Integration of Control Flashcards
Coordination and control of flux in mammals?
Hormones
Tissue-specific metabolism (dividing labour - screenshot part I)
Glucose in the liver?
Related to transport of G6P
Entry of glucose through GLUT2 (as no conc gradient)
Phosphorylated by glucokinase
G6P formed
G6P in the liver?
Dephos -- glucose to other tissues Liver glycogen Glycolysis for acCoA/ATP Glycolysis for acCoA/FAs/TAGs for export Pentose phosphate pathway for NADPH and ribose-5-phosphate for nucleotides
AAs in liver?
Proteins for liver /other tissues
Precursors of hormones/nucleotides
Transamination to CAC intermediates or pyruvate for gluconeogenesis
Converted to acCoA for energy in liver or lipid conversion
AAs from muscle degradation?
Starvation states
Enter glucose alanine cycle – alanine to liver for urea synthesis
FAs in liver?
Liver lipid synthesis
Oxidised to acCoA and NADH for CAC and oxphos = ATP for liver cells
Excess acCoA = ketone bodies or cholesterol
Converted to phospholipids/TAGs/exported
Cori cycle; activity effect on muscle
Between liver and muscle to support exercise/movement
Moderate activity = ATP from aerobic FA and glucose oxidation
Intense = anaerobic = muscle glycogen broken down, building up pyruvate (+NADPH = lactate)
To recover from intense activity, lactic acid is exported to the liver — pyruvate – gluconeogenesis — glucose — muscle export to replenish glycogen
This requires oxygen - O2 debt
Glucose-alanine cycle
Acts with the Cori cycle
Reduces lactate, converting pyruvate to alanine in muscle — liver
AAs transferred onto alanine (a-keto – glutamate reaction) forms pyruvate for gluconeogenesis
Overall, what does insulin do?
Indicates high glucose
Synthesis of fat, glycogen and protein, inhibits breakdown of such
Glucose uptake into cells
Overall, what does glucagon do?
Low glucose
Breakdown of fat, glycogen and protein, inhibits synthesis of such
Overall, what does adrenaline do?
Signals urgent need for energy (immediate impact)
Breakdown of fat, glycogen and protein, inhibits synthesis of such
Role of pancreas?
B cells = insulin
A cells = glucagon
Secreted into hepatic portal vein = directly to the liver for greatest effect
Mechanisms of insulin action
Binds tyrosine kinase cell-surface receptor, autophosphorylates itself and IRS-1
IRS-1 activates MAPK = TFs and PKB/Akt = fine enzyme control, regulatory proteins like phosphatases, vesicles,
Glucagon signalling
GPCRs – activate adenylyl cyclase for ATP — cAMP, acting in turn on PKA
Adrenaline signalling
Stimulated by stress signals, released from adrenal medulla
Acts with PKA cascade
Long-term regulation
Due to lifestyle e.g. diet and exercise
Changes at transcriptional level through TFs
Insulin = FOXO1 TF, where high insulin activating PKB moves FOXO1 to cytosol for degradation, suppressing gluconeogenic genes
ChREBP (respond to carbs, in liver and adipose tissue)
PPARs (respond to FAs from dietary lipids) - isoforms of this act in liver, muscle, adipose tissue
Therapeutic uses of PPAR isoforms?
Peroxisome proliferator-activated receptors
PPARy ligands - type 2 diabetes
PPARa - in liver/muscle, allow FA uptake and b oxidation
PPARd - muscle/adipose, obesity
Feeding/starvation in different species
Rat/mouse models have different feeding habits to us (e.g. during darkness)
e.g. mouse models = alternate day starvation improves synapse connections, but defo not in humans
Potential advantages of food restriction?
Regenerating diabetic pancreases
Promoting cell regeneration
Glucose metabolism in starvation?
Can occur in most cells e.g. from muscle/lipid breakdown
Sometimes cells cannot do this e.g. in anaerobic conditions, no mitochondria like RBCs, those that cannot metabolise AAs or FAs
Protein breakdown in tissues without glucose?
Brain neurones - produce lactate and CO2
RBCs and renal medulla - lactate and pyruvate
Muscle - alanine
Sources of glucose through starvation
Fed = from bloodstream
About 24 hours in = liver glycogen, gluconeogensis activated by glucagon
From 36 hours on = amino acids, first derived from gluconeogenesis and then from muscles
About day 30 = ketone bodies used
Early starvation?
Glycogen breakdown in liver switched on, TAG breakdown in adipocytes
Providing glucose to tissues with absolute requirement like the brain
2-4 days into starvation?
No glycogen = AA generation increased form proteins
TAG breakdown increased
FAs in liver – ketone bodies
GLUT4 changes = reduced glucose uptake, ketone bodies used instead along with FAs; carnitine biosynthetic pathways activate
Prolonged starvation?
Ketone bodies become primary source, proteins degraded
Brain/neural mechanisms in starvation?
Satiety centre stimulated by peptides releases from GI tract
Satiety centre invokes neuronal control e.g. affects liver metabolism
Higher regions control satiety centre e.g. hypothalamus
Diabetes
Unbalanced insulin; detected through GTT
Many types with varying causes even within each one:
Type I
Type II
Gestational
MODY
Effect of untreated diabetes?
Acute effects - nerve cells impaired in response to hypoglycaemia
Chronic effects - usually on blood cells causing heart disease, as well as neuropathies, retinopathies (blindness), nephropathy
Type 1 diabetes
Can be virally/chemically induced, causing an autoimmune condition
Genetic cause - beta cells cannot secrete insulin
Therapies for type 1 diabetes
Insulin injection e.g. E. coli derived
Beta cell replacement
Prevention of disease development (stopping viral.
/chemical causes); some antibodies block the autoimmune response
Type II
Insulin may be present, but cells are unresponsive
Linked to age and obesity, plus includes gestational forms
Treatments for type 2?
Improving function of beta cells like secretagogues
Improving insulin action thorough mimetics or sensitisers
Lifestyle changes
Insulin secretagogues - bind SUR
e.g. Glibenclamide
Inhibits ATP dependent K+ channels to cause a potassium build up, inducing calcium channel opening and thus insulin secretion
Insulin mimetics (usually first line choice)
Activate AMPK to increase glucose uptake
Insulin sensitisers - bind PPARy
Improves signalling of insulin i.e. acts on various components of signalling pathway (not well understood) through transcriptional activation of insulin target genes
“Coca colonisation”
Unhealthy food choices/industry underly many current health risks
Mechanisms of obesity in white and brown adipose tissue?
Progenitor cells determine the number of adipocytes in white tissue, which is not changeable
Brown tissue uncouples the proton gradient for FA metabolism = heat, and can be favoured by certain food types
Genetic components of obesity?
High heritability - 50,90%
Obesity genes linked to physiological regulation of adiposity and body weight, triggered by environment e.g. thrifty phenotype
Specific genes - linkage and mutation in obesity
Leptin and leptin receptor, involved in cascade impacting transcription
Naturally produced in adipocytes to promote fullness, and prevent laying down of TAGs
Leptin receptors in hypothalamus regulate satiety centre
Believed to set body weight
Proteolytic cleavage of neuropeptide precursors in appetite brain areas also involved - proteases not encoded = impairment
FTO - hypothalamus, unclear mechanism
Treatments for obesity
Lifestyle/genetics Food intake decreasing Blocking nutrient absorption in gut Increasing thermogenesis Modulate fat storage/metabolism Modulate central control of body weight e.g. brain areas, hormones, leptin
