Regulating Metabolism - Lecture 159

Regulating Metabolism - Lecture 159

1. Explain how insulin affects metabolic pathways, especially in the liver, to store fuels during times of plenty, and comparing carnivores with omnivores

Effects of Insulin: 

• released in response to high blood sugar level and via PNS signals
• indicates fed state
• stimulates use and storage of fuels
• stimulates glycogen deposition in muscle and liver
• stimulates glycolysis in liver
• producing more substrates for FA synthesis
• increases protein synthesis, especially in muscle
• excess ingested amino acids are converted into metabolic intermediates

Normal blood glucose: ~4.5-5.5 mM 

Fasting: ~3-4 mM, ruminants ~2-3 mM

After meal: ~7mM

Animals with diabetes: ~10-12 mM

mM = milliMolar: moles/litre

Fed state pathways - Insulin present - Omnivore

Fed state pathways - Insulin present - Carnivores

• carnivores rely on amino acids, no carbohydrates
• Thus, the pathways are through glucogenic and ketogenic amino acids
• gluconeogenesis and ketone breakdown
• Carnivores are not suited to a carbohydrate diet

Glucose uptake to tissues - Regulation

Glucose transporters (GLUT 1-5) act at different glucose concentrations and are expressed in different tissues
(Km = the substrate concentration at which the reaction rate is half of V_max)

• GLUT 1 & 3 - all cells
• Km ~1mM - basal slow uptake
• GLUT 2 - pancreatic β cells and hepatocytes
• Km ~ 15mM - uptake when hyperglycemic
• GLUT 4 - muscle and adipocytes 
• Km ~5mM
• contained in vesicles inside cells
• Insulin causes vesicles to fuse with membrane
• therefore only rapid glucose uptake when insulin is present
• GLUT 5 - small intestine for absorption

Uptake/Storage via glycogenesis and Fatty Acid Synthesis

• only when the supply is plenty

After meal: 

• Uptake into pancreatic β cells (GLUT 2) triggers insulin release
• GLUT 4 - muscle and fat cells respond with rapid glucose uptake for storage
• And uptake into hepatocytes increases (GLUT 2) 
• stored or used to synthesize fatty acids
  
  

2. Explain the effect of glucagon on metabolic pathways, to buffer blood glucose and provide alternative energy sources between meals

Fasting state: 

• released in response to low blood sugar
• main target is the liver - it has glucagon receptors
• releases stored fuels and changes fuel usage
• stimulates glycogen breakdown in the liver
• stimulates gluconeogenesis in liver - amino acids and glycerol
• changes fuel usage from carbs to fats
• stimulates hormone-sensitive lipase in adipose tissue
• releases FAs
• aerobic FA metabolism
• preserves glucose for essential organs

Stores of Energy:

Glycogen - 24 hr available - short-term store

Fatty Acids/TAGs - 1-3 months available - major store

Proteins - dynamic store --> muscles

Fasting state: 

• AcetylCoA levels rise
• It is converted to ketone bodies via ketogenesis

Ketogenesis: ONLY in Liver

• hepatocytes contain the required enzyme
• Converts acetylCoA into ketone bodies


• β-hydroxybutyrate, acetoacetate (acetate is expelled in air as waste product)


• Only happens when AcetylCoA level are increased
• During fast, level of AcetylCoA in hepatocytes increase via 2 methods:
• increased production
• Fatty acids are mobilised from adipose tissue, raising blood levels - most are taken up by the liver
• most of FAs are converted to AcetylCoA via β-Oxidation
• decreased usage (CAC is slowed)
• CAC intermediates are depleted by gluconeogenesis
• cells energy charge increases (cause: ATP from β-Oxidation) which also inhibits the CAC

3. Describe the formation and function of ketone bodies as part of the fasting response, comparing this with the perception of starvation during diabetes mellitus

Ketone bodies: 

• used in other tissues - converted back to acetylCoA for CAC
• production/use part of normal fasting response
• important fuel for brain
• brain relies largely on glucose
• but will use ketone bodies
• cannot use fatty acids because long chain fatty acids cannot pass through blood-brain barrier - brain needs small, water soluble energy

Excessive production of ketone bodies:

• leads to ketoacidosis - change in blood pH
• part of severe metabolic diseases
• ruminant production diseases
• severe diabetes mellitus

Muscle metabolism is also regulated - via Insulin

• muscles do not have glucagon receptors, so can't be controlled by glucagon
• controlled in response to exercise

Resting:
1. Energy from β-Oxidation

Exercise: 
1. Energy from β-Oxidation
2. Energy from glycogenolysis---> glycolysis ---> link reaction ---> CAC