Glucose Regulation (Peripheral Tissues)

Question 1

What organs repsond to glucose?

Answer 1

Pancreas
Muscle
Adipose tissue
Liver

Question 2

How does insulin affect the liver?

Answer 2

Inhibits glucose synthesis by the liver

Uptake glucose and store as glycogen = activates GLYCOGEN synthase

Promotes excess glucose conversion to fatty acids

Question 3

How does insulin affect muscle?

Answer 3

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

Question 4

How does insulin affect adipose tissue?

Answer 4

Promotes glucose uptake and conversion to glycerol for fat production

Inhibits lipolysis (breakdown of triglycerides)

Question 5

What is the role of the pancreas?

Answer 5

Secrete digestive enzymes = trypsin, amylase, lipase, and protease

Secrete hormone messengers = insulin and glucagon

Secretes insulin in response to glucose increase

Question 6

What processes does insulin STIMULATE?

Answer 6

Glucose uptake in muscle and adipose tissue
Glycolysis
Glycogen synthesis
Protein and lipid synthesis
Ion tranpsorters (NaK ATPase)

Question 7

What processes does insulin INHIBIT?

Answer 7

Gluconeogenesis
Ketogenesis

Glycogenoysis
Lipolysis
Proteolysis

Question 8

What does insulin do in target tissues?

Answer 8

Modulates phosphorylation of intracellular proteins (minutes)

And affects gene transcription and protein synthesis (hours)

Question 9

What is the cascade insulin causes?

Answer 9

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

Question 10

Which two sites is PKB (Akt) phosphorylated on?

Answer 10

T308 by PDK1
S473 by TORC2

Question 11

How does Akt/PKB regulate glucose uptake?

Answer 11

Inhibiting AS160

Question 12

How does PKB regulate angiogenesis?

Answer 12

Upregulates eNOS

Question 13

How does Akt/PKB regulate GSK3?

Answer 13

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

Question 14

Can muscle take up glucose without insulin?

Answer 14

Exercising muscle can also take up glucose without insulin

Question 15

What happens when the pancreas is removed?

Answer 15

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)

Question 16

Define insulin resistance

Answer 16

Pathological condition in which cells fail to respond normally to insulin

Question 17

What happens when insulin resistance occurs?

Answer 17

High levels of insulin but message is not getting to the organs

Increase in blood glucose levels because not being taken up by organs

Question 18

Why is muscle one of the major sites of insulin resistance?

Answer 18

Because skeletal muscle accounts for 60%-70% of whole body insulin-stimulated glucose uptake

Question 19

When does insulin resistance occur in muscle?

Answer 19

During obesity or T2D

Question 20

What happens when there is insulin resistance in the muscle?

Answer 20

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!

Question 21

What happens in mice lacking both IRS1 and IRS2 in skeletal and cardiac muscle?***

Answer 21

Impaired glucose uptake

WITHOUT hyperglycaemia or hyperinsulinemia

Question 22

Why is fat mass increased when there is muscle insulin resistance?

Answer 22

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

Question 23

What happens when IRS1 and IRS2 are BOTH KO’d in muscle?

Answer 23

Decrease in survival

Naturally have higher BASAL glucose uptake (this is without the presence of insulin)

Question 24

How did IRS1 and IRS2 KO affect glucose utilization in mice in muscle?

Answer 24

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

Question 25

What does HGP stand for?

Answer 25

Hepatic glucose production

Question 26

How does insulin suppress liver glucose production?

Answer 26

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)

Question 27

What does central insulin do?***

Answer 27

Activates hepatic IL6-STAT3 signalling through liver-brain axis

Question 28

What occurs when insulin receptors are KO'd in the liver?

Answer 28

Mice are hyperlgycaemic and hyperinsulinemic Display reduced liver size compared to WT mice

Question 29

What occurs when ONLY IRS1 is KO'd in the liver?

Answer 29

Mice show insulin resistance after REFEEDING But fail to show insulin resistance during fasting

Question 30

What occurs when ONLY IRS2 is KO'd in the liver?

Answer 30

Mice show insulin resistance during FASTING But fail to show insulin resistance after refeeding

Question 31

What occurs when both IRS1 and IRS2 are KO'd in the liver?

Answer 31

Mice have severe glucose intolerance and impaired lipid metbolism

Question 32

What is the benefit of adipose tissue expansion?

Answer 32

Exerts buffering effet Prevents lipids ectopically depositing in other organs (liver, muscle, and pancreas)

Question 33

How does insulin regulate lipolysis?

Answer 33

Inhibits lipolysis in adipocytes Breakdown of triglycerides into glycerol and FFA

Question 34

What does diet-induced obesity cause?

Answer 34

Insulin resistance This occurs under excess nutrition

Question 35

How does insulin regulate glucose uptake in adipocytes?

Answer 35

Insulin stimulates glucose uptake in adipocytes Where it converts lipids as more efficient form of energy storage

Question 36

How does T2D affect adipose tissue?

Answer 36

When insulin binds = tyrosine phosphorylation of IRS1 and activation of PI3K are DECREASED

Question 37

What happens when insulin receptors are deleted from adipocytes?

Answer 37

Reduced fat mass because less glucose uptake Protects against obesity and obesity-related glucose intolerance (respond to insulin more effectively) = increased longevity

Question 38

What happens when GLUT4 is deleted in fat cells?

Answer 38

Decrease in insulin-stimulated glucose uptake in fat and muscle Impairement in insulin-mediated suppression of hepatic glucose uptake

Question 39

What are BAT and WAT?

Answer 39

Brown/White adipose tissue

Question 40

How do carbohydrates regulate gene expression?

Answer 40

Glucose acts via Cho response element

Question 41

How do lipids regulate gene expression?

Answer 41

Polyunsturated FA = transcriptional regulation via PPARs (peroximsome proliferator) Cholesterol via SREBP (sterol regulatory element BP)

Question 42

How do amino acids regulate gene expression?

Answer 42

Effects on transcription, ribosomes, signalling, amino acid transport

Question 43

How does a carbohydrate diet affect fat?

Answer 43

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

Question 44

What sequence motifs do ChoREs contain?

Answer 44

2 E-box sequence motics separated by 5bp

Question 45

What it the correct spacing of E boxes in ChoRE and why is it important??

Answer 45

Separated by 5 bp Correct spacing = critical for carbohydrate control of gene transcription

Question 46

What is carbohydrate response factors aka?

Answer 46

ChREBP

Question 47

What domains does ChREBP/ChoRF have?

Answer 47

NLS = nuclear localization signal Poly proline domain bHLH-leucine zipper domain Leucine-like domain

Question 48

What phosphorylation sites does ChREBP contain?

Answer 48

Phosphorylation sites for PK = P1-P3 AMPK phosphorylation side = P4

Question 49

Where is ChREBP predominantly expressed?

Answer 49

Liver Kidney WAT/BAT

Question 50

Where is ChREBP located in LOW glucose conditions?

Answer 50

Cytosol

Question 51

Where is ChREBP located in HIGH glucose?

Answer 51

Translocates from cytosol to nucleus

Question 52

What complex does ChREBP act with?

Answer 52

Heterodimeric complex with Max-like ptorin X (Mlx)

Question 53

What controls ChREBP location?

Answer 53

Dependent on phosphorylation state Ser196 phosphorylation site = retains it in cytosol (P1 PKA site) Dephosphorylation of P1 = nuclear localization

Question 54

What happens with P2 and P3 are dephosphorylated?

Answer 54

Allows ChREBP to bind to DNA

Question 55

When can ChREBP bind to DNA?

Answer 55

When other two PKA phosphorylation site are DEPHOSPHORYLATED

Question 56

What is dephosphorylation of P1-P3 dependent on?

Answer 56

Activation of protein phosphatase 2A (PP2A) Activated by X5P

Question 57

What activates protein phosphatase 2A (PP2A)?

Answer 57

Xylulose 5-P

Question 58

What is the role of proetin phosphatase 2A (PPA2)?

Answer 58

Dephorphorylation of ChREBP P1-P3 sites Allowing localization in the nucleus and DNA binding

Question 59

Under what conditions is X5P generated?

Answer 59

High glucose conditions X5P is made from G6P by phentose phosphate pathway

Question 60

What other BP acts in synergy with ChREBP?

Answer 60

Sterol regualtory element BP (SREBP)

Question 61

What is the effect of ChREBP and SREBP activation?

Answer 61

Both work together to promote lipogeneis

Question 62

What pathways is glucose requied to fully activate?

Answer 62

Insulin and GF-stimulated signalling pahtways

Question 63

What is the role of nutrient sensing response elements 1 and 2?

Answer 63

Involved in response to glucose DEPRIVATION

Question 64

What is the role of PGC-1a?

Answer 64

Co-activator of transcription of gluconeogenic enzymes These are activated under glucose DEPRIVATION

Question 65

What is the net effect of stress?

Answer 65

Stimulates glucose output

Question 66

What happens when glucagon binds its receptor?

Answer 66

Increase in cAMP Activates PKA = phosphorylates CREB CREB = activates PGC1 gene expression PGC-1 = coactivator protein stimulating PEPCK gene expression (GLUCONEOGENSIS)