integration of metabolism

What is metabolism

Conversion of food into energy and body materials (like proteins, fats, DNA) that the body uses to build, repair, and function.

What is intermediary metabolism and what hormones control it

• intermeiary metabolism: both the breaking down and the stroage/building of molecules 

• insulin ⇒ only hypoglycemic hormone (reduced BGC)

• Glucagon ⇒ a hyperglycemic hormone (increases BGC)

•  Other opposing insulin hormones adrenaline (adrenal medulla) - increase fat breakdown 

• adrenaline (adrenal medulla) - increase fat breakdown 

• cortisol (adrenal cortex) - increase BGc

• growth hormone (anterior pituitary - increase fat use 

What do changes in the circulating concentrations of hormones allow the body to do

Store metabolic fuel when it's available and mobilise it in starvation, injury & stress

How is the rate of metabolism regulated

1. Substrate availability – high glucose = glycolysis; low glucose = fatty acid oxidation.

2. Allosteric regulation – a molecule binding to the allosteric site changing thens hape of the active site on enzymes which can either increase or decrease metabplism e.g. AMP activates PFK (↑ glycolysis).

3. Covalent modification – phosphorylation turns enzymes on/off.

4. Enzyme synthesis – diet changes enzyme amount (e.g. glucokinase ↑ with high carbs).

How does the location of the pancreatic islets help their function

- it's in close proximity to the gut, pancreas and liver which is useful as it produces glucagon & insulin

What do the Islets of Langerhans contain, how much, and what do they secrete

- beta cells (60-70%) secrete insulin

- alpha cells (30-40%) secrete glucagon

- delta cells (<10%) secrete somatostatin

What is insulin secretion stimulated and inhibited by

stimulated: 

• - rise in blood glucose

• - rise in amino acid concentration in the blood

• - gut hormones (e.g. secretin)

• - glucagon (it leads to insulin secretion providing fine tuning of blood glucose homeostasis)

What is glucagon secretion stimulated by

• low blood glucose

• low amino acid  concentration in blood

• adrenaline (glucagon secretion is stimulated in periods of stress regardless of blood glucose)

What is the structure of the insulin receptor

• has 2 subunits 

• each subunit is made of 1 aplha 1 beta subunit

• alpha is extra cellular 

• beta is intracellular

Why is the insulin receptor a catalytic receptor

Because it's also an enzyme, it has tyrosine kinase on it

What happens when insulin binds to the receptor extracellularly

The receptor phosphorylates itself and the 3 sites of receptor phosphorylation have different functions

How does the insulin receptor work and what are the functions of the three autophosphorylation sites

•  after insulin binds it phosphorylates itself making it activated

the function of the 3 sites are 

1. Nearest membrane: docking site for insulin receptor substrates.

2. Middle: activates kinase activity.

3. Furthest: growth-promoting functions.

What are the effects of insulin

• Promotes GLUT4 ( glucose transporter) transporters in muscle & fat.

• Brain, liver, RBCs, pancreas = insulin-independent GLUT.

• High insulin → receptor downregulation (negative feedback).

• Fast effects: glucose transport & enzyme activation.

• Slow effects: enzyme synthesis.

What are the metabolic effects of insulin

• promotes fuel storage after a meal

• promotes growth

• stimulates glycogen synthesis and storage

• stimulates fatty acid synthesis and storage from CHO when the intake exceeds glycogen storing capacity

• stimulates amino acid uptake and protein synthesis

What is the metabolic effect of adrenaline

mobilises fuel during stress

– stimulates glycogenolysis (muscle and liver)

– stimulates fatty acid release from adipose tissue

What is the metabolic effect of cortisol

provides for long term requirements

– stimulates amino acid mobilisation from muscle

– stimulates gluconeogenesis

– stimulates FA release from adipose tissue

Explain the fed state

• 2-4 hours after a meal 

• ↑ Insulin, ↓ Glucagon

• Key processes:

  • Digestion → absorption → blood: glucose, amino acids, chylomicrons

  • increase in blood Glucose, Amino acids, TAGs (from chylomicrons & VLDL)

• Liver:

  • Takes up glucose via GLUT2

  • Glycogen synthesis (storage)

  • Excess glucose → fatty acids → TAGs → VLDL

  • Amino acids → protein synthesis

• Muscle: takes up glucose (via insulin-activated GLUT4) → stores glycogen & makes protein

• Adipose tissue: glucose & fatty acids→ forms TAGs

• Brain & RBCs: use glucose (insulin-independent)

Overall summary:
→ Energy storage phase:

• Nutrients absorbed

• Insulin promotes storage of glycogen, fat, and protein

• Liver = main controller (receives nutrients first via hepatic portal vein)

Explain carbohydrate metabolism in the liver in the fed state

Glycolysis

• Glucokinase activated → converts glucose → glucose-6-phosphate.

• PFK and pyruvate kinase activated → push glycolysis forward to make pyruvate → acetyl-CoA → energy or fat.

• Glucokinase has high Km → only works when glucose is high, so it doesn’t take glucose needed by the brain.

Glycogen synthesis ON

• Glycogen synthase activated → stores glucose as glycogen.

• Glycogen phosphorylase (breakdown enzyme) is inhibited.

Gluconeogenesis OFF

• No need to make new glucose since blood glucose is already high.

• Insulin suppresses enzymes that drive gluconeogenesis.

Explain fat metabolism in the liver in the fed state

• insulin activates Fatty acid and Tryacylglycerol synthesis 

• Acetyl Co A carboxylase is activated turning acetyl co a to malonyl-co a (rate limiting step)

• malonyl Co A inhibits carnitine transferase which is normaly used to move fatty acids into mitchondria for breakdown 

• this means new fatty acids cant be broken down and are joined to glycerol to make triacylglycerols for storage or export 

Describe metabolism in muscle during the fed state

• after fed insulin concentration increase

• inslulin increases GLUT4 so more glucose transport into muscle i

• Glycogen synthetase is activated so more glucose stored as glycogen and phosphorylase inhibited in liver so less glycogen broken down 

• amino acid uptake is activated and protein synthesis is increased so msucles build more protein 

Describe metabolism in adipose tissue during the fed state- ( role of inulin)

1. Insulin activates lipoprotein lipase .

2. the lipoprotein lipase breaks down Tryacylglycerol into fatty acids 

3. the fatty acids enter the fat cells  and join together making new TAG s

4. insulin also increases Glucose transport is increased through GLUT4 ( glucose transport type 4) so more glucose can enetr the fat cell 

5. glucose turns into glycerol phosphate which is needed to help join fatty acids together makig tryacylglcerol 

6. Hormone sensitive lipase breaks down stored TAG into fatty acids but inslulin inhibits this so the fat isnt broken down and more fat is stored

Describe metabolism in the brain and erythrocytes

• Both rely on glucose. Fatty Acids cannot cross the blood-brain barrier and erythrocyte has no mitochondria

• Glucose transport into brain and erythrocyte wihtout insulin

• This allows use of glucose at both high and low concentrations of insulin

What happens to hormone, insulin and glucose concentrations during the post-absorptive state

• Blood glucose peaks after 1 hour and returns to normal by 2 hours.

• Glucose is removed for oxidation or stored as glycogen.

• Insulin levels fall while glucagon levels rise.

What is the body’s first response when fasting begins

• The liver maintains blood glucose around 4 mM by breaking down glycogen and beginning gluconeogenesis

• Adipose tissue becomes the main energy source by breaking down stored TAGs (triacylglycerols) into fatty acids and glycerol.

• Hormone-sensitive lipase is activated by glucagon and adrenaline, triggering the release of fatty acids from adipose tissue.

•  The released fatty acids are transported to the liver bound to albumin in the blood so they can be used for energy production.

Explain metabolism in the liver during the fasting state

• glycogen starts being used 

• Glucagon breaks down glycogen → glucose for brain + RBCs.

• Activates Hormone Sensitive Lipase breaking down  TAGs → fatty acids.

• Fatty acids go to liver → converted to ketone bodies → used by muscle.

after prelonged fasting

• gluconeogensis starts: Lactate from RBCs → glucose and Amino acids from muscle broken down → glucose.

• ↑ Urea production due to protein breakdown.

Explain glucose production by the liver

• glycogenolysis: glycogen -> glucose 

• gluconeogenesis happens from lactate,glycerol and amino acids 

What is a gluconeogenic precursor

any substance that can be turned into glucose by the liver.

Why fatty acids are not gluconeogenic

• Fatty acids are broken down into acetyl-CoA.

• But the reaction pyruvate → acetyl-CoA (done by pyruvate dehydrogenase) is irreversible — you can’t go back from acetyl-CoA to pyruvate or glucose.

• Therefore, fatty acids cannot become glucose — they can only make energy (ATP) or ketone bodies, not glucose.

Explain ketone body formation

• Fatty acid oxidation in liver produces high concentrations of acetyl-CoA. 

• When the TCA cycle cannot process all the acetyl-CoA, the excess is converted into ketone bodies. 

• The main ketone bodies are acetoacetate and beta-hydroxybutyrate, which are released into the bloodstream.

What fuels do different tissues primarily use for energy

• most tissues oxidise a mixture of Fatty Acids and Ketone Bodies

• erythrocyte uses glucose

• brain uses glucose and small amount Ketone Bodies

Explain metabolism in starvation

• Ketone bodies (from fat) become the main alternative fuel.

• Pancreas releases a little insulin in response to ketone bodies, which limits muscle protein breakdown and slows down fat breakdown (lipolysis).

• Muscle shifts to using fatty acids for energy instead of ketone bodies.

• Ketone body levels rise in the blood, while fatty acid levels plateau.

• Brain starts using more ketone bodies and less glucose 

• Gluconeogenesis decreases because less glucose is needed.

• Urea production falls since less protein is broken down.

• Ketone bodies are also partially recovered by the kidneys for reuse.

What do ketone bodies do apart from being used as fuel by the brain

• act on the pancreas to stimulate insulin release

• this limits muscle proteolysis limits adipose tissue lipolysis  (stopping the breakdown of them) so muscle tissue is conserved

What happens with ketone bodies that cannot happen in type 1 diabetes

• In starvation ketone bodies stimulate some insulin release

• In diabetes type 1 there is no insulin production 

Explain diabetes mellitus

• Type I or Insulin dependent diabetes mellitus (IDDM) - they cant make insulin

• Type II or non-insulin dependent diabetes mellitus (NIDDM)

Explain type 1 diabetes mellitus

• autoimmune disease, destroying of β cells

• start early

• symptoms: thirst, excessive urination, weight loss, muscle wasting,weakness

• charcteristics of diabetes 1 patients: are hyperglycaemia (high blood glucose due to lack of insulin) and ketoacidosis ( Fat breakdown → acetyl-CoA → ketone bodies accumulate → blood becomes acidic)

• treatment: needs insulin treatment

Explain type 2 diabetes mellitus

• usually later onset

• insulin resistance (target tissues non responsive

• association with diet and lifestyle e.g. obesity

• hyperglycaemia but usually no ketoacidosis

• often responds to diet and oral hypoglycaemic agents

Explain metabolism in diabetes

• normally insulin helps to store but in diabtes theres no insulin so  There is uncontrolled protein breakdown

• There is uncontrolled production in the liver - gluconeogenesis going out into the bloodstream and uncontrolled fatty acid production again

Compare the metabolic pattern in uncontrolled diabetes mellitus with starvation

• In starvation insulin is low -  in type 1 diabetes insulin is absent

• Glucagon acts normally for both 

• Ketone Bodies produced in starvation stimulate insulin release, but doesn`t in metabolism

• muscle protein is partially broken down in starvation but rapid brekadown diabetes 1