Integration Flashcards
Insulin is synthesised as __________ in ___ cells of the pancreas
______________ → _______________ → Insulin + _____________ (marker of insulin secretion)
Preproinsulin → Proinsulin (A+B+C) → Insulin (A+B) + C-peptide
- ß-cells of pancreas
How is insulin secretion measured?
Indirectly via measurement of C-peptide
Describe the signal transduction pathway of insulin.
→ bind to RTK → P IRS (insulin receptor substrate)
1) → Activate Protein phosphatase-1
a) Dephosphorylate glycogen synthase → active → ↑glycogenesis
b) Dephosphorylate glycogen phosphorylase → inactive → ↓glycogenolysis
2)
What are 3 metabolic effects of insulin?
Anabolic hormone:
1) ↑Glycogenesis
2) ↑FA synthesis and storage
3) ↑ Protein synthesis
4) ↑ Glucose uptake (via GLUT4)
- in skeletal muscle and adipocytes
5) ↑Cell proliferation and differentiation
What type of membrane receptor is activated by insulin?
Tyrosine Kinase Receptor
Glucagon is synthesised as a (active/inactive) precursor and secreted by ___ cells in the pancreas is inhibited by __________ and activated by _______________
Glucagon (inactive) ← α cells
+: Amino acids
-: Insulin
What are 2 biochemical effects of glucagon?
Liver:
1) ↑Glycogenolysis
2) ↑Gluconeogenesis
Adipose tissue:
3) ↑Lipolysis
What type of membrane receptor is activated by glucagon?
GPCR
Describe the cell signalling pathway for glucagon.
→ bind to GPCR → release α-subunit
→ activate adenylate cyclase → (ATP→cAMP)
→ activate Protein Kinase A
a) → P glycogen synthase (inactive)
→ ↓glycogenesis
b) → P phosphorylase kinase → P glycogen phosphorylase
→ ↑glycogenolysis
Adrenaline is a ___________ synthesised from __________ by the ________________. It is stimulated by ______________.
Catecholamine from Tyrosine by Adrenal glands.
+: Acute stress
What are 2 receptors and their organ locations that respond to adrenaline.
1) α-adrenergic receptor (eg. liver and pancreas)
2) ß-adrenergic receptor (eg. liver, skeletal muscle, adipose tissue)
What type of membrane receptors respond to adrenaline (RTK or GPCR)?
GPCR
What are 3 metabolic effects of adrenaline?
1) ↑Glycogenolysis in liver and muscles
2) ↑Lipolysis
3) ↑Gluconeogenesis
4) ↑Glucagon ↓Insulin by pancreas
Describe the cell signalling pathway in adrenaline via the α-receptor.
→ bind to α-adrenergic GPCR
→ Activate PLCß
→ PIP2 → IP3 + DAG
IP3 → IP3-gated Ca2+ channel on ER
Ca2+ + DAG → Protein kinase C
Adrenaline ________ insulin secretion and _________ glucagon secretion.
↓Insulin
↑Glucagon
What is the moa of cholera toxin from Vibrio cholera?
ß-subunit bind to intestinal cells → allow α-subunit entry
α-subunit → ARF → ribosylation of GPCR → active
α-subunit of GPCR → cAMP → PKA activation → Pi of CFTR → efflux of Cl- and water → diarrhoea
What are the biochemical pathways affected in a early refed state and how are they affected?
Early refed → ↑insulin ↓glucagon
Liver:
↑Gluconeogenesis → ↑Glycogenesis
- rate of gluconeogenesis declines as insulin ↑
How does blood glucose ↓ after a meal?
1) ↑ Liver uptake by GLUT 2
2) ↑insulin → ↑muscle and adipose tissue uptake by GLUT 4
What are the biochemical pathways affected in a well fed state and how are they affected?
Well fed → High insulin, low glucagon
Liver:
1) ↑Glycogenesis
2) ↑Glycolysis
3) ↑TG synthesis
Adipose tissue:
1) ↑TG synthesis (↑LDL + ↑GLUT4)
Muscles:
1) ↑Glycogenesis (↑GLUT4)
All tissues:
↑ Protein synthesis
What happens to lactate produced in RBC?
Handled by Cori cycle → Liver → NAD+ → Pyruvate
Why does the muscle use FAs and KBs instead of glucose in a early fasting state?
During fasting → ↓insulin → GLUT 4 is endocytosed to be stored in vesicles
→ ↓ glucose uptake
What are the biochemical pathways affected in a early fasting state and how are they affected?
Early fast: High glucagon, low insulin
Liver:
1) ↑Glycogenolysis
2) ↑Gluconeogenesis (esp from glucogenic amino acids)
3) Ketogenesis (if excess Acetyl CoA)
Adipose tissue:
1) ↑ß-oxidation
2) ↑Lipolysis (↑HSL)
Why do patients doing blood tests for annual checkups need to fast overnight?
Removes confounding factor of meal contents
Why are patients doing blood tests for annual checkups not tested for chylomicrons and VLDL?
Chylomicrons and VLDL removed by liver in prolonged fast → too low for meaningful measurement
Describe the changes in liver glycogenolysis and gluconeogenesis from early to prolonged fasting.
Early:
Liver glycogenolysis peak @8-10hrs → ↓rate
Glucogenic phase:
- glycogen stores depletes by day 1.5-2
- rising and peak gluconeogenesis
What is the glucogenic phase (3 features)?
Phase where early and prolonged fasting overlap:
1) Brain uses glucose
2) Glucose mainly from gluconeogenesis
3) High rate of proteolysis
What is the protein conservation phase (2 features)?
Prolonged fasting:
1) Brain progressively use > ketone bodies
2) ↓Proteolysis as rate of gluconeogenesis ↓ (still occurring but lower rate)
What are the hormones produced in prolonged fast?
Glucagon and cortisol
What are the biochemical pathways affected in a prolonged fasting state and how are they affected?
Prolonged fast → high glucagon and cortisol
Liver:
- gluconeogenesis
Adipose tissue:
- Lipolysis
Skeletal muscle:
- Proteolysis
What is the effect of elevated cortisol in a prolonged fast?
1) Lipolysis → glycerol → gluconeogenesis
2) Proteolysis → Glucogenic amino acids → gluconeogenesis
Describe the process of cortisol secretion during starvation.
Starvation → hypoglycemia
Hypothalamic regulation center
→ ACTH from pituitary
→ Cortisol from adrenal gland
How does the main fuel of the liver and brain differ in (i) well fed, (ii) overnight fasting, (iii) prolonged fasting?
Liver:
i) Glucose
ii) FA
iii) FA
Brain:
i) Glucose
ii) Glucose
iii) KB/Glucose
What is the range for moderate BMI in singapore?
23 - 27.4
Why is waist circumference measured?
For abdominal obesity:
- most practical anthropometric measurement
- must be used in conjuction with BMI
What is the cutoff for waist circumference for abdominal obesity?
M: <90cm
F: <80cm
What are the 2 types of adipose tissue?
1) Subcutaneous
2) Visceral
What is the difference between subcutaneous and visceral obesity?
Subcutaneous:
- can expand through hyperplasia
- safe and normal
Visceral:
- stores excess fat from SAT
- enlargement of VAT (hypertrophy) → pathology (M2 → M1/proinflammatory macrophage)
What are 2 functions of adipocytes?
1) Storage of fats
2) Production and secretion of adipokines and cytokines
How does visceral obesity lead to insulin resistance?
Accumulation of visceral fat
→ M2 → M1
→ ↑pro-inflammatory cytokines → ↑FFA release
FFA → inhibit insulin signalling pathway → insulin resistance → ↓uptake by GLUT 4 + ↑gluconeogenesis
What is the criteria for metabolic syndrome?
≥ 3 of:
1) ↑Waist circumference (>80/90)
2) ↑HDL (<1.3/1mmol/L)
3) ↑Fasting blood glucose (6.1mmol/L)
4) ↑BP (>130/85mmHg)
What is the significance of having metabolic syndrome?
- 2x more likely to have heart disease
- 5x more likely to have DM
- even 1 risk factor → heart disease
With a low carbohydrate diet, what happens after feeding?
Low carbohydrate → no ↑blood glucose
→ low insulin, high glucagon
→ Liver remains in gluconeogenic and ketogenic mode
Why is there a loss in lean body mass/muscle in a low-carbohydrate diet? How is it prevented?
Low carb diet → Liver maintain gluconeogenesis (must come from glucogenic amino acids)
→ proteins undergo proteolysis to provide glucogenic amino acids
- Ensure sufficient protein in diet
What happens hormonally after a low carb, high protein meal?
1) Significant ↑↑glucagon
→ ↑gluconeogenesis
→ ↑lipolysis → ↑ketogenesis
2) Small ↑insulin
→ protein synthesis
Why is a high protein diet not suitable for px with renal dysfunction?
↑↑Urea need to be excreted
What are 2 anti-obesity medications approved in singapore and what are their moas?
1) Orlistat
- lipase inhibitor → ↓TG digestion and absorption
2) Phentermine
- stimulate NE release → ↑satiety → ↓appetite
- may trigger NE/E from adrenal glands → fuel mobilisation
What is the moa of GLP-1 receptor agonists (eg. semaglutide)?
Mimic endogenous incretins (eg. GLP-1) → Stimulate GLP-1 receptor:
1) Stimulate insulin secretion
2) ↓appetite and hunger
What is high fructose corn syrup?
Corn syrup subjected to enzymatic rxn to convert glucose and fructose → sweeter
Why does the consumption of high fructose corn syrup lead to increased lipogenesis?
Fructose metabolised in liver a) Dihydroxyacetone-P→ G3P → Lipogenesis
b) Dihydroxyacetone-P or Glyceraldehyde-3-P → Glycolysis → Acetyl-CoA → Lipogensis
Which reducing equivalent is produced in ethanol metabolism?
NADH
What are 2 ways ethanol is metabolised?
1) Alcohol dehydrogenase (ADH) in cytoplasm
2) Microsomal ethanol oxidising system (MEOS, CYP2E1) in ER
→ Acetaldehyde (very reactive)
→ Acetaldehyde dehydrogenase
→ Acetate (non-toxic) in mitochondria
Acetate produced from the detoxification of acetaldehyde produces ____________ when metabolised.
Acetyl CoA and AMP
What is alcohol flushing syndrome?
Flushing after drinking alcohol due to high levels of acetaldehyde by:
1) Deficient ALDH2 (↓conversion to acetate)
2) Super-active ADH (↑production of acetaldehyde)
3) Alcohol itself → vasodilation under skin → flushing
How does ethanol consumption affect (i) glucose, (ii) lactate and (iii) blood pH?
Ethanol metabolism → ↑NADH
→ ↓gluconeogenesis
→ ↓glucose, ↑lactic acidosis
Why do alcoholics have increased risk of fatty liver?
↑Ethanol metabolism → ↑NADH
→ ↑ß-oxidation → ↑FA → ↑TG by:
1) ↑catalysis by ethanol (via acyltransferases)
2) ↓secretion of VLDL due to liver dmg
3) ↑NADH → ↑glycerol-3-P from dihydroxyacetone phosphate
When rate TG synthesis»_space; VLDL packaging → Fatty liver
What are 3 reasons why acetaldehyde is toxic?
1) Forms covalent bonds with functional groups in proteins, nucleotides and phospholipid
2) Binds to glutathione → ↓antioxidant capacity
3) Inhibit tubulin polymerisation/damage microtubules → ↓secretion of VLDL secretion
Why are px with gout advised against consuming excessive alcohol?
↑Alcohol → ↑Acetate (+ AMP)
AMP→…→Uric acid
(beer also contains purines → uric acid)
What is the order of fuel consumption during anaerobic exercise?
1) Muscle ATP (1.2s)
2) Creatine phosphate (9s)
3) Muscle glycogen (anaerobic glycolysis)
What are 3 ways glycogenolysis is stimulated specifically during exercise?
1) Muscle contraction
- AMP → P-ed Glycogen phosphorylase (active)
→ ↑glycogenolysis
2) Nerve impulse → Ca2+ → Calmodulin
→ P-ed Phosphorylase kinase
→ P-ed Glycogen phosphorylase (active) → ↑glycogenolysis
3) Epinephrine → cAMP → Protein Kinase A
→ P-ed Glycogen phosphorylase (active) → ↑glycogenolysis
What are the fuel(s) consumed during anaerobic exercise?
1) Glucose
2) Fatty acid
3) Amino acids
What 2 main hormonal control of metabolic events?
1) ↓Glucose → ↑Glucagon:
- lipolysis → FA
- Glycogenolysis + Gluconeogenesis → glucose
2) Epinephrine:
- lipolysis → FA
- glycogenolysis and gluconeogenesis in liver → glucose
- glycogenolysis in skeletal muscle → G1P → G6P
What is the preferred fuel during aerobic exercise. Why?
Fatty acid.
ß-oxidation → >ATP per C than glycolysis
What are 2 roles of AMP during exercise?
1) Allosteric activator of glycogen phosphorylase (glycogenolysis) and PFK-1 (glycolysis)
2) Activate AMPK
Skeletal muscle:
→ ↑glucose uptake
→ ↑ß-oxidation
Liver:
→ inhibit gluconeogenesis
→ inhibit TG and cholesterol synthesis → ß-oxidation
How does muscle contraction increase the muscle’s sensitivity to insulin?
AMP activates AMPK:
→ exocytosis of GLUT4 vesicles
What are 3 situations during exercise where lactate/anaerobic metabolism occurs?
1) Short, intense exercise and only fast twitch
2) Initial period of exercise (>1 min lag time for sympathetic ↑ in blood flow)
3) Prolonged exercise (ATP Dd>Ss by oxphos)
What are 3 types of muscle fibres and how are they different?
Type 1 (slow twitch)
- prolonged aerobic exercise
- low glycogen stores
- high myoglobin and capillaries
- high aerobic capacity
Type 2b (fast twitch)
- sprinting and resistance
- high glycogen stores
- low myoglobin and mitochondria
- mainly anaerobic → easily fatigued
What are the metabolic effects of training?
General:
↑glycogen stores
↑no. and size of mitochondria → > efficient oxidation of fuels
Resistance training:
↑strength, power, endurance
Hypertrophy of muscle via ↑protein synthesis and ↓proteolysis
What fuels are used by cardiac muscles in descending order?
1) fatty acids
2) glucose
Glucose transport in the heart is 90% via _____________, but also expresses ____________, despite having ___________ stores.
90% GLUT4
express GLUT 1
has glycogen stores
How does fuel metabolism in cardiac muscles differ in normal and ischemic conditions?
Normal: Aerobic (FA > glucose)
Ischemic: Anaerobic → ↑lactate
