortisone to cortisol)
- Leads to increased local cortisol production (lipolysis)
How does hormone sensitive lipase (HSL) leads to hyperlipidemia (increased FFA in the blood)?
Lipolysis
True or False: Unhealthy adipose expansion and inflammation leads to lipotoxicity and ectopic lipid deposition
True
High: cell hypertrophy, inflammation, macrophage infiltration
Low: adipogenesis and insulin sensitivity
A. Healthy expansion
B. Unhealthy expansion
B. Unhealthy expansion
How does excessive fatty acyl-CoA beta oxidation affect glycolysis and glucose entry? intermediates?
1) Limits it
2) Increased intermediates (e.g DAG, ceramides)
Diacylglycerol (DAG) activates ___, which blocks ___ through ____ phosphorylation
PKC; IRS-1; serine
DAG activates ____, leading to inflammatory response and insulin resistance
Diacylglycerol kinase (DGK)
Increased fat oxidation in muscle leads to an increased in intermediates, such as: ___
DAG
What are the four main outcomes of excessive FFA oxidation?
1) Excessive generation of fatty acyl CoA
2) Accumulation of DAG
3) Activation of serine kinase (protein kinase C)
4) Serine phosphorylation of IRS proteins
What can drive mitochondrial dysfunction?
Chronically elevated plasma lipids
Dysfunction of which organelle can lead to increased generation of ROS by that very organelle?
Mitochondria
What are two effects of chronically elevated plasma lipids?
1) Make intracellular cytokines via TLR’s
2) Excess FFA B-oxidation
True or False: Mitochondrial dysfunction does not harm proteins, lipids, nucleic acids
False - mitochondrial dysfunction DOES damage protein, lipids, and nucleic acids
How does mitochondrial dysfunction affect:
- # of mitochondria
- mitochondrial function
- oxidative capacity
- GLUT4 transcription
Decreases all of the above
How can impaired mitochondrial function decreased insulin response?
Activates MAPK/NF-kB, increase IRS1 phosphorylation of serine and decrease phosphorylation of tyrosine
True or False: When there is impaired mitochondrial function, both increase in FFA derivatives and ROS can lead to activation of MAPK and NF-kB
True
How does mitochondrial dysfunction affect IRS proteins?
Leads to their nitrosylation and degradation
What are four characteristics of beta cell dysfunction?
1) Altered pattern of insulin secretion
2) Decreased sensitivity to glucose
3) Reduced processing of proinsulin
4) Hyperglycemia induced changes in gene expression
True or False: Improved glucose clearance and increased sensitivity to glucose are features of dysfunctional pancreatic beta cel
False - IMPAIRED glucose clearance and DECREASED sensitivity to glucose
