Metabolic Integration Flashcards
The Well-Fed and Starved States
- The liver of a well-fed person is glycogenic, glycolytic and lipogenic
- The liver of a fasting person is glycogenolytic, gluconeogenic, ketogenic and proteolytic
when does glucagon rises
glucagon rises when glucose levels are low and insulin rises when glucose is high
The Well-Fed State
- Glucose and amino acids (from food) enter the blood stream and reach the liver via the portal vein
- Triacylglycerol (from food)is packed into chylomicrons and absorbed via lymphatic system (“lacteal”)
- Insulin is secreted to stimulate the storage of fuels
- Glycogen synthesis occurs in liver and muscles
- Glycolysis occurs in the liver which generates acetyl-CoA for fatty acid synthesis
- Triglycerides are stored in adipose tissue
Insulin Effects on liver
• Liver
– Switch off glycogenolysis & gluconeogenesis
-> Reduced glucose output
– Switch on glycolysis – increased acetylCoA
-> Increased fatty acid synthesis
Insulin leads to:
– Glucose storage as glycogen in muscle & liver
– Storage from calories from glucose & amino acids in fatty acids
– Storage of fat as triglycerides in adipose tissue
The Early Fasting (Between-meals) State
- Blood glucose levels drop
- Glucagon is secreted
- Glycogenolysis is stimulated to release glucose
- Glucose is taken up primarily by the brain
- Fatty acid release from adipose tissue increased
- Muscle uses fatty acids as primary fuel source as they have no GLUT4
- (Gluconeogenesis is stimulated) when there is alot of glycogen - glycogen will breakdown to glucose 6 phosphate and that will feedback to inhibit gluconeogenesis
The Fasting State
- Glucose is no longer taken up by the muscles • Muscles use fatty acids and ketone bodies
- Proteins are broken down, leading to atrophy
- Amino acids, lactate and glycerol are all used to maintain a supply of glucose for the brain
- The brain begins to rely more upon ketone bodies
- Long-term starvation leads to brain malfunction
Metabolic Disorders
• Fundamental breakdown in metabolism tends to be fatal
– Few monogenic disorders in glycolysis, TCA or OxPhos
• Disorders of glycogen storage, gluconeogenesis and β-oxidation
– Life-limiting
– Often result in neurological deficits and encephalopathy
Encephalopathy
•Reduced gluconeogenesis, glycogen storage – Inadequate hepatic glucose production • Reduced fatty acid oxidation – Inadequate ketone body production – Inadequate energy for gluconeogenesis • Brain “runs out of energy” – Toxic metabolites accumulate in brain cells – Causes brain swelling and coma.
Obesity
- A consequence of the body being maintained in the ‘well fed’ state
- Excess calories stored as fat
- Obesity can confer resistance to insulin
- Ability of adipose tissue to store fat exceeded
- Fat accumulates in liver “ability to respond to insulin (Insulin resistance and hyperinsulinaemia)
- May lead to onset of type 2 diabetes
- Insulin does not switch off hepatic glucose production
- Mealtime hyperglycemia
Type 2 Diabetes Mellitus
• Patients are resistant to insulin and can not raise [insulin] sufficiently to promote glucose uptake in muscle or control glucose production by the liver
- Often a consequence of obesity
- Normal ↑[fructose 2,6-bisphosphate] and down- regulation of phosphoenolpyruvate carboxylase does not occur
- Translocation of GLUT4 to plasma membrane is decreased
- Ketoacidosis rarely develops, observed increase in VLDL (may be associated with the macroovascular effects)
atopic fat leads to
atopic fat leads to insulin resistance
Type 1 Diabetes Mellitus
• Complete absence of insulin production by pancreas
• Patients are effectively stuck in the ‘starved’ state
• Liver is always gluconeogenic & glycogenolytic -> hyperglycemia
• Uncontrolled proteolysis -> muscle wasting & provides substrates for gluconeogenesis
• Uncontrolled adipose tissue lipolysis increases plasma [fatty acid]
-> liver ketone body production, uncontrolled by insulin leading to ketoacidosis
lipolysis usually switched off by
insulin
What happens in fasting state
Plasma glucagon increased Plasma insulin decreased Plasma free fatty acids increased Blood ketone bodies increased Blood glucose decreased Liver glycogen decreased
