integration of metabolism Flashcards
entrance of hormones (polypeptide (insulin, glucagon); catecholamines (adrenaline); steroids (cholesterol)) into cells
- polypeptide & catecholamines: bind to receptor -> trigger response
- steroids: diffuse into cell
what is metabolic homeostasis + hormones that regulate it
balance between fuel availability and the needs of different tissues for different types of fuels
- insulin, glucagon, adrenaline
synthesis of insulin
- POLYPEPTIDE
- synthesis occurs in B cells of pancreas
- synthesized as inactive precursor (C peptide + A&B chains) -> processing in pancreas forms active insulin (A&B chains)
- both C-peptide and active insulin are released into blood
metabolic effects of insulin - what does it STIMULATE (2)
synthesis and storage pathways
- glycogenesis
- fatty acid synthesis & storage
- protein synthesis
uptake of glucose by GLUT 4 transporters in skeletal muscles + adipocytes
signal transduction process of insulin (5)
- binds to insulin receptor (RTK) -> kinase domain is phosphorylated and activated
- IRS (insulin receptor substrate) binds to RTK -> gets phosphorylated
- PI3 kinase docks at
IRS -> activated & converts PIP2 to PIP3 - docking of PDK1 and AKT to PIP3 -> cause phosphorylation of AKT by PDK1 and mTOR
- phosphorylation of AKT makes it active, and it dissociate from PIP3 -> AKT causes effects on metabolism
*key molecules: IRS, PI3-kinase, PIP3, PDK1, mTOR, AKT
synthesis of glucagon
- POLYPEPTIDE
- synthesized as inactive precursor in a cells of pancreas
- synthesis inhibited by insulin, upregulated by amino acids
effects of glucagon (2)
Liver:
- stimulates GLYCOGENOLYSIS and GLUCONEOGENESIS
Adipose tissue:
- stimulate LIPOLYSIS (triglyceride -> fatty acid acid + glycerol)
**muscles do not express glucagon receptors (glucagon has NO EFFECT on muscle glycogen stores)
signal transduction process of glucagon
- binds to GPCR -> activate glucagon receptor
- glucagon receptor binds to G protein
- G protein releases bound GDP and binds to GTP -> a subunit dissociates from BY subunit
- a subunit bind and activate adenylyl cyclase
- activated adenylyl cyclase -> converts ATP to cAMP
- cAMP activate PKA -> PKA cause effect on metabolism
synthesis of adrenaline
- CATECHOLAMINE (synthesized from tyrosine)
- produced by the adrenal glands, released in response to acute stress
effect of adrenaline (2)
binds to B-receptor
- in LIVER, SKELETAL MUSCLES, ADIPOSE
- glycogenolysis in liver and muscles; gluconeogenesis; lipolysis (SAME AS GLUCAGON)
binds to a-receptor
- in LIVER, PANCREAS
inhibit insulin secretion + stimulate glucagon secretion
signal transduction process of adrenaline
B-receptor
- binds to B-adrenergic receptor -> dissociation of G protein + activate adenylyl cyclase + cAMP (SAME AS GLUCAGON)
- cAMP directly causes smooth muscle relaxation, vasodilation
- cAMP can activate PKA -> effects on metabolism (glycogenolysis in liver and muscles; gluconeogenesis; lipolysis)
a-receptor
- binds to a-receptor -> activate G protein causing dissociation of a-subunit and BY-subunit
- both a-subunit and BY-subunit activates (PLCB) phospholipase C-B
- activated PLCB cleaves PIP2 -> form IP3 and DAG
- IP3 activates release of Ca2+ from endoplasmic reticulum
- Ca2+ and DAG activates protein kinase C
- protein kinase C -> effects on fuel metabolism + smooth muscle contraction, vasoconstriction in peripheral organs w a-receptors
vibrio cholerae pathogenesis
- produces cholera toxin
- cholera toxin contains A & B subunit -> B-subunit binds to intestinal cells + processes A subunit -> allows A subunit to enter cell
- interact with Arf protein -> promote ribosylation of a-subunit of G-protein -> activates G-protein
- produce cAMP and PKA activation
- PKA phosphorylates CFTR chloride channel -> efflux of Cl- and water from intestinal cells into intestinal lumen -> diarrhea
what is fed state vs fasting state
- fed: high insulin, low glucagon
- fasting: low insulin, high glucagon
what are the events in fed starve cycle that a person can undergo (4)
- EARLY REFED state (immediately after a meal)
- WELL FED state (last a while after a meal
- EARLY FASTING state (begins after well fed state, usually only during overnight sleep)
- PROLONG FASTING state (rare)
insulin and glucagon during early refed state
- insulin rises sharply in reaction to sharp increase in blood glucose
- glucagon begins to fall sharply
what happens during early refed state
- liver remains in GLUCONEOGENIC mode -> generate glucose from lactate & glucogenic amino acids
- glucose-6-P from gluconeogenesis is used for glycogen synthesis
types of GLUT (glucose transporters) in different tissues (activated during well fed states for uptake of glucose)
GLUT 2
- liver & pancreatic cell, LOWEST affinity for glucose (starts taking in glucose at high [glucose])
- always expressed on cell membrane
GLUT 4
- skeletal muscles & adipocytes, moderate affinity for glucose
- location of GLUT 4 INFLUENCED BY INSULIN
GLUT 3
- brain & nerve tissues, HIGHEST affinity for glucose (allow uptake of glucose even at basal [glucose])
- always expressed on cell membrane
main organs involved in well fed state (ie stimulated by insulin)
LIVER
- insulin stimulate glycolysis; glycogen synthesis; FA/TG synthesis
- uptake of glucose by GLUT2 (NOT due to insulin)
ADIPOSE
- insulin stimulate GLUT4 expression & uptake of glucose
- insulin stimulate synthesis and secretion of lipoprotein lipase + TG synthesis
MUSCLE
- insulin stimulate GLUT4 expression & uptake of glucose
- insulin stimulate glycogen synthesis
ALL TISSUES
- stimulate protein synthesis
*Cori cycle is inhibited -> lactate is brought to liver and converted to pyruvate -> acetyl CoA instead
specific processes in LIVER during well fed state
protein synthesis
glycolysis
- insulin activates phosphofructokinase 1 (PFK1) via fructose-2-6-bisphosphate
glycogen synthesis
- insulin and high levels of glucose leads to the activation of glycogen synthase
lipogenesis (FA synthesis)
- insulin activates acetyl CoA carboxylase (ACC)
- glucose -> pyruvate -> acetyl coA -> malonyl coA -> FA -> TG -> VLDL which is release into the bloodstream
specific processes in ADIPOCYTES during well fed state
insulin stimulates glucose uptake by GLUT4 (similar to muscles)
- for synthesis of glycerol-3- phosphate which forms the backbone of TG
insulin stimulates production and secretion of lipoprotein lipase (LPL)
- digestion of TGs in chylomicrons (dietary TG) and VLDL (TG synthesized by liver)
- uptake of FAs into adipocytes
- TG synthesis and storage
specific processes in MUSCLES during well fed state
Insulin stimulates the uptake of glucose by GLUT4, glucose is used for:
- glycogen synthesis
- glycolysis -> TCA -> oxidative
phosphorylation (ATP)
Protein synthesis
insulin and glucagon during early fasting state
- high glucagon, low insulin
what happens during early fasting state
LIVER
- glucagon stimulates glycogen breakdown and gluconeogenesis -> glucose exported by liver is used mainly be BRAIN and RBC
- uses FA for its ATP needs and excess acetyl coA is used for ketogenesis (ketone bodies later used to supply muscles)
ADIPOCYTES
- glucagon stimulates lipolysis
- glucagon activates hormone sensitive lipase -> breakdown TGs to glycerol and fatty acids
-> release from adipocytes
**glucagon has no effects on muscles (but will hvae some turnover of muscle proteins -> release of amino acids -> glucogenic amino acids will be used for gluconeogenesis in the liver
why do muscles use FA and ketone bodies as a source of energy instead of blood glucose
- low insulin -> NO GLUT4 transporters (exocytosis) -> cannot take up glucose
will there be chylomicrons present in blood test after overnight sleep
- no -> all converted to remnant chylomicrons and taken up by liver
will there be VLDL/ VLDL remnants in blood test after overnight sleep?
- no -> all converted to IDL or LDL
what happens during conversion of early fasting (overnight sleep) to prolonged fasting (starvation >3 days)
- decrease liver glycogenolysis to 0; increase gluconeogenesis (MAIN SOURCE OF BLOOD GLUCOSE)
- rate of proteolysis decreases (initially high in early fasting) -> PROTEIN CONSERVATION
- brain progressively uses more ketone bodies for source of glucose (rather than glucose)
hormonal levels in prolonged fasting state
- high glucagon and cortisol; low insulin
what happens in prolonged fasting state
increased release of cortisol
MUSCLES
- cortisol activates proteolysis -> glucogenic amino acids -> used for gluconeogenesis in liver
ADIPOCYTE:
- glucagon and cortisol activate lipolysis -> FA + glycerol -> both are transported to liver
LIVER
- glycerol used for gluconeogenesis
- FA used for ATP production and for production of ketone bodies (ketogenesis)
- gluconeogenesis, production of ketone bodies
how is cortisol released by cells
- low blood glucose -> detected by hypothalamic regulation center -> release ACTH from pituitary -> induce cortisol release from ADRENAL GLAND
Marasmus pathogenesis
- severe MALNUTRITION (prolonged fasting state) -> inadequate caloric intake
- BW < 60% of normal, severe muscle wasting
- no edema
Kwashiorkor pathogenesis
- inadequate PROTEIN intake but caloric intake is sufficient
- BW 60-80% of normal, some muscle wasting
- EDEMA -> lack of serum albumin (insufficient protein) -> decrease colloid osmotic pressure
- HEPATOMEGALY -> lack of lipoprotein synthesis (insufficient protein) -> liver cannot transport fats out -> deposit in hepatocyte -> fatty liver
cachexia pathogenesis
- UNINTENTIONAL muscle wasting and severe weight loss (despite adequate nutrition)
- associated with cancer
what happens in obesity
- body is continuously in WELL FED STATE -> metabolism driven by insulin
- glucose, aa, lactate converted to FA, stored as fats (accumulates)
how does obesity lead to Type 2 diabetes
- constant secretion of insulin by pancreas -> insulin resistance over time -> pancreas secrete more insulin -> type 2 DM
types of adipose tissues
- subcutaneous adipose tissue (SAT)
- visceral adipose tissue (VAT)
subcutaneous vs visceral obesity
subcutaneous obesity
- SAT can expand through hyperplasia (generation of new fat cells)
- storage of excess fat in SAT is safe and the adipocytes remains normal
visceral obesity
- when storage in SAT becomes saturated, excess fats are stored in VAT
- enlargement of VAT (hypertrophy) -> pathological situation
what are the adverse effects of visceral obesity
- Accumulation of visceral fat
-> enlargement of adipocytes -> macrophages: switch from anti inflammatory (M2) to pro inflammatory (M1) - Enlarged adipocytes & M1 macrophages -> increased production of pro- inflammatory cytokines and release of free fatty acids (FFA)
- Pro-inflammatory cytokines + FFA -> negatively affect insulin signaling pathway -> insulin resistance
- insulin resistance -> reduced uptake of glucose by GLUT4 in skeletal muscles and adipocytes + increase gluconeogenesis in liver -> high blood glucose
how is visceral obesity measured
- waist circumference
what is metabolic syndrome (commonly associated with obesity)
group of characteristics (at least 3 of 5 = metabolic syndrome)
- large waist circumference
- HDL-cholesterol
- fasting blood triglyceride
- fasting blood glucose
- fasting BP
*metabolic syndrome -> GREATLY increase chance of developing DIABETES & HEART DISEASES
what happens after a low carbs diet
- no significant increase in blood glucose level -> LOW INSULIN, HIGH GLUCAGON
- liver remains in glucogenic & ketogenic mode
why is a person with low carbs diet lean
- low carbs diet -> muscles continue to undergo proteolysis (not inhibited due to low insulin) to provide glucogenic aa for gluconeogenesis -> loss of muscle protein -> lean
*to prevent excess loss of muscle -> ensure HIGH PROTEIN diet
what happens after a low carbs, HIGH PROTEIN meal
- significant increase in glucagon -> stimulate gluconeogenesis in liver, lipolysis at adipose tissue + ketogenesis in liver
- small increase in insulin -> enough to enable protein synthesis (due to high aa intake) but will NOT inhibit gluconeogenesis -> excess aa not needed for protein synthesis will be used for gluconeogenesis & ketogenesis
why is a high protein meal not suitable for pts with renal problems
- metabolize aa -> produce urea -> renal problems cause urea accumulation
how does fructose lead to synthesis of lipid (ie TGs)
broken down to form dihydroxyacetone-P and glyceraldehyde
- dihydroxyacetone-P can form glycerol-3-P (glycerol backbone)
- glyceraldehyde-3-P undergo glycolysis -> pyruvate -> acetyl coA -> FA
FA + GLYCEROL = TG
effect of caffeine on fuel metabolism
- caffeine inhibit PDE -> cAMP not broken down -> enhance metabolic effects of epinephrine & glucagon
how is alcohol metabolized
metabolized to form acetate (2 pathways):
- ethanol metabolized by ADH (alcohol dehydrogenase) in cytoplasm to form acetyldehyde -> converted to acetate by ALDH
- ethanol metabolized by microsomal ethanol oxidising system (MEOS, CYP2E1) in endoplasmic reticulum
acetate is then converted to acetyl coA (by acetyl coA synthetase & CoASH) -> fed into TCA cycle
what causes flushing syndrome
- deficient hepatic ALDH2 (acetyldehyde not converted to acetate) -> accumulate -> cause flushing
blood concentrations of glucose, lactate, pH in alcohol intoxication
glucose:
- NADH builds up from alcohol metabolism to acetate -> inhibit gluconeogenesis -> LOW GLUCOSE
lactate
- pyruvate converted to lactate to oxidise excess NADH to NAD+ -> lactate builds up -> HIGH LACTATE
pH
- acidosis from lactate -> LOW pH
why do alcoholics have fatty liver
- high NADH levels -> reduce rate of beta oxidation of FA -> FA accumulates in liver
- high NADH also favours glycerol-3-P pdn from dihydroxyacetone phosphate -> combine with FA for resterification
- acyltransferase (catalyse resterification, ie combine glycerol & FA) -> inducible by ethanol
- when rate of TG formation > rate of VLDL packaging -> fatty liver
adverse effects of acetaldehyde pdn and accumulation
- binds to glutathione -> reduce antioxidant capacity of liver
- inhibits tubulin polymerization -> decreased
microtubules formation, OR binds directly to and damage microtubules -> prevent secretion of VLDL from the liver
why are gout pts not allowed to consume alcohol
- acetate is produced from alcohol -> converted to acetyl-coA -> results in production of AMP
- AMP -> metabolized to uric acid
- beer also contains purines which are absorbed and metabolised to uric acid
- increase uric acid production -> worsen gout
why is there little organ cooperation during intense exercise
- peak contraction, blood vessels are compressed, and muscle is isolated from the rest of the body
fuel used during anaerobic exercise by muscles
Muscle ATP – can last for about 1.2s
Creatine phosphate (lasts about 9s if not regenerated)
- high energy source for ATP synthesis until glycogenolysis and glycolysis sets in
- Creatine phosphate + ADP -> Creatine + ATP (creatine kinase, reaction is reversible)
Muscle glycogen -> glucose-1-phosphate -> glucose-6-phosphate for anaerobic glycolysis (main source of ATP) -> lactate
3 ways to activate muscle glycogen phosphorylase (breakdown glycogen) DURING EXERCISE
- AMP produced during muscle contraction -> allosteric activator of glycogen phosphorylase
- Ca2+ produced in sarcoplasmic reticulum -> form Ca-calmodulin complex -> activate phosphorylase kinase -> phosphorylate & activate glycogen phosphorylase
- adrenaline produced -> activate cAMP -> activate PKA -> activate phosphorylase kinase -> activate glycogen phosphorylase
key metabolic events during AEROBIC EXERCISE (all stored fuel are mobilized for the run)
Low blood glucose -> high glucagon / low insulin -> glucagon will activate:
- lipolysis in adipose tissues -> release of FAs
- hepatic glycogenolysis and gluconeogenesis -> release of glucose
Adrenaline released during the run will activate:
- lipolysis in adipose tissues -> release of FAs
- glycogenolysis and gluconeogenesis in liver -> release of glucose
- glycogenolysis in skeletal muscles -> G1P -> G6P for glycolysis
Blood glucose (released from liver) can be used by the muscle -> glycogenolysis in muscles provide G1P -> G6P for glycolysis
FAs released by adipose tissues -> used directly by the muscle or used by liver to produce ketone bodies -> then exported for use as fuel by muscle
*PREFERRED FUEL: FA -> MORE ENERGY PER MOLECULE)
function of AMP in exercise (produced in large amounts during muscle contraction, 2ADP -> ATP + AMP) (2)
- activate glycogen phosphorylase
- activate PFK-1
how is AMPK (AMP dependent protein kinase) activated
- activated by AMP
- inhibited by ATP
effects of activated AMPK
skeletal muscles:
- increase glucose uptake by exocytosis of GLUT4 transporters on muscle cell surface
- increase fatty acid oxidation
liver:
- inhibition of gluconeogenesis (so that glycolysis can take place)
- inhibition of fatty acid and cholesterol synthesis so fatty acid oxidation can occur
*metformin (diabetes med) activates AMPK
types of muscle fibres
Type 1:
- low glycogen stores, high blood capillaries
- for aerobic respiration
Type 2b:
- high glycogen stores, low mitochondria
- for anaerobic respiration, easily fatigued
Type 2a:
- intermediate of 1 & 2b
types of fuel used by cardiac muscles
- 60-80% FA
- 20-40% glucose
*cardiac muscles contain glycogen stores
how is glucose transported to cardiac muscles
- 90% GLUT 4 - RESPONSIVE to insulin
- also express GLUT1
normal metabolism vs ischemic metabolism of cardiac muscles
normal: aerobic
ischemic: anaerobic -> lactate build up
