Endocrine Control of Metabolism Flashcards
How can different molecules be used to generate ATP?
There are a variety of molecules that the body can use as fuel
ATP is used in energy metabolism
Anything that can be converted into acetyl CoA can be used in the TCA cycle to generate ATP
Fatty acids by beta-oxidation
In the absence of oxygen ATP can be created via glycolysis
Lactate can be converted to pyruvate and then Acetyl CoA
And ketone bodies can be converted to Acetyl CoA an vice versa depending on the demand
What is the difference between stored and circulating nutrients?
Circulating: Glucose Fatty acids (FA, FFA, Non esterified fatty acids) Amino acids Ketone bodies Lactate Stored: Glycogen Triglycerides (TG, TAG)- the storage form of FA Body proteins
Why is plasma glucose kept constant?
Plasma glucose concentration is remarkably constant around 5 mmol L-1
Brain depends on glucose metabolism
Hypoglycemia: ultimately coma and death
< ~2.5 mmol L-1 is critical
Hyperglycemia: chronic exposure to raised glucose concentrations leads to protein damage via non-enzymatic glycation
How much glucose is used up?
Remember the 60/40/20 rule?
60% of body weight is water (for males, females more 50)
40% of body weight is intracellular water
20% of body weight is extracellular water
70 kg male, 14 L extracellular water gives total of 14x5 = 70 mmol glucose.
How long will this last?
The brain will use the 70 mmol glucose in 2 hours
The skeletal muscles would use even more
Where does the constant supply circulating glucose come from?
Two sources of plasma glucose
Diet
Organs that can export glucose into the circulation
Diet could provide up to 3000 mmol day-1
What prevents plasma glucose surging after a meal and plummeting between meals?
-Hormones regulate the integration of carbohydrate, fat and protein metabolism to maintain constant plasma glucose levels.
What are the two phases of metabolism?
Two phases of metabolism: absorptive and fasting
Storage of nutrients in the absorptive phase (fed state)
Release of nutrients in the fasting phase (between meals, also called postabsorptive phase)
Hormones regulate metabolic pathways promoting energy storage or release
Insulin: promotes storage, decreases plasma glucose
Counter-regulatory hormones: promote nutrient release, raise plasma glucose
Glucagon released by the endocrine cells of the pancreas
Adrenaline (epinephrine)
Cortisol, growth hormone (somatotrophin)
What are the major effects of insulin?
Stimulates nutrient storage:
Uptake of glucose by skeletal muscle, adipose and other tissues
Glycogen synthesis in liver, skeletal muscle,
Uptake of FA and amino acids
Inhibits nutrient release:
Inhibits release of glucose from liver (hepatic glucose production)
Inhibits fat and protein breakdown (lipolysis and proteolysis)
What are the major effects of counter-regulatory hormones?
Glucagon: principal effects in liver
Stimulates hepatic glucose production
Adrenaline (and sympathetic NS)
Stimulates hepatic glucose production
Stimulates lipolysis: release of FA from adipose tissue stores
Growth hormone
Stimulates hepatic glucose production, lipolysis
Cortisol
Stimulates hepatic glucose production, lipolysis
Stimulates proteolysis: release of amino acids from body proteins (skeletal muscle)
What are the metabolic pathways serving energy storage?
When energy balance is positive and we need to lower plasma glucose Glycogenesis -Synthesis of glycogen from glucose Lipogenesis -Synthesis of FA from acetyl CoA Triglyceride synthesis -Esterification of FA for storage as TG
What are the metabolic pathways serving energy release?
When energy balance is negative, when we need plasma glucose to stop falling
Glycogenolysis
-Release of glucose from glycogen stores
Gluconeogenesis
-De novo synthesis of glucose from non-carbohydrate substrates
These two pathways provide glucose directly while the bottom three spare glucose by switching to alternative energy
Lipolysis
-Release of FA from TG breakdown
Beta-oxidation
-FA to Acetyl Co A where they then enter the TCA cycle
-If there is no need the Acetyl CoA turn to ketone bodies
Ketogenesis
-Production of ketone bodies from Acetyl CoA
What are the metabolic responses to hypoglycaemia?
If the glucose concentration drops the drop is detected by several sensors
There’s the pancreas itself, specifically the endocrine pancreas made by cells called the Islets of Langerhans
If there is a fall in plasma glucose the response is to increase glucagon secretion which will stimulate the liver to increase hepatic glucose production
As well as this we have glucose sensing neurons in the CNS, in the brain stem.
Again, if the glucose concentration happens to fall the CNS increases sympathetic outflow
The sympathetic outflow can directly stimulate the liver to increase gluconeogenesis
It can also directly stimulate the endocrine pancreas to increase alpha cells secretion of glucagon
There is also a neuroendocrine reflex component, where a fall in plasma glucose activate the sympathetic outflow, which activates the neuroendocrine cells of the adrenal medulla
The chromaffin cells release adrenaline, which in the circulation stimulates pancreatic alpha cells and the liver
What are the short-term and long-term defences against hypoglycaemia?
In the short-term:
Glucagon
Epinephrine
Sympathetic NS
In the medium-term(e.g. with prolonged fasting (12 to 24hrs)):
Ketogenesis: fat reserves can provides a partial substitute for glucose, sparing muscle tissue from the destruction that would otherwise be needed to provide amino acid substrates for gluconeogenesis
In the long-term (up to like 30 days):
Cortisol stimulates proteolysis to supply amino acid substrates for gluconeogenesis
What are the defences against hyperglycaemia?
This is not an immediate life threatening condition like hypoglycaemia
Insulin:
Stimulates glucose uptake by tissues
Inhibits hepatic glucose production
Lack of insulin action leads to hyperglycaemia, diabetes mellitus:
Type 1 DM: insulin deficiency
Type 2 DM: insulin insufficiency combined with insulin resistance
What are the flexible uses of glucose?
Glucose has to be taken up into the tissue cells via glucose transporters-GLUTs, some present in the membrane while others are insulin dependent
Glucose is immediately metabolised to gluos-6-phosphate
Glucose can be used by the cells of the tissue to meet the immediate need of energy
It does this by going through glycolysis then the TCA cycle as pyruvate
Glucose can be stored as glycogen- called glycogenesis (reverse is glycogenolysis)
If glycogen stores are full then glucose undergoes lipogenesis (instead of pyruvate going into the TCA cycle) it is stored into fat and taken to adipose tissue (lipolysis is the reverse)
Protein can sometimes be converted to pyruvate then to G6P via glycolysis
What are the major metabolic pathways in adipose tissue?
Adipose tissue functions to store fat for energy use and release it when needed
The stored fat is in the form of triglycerides
Triglycerides are not water soluble so lipids have to be packaged as lipoprotein particles
TGs as either chylomicrons or VLDL
Getting the TG into from the capillary into the adipocyte involves and enzyme called lipoprotein lipase
The enzyme breaks the contained triglyceride back down into free fatty acids which can then be transported across the adipocyte membrane where the fatty acids are then re-esterified back to TGs for storage
This enzyme is stimulated by insulin
Adipocytes also express GLUT4 which is insulin dependent (wont be there when insulin is not there)
So glucose itself can be taken up by the adipocyte where it will undergo lipogenesis into FAs and then esterification to TG form
When energy balance is negative, the processes are reversed
The stored TGs are broken down into FFAs
An important enzyme involved in this is called hormone-sensitive lipase which is stimulated by adrenaline and noradrenaline
This will release free fatty acids and glycerol into circulation where they might undergo beta-oxidation or ketogenesis
