Glucose Regulation (Peripheral Tissues) Flashcards
What organs repsond to glucose?
Pancreas
Muscle
Adipose tissue
Liver
How does insulin affect the liver?
Inhibits glucose synthesis by the liver
Uptake glucose and store as glycogen = activates GLYCOGEN synthase
Promotes excess glucose conversion to fatty acids
How does insulin affect muscle?
Stimulates glucose utilization by muscle
Uptake of glucose and immeduate use (exercise) or storage as glycogen
Exercising muscle can also take up glucose without insulin
How does insulin affect adipose tissue?
Promotes glucose uptake and conversion to glycerol for fat production
Inhibits lipolysis (breakdown of triglycerides)
What is the role of the pancreas?
Secrete digestive enzymes = trypsin, amylase, lipase, and protease
Secrete hormone messengers = insulin and glucagon
Secretes insulin in response to glucose increase
What processes does insulin STIMULATE?
Glucose uptake in muscle and adipose tissue
Glycolysis
Glycogen synthesis
Protein and lipid synthesis
Ion tranpsorters (NaK ATPase)
What processes does insulin INHIBIT?
Gluconeogenesis
Ketogenesis
Glycogenoysis
Lipolysis
Proteolysis
What does insulin do in target tissues?
Modulates phosphorylation of intracellular proteins (minutes)
And affects gene transcription and protein synthesis (hours)
What is the cascae insulin causes?
Inulin binds its receptor = causing conformational change
Autophosphorylation of insulin receptor
Phosphorylation of insulin receptor substrates (IRS)
Stimulates activaiton of PI3K = phosphorylates PIP2 to PIP3
PIP3 binds PDK1
PDK1 phosphorylates PKB at the threonine 308 residue (T308) in the activation loop,
While TORC2 phosphorylates PKB at the serine 473 residue (S473) in the hydrophobic motif, essentially requiring both kinases for full PKB activation
Which two sites is PKB (Akt) phosphorylated on?
T308 by PDK1
S473 by TORC2
How does PKB regulate glucose uptake?
Inhibiting AS160
How does PKB regulate angiogenesis?
Upregulates eNOS
How does PKB (Akt) regulate GSK3?
PKB/Akt directly phosphorylates GSK3 on specific serine residues, acting as a negative regulator of GSK3 activity
By inhibiting GSK3, PKB/Akt signaling pathway can promote cell survival, inhibit apoptosis, and regulate metabolic processes like glycogen synthesis.
PKB prevents GSK-3 from phosphorylating and inhibiting glycogen synthase, thus promoting glycogen synthesis (because INSULIN)
Glucose uptake GLUT4
Can muscle take up glucose without insulin?
Exercising muscle can also take up glucose without insulin
What happens when the pancreas is removed?
Mimics T1D = no insulin
Blood glucose increases after eating
Cells are starved for fuel despite high glucose
So cells will breakdown triglycerides to fatty acids
FA oxidized to to make energy = leads to high ketone (acetoacetic acid)
Define insulin resistance
Pathological condition in which cells fail to respond normally to insulin
What happens when insulin resistance occurs?
High levels of insulin but message is not getting to the organs
Increase in blood glucose levels because not being taken up by organs
Why is muscle one of the major sites of insulin resistance?
Because skeletal muscle accounts for 60%-70% of whole body insulin-stimulated glucose uptake
When does insulin resistance occur in muscle?
During obesity or T2D
What happens when there is insulin resistance in the muscle?
Muscle-specific KO or insulin receptor = increased fat mass, increased serum triglyceride levels, and muscle insulin resistance in MICE
No significant effects on global glucose tolerance!
What happens in mice lacking both IRS1 and IRS2 in skeletal and cardiac muscle?***
Impaired glucose uptake
WITHOUT hyperglycaemia or hyperinsulinemia
Why is fat mass increased when there is muscle insulin resistance?
Possible that glucose is shunted form insulin-resistance muscle to relateively more insulin sensitive adipose tissue
Where glucose is converted into triglycerides for storage = compensating for reduced muscle insulin sensitivity at whole body level
What happens when IRS1 and IRS2 are BOTH KO’d in muscle?
Decrease in survival
Naturally have higher BASAL glucose uptake (this is without the presence of insulin)
How did IRS1 and IRS2 KO affect glucose utilization in mice in muscle?
Shifted utilization from oxidation to lactate production
Accompanied by increased AMP/ATp ratio = increasing AMPK actiivty
AMPK then phosphorylated ACC = stimulating skeletal muscle fatty acid oxidation
What does HGP stand for?
Hepatic glucose production
How does insulin suppress liver glucose production?
By inhibiting gluconeogenic enzymes
Activating glycolytic and FA synthestic enzymes
Resulting in switch from FA oxidation to synthesis
And by inhibiting glucagon secretion from alpha-cells (pancreas)
What does central insulin do?***
Activates hepatic IL6-STAT3 signalling through liver-brain axis
What occurs when insulin receptors are KO’d in the liver?
Mice are hyperlgycaemic and hyperinsulinemic
Display reduced liver size compared to WT mice
What occurs when ONLY IRS1 is KO’d in the liver?
Mice show insulin resistance after REFEEDING
But fail to show insulin resistance during fasting
What occurs when ONLY IRS2 is KO’d in the liver?
Mice show insulin resistance during FASTING
But fail to show insulin resistance after refeeding
What occurs when both IRS1 and IRS2 are KO’d in the liver?
Mice have severe glucose intolerance and impaired lipid metbolism
What is the benefit of adipose tissue expansion?
Exerts buffering effet
Prevents lipids ectopically depositing in other organs (liver, muscle, and pancreas)
How does insulin regulate lipolysis?
Inhibits lipolysis in adipocytes
Breakdown of triglycerides into glycerol and FFA
What does diet-induced obesity cause?
Insulin resistance
This occurs under excess nutrition
How does insulin regulate glucose uptake in adipocytes?
Insulin stimulates glucose uptake in adipocytes
Where it converts lipids as more efficient form of energy storage
How does T2D affect adipose tissue?
When insulin binds = tyrosine phosphorylation of IRS1 and activation of PI3K are DECREASED
What happens when insulin receptors are deleted from adipocytes?
Reduced fat mass because less glucose uptake
Protects against obesity and obesity-related glucose intolerance (respond to insulin more effectively) = increased longevity
What happens when GLUT4 is deleted in fat cells?
Decrease in insulin-stimulated glucose uptake in fat and muscle
Impairement in insulin-mediated suppression of hepatic glucose uptake
What are BAT and WAT?
Brown/White adipose tissue
How do carbohydrates regulate gene expression?
Glucose acts via Cho response element
How do lipids regulate gene expression?
Polyunsturated FA = transcriptional regulation via PPARs (peroximsome proliferator)
Cholesterol via SREBP (sterol regulatory element BP)
How do amino acids eregulate gene expression?
Effects on transcription, ribosomes, signalling, amino acid transport
How does a carbohydrate diet affect fat?
Increases fat accumulation
Can increase lipogenic capacity of liver and adipose to make us synthesize more fat
ChoREBP = binds reponse element and promotes transcription of these lipogenic genes
What sequence motifs do ChoREs contain?
2 E-box sequence motics separated by 5bp
What it the correct spacing of E boxes in ChoRE and why is it important??
Separated by 5 bp
Correct spacing = critical for carbohydrate control of gene transcription
What is carbohydrate response factors aka?
ChREBP
What domains does ChREBP/ChoRF have?
NLS = nuclear localization signal
Poly proline domain
bHLH-leucine zipper domain
Leucine-like domain
What phosphorylation sites does ChREBP contain?
Phosphorylation sites for PK = P1-P3
AMPK phosphorylation side = P4
Where id ChREBP predominantly expressed?
Liver
Kidney
WAT/BAT
Where is ChREBP located in LOW glucose conditions?
Cytosol
Where is ChREBP located in HIGH glucose?
Translocates from cytosol to nucleus
What complex does ChREBP act with?
Heterodimeric complex with Max-like ptorin X (Mlx)
What controls ChREBP location?
Dependent on phosphorylation state
Ser196 phosphorylation site = retains it in cytosol (P1 PKA site)
Dephosphorylation of P1 = nuclear localization
What happens with P2 and P3 are dephosphorylated?
Allows ChREBP to bind to DNA
When can ChREBP bind to DNA?
When other two PKA phosphorylation site are DEPHOSPHORYLATED
What is dephosphorylation of P1-P3 dependent on?
Activation of protein phosphatase 2A (PP2A)
Activated by X5P
What activates protein phosphatase 2A (PP2A)?
Xylulose 5-P
What is the role of proetin phosphatase 2A (PPA2)?
Dephorphorylation of ChREBP P1-P3 sites
Allowing localization in the nucleus and DNA binding
Under what conditions is X5P generated?
High glucose conditions
X5P is made from G6P by phentose phosphate pathway
What other BP acts in synergy with ChREBP?
Sterol regualtory element BP (SREBP)
What is the effect of ChREBP and SREBP activation?
Both work together to promote lipogeneis
What pathways is glucose requied to fully activate?
Insulin and GF-stimulated signalling pahtways
What is the role of nutrient sensing response elements 1 and 2?
Involved in response to glucose DEPRIVATION
What is the role of PGC-1a?
Co-activator of transcription of gluconeogenic enzymes
These are activated under glucose DEPRIVATION
What is the net effect of stress?
Stimulates glucose output
What happens when glucagon binds its receptor?
Increase in cAMP
Activates PKA = phosphorylates CREB
CREB = activates PGC1 gene expression
PGC-1 = coactivator protein stimulating PEPCK gene expression (GLUCONEOGENSIS)
