Metabolism and Homeostasis Flashcards
Circulating nutrients
Glucose Fatty acids (FA, FFA, NEFA) Amino acids Ketone bodies Lactate
Stored nutrients
Glycogen
Triglycerides (TG, TAG)
Body proteins
Critical glucose levels in hypoglycaemia
Hypoglycemia: ultimately coma and death
< ~2.5 mmol L-1 is critical
Long term damage in hyperglycaemia
Hyperglycemia: chronic exposure to raised glucose concentrations leads to protein damage via non-enzymatic glycation
Hyperglycemia is not an emergency in the same sense, in that high glucose concentrations will not kill you quickly. Nevertheless, persistent hyperglycemia, as in poorly-controlled diabetes mellitus, can have devastating effects. The complications of DM are due to the fact that glucose is a reactive molecule, and non-specific glycation reactions (i.e., not through controlled metabolic pathways) can damage proteins, such as those in the walls of blood vessels. This is what leads to the devastating vascular complications associated with DM
Concentration of glucose in blood plasma
5mM
60/40/20 rule
60% of body weight is water
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.
What are the 2 sources of plasma glucose?
Diet
Organs that can export glucose into circulatiion
What are the 2 phases of metabolism?
Absorptive and fasting
Storage of nutrients in absorptive phase is the…
Fed state
Release of nutrients in the fasting phase is the…
Postabsorptive phase (between meals)
What are insulin’s counter-regulatory hormones?
Insulin: promotes storage, decreases plasma glucose
Counter-regulatory hormones: promote nutrient release, raise plasma glucose:
- Glucagon
- Adrenaline (epinephrine)
- Cortisol, growth hormone (somatotrophin)
Hormone action when plasma glucose rises vs when it falls
When plasma glucose rises insulin is released and acts to decrease plasma glucose by promoting uptake and metabolism of glucose by tissue cells. Insulin itself is a signal of the fed state. It is THE anabolic hormone. It also promotes uptake and storage of fats and uptake of amino acids for protein synthesis.
When plasma glucose falls hormones that raise plasma glucose are released. These are called counter-regulatory hormones. They increase the release of stored nutrients that can be used as fuel for metabolism.
Glucagon and insulin are both pancreatic hormones and work together to maintain plasma glucose within limits.
Insulin’s main actions…
- 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)
Where is insulin synthesised and secreted?
Insulin is synthesized and secreted by the islets of Langerhans in the pancreas.
Main actions of glucagon
principal effects in liver
Stimulates hepatic glucose production
Main actions of adrenaline
(and sympathetic NS)
Stimulates hepatic glucose production
Stimulates lipolysis: release of FA from adipose tissue stores
Main actions of growth hormone
Stimulates hepatic glucose production, lipolysis
Main actions of 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 and what hormone stimulates them
Glycogenesis
Synthesis of glycogen from glucose
Lipogenesis
Synthesis of FA from acetyl CoA
Triglyceride synthesis
Esterification of FA for storage as TG
stimulated by INSULIN
How can glucose be returned to the circulation?
Glucose can be returned to the circulation in two ways: (1) from liver glycogen stores. However, these are good for hours rather than days. (2) gluconeogenesis. This occurs normally in tandem with glycogenolysis, using lactate, glycerol and AAs as substrates.
During starvation AAs are the only substrate, which have to be provided by breakdown of muscle protein. This is why humans and other mammals can survive many days of starvation without becoming severely hypoglycaemic. It also illustrates the priority given to glucose homeostasis.
Lipolysis
Lipolysis and beta-oxidation. Lipolysis is the breakdown of stored fat (TG). The resulting FFA can be transported into the mitochondria and used as fuel via the process of beta oxidation, which yields acetyl Co A, which can enter the TCA cycle for oxidative phosphorylation and ATP generation.
Ketogenesis
during fasting, FFA can be converted to ketone bodies via beta oxidation. Rather than entering the TCA cycle, the acetyl Co A produced is fed into ketogenesis. This enables the brain to utilize the energy stored as fat. The brain cannot directly metabolize FA, but it can metabolize ketone bodies, which can serve as a partial substitute for glucose.
How can metabolic pathways be mobilised to prevent hypoglycaemia?
(1) directly increase plasma glucose via release from liver glycogen stores (glycogenolysis) or de-novo synthesis (gluconeogenesis).
(2) Conserve plasma glucose by switching to other metabolic fuels where possible, preserving glucose for the brain (lipolysis, beta-oxidation, ketogenesis).
Metabolic response to hypoglycaemia
The immediate response is glucagon release from the pancreas. The fall in plasma glucose is detected in the pancreas itself, and the response is to turn up the rate of glucagon secretion, from pancreatic endocrine cells called alpha cells, to be considered later. Glucose is also sensed in the brainstem and hypothalamus, where a fall increases sympathetic outflow, which directly and indirectly stimulates hepatic glucose output.
Note that this is a –ve fb system. If plasma glucose falls the responses are such as to raise it. If plasma glucose rises these responses would be inhibited, reducing hepatic glucose output.
Note also that the –ve fb involves endocrine, neural, and neuroendocrine reflex loops. Purely endocrine: pancreas senses falling glucose, increases glucagon secretion, which in turn increases hepatic glucose output. Neuroendocrine reflex involves glucose sensing by neurons, sympathetic output to adrenal, stimulating adrenaline secretion.
Short term defences against hypoglycaemia
Glucagon
Epinephrine
Sympathetic NS
Medium term defences against hypoglycaemia
Ketogenesis: fat reserves can provide a partial substitute for glucose, sparing muscle tissue from the destruction that would otherwise be needed to provide amino acid substrates for gluconeogenesis
Long term defences against hypoglycaemia
Cortisol stimulates proteolysis to supply amino acid substrates for gluconeogenesis
What are the defences against hyperglycaemia?
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
Important to remember that inhibition of hepatic glucose production by insulin is needed to prevent hyperglycaemia.
Major insulin sensitive tissues
major insulin sensitive tissues: liver, skeletal muscle, adipose tissue.
Skeletal muscle (large mass) is most important in buffering rise in plasma glucose that would otherwise occur following carbohydrate ingestion. Liver is most important for controlling plasma glucose during fasting phase.
Possible fates of glucose in various cells/tissues
- Uptake. Via GLUT. This may be insulin-dependent (Glut4: muscle, adipose tissue) or insulin-independent, or constitutive (Glut1/2: liver, pancreas, brain, RBCs)
- Energy, glycolysis, TCA
- Beyond energy needs, glycogenesis
- Glycogen stores full, lipogenesis. In liver, the FFAs formed from lipogenesis are esterified into TGs and packaged into lipoprotein particles (VLDLs) for export and storage in adipose tissue.
Adipose tissue metabolic pathways
Triglycerides (TGs or TAGs) are transported in lipoprotein particles: chylomicrons, if absorbed from the gut, or very-low-density lipoproteins if exported from the liver.
In times of positive energy balance, insulin stimulates uptake (lipoprotein lipase, GLUT4). LPL, found on capillary endothelium, hydrolyses TGs into FFAs, so they can enter the adipocyte. Then they are re-esterified to TGs for storage. Glucose will diffuse into the adipocyte via the insulin-dependent GLUT4 channel. It’s then converted into FA via lipogenesis.
In times of negative energy balance, counter-regulatory hormones (mainly adrenalin) stimulate lipolysis and release of FFA to circulation, from where, bound to plasma proteins, they can be distributed to tissues for uptake and energy metabolism.
Muscle metabolic pathways
Glucose diffuses into muscle cells via GLUT4, which are only present at low density in basal conditions. There are two ways to increase GLUT4 density in the muscle cell membrane: (1) presence of insulin and (2) the process of muscle contraction (i.e., exercise – hence its beneficial effect). Note that during exercise insulin levels normally decrease, but the contraction induced increase in GLUT4 allows continued glucose uptake. In resting muscle most of the glucose is stored as glycogen. Note also that this stored glycogen can only be used for later energy use in the muscle fibre, since muscle lacks the phosphatase enzyme to convert G-6-P back to glucose for export to the circulation.
Muscle can also oxidise FFAs for energy. These may either circulating FFAs (bound to plasma albumin following release from adipose tissue TG stores), or circulating TGs in lipoprotein particles. In the latter case the enzyme LPL releases the FFA from the TG for uptake. The ability of muscle to oxidise FFA is important for endurance exercise and for prolonged fasting, where it serves to spare glucose for the brain.
Liver glucose and amino acid metabolism
“The strategy of amino acid degradation is to transform the carbon skeletons into major metabolic intermediates that can be converted into glucose or oxidized by the citric acid cycle. ” (Berg, Tymoczko & Stryer, 2002, Biochemistry). Ketogenic, converted into Ac CoA or Aceto-AcCoA, can further give rise to ketone bodies or fatty acids. Glucogenic amino acids are converted into pyruvate or citric acid cycle intermediates. Net synthesis of glucose from these is possible, via phosphoenol pyruvate. Oxaloacetate is converted to phosphoenolpyruvate (PEP) by the enzyme PEP carboxykinase (PEPCK).
Take-home: with high insulin/low glucagon glucose metabolism is directed towards glycogen storage; when these are full glucose enters glycolysis and the resulting Acetyl CoA is fed into lipogenesis. With low insulin/high glucagon AAs are diverted away from protein synthesis into gluconeogenesis (multiple pathways for individual AAs, via pyruvate and/or TCA intermediates). A few AAs can be directly converted to Acetyl CoA (ketogenic AAs); these are fed into ketogenesis.
Liver fatty acid metabolism
B oxidation. FA converted to fatty acyl-CoA, then acetyl CoA (in mitochondria – not shown). Acetyl CoA can be used to generate ATP via TCA. However, if in excess, acetyl CoA goes instead into ketogenesis as shown here.
Glucose also converted to acetyl CoA. If in excess (of requirement for ATP generation) and in presence of insulin, acetyl CoA goes instead into lipogenesis, back to FAs (which will then be esterified to form TGs). The first intermediate in lipogenesis is malonyl CoA, which then goes through further intermediates to produce FAs. Malonyl CoA also has the effect of inhibiting CPT, which is required to get fatty acyl-CoA into mitochondria for oxidation (or ketogenesis). Thus, insulin indirectly inhibits B-oxidation (and ketogenesis).
Insulin and glucagon thus partition liver FA metabolism between lipogenesis and ketogenesis. Stimulation of lipogenesis (insulin) prevents FA entry to mitochondria, inhibiting beta oxidation. In absence of insulin, acetyl CoA not converted to malonyl CoA, FA can enter mitochondria and Acetyl CoA shuttled into ketogenesis.
Importance of ketogenesis (synthesis of acetoacetate and hydroxybutyrate (ketone bodies) from Acetyl Co A). Ketone bodies exported from liver are freely transported in circulation, reconverted back to acetyl CoA, in brain and other tissues, and metabolised in TCA cycle for energy (thus sparing glucose).
CPT: carnitine-palmitoyl transferase
What happens in diabetic ketoacidosis?
DKA is the terminal event in uncontrolled T1DM.
In absence of insulin, gluconeogenesis and beta oxidation are running unopposed. In the liver, oxidation of fatty acids and gluconeogenesis can compete for substrates
Beta-oxidation of FA produces acetyl Co A, which combines with oxaloacetate (OAA) to form citrate, entering the TCA cycle for complete oxidative phosphorylation
However, OAA is also used as a substrate in gluconeogenesis
In absence of sufficient OAA, acetyl Co A builds up and is funnelled into ketogenesis
Ketone bodies are acids: excess in circulation overwhelm buffering capacity of blood, leading to metabolic acidosis.
Homeostasis
the ability of living organisms to maintain a steady and uniform internal environment - to allow the normal functioning of the systems.
Aims of body fluid homeostasis
maintain a constant blood volume, a constant blood pressure, maintain tonicity, and maintain the composition of plasma & interstitial fluid.
What is osmolality?
Remember that osmosis is the passive/simple diffusion of water across a semi-permeable membrane.
Osmolality - the number of osmoles of a solute in a kg of solvent - measured in mOsm/kg or mmol/kg
Osmotic pressure - the pressure needed to stop osmosis.
Osmole - the osmosis caused by a single mole of solute.
Osmolality - the number of osmoles of a solute in a kg of solvent - measured in mOsm/kg or mmol/kg
Osmolarity - number of osmoles of a solute in a litre of solvent - measured in mOsm/L
(normal plasma osmolality 290 mOsm/kg)
What is tonicity?
Tonicity refers to the relative solute concentration between two solutions separated by a semi-permeable membrane. Tonicity is the effective osmolalityand is equal to the sum of the concentrations of the solutes which have the capacity to exert an osmotic force across the membrane. Tends to refer to non permeable solutes
Water moves by osmosis (diffusion of water across a semi-permeable membrane) from an area of low solute concentration (hypotonic) to an area of higher solute concentration (hypertonic) until the two solutions are isotonic. So water moves towards areas of high salt or sugar concentrations.
Where is the water?
[batman voice] wHERE IS SHE????
Total body water is around 60% of body weight – or around 42 L of a 70 kg human.
The body then has two main compartments – in the cells (intracellular fluid or ICF) – containing 2/3 of the water (or around 28/42 L), and outside the cells (extracellular fluid or ECF) –containing the remaining 1/3 of the water (or around 14/42 L)
The ECF compartment is then divided into the Interstitial fluid (ISF) – containing 2/3 of the ECF (around 9L) and the Plasma and Lymphatic systems – containing 1/3 of the ECF (or around 5L)
Fluid depletion
Loss of isotonic fluid
- Sodium and water
OR
Loss of water
- dehydration
CASE:
A 78 year old female was found collapsed at home. On arrival in the accident and emergency department the following blood results were obtained.
What’s happened?
The patient has become very decompensated – and has lost free water – they are dehydrated – leading to an increase in the sodium concentration, as well as of other solutes in the blood. Potassium is predominantly intracellular, so it remains in the normal range.
What is the response to hypertonicity?
Conservation of water
gatekeep. gaslight. girlboss
How do we conserve water in response to hypertonicity?
First, osmoreceptors in the anteroventral third of the hypothalamus detect hypertonicity, stimulating thirst centres in the brain – so that we drink, and also sends signals to the posterior pituitary gland to secrete vasopressin/ADH, and return the plasma osmolality to normal.
Then to kidney: Blood passes from the renal artery into afferent arterioles into the glomerulus, where it is filtered by the surrounding bowman’s capsule (and together they form the renal capsule). Blood then passes out of the efferent arteriole, and follows the tubules into the renal medulla, and onward to the renal vein.
The plasma filtrate passes into the urinary space, into the PCT, the descending loop of henle, deep in the medulla, then passes out of the ascending loop of henle to the DCT – and onward to the collecting tubules – before passing down the collecting ducts to the renal pelvis, and the ureters to the bladder.
How is urine concentrated?
done in the renal tubules – particularly PCT, DCT, the loop of henle, and the collecting tubules.
tissue osmolality in the interstitium of the cortex and medulla of the kidney, and the corresponding urine osmolality.
As urine passes down the descending loop of henle, water diffuses passively out of the tubule into the interstitium, leading to an increase in osmolality of the urine. As the urine passes into up the ascending loop of henle, sodium is then actively transported into the interstitium, so the osmolality of the urine decreases, with both sodium and water retained.
As urine then passes into the collecting tubules, in the presence of AVP/ADH, water channels in the collecting tubules open, allowing free water passage from the collecting tubules into the interstitium, so water is resorbed by the body, and the resulting urine is concentrated, with the resulting urine osmolality that has gone from 285 mosm/kg at the PCT to 1200 mosmol/kg in the urine.
Tubular reabsorption
In the renal tubules, the body filters around 180 litres of plasma per day, but just 0.5-3L of urine are produced, so that’s around 98-99% resorption.. The normal kidney is similarly able to conserve the vast majority of the salt, chloride, bicarbonate and potassium it filters, but excretes most of the urea (waste product) – which is what we want..
How does the body maintain blood pressure and blood volume?
Baroreceptor response
Baroreceptors in carotid body, bifurcation of internal + external carotid artery and aortic arch.
There are also low pressure volume receptors in the large systemic veins, pulmonary vessels and walls of the right atrium and ventricles of the heart – the atrial volume receptors. These low pressure baroreceptors are involved with the regulation of blood volume, and hence the mean pressure of the system, in particular on the venous side, where most blood is held.
Fall in BP has what effect on vasopressin?
a reduction in blood pressure or blood volume is associated with an increase in plasma AVP/ADH concentration, increases in plasma osmolality are also associated with increased AVP levels.
Juxtaglomerular apparatus
In the nephron, blood passes from the afferent arteriole, into the glomerulus, and then into the efferent arteriole. Here, the juxtaglomerular apparatus is a specialized structure formed from the DCT and the glomerular afferent arteriole.
It is made up of specialized epithelial cells - part of the DCT, called the macula densa, that detects the sodium concentration of fluid in the tubule, and the juxtaglomerular cells – derived from smooth muscle cells of the afferent arteriole, which are highly innervated, and secrete a hormone called renin in response to a drop in blood pressure in the arteriole.
So a fall in blood pressure, a fall in tubular sodium concentration, and sympathetic nerve stimulation can all lead to secretion of this renin.
RAAAAAAAAAAAAAAAAAAAAS
The Renin-Angiotensin-Aldosterone system is triggered thus – renal hypoperfusion leads to renin secretion by the JG cells, leading to angiotensinogen conversion to angiotensin-1 in the liver. Angiotensin converting enzyme, produced in both the liver and the lung, converts angiotensin-1 to angiotensin 2, which is a potent vasoconstrictor, leading to increased systemic blood pressure, and also triggers thirst, and aldosterone secretion by the adrenal gland, leading to salt and water retention, and increased blood pressure. As you learn more about renal physiology, you will note a number of blood pressure or antihypertensive agents that target different parts of this pathway.
Raised aldosterone levels mean what for sodium?
Aldosterone increases sodium reabsorption
Raised Aldosterone levels in response to low renal perfusion, and downstream from renin excretion, leads to increased active sodium reabsorption at the DCT, and increased water retention, and hence increased blood pressure.
ANP impact on sodium levels?
Reduced sodium reabsorption
increased blood volume can stimulate stretch receptors in the atria and ventricles to secrete ANP, which leads to natriuresis – reduced sodium reabsorption at the PCT and DCT; water follows the sodium, increasing diuresis, and hence lowering blood pressure
