Metabolism Flashcards
Define Catabolism
Break down molecules to release energy and reducing power
Define Anabolism
Uses energy, reducing power and raw materials to make molecules for growth and maintenance.
What are the main components of daily energy expenditure?
Basal Metabolic Rate
Voluntary Physical Exercise
Diet induced thermogenesis, processing the food we eat. (+10% of BMR and VPE)
What is the average daily expenditure for males and females?
M: 70kg. 12,000 kJ.
F: 58kg, 9500kJ.
Why are fats essential in the diet?
Produce 2.2 times the amount of energy as same mass of protein and carbs. But not essential for energy source.
Needed to absorb fat soluble vitamins.
Essential fatty acids, linoleic acids are structural components of cell membranes and precursors of important regulatory molecules.
What are the fat soluble vitamins?
A
D
E
K
Why are proteins essential in the diet?
Needed to synthesise essential N containing compounds: creatine, nucleotides, haem
Needed to provide essential amino acids which can not be synthesised in the body.
Needed to maintain nitrogen balance, 35g excreted as urea per day.
Why are carbohydrates essential in the diet?
The major energy containing component in the diet. Glucose required constantly by tissues such as the brain and RBCs.
Why is water essential in the diet?
Body weight is 50-60% water.
2.5l of water is lost per day in the urine, expired air, faeces.
Some water is produced by cellular metabolism, the rest is replaced by drinking.
Why is dietary fibre essential?
Non digestible plant material is needed for normal bowel function, for example cellulose.
Why are minerals and vitamins essential in the diet?
What is malnutrition?
Any condition caused by an inbalance between what an individual eats, and what an individual requires to maintain health
What causes weight loss?
Loss of subcutaeous fat and muscle wasting
What are common effects of starvation?
Cold
Weakness
Infections of the GI tract and lungs
What is marasmus caused by?
Protein energy deficiency
What are some signs of marasmus?
Emaciated, muscle wasting, loss of body fat, NO OEDEMA, thin dry hair, diarrhoea, anaemia possibly
What is kwashiokor caused by?
Protein deficiency but enough carbohydrate in the diet
What are some signs of kwashiokor?
Lethargic, anorexic
Distended abdomen: hepatomegaly, ascites (accumulation of fluid in peritoneum), oedema
Low serum albumin
Anaemia
Why is oedema present in Kwashiokor sufferers?
Protein deficiency but enough carbohydrate for energy, so no proteolysis for gluconeogenesis. Therefore protein not replaced in the blood, low serum albumin creating a low oncotic pressure. Draws water out into tissues.
How is BMI calculated?
weight (kg) / height2 (M)
How are BMI values interpreted?
Underweight: <18.5
Desirable: 18.5 - 24.9
Overweight: 25- 29.9
Obese: 30- 34.9
Severely obese: >35
What is an alternative to BMI?
Waist hip ratio, circumference
Define Obesity
Excess body fat has accumulated to the extent that it may have an adverse effect on health. BMI is greater than 30
What factors contribute to obesity?
Mainly: difference between energy intake and expenditure
Genetics
Drug therapy
Endocrine disorders
What are the increased health risks associated with obesity?
Hypertension
Heart disease
Stroke
Type 2 Diabetes Mellitus
Some cancers
Gall bladder disease
Osteoarthiritis
What is homeostasis?
The maintenance of a stable internal environment within set limits, in a dynamic equilibrium.
Generally, what causes disease?
A failure to maintain homeostasis.
What is cell metabolism?
A highly integrated network of chemical reactions that occur within cells.
What do cells metabolise nutrients to provide? 4 key things
- Energy for cell function and biosynthesis
- Building block molecules
- Organic precursor molecules
- Biosynthetic reducing power
What are 3 origins of cell nutrients?
The diet
Synthesis in the body from precursors
Body tissue storage
What are 5 fates of cell nutrients?
Degradation to release energy in all tissues
Synthesis of cell components, all except RBCs
Storage: liver, adipose, skeletal muscle
Interconversion to other nutrients
Excretion
What is catabolism?
The breakdown of larger molecules into smaller ones
What are features of catabolism?
Exergonic, oxidative (releases H atoms and reducing power), produces intermediary metabolites
What is anabolism?
Smaller molecules being built up into larger ones from intermediary metabolites
What are features of anabolism?
Uses energy released from catabolism (endergonic), reductive (uses H released in catabolism, uses intermediary metabolites.
Why do cells need a continuous supply of energy?
The ATP/ADP cycle releases energy by oxidation for
movement
membrane transport
biosynthesis
growth and repair
Why are phosphorylated compounds good for providing energy?
Many of them have a high energy of hydrolysis
When [ATP] is high, what pathways are activated?
Anabolic
When [ATP] is low, and [ADP] and [AMP] are high, what pathways are activated?
Catabolic
What is creatine phosphate used for?
When is it created?
What is it important for?
A high energy fuel store that can be used immediately when ATP is low
It is created when ATP levels are high
Sudden vigorous muscle activity
What enzyme catalyses the formation of creatine phosphate from creatine and ATP?
Creatine Kinase
What is the daily excretion of creatinine proportional to?
Skeletal muscle mass
What is an oxidative reaction?
What are the products transferred to?
When electrons are removed (hydrogen atoms - H+ and e-)
The products are transferred to carrier molecules
What are carriers?
Complex molecules derived from vitamins (B), which are reduced by the addition of 2 H atoms
What are the reduced forms of these oxidised carriers?
NAD+
NADP+
FAD
NADH + H+
NADPH + H+
FAD2H
Catabolic pathways are generally activated when…
The concentration of ATP falls and the concentration of ADP and AMP increases
Anabolic pathways tend to be activated when…
The concentration of ATP rises
What are two important properties of sugars? explain
Hydrophilic: do not readily cross cell membranes
Partially oxidised: need less oxygen thsn fatty acids for complete oxidation
What sort of signal is ATP and why?
A high energy signal
It signifies that the cell has adequate energy for its immediate needs
What sort of signal is ADP and AMP.
Low energy, need more
Give 3 high energy signals (not ATP)
NADPH, NADH, FAD2H
Give 3 low energy signals (not AMP/ADP)
NAD+. NADP+ and FAD
What is the general formula of a carbohydrate?
C(H20)n
What sort of chemical groups do they contain?
Keto C=O
Aldehyde -CHO
Hydroxyl -OH
What are the most common forms of monosaccharides?
How many C atoms can a monosaccharide have?
Triose, pentose, hexose
3Cs to 9Cs
Why do monosaccharides exist mainly as rings?
The aldehyde or ketone group reacts with a hydroxyl group
What is the structure of alpha glucose?
What is different in beta glucose?
What is the chiral carbon in an isomer of aldose (C1) or of a ketose (C2) called?
Anomeric C atom
What is a dissacharide?
Two monosaccharides joined together by a condensation reaction eliminating a molecule of water and forming an O-glycosidic bond.
What are the major dietary dissacharides and what monosaccharides are they made from?
Lactose: galactose and glucose
Maltose: glucose and glucose
Sucrose: fructose and glucose
When is a dissacharide non reducing?
If the aldo and keto groups from both molecules are involved in forming the glycosidic bond
What is a polysccharide?
A polymer of monosaccharide units linked by glycosidic bonds
What type of polysaccharide are most?
Homo polymers
What are 3 glucose polysaccharides?
Glycogen
Starch
Cellulose
Properties of glycogen
Glucose polymer
Animals
Alpha 1,4 and alpha 1.6 glycosidic bonds
Highly branched
Stored in the liver and skeletal muscle
Properties of Starch
Glucose polymer
Found in plants
Amylose, alpha 1, 4 links
Amylopectin, alpha 1,4 and alpha 1.6
Hydrolysed to maltose and glucose in GI system
Properties of cellulose
Glucose polymer
Plant cell walls, structural role
Beta 1,4 linkages
Linear polymer
Needed in human diet as fibre for good GI function
Humans can not digest, as they do not have the required enzymes to process the beta 1,4 links
What are the dietary polysaccharides and how are they broken down?
What products are they broken down to?
Glycogen and starch, by glycosidase enzymes
Glucose, maltose, dextrins (smaller polysaccharides)
What enzymes break down dietary polysaccharides and where?
Salivary amylase in the buccal cavity
Pancreatic amylase in the duodenum
Where does digestion of dietary disaccharides and dextrins occur?
The duodenum and jejunum
Where are glycosidase enzymes found that break down dissacharides, and what are they made from?
Found on brushborder membrane of epthelial cells of duodenum and jejunum
They are large glycoprotein complexes
What are the main glycosidase enzymes which break down dietary dissacharides?
Lactase
Isomaltase/sucrase
Glycoamylase
What condition is low lactase activity associated with?
Lactose intolerance
Can not digest the lactose in milk products properly
Explain the symptoms of lactose intolerance and why they occur.
Lactose persists in the colon
As lactase activity is low
Lactose has an osmotic effect drawing water into the lumen
This causes diarrhoea
Bacteria in the colon break down lactose
This produces gases such as CO2, H2, and CH4
This causes bloating and discomfort
How are monosaccharides transported into the blood from the GI tract?
Active transport into the epithelial cells of the intestine
Facilitated diffusion from epithelium to blood
Uses GLUT transport proteins, which can be hormonally controlled
What monosaccharide to all tissues metabolise?
Glucose
Where is the main site of galactose and fructose metabolism?
Liver
What is the concentration of glucose in the blood regulated at?
5mM
What is the glucose requirement of the body per day?
180g per day
40g in tissues with an absolute requirement
140g per day in the CNS
Variable amounts needed in other tissues for specific functions, eg glycerol phosphate for TAGs in adipose is provided by glucose metabolism
What tissues have an absolute requirement for glucose?
Red blood cells
White blood cells
Kidney medulla
Lens of the eye
CNS prefers glucose but can use ketone bodies too
Describe features of glycolysis
Central pathway in sugar catabolism, exergonic
10 enzyme catalysed steps
Cytoplasm
Active in all tissues
Can be anaerobic
Start and end products either C3 or C6
No loss of CO2
What are the functions of glycoslysis?
Generate ATP, 2 net (4 produced, 2 used)
Generate NADH from NAD+, reduce
Building block molecules for anabolism
Useful C3 intermediates
Produce pyruvate by oxidising glucose
Substrate level phosphorylation
Which steps of glycolysis are irreversible?
Which enzymes catalyse each step?
1, 3 and 10
Step 1: Hexokinase in muscle, Glucokinase in the liver
Step 3: Phosphofructakinase
Step 10: Pyruvate Kinase
What reaction does hexokinase catalyse?
Glucose to glucose 6 phosphate.
Uses ATP
Makes the sugar ionic so it can not cross the plasma membrane, increases reactivity
What reaction does phosphofructokinase catalyse?
Conversion of fructose 6 phosphate, to fructose 1, 6 bisphosphate
Committing step, irreversible
Which steps of glycolysis make ATP?
7 and 10
through substrate level phosphorylation
Which step of glycolysis makes NADH?
6
What reaction does pyruvate kinase catalyse?
Phosphoenolpyruvate to pyruvate, producing ATP x2
irreversible
What are important intermediates from glycolysis?
Glycerol phosphate: from DHAP, needed for glycerol synthesis
2, 3 BPG: Hb regulator, from 1, 3 BPG in glycolysis
What is produced in glycolysis in anaerobic conditions?
In anaerobic or cells without mitochondria
Pyruvate is reduced to lactate by lactate dehyrdogenase
Produces NAD+
Produces ATP
How is lactate disposed of?
Released into circulation
Converted back to pyruvate and oxidised to CO2 in heart
Or converted to glucose in the liver
What are the levels of lactate in the plasma?
1mM
Lactate production = utilisation
Describe the differences between hyperlactaemia and lactic acidosis
Hyperlactaemia: 2mM - 5mM in the blood. Below renal threshold, no change in blood pH, within buffering capacity.
Lactic acidosis: above 5mM, above renal threshold, blood pH lowered.
Where does galactose metabolism take place?
What sort of enzymes?
Liver
Soluble enzymes
How is fructose metabolised?
By soluble enzymes in the liver
Fructose to fructose 1 phosphate
then to 2 glyceraldehyde 3 phosphate/DHAP which feeds into glycolysis
Clinical problems with fructose metabolism
Fructokinase missing, causes fructose to build up in urine, essential fructosuria, no clinical signs
Frctos intolerance, aldolase missing, fructose 1 phosphate accumulated inliver, damage, treatment, remove fructose from diet
What enzymes are involved in galactose metabolism, and what to they do?
Galactokinase, galactose to galactose 1 phosphate
Galactose 1 phosphate uridyl transferase, to glucose 1 phosphate, which can transfer into glycolysis
What is galactosaemia?
Individuals are unable to utrilise galactose obtained in the diet because of a lack of galactokinase of glactose 1 phosphate uridyl transferase
What are the two types of galactosaemia, how common are they and which is more serious?
Either galactokinase or galactose 1 phospahte uridyl transferse can be deficient.
Loss of transferase is more common
Loss of transferase is more serious because galactose 1 phosphate accumulates which is toxic to the liver, kidney, brain as does galactose.
What happens when galactose builds up in tissues?
Galactose is reduced to galactitol by aldose reductase, which depletes some tissues of NADPH.
Explain why lack of NADPH caused by galactosaemia causes problems in the lense of the eye.
NADPH is needed in the eye to keep cysteine residues in proteins reduced.
If there is a lack of NADPH, S-S bonds form, cross linking proteins, damaging the len structure and causing cataracts.
Non enzymatic glycosylation of lens proteins due to high galactose concentration - may also contribute to cataracts
Accumulation of galactose and galactitol in the eye leads to increased intraocular pressure, may cause glaucoma
What is the treatment for galactosaemia?
No lactose in diet
Should be detected early for effective management. Heel prick test
What are the main functions of the pentose phosphate pathway?
PRODUCE NADPH IN THE CYTOPLASM
PRODUCE C5 SUGARS FOR NUCLEOTIDES
Reducing power for anabolic processes like lipid synthesis
In RBCs maintain free -SH groups on cysteine residues
Detoxification
In what tissues is the pentose phosphate pathway important?
Liver
Red blood cells
Adipose
Dividing tissues
What are the enzymes in the pentose phosphate pathway and what do they do?
Glucose 6 phosphate to 5C sugar phosphates by glucose 6 phosphate dehydrogenase and 6 phosphogluconte dehydrogenase. This reaction produces NADPH and CO2.
Any unused C5 sugar phosphates back to glycolysis.
What occurs in glucose 6 phosphate dehydrogenase deficiency?
What sort of inheritance?
Reduced activity of this rate limiting enzyme. Low levels of NADPH.
X linked recessive , point mutation.
What occurs in red blood cells in an individual with G6PDH deficiency?
Lack of NADPH in cells
Can not maintain free -SH cysteine residues
Disulphide bridges form.
Hb and other proteins cross linked
Heinz bodies, insoluble aggregates. GSSG (glutathione)
Premature destruction of RBCs, haemolysis. Jaundice etc complications
Acute haemolytic episodes from antimalarials, oxidants
What enzyme converts pyruvate to Acetyl - CoA?
Pyruvate dehyrdogenase, a multi enxume complex.
Where does pyruvate dehyrdrogenase work?
Mitochondrial matrix
What are features of the pyruvate dehydrogenase reaction?
Irreversible, can’t convert acetyl coA back to pyruvate for gluconeogenesis
Loss of CO2
What are some control mechanisms that PDH reaction is subject to?
Under certain conditions acetyl coA from B oxidation of FAs is used rather than from glucose in stage 3 catabolism, acetyl coA allosterically inhibits PDH
Reaction is energy sensitive: ATP/NADH inhibit, ADP promotes allosterically
Activated when there is a lot of glucose, insulin activates by dephosphorylating PDH
What is the TCA cycle?
A central pathway in the metabolism of sugars, fatty acids, ketone bodies, alcohol and aminoacids.
What are the anabolic functions of the TCA cycle?
C4 intermediates: Haem and glucose synthesis, non essential amino acids (from succinate, fumarate, oxaloacetate)
C5 intermediates: non essential amino acids (from alpha ketoglutarate)
C6 intermediates: fatty acids (from citrate)
What are the key features of the TCA cycle?
Oxidative
Produces NADH and FAD2H
Needs NAD+, FAD and oxaloacetate
Main function is to break C-C bond in acetate and oxidise the C atoms to CO2
Some ATP produced directly by substrate level phosphorylation
Produces C4 acids that are interconvertible
What is produced by the TCA cycle per molecule of glucose?
2 turns
6 NADH
2 FAD2H
2 GTP
(after ETC 32 ATP)
How is the TCA cycle regulated?
ATP/ADP ratio
NADH/NAD+ ratio
Activated by low energy, inhibited by low energy
Irreversible step, isocitrate dehydrogenase, activated by ADP, inhibited by NADPH
Explain where all the energy is at the end of the TCA cycle.
All C-C bonds have been broken, and C atoms oxidised to CO2.
All C-H bonds have been broken and H atoms have been transferred to NAD+ and FAD.
The energy is either in ATP/GTP formation, 2 in each of glycolysis and TCA cycle
Chemical bond energy is in the e- in NADH and FAD2H.
What are the key features of oxidative phosphorylation?
Takes place on the inner mitochondrial membrane
Electron transport is coupled with ATP synthesis
NADH and FAD2H are reoxidised
O2 is required, it is reduced to water
Large amounts of ATP are produced
What are the 2 processes of oxidative phosphorylation? Explain
NADH and FAD2H contain high energy electrons that can be transferred to oxygen through a series of carrier molecules with the release of large amounts of free energy.
The free energy released in ETC drives ATP synthesis from ADP and Pi
Which of the inner and outer mitochondrial membranes are permeable to H+ ions?
Outer
Describe electron transport
Carrier molecules transferring electrons to molecular oxygen are in a series of 4 specialised protein complexes
Spanning inner mitochondrial membrane
Electrons are transferred from NADH and FAD2H through the complexes releasing free energy
Three of the complexes are proton translocating complexes.
Describe how the proton motive force is created
Free energy from electron transport is used to pump H+ ions across the membrane
into the intermembrane space
Inner membrance impermeable
H + Concentration outside inner membrance increases
Creates electrochemical gradient
Which is known as the proton motive force
How many ptcs do NADH and FAD2H use?
NADH : 3
FAD2H: 2
Describe ATP synthesis
Energetically favourable for protons to move back to matrix due to pmf
Can only return through ATP synthase, inner mitochondrial membrane impermeable to H+ ions
Energy from movement drives the synthesis of ATP from ADP and Pi
Greater PMF more ATP made
How much ATP is produced by :
2 moles of NADH
2 moles of FAD2H
5 moles of ATP from 2 NADH
3 moles of ATP from 2 FAD2H
Describe the coupling of the ETC and ATP synthesis.
Explain how concentration of ATP in the mitochondria regulates both processes
ET and ATP synthesis do not occur without each other.
When [ATP] is high, ATP synthesis stops as [ADP] is low, a lack of substrate. This stops H+ transport back to mitochondria.
H+ concentration outside increases so that more can not be pumped out.
In absence of proton pumping, ETC stops.
REVERSE OCCURS WHEN ATP IS LOW
What do inhibitors of oxidative phosphorylation do?
What are some examples?
They block electron transport by preventing oxygen accepting electrons.
Examples are cyanice, carbon monoxide. They have a higher affinity
What are some examples of uncoupling proteins and what do they do?
Function is to uncouple ET from ATP synthesis to produce heat
Proteins in the inner mitochondrial membrane
UCPs 1 - 5 (first 3 most important)
UCP1: thermogenin, brown adipose tissue, non shivering thermogenesis
What do uncoupling substances do?
Increase the permeability of the inner mitochondrial membrane to protons
Protons being pumped out by ET can re enter without the synthesis of ATP.
Pmf is dissapated as heat
Makes up 20-25% of BMR
Name 2 substances which act as uncouplers in mitochondria
Dinitrophenol
Dinitrocresol
In response to cold what does noradrenaline do?
Sympathetic nervous system
Stimulates lipolysis releasing FAs for oxidation in brown adipose
NADH and FAD2H produced
Drive electron transport and produce pmf
Noradrenalin activates UCP1
Pmf dissapated as heat
Compare oxidative and substrate level phosphorylation
O: membrane associated complexes. SL: soluble enzymes
O: inner mitochondrial membrane. SL: cytoplasm and mitochondrial matrix
O:Indirect energy coupling, generation and usage of a pmf. SL: Direct energy coupling through formation of a high energy of hydrolysis bond
O: Can not occur without oxygen. SL: can occur to limited extent with oxygen.
O: Major process ATP synthesis. SL: Minor process for ATP synthesis
Give some properties of lipids
Generally insoluble in water, hydrophobic
Soluble in organic solvents
No general formula
Most contain C, H and O (phospholipids P and N too)
More reduced than carbohydrates (less O and more H per C atom)
What are the classes of lipids?
Give examples of each
- FATTY ACID DERIVATIVES: fatty acids (fuel molecules), triacylglycerols (fuel storage and insulation), phospholipids (components of membranes and plasma lipoproteins), eicosanoids (local mediators)
- HYDROXY-METHYL-GLUTARIC ACID DERIVATIVES (C6 compound): ketone bodies (C4, water soluble fuel molecule), cholesterol (C27, membranes and steroid hormone synthesis), cholesterol esters (cholesterol storage), bile acids and salts (C24, lipid digestion)
- FAT SOLUBLE VITAMINS: A, D, E, K
Describe how TAGs are hydrolysed in the small intestine
By pancreatic lipase
To release glycerol and fatty acids
Complex process
Needs bile salts
Needs protein factor: colipase
How is glycerol metabolised?
Enters the blood stream
Transported to liver
Phosphorylated by glycerol kinase
Either goes to TAG synthesis
Or oxidised to DHAP which enters glycolysis
Describe properties of fatty acids
Long chain molecules
Even no of C atoms
Hydrophobic
Highly reduced - so ideal for energy storage
Saturated or unsaturated
Saturated are non essential, can be synthesised
How are TAGs stored and what for?
Stored anhydrously in adipose tissue
Store of fuel for prolonged aerobic exercise, starvation and pregnancy
Which hormones promote TAG storage?
Which hormones reduce TAG storage?
Insulin
Glucagon, adrenaline, growth hormone, thyroxine, cortisol
How are fatty acids transported in the blood?
Bound to albumin
Which tissues can metabolise fatty acids for energy?
Heart muscle
liver
skeletal muscle
How are fatty acids activated for beta oxidation?
Links to coenzyme A outside the mitochondrion
Linked via S atom in free -SH group
Forms a high energy of hydrolysis bond
This process needs ATP and Fatty acyl coA synthase
How are fatty acids transported across the mitochondrial membrane?
What does a defect in the transport cause?
Cartinine transport shuttle- also helps to regulate the rate of FA oxidation
Converted to acyl cartinine and back
Inhibited by malonyl coA which is an intermediate in FA synthesis
Defect in transport causes poor exercise tolerance, lipid droplets in muscle
Describe beta oxidation
Sequence of reactions that oxidises the fatty acid
Removes an acetate
Cucled repeatedly until only 2 carbons remain
Needs NAD+ and FAD
Needs oxygen for ETC to reoxidise NADH and FAD2H
No direct ATP synthesis
All intermediates linked to co A.
What are the three ketone bodies produced in the body?
How are they produced?
Acetoacetate
B-hydroxybutarate
(synthesised in the liver from acetyl coA)
Acetone: spontaneous non enzymatic decarboylation of acetoacetate
What are normal and abnormal levels of ketones in the blood?
What can cause abnormal levels?
Usually ketones less than 1mM in the blood
Increases in starvation: 2mM to 10mM (physiological ketosis)
In untreated type 1 diabetes, bove 10mM
Properties of ketone bodies
Water soluble
So can have high plasma concentration, can cross blood brain barrier, can be excreted in urine
Acetoacetate and b hydroxybutarate are quite strong organic acids so can cause acidosis
Acetone is volatile and can be excreted via the lungs (on breath of untreated type 1 diabetics for example)
What is required for ketone bodies to be produced?
Fatty acids for oxidation in the liver: substrate
Plasma insulin:glucagon ratio is low, activates lyase, inhibits reductase
Describe how ketones are produced from acetyl coA
Acetyl co A to HMG coA via synthase enzymes
HMG coA to acetoacetate via lyase
What is acetyl coA produced by?
Catabolism of
Fatty acids
Sugars
Alcohol
Certain amino acids
Why is acetyle coA central in metabolism
It can be oxidised in stage 3 of catabolism, the TCA cycle
It is an important intermediate in lipid biosynthesis (anabolism), in the liver and some adipose tissue
What are the major energy stores in a 70kg man?
TAGs: 15kg
Glycogen: 400g
Muscle protein: 6kg
How is glycogen synthesised from glucose?
- Using ATP is phosphorylated to glucose 6 phosphate by hexokinase/glucokinase
- Glucose 6 phosphate to glucose 1 phosphate by phosphoglucomutase
- Glucose 1 phosphate + UTP + water makes UDP glucose (high energy) and 2 Pi
- Glycogen (n residues) + UDP glucose makes glucogen (n+1 residues_ and UDP. Step 4 is catalysed by glycogen synthase which adds alpha 1,4 links, and branching enzyme which adds alpha 1,6 links about every 10 units
What is glycogen degraded in response to?
Exercise in skeletal muscle.
Fasting in the liver, or stress response
Never degraded fully, a small amount of primer is preserved
How is glycogen degraded?
Glycogen phosphorylase creates glucose 1 phosphate by attacking the alpha 1,4 bonds. Debranching enzyme attacks the alpha 1,6 bonds and releases glucose.
Phosphoglucomutase moves the phosphate from carbon 1 to carbon six producing glucose 6 phosphate. This enters glycolysis in skeletal muscle.
In the liver, the addition of water to glucose 6 phosphate by glucose 6 phosphatase makes glucose and Pi. Therefore glycogen in the liver supplies glucose for all tissues through the blood stream.
Compare the functions of liver and muscle glycogen.
LIVER: glucose store for all tissues of the body, in response to fasting or stress. Glucose 6 phosphate to glucose by glucose 6 phosphatase.
MUSCLE: glucose 6 phosphate store, can only be used by muscle as it enters glycolysis.
Abnormalities in which enzymes can cause glycogen storage diseases?
What are the consequences?
- Glycogen phosphorylase
- Phosphoglucomutase
Glucose 6-phosphatase in liver
Increase or decreased amounts of glycogen.
Tissue damage if too much storage
Fasting hypoglycaemia
Poor exercise tolerance
Abnormal structure of glycogen
Describe regulation of glycogen metabolism
Allosteric control of glycogenolysis, glycogen phosphorylase: AMP activates
Synthesis: glycogen synthase, activated by insulin dephosphorylating. It is inhibited by glucagon and adrenaline, which phosphorylate.
Glycogen phosphorylase: activated by glucagon and adrenaline phosphorylating. Deactivated by insulin dephosphorylating.
What is gluconeogenesis?
The production of glucose when carbohydrates are absent.
What are possible substrates for gluconeogenesis?
What is the main site?
Pyruvate, lactate, glycerol
Essential and non essential amino acids whose metabolism involves pyruvate or TCA intermediates
NOT ACETYL COA
Describe the process of gluconeogenesis
Uses the reversible steps of glycolysis and bypasses the irreversible ones.
Steps 1 and 3 are bypassed by thermodynamically spontaneous reactions, catalysed by phosphatases. Glucose 6 phosphatase (to make glucose) and fructose 1,6 bisphosphatase (to make fructose 6 phosphate).
Step 10 is bypassed by reactions drived by ATP and GTP hydrolysis. Catalysed by pyruvate carboxylase and phosphoenolpyruvate caroxykinase (PEPCK). This produces oxaloacetate and phosphoenolpyruvate. Link to TCA
How is gluconeogenesis regulated?
Response to starvation, exercise, stress
Glucagon and cortisol stimulate PEPCK and glucagon stimulates Fructose 1,6 bisphosphatase
Insulin inhibits PEPCK and fructose 1,6 bisphosphatase
What reaction converts glycerol and fatty acids to TAGs?
And back again?
Esterification
Lipolysis
Which hormones promote and deplete TAG storage?
Promote: Insulin
Deplete: glucagon, adrenaline, growth hormon, cortisol, thyroxine
How are fatty acids synthesised?
From acetyl coA, using ATP and NADPH
Cytoplasm
Carried out by mlti enzyme complex: fatty acid synthase complex
C2 units added as malonyl coA, with loss of CO2
Malonyl coA is made from acetyl coA byt acetyl coA carboxylase
How is glycerol transported in the blood stream to adipose?
Chylomicrons to store as TAGs
How is acetyl coA carboxylase regulated?
Allosteric regulation: citrate activates and AMP inhibits
Covalent modification:
Insulin activates by dephosphorylation
Glucagon and adrenaline inhibit by promoting phosphorylation
Compare FA oxidation and synthesis
O: removes C2. S: adds C2.
O: Removed as acetyl coA. S: Added as malonyl coA with loss of CO2.
O: Produces acetyl coA. S: consumes acetyl coA.
O: In mitochondria. S: in cytoplasm.
O: Oxidative. S: reductive, uses NADPH
O: Seperate enzymes. S: enzyme complex.
O: Needs small amount of ATP to activate the FA. S: needs lots of ATP to drive the process.
O: Regulated indirect by FA availability. S: directly regulated by acetyl coA carboxylase.
What are amino acids used for?
protein synthesis
synthesis of purines and pyrimidines in DNA and RNA
small amounts of porphyrins (haem), creatine, nerotransmitters, hormones
Which amino acids are essential in the diet?
PVT. TIM HALL
Phenylalanine
Valine
Tryptophan
Threonine
Isoleucine
Methionine
Histidine (semi)
Arginine (semi)
Leucine
Lysine
Tyrosine and cysteine may become essential
How can the amino group of an amino acid be removed?
Transamination
Or deamination
What can the remaining C skeleton of a deaminated amino acid be converted to?
Pyruvate
Oxaloacetate
Fumarate
Alpha ketoglutarate
Succinate
Acetyl coA
What is the difference between ketogenic and glucogenic amino acids?
Ketogenic amino acids are broke down to acetyl coA which makes ketone bodies by synthase and lyase.
Glucogenic amino acids make the other products which can make glucose by gluconeogenesis.
Which amino acids are ketogenic and glucogenic?
Isoleucine, threonine, phenylalanine
What enzymes carry out transamination?
Write out the equations
Aminotransferases
ALT, Alanine aminotransferase: GPT
Alanine+alpha ketoglutarate TO glutamate+pyruvate
AST, Aspartate amino transferase:vGOT
Aspartate+alpha ketoglutarate TO oxaloacetate and glutamate
Most use alpha ketoglutarate as keto acid 2. If oxaloacetate is used, it is converted to aspartate.
What are AST and ALT used for in clinical practice?
Liver function test
Which hormone stimulates transaminase synthesis in the liver?
Cortisol
Describe the process of deamination
L and D amino acid oxidases
Convert amin acids to keto acids and NH3, to ammonium ion
D amino acids from diet, can’t be used for protein synthesis. High activity of D amino acid oxidases in the liver.
Glutaminase converts glutamine to glutamate and NH3.
Glutamate dehydrogease makes alpha ketoglutarate, ammonia and reduced NAD.
Which hormones stimulate protein synthesis and breakdown?
Synthesis is promoted by insulin and inhibited by glucocorticoids
Breakdown is promoted by glucocorticoids and inhibited by insulin
What is phenylketonuria?
An inherited autosomal recessive disorder in which the urine contains large amounts of phenylketones produced from phenylalanine.
Describe how PKU arises and its effects
Phenylalanine hydroxylase enzyme is defective
This oxidises phenylalanine to tyrosine
Excess phenylalanine combines with alpha ketoglutarate to make phenylpyruvate, ketone
Phenylalanine and phenylpyruvate accumulate in the blood.
Phenylalanine saturates transporter LNAAT carrier, this transports amino acids across blood brain barrier. Mental reatrdation due to decreased brain metabolism.
Lack of tyrosine, has to be supplemented in diet. Useful precursor for hormones (thyroid) and neurotransmitters.
Describe homocystinuria
A rare inherited autosomal recessive defet
In methionine metabolism
Excess homocystine in urine
Caused by defect in CBS enzyme
cystathionine beta synthase
What does cystathionine beta synthase usually do?
Converts homocysteine to cystathionine, which is further converted to cysteine.
What happens is homocysteine increases in the blood when CBS is deficient?
Methionine builds up in the plasma, as does homocystine, oxidised form
Homocysteine causes disorders of connective tissue, muscle, CNS and CVA is elevated in plasma.
Similar to Marfans syndrome, tight joints, intellectual disability, long limbs, near sightedness, arachnodactyly, damages FIBRILLIN
How to treat homocystinuria
B6 supplement, increases deficient CBS, as cofactor
B12 supplement, more homocysteine to methionine, which can be excreted. Add cysteine to diet.
What symptoms are associated with hyperammonaemia?
Why?
What disease is it commonly seen in?
Blurred vision
Tremors
Slurred speech
Coma
Death
Removes alpha ketoglurate from the TCA cycle as reacts to form glutamate via glutamate dehydrogenase
Affects the pH in CNS
Interferes with neurotransmitter sunthesis and release.
Commonly seen in liver disease
How is ammonia detoxified?
Describe glutamine synthesis and how it is disposed of
Either by synthesis of N compounds like glutamine or conversion to urea.
Glutamine can be synthesised from glutamate and ammonis via glutamine synthetase, requiring ATP. It is transported to the liver and kidney where it is hydrolysed to release ammonia.
In the kidney ammonia is excreted and in the liver it is converted to urea.
Why is urea a good molecule to excrete?
Very soluble in water
Non toxic
Metabolically inert
High nitrogen content
How is urea synthesised?
NH2 groups of urea come from ammonium and aspartate.
5 enzymes
Occurs in the liver, transported via blood to the kidney for excretion.
Orthinine to citrulline in the mitochondrial matrix. To argininosuccinate and arginine.
Describe regulation of urea synthesis
Not subject to feedback inhibition
Enzymes are inducible
Refeeding syndrome, hyperammonaemia
Describe inherited diseases of the urea cycle and their effects
All defects cause hyperammonaemia and accumulation or excretion of urea cycle intermediates
Depends on extent of defect
Vomiting, lethargy, irritability, mental retardation, seizures, coma, death
Treat with low protein diet, replace essential amino acids with ketoacids that use up ammonium when converted to amino acids.
What happens to urea?
Diffuses from liver cells to blood to kidney where it is filtered and excreted in the urine
Some urea diffuses into the intestine, bacteria break down to release ammonia which is reabsorbed
Kidney failure: urea conc in blood is high, production of ammonia from urea by bacteria in the gut can cause hyperammonaemia.
How are lipids transported?
98% as lipoprotein particles
2%, mainly fatty acids, bound non covalently to albumin
What are the usual maximum fatty acid levels in the blood?
3mM
What diseases are disorders in plasma lipoprotein metabolism associated with?
Atheroschlerosis
Coronary artery disease
Describe lipoprotein structure
Small assemblies of hydrophobic lipid molecules surrounded by polar molecules (micelles)
Protein components: apoproteins
Spherical particles, surface coat and core
Hydrophobic core: TAGs and cholesterol esters
Surface coat: proteins, phospholipids, cholesterol
Only stable if spherical shape is maintained: ratio of core to surface lipids. LCAT
Non covalent
What are the 4 types of lipoproteins and their function?
Chylomicrons: dietary TAGs from the intestine to tissue such as adipose.
VLDL:Transport of TAGs synthesised in the liver to adipose for storage.
LDL: Transport of cholesterol synthesised in the liver to the tissues.
HDL: Transport of excess tissue cholesterol to the liver for disposal as bile salts.
How are dietary lipids transported for storage?
Hydrolysed in small intestine by pancreatic lipase
Fatty acids enter epithelial cells of small intestine
FAs reesterified back to TAGs using glycerol phosphate from glucose metabolism.
Packaged into chylomicrons with other dietary lipids
Released into blood stream via the lymphatic system
Carried to tissues like adipose that express lipoprotein lipase.
Hydrolysed and FAs enter the adipose cells where they are converted to TAGs for storage
When are chylmicrons present in the blood?
4 to 6 hours after a meal
Why are chylomicrons transported in the lymphatic system?
They go via the thoracic duct to the left subclavian vein
This bypasses the liver and hepatic portal vein
Explain how HDL and LDL levels affect the risk of cardiovascular disease?
High LDL levels deposit cholesterol on blood vessel walls.
Plaques.
Risk factor for atheroschlerosis
HDLs remove cholesterol from tissues
Prevent excessive cholesterol build up
Beneficial in blood vessels
Describe properties of cholesterol
Tetracyclic
Can be esterified with a fatty acid, eliminated the polar OH group
Major membrane component
Precursor of steroid hormones
Precursor of bile acids
Mainly synthesised in the liver, some in the diet
Describe properties of phospholipids
Diacylglycerol with a phosphate group
Major component of membrances
Phosphate is polar
Amphipathic
Naturally forms micelles
Describe the action and control of lipoprotein lipase
Removes core TAGs from lipoproteins like chylomicrons and VLDLs
Attached to inner surface of capillaries in tissues such as adipose and muscle
Hydrolyses TAGs to fatty acids and glycerol
Tissues then take up fatty acids, glycerol to the liver
Insulin increases the synthesis of this enzyme
What is LCAT?
Describe its action
What happens when it is deficient?
Lecitihin: Cholesterol AcylTransferase
Restores the stability of lipoproteins
Converts surface lipid to core lipid
Converts cholesterol to cholesterol ester with FA derived from lecithin
Defiency: unstable lipoproteins of abnormal structure.
Failure of lipid transport
Deposits in tissues
Atheroschlerosis
Describe LDL metabolism
(all cells except erthryocytes could in theory synthesise cholesterol, but prefer to take it up pre formed in practice)
Receptor mediated endocytosis
Complex proteins on cell surface bind LDL apoprotein B100
LDL receptor with LDL taken in by endocytosis
Subject to lysosomal digestion
Cholesterol released inside the cell from cholesterol esters
Inhibits cholesterol synthesis in cell and reduces synthesis and exposure of LDL receptors, uptake stimulated by need
What is Hyperlipoproteinaemia?
How many types are there and what are they called?
Describe the 3 types with known defects
Raised levels of one or more of the plasma lipoproteins
There are 6 types, I, IIa, IIb, III, IV, V
Type I: chylomicrons in fasting plasma, no link to coronary artery disease, caused by defective lipoprotein lipase
Type II: raised LDL, associated with CAD may be severe, caused by defective LDL receptor
Type III: Raised IDL and chylomicrons remnants, associated with CAD, caused by defective apoprotein E
What is a dyslipoproteinaemia and what are the two main types?
Defect in metabolism of plasma lipoproteins
Primary: inborn
Secondary: acquired as a result of diet, drugs, underlying diseases like diabetes.
What are clinical signs of hyperlipoproteinaemia?
Xanthelasma: lipid deposits by eyelids
Tendon xanthoma
Corneal arcus in iris
What is familial hypercholesterolaemia?
Describe it
Type II
Absence - homozygous
or
deficiency - heterozygous
of functional LDL receptors
Elevated levels of LDL and cholesterol in the blood
Atheroschlerosis early in life in homozygotes and later in heterozygotes
Describe the formation of an atheroma
Clinical significance?
Oxidised LDL
Macrophages engulf faulty LDLs
Form foam cells
Accumulate in intima of blood vessel wall lining, swelling
Fatty streak - lighter patch
Atheroma, swelling of vessel
Initially clinically silent
Swelling narrows lumen, if a thrombosis occludes the vessel, myocardial infarction if in coronary vessel.
Explain how hyperlipoproteinaemias may be treated
Diet and lifestyle modifications first, reduce eliminate cholesterol and TAGs, more exercise
If little effect
Drug therapy: statins. Lower plasma cholesterol by inhibiting HMG co A reductase.
Bile salt sequestrants: dispose of cholesterol by converting to bile salts. This prevents reabsorbtion in GI into hepatic portal circulation, more lost in faeces
Describe the production of superoxide radicals in mitochondria
Some electrons are leaked for the ETC prematurely at complexes 1 and 3
They reduce oxygen to form superoxide radicals
O2-
Superoxide radicals have an unpaired electron
Free radical
Highly reactive
Know as Reactive Oxygen Species ROS
Constantly leaking out of mirochondria so must be protected against
How are ROS protected against in the cell?
How do ROS cause damage?
Superoxide radicals converted to hydrogen peroxide by SUPEROXIDE DISMUTASE (SOD)
Hydrrogen peroxide converted to water and oxygen by CATALASE
ROS cause damage to DNA, protein and membranes
What are some other examples of ROS and how are they formed?
HYDROXYL RADICALS, -OH: produced in all cells. By ionising radiation, from hydrogen peroxide with addition of iron ions. Damage to cells membrane and can’t be eliminated by enzymes.
NITRIC OXIDE, NO: produced from arginine by the inducible enzyme nitric oxide synthase (iNOS).
PEROXYNITRITE, ONOO-: produced when nitric oxide and oxygen react. Involved in inflammation
EXOGENEOUS: Antimalarials like primaquine, powerful oxidants, dangerous in G6PDH. Paracetamol overdose. Paraquat, a herbicide, causes superoxide radical production.
Outline other defences against ROS (other than SOD and catalase)
Glutathione (GSH), trispeptide, anti oxidant. Free -SH on cysteine are oxidised to GSSG, donate their Hs. Abundant in cells. Recycled by reducing with NADPH, which is produuced by glucose 6 phosphate dehyrdogenase.
Antioxidant vitamins A C and E
Flavenoids: polyphenols, beta carotene
Minerals such as selenium and zinc
How do some white blood cells use ROS in an immune response?
Neutrophils and monocytes
When stimulated release an oxidative burst
Enzyme: NADPH oxidase
Cell usually destroyed
As is surrounding bacteria/ fungi
What is pharmacoDynamics?
What is pharmacokinetics?
What a Drug Does to the body
What the body does to the drug
Some metabolites of drugs are more pharmacologically active than the pro drug, and are converted in the body.
What are some examples of this?
Primidone to phenobarbitone
Pethidine to norpethidine
Codeine to morphine
What does pharmokinetics cover? (acronym)
ADME
Adsorption
Distribution
Metabolism
Elimination.. of a drug
What occurs in phase 1 of drug metabolism?
A reactive group is exposed or added to the parent molecule
Generates a reactive intermediate
Most common reactions: reduction, oxidation, hydrolysis
Cytochrome p450, complex enzyme system
High energy cofactor, NADPH
Some bypass phase 1 as they already have a reactive group, for example morphine. Straight to phase 2
What occurs in phase 2 of drug metabolism?
Conjugation with a water soluble molecule to form a water soluble complex
Glucaronic acid most commonly
Suplhate ions
Glutathione
High energy co factor: UDPGA (uridine diphosphate glucaronic acid)
Clinically, what can a lack of cholinesterase enzymes cause?
Prolonging of anaesthesia effects
What is pharmacology?
How chemical agents affect the functioning of living systems
What is pharmacoepidemiology?
What is pharmacovigilance?
Study of the drug effects in a large population.
Reporting of adverse drug reactions (ADRs) post marketing eg thalidomide
Describe the importance of the cytochrome p450 system
CYP
Complex enzyme system
50 different haem containing enzymes
Polymorphisms in the population
Isoform CYP3 A4 is most important, 55% of drug metabolism
Co factor is NADPH
Explain the variation in drug metabolism in the human population
Genetics and environment
GENETICS:
Differences in the level of expression of metabolic enzymes
May lack a gene that codes for an enzyme
Polymorphisms
Different times to metabolise drugs
Gene deletions
Slow acetylators: lack enzyme that acetylates in phase II.
Low levels of pseudocholinesterase enzymes in plasma: affects ability to metabolise drugs with an ester bond, such as some anaesthetics.
ENVIRONMENT:
Inhibition: other drugs: polytherapy, cranberry, grapefruit juice
Induction: increased metabolism of other drugs, ethanol, nicotine, barbiturates, some pesticides
Describe the first pass effect
Substances absorbed in the lumen of the ileum
Enters venous blood which drains into the hepatic portal vein
Direct to the liver, main site of drug metabolism
All necessary enzyme systems
Any drug absorbed from the ileum may be mostly meatbolised in first pass through liver.
Only small amount passes to the rest of the circulatory system
90% of paracetamol metabolised in first pass, so large dose of 1g is needed.
Describe alcohol metabolism
Alcohol to acetaldehyde by alcohol dehydrogenase
Acetaldehyde to acetate (to acetyl coA) by aldehyde dehydrogenase
Complete oxidation needs NAD+, forms NADH
Aldehyde dehydrogenase has a low Km so keeps toxic acetaldehyde to a minimum
CYP2E1 also metabolises alcohol via oxidation, and is inducible
Alcohol consumption reduces the NAD+/NADH ratio, what are the effects of this?
NAD+ is used for fatty acid oxidation, conversion of lactate to pyruvate and glycerol metabolism
So stimulates fat deposition, inadequate amounts for beta oxidaiton
Lactate builds up, could cause lactic acidosis
Reduces ability of the kidney to excrete uric acid, urate may build up in tissues causing gout
Gluconeogenesis cannot be activated. Fasting hypoglycaemia
Alcohol consumption increases the amount of acetyl coA. What are the effects of this?
Not enough NAD+ to be oxidised
Increase fatty acid and ketone body synthesis
Converts to TAGs: fatty liver as lack of lipoproteins
Can cause ketoacidosis
How is the liver damaged by alcohol and what are the effects of this?
Toxic acetaldehyde damages liver cells. Alcoholic hepatitis/cirrhosis
Leaky plasma membrane
AST and ALT in blood, liver function test
Reduced liver function can result in:
Decreased:
= uptake of conjugate bilirubin, hyperbilirubinaemia, Jaundice
=urea production, hyoerammonaia and high glutamine
=protein synthesis, low albumin (oedema), clotting factors (slow clotting) and lipoproteins (fatty liver)
What are the indirect and direct effects of alcohol on the body?
Indirect: likely vitamin and mineral deficiencies, inadequate protein and carbohydrate uptake, CNS
Direct effect: on GI tract
Loss of appetite, diarrhoea, impaired absorption of nutrients due to damage of lining cells (vitamin K, folic acid, haemotological problems, pyridoxine and thiamine, neuro symptoms)
Thiamine deficiency can lead to Wernicke Korsakoff syndrome with mental confusion and unsteady gait
How is alcohol dependency treated with drugs?
Disulfarim
Aldehyde dehydrogenase inhibitor
If alcohol is consumed, acetaldehyde accumulates in the blood, giving hangover symptoms
Describe normal metabolism of paracetamol
Straight to phase 2 metabolism
Conjugates with glucaronide or sulphate
Describe metabolism of paracetamol in an overdose
How is it treated?
Conjugation in phase 2 by glutathione or sulphate is quickly saturated
Undergoes phase 1 metabolism
Produces toxic metabolite NAPQI
Toxic to hepatocytes
Phase II conjugation with glutathione, an important antioxidant, subject to ROS attack
Liver failure over several days
Treatment with N-acetylcysteine, an antioxidant, RAPIDLY
What are the major metabolic fuels and their sources in an individual?
Glucose/glycogen: glucose used by all cells, preferred fuel. Only 12g in solution can support CNS for 2 hours. Stored as glycogen in liver and muscle. Only liver glycogen can be used by the CNS.
Fatty acids/ketone bodies: many cells except RBCs and CNS can use fatty acids as fuels. Fatty acids from TAGs in adipose can supply fuel for two months, the main fuel reserves. Fatty acids can be converted to ketones for CNS fuel when glucose is low in starvation.
Proteins can be hydrolysed to amino acids that can be converted to glucose, ketone bodies or directly oxidised.
What are the communication pathways in humans?
Nervous, by action potentional. Afferent to brain, efferent from brain.
Endocrine, by hormones
Paracrine, local hormones via ducts, exocrine
Autocrine, agents being released affect the releasing cell, self control
What are the major features of control systems in the human body?
Communication
Control centre
Receptor
Effector
What is a receptor?
Sensors that detect stimuli such as changes to the internal environment
Usually specialised nerve endings such as thermoreceptors and chemoreceptors
Sensors communicate input to the control centre via afferent nerves
What is a control centre?
Establishes the reference set point
Analyses afferent input
Determines appropriate response
Examples in the brain:
Hypothalamus in the diencephalon: endocrine system
Medulla oblongata in the brain stem: ventilation and CVS control
Trauma to these regions is usually fatal
What is an effector?
Agents that cause change
The control centre produces an output
Ouput is communicated by the efferent pathway to the effectors
Eg sweat glands are activated to produce more sweat causing heat loss
In paraplegic patients heat loss is affected
What is positive feedback?
(feedforward)
Stimulus produces a response which increases its effect
Forces system out of ocntrol
Rapid catastrophic change
Exampkes: blood clotting, ovulation
What is a feedback loop?
When the output/effect affects the control centre
What is negative feedback?
Output inhibits functino of the control centre
Effector opposes stimulus
Stabilises control systems can control set point in fine limits
In most homeostatic control mechanisms
Tendency to overshoot set point several times, hunting behaviour
Examples: insulin and hyperglycaemia, HPA axis
Discuss examples of biological rhythms and what they are
Rather than the set point being fixed it can change over time
Cortisol: levels vary throughout the day. Peak at 7am, trough at 7pm. CIRCADIAN RHYTHM. So time should always be noted when taking a cortisol sample, when repeated shouled be at the same time of day, of 24hour urine.
Menstrual cycle: woman’s core body temperature varies in the cycle. Sudden increase in core body temperature is a marker for ovulation.
Biological clock in brain: suprachiasmatic nucleus in hypothalamus, small group of neurones. Natural diurnal cycl. Zeitgabers, keys from the envuronment keep us on 24 hours, long haul flights mismatch. Melatonin hormone in pineal gland helps set clock, no light on retina stimulates melatonin.
Define the term hormone
chemical signals produced in endocrine glands or tissues, that travel in the blood stream to cause an effect on tissues.
Generally how do hormones work?
Change in concentration of hormones causes a cell response
About 30 seconds to reach all body parts
Only interact where there are receptors
Can have different effects in differet places
Good for coordinated multiple responses
Path: endocrine tissue releases hormone, transported in blood to target cells, receptors and respsonse, inactivation of chemical by liver or sometimes kidney
What are the 4 classes of hormone
Give examples of each
Polypeptide: short or long chains of amino acids, largest group, insulin, glucagon, growth hormone, placental lactogen
Steroid: all derived from cholesterol, cortisol, aldosterone, oestrogen, testosterone. Classified by carbon number
Amino acid derivatives: small molecules synthesised from amino acids, thyroid hormones, adrenaline (a catecholamine)
Glycoprotein:large protein molecules with carbohydrate side chains. Anterior pituitary hormones. LH, FSH, TSH
How are hormones transported?
Polypeptide, glycoprotein and adrenaline: relatively hydrophilic and are transported in the blood by dissolving in the plasma.
Steroid and thyroid hormones are lipophilic and need specialised transport proteins like thyroxine binding globulin or albumin
How do hormones act on target cells?
Effect of a hormone depends on concentration in the blood stream
Only unbound or free hormones can interact with receptors
Bind to specific high affinity receptors on or in the cell. Hormones that can cross cell membrance and are lipophilic bind to receptors inside the cell. Hydrophilic hormones bind to a receptor on the cell surface.
Then binding hormon triggers a change i the target cells, which may be in enzyme/functional activity (short term) or gene expression (long term). Cell surface receptors often trigger a secondary messenger that influences the cells activity.
Some hormones have one major target tissue whereas others have many.
Name ways in which hormones may be controlled
Negative feedback
One hormone controlling another
Releasing or inhibiting hormones
Inactivating hormones
Describe control of hormones by negative feedback
Hormones constantly lost from circulation as they are excreted or broken down
Secretion rate must be adjusted to maintain concentration
Rate of secretion directly affected by blood concentration
If the concentration falls below a critical levels hormone secretion increases until the correct level is acheived again
Example: pancreatic beta cells secrete insulin, are directly sensitive to blood hormone concentration, if it rises abouve 5mM, insulin is secreted until it is brought down to the right level, then it is switched off
Describe how one hormone can control another
Controlling hormone is a trophic hormone
Secreted from anterior pituitary gland
Example: Secretion of cortisol is controlled by ACTH
negative feedback in some trophic hormones
What are the 6 anterior pituitary hormones?
What do they do?
ACTH: adrenocorticotrophic hormone, affects the adrenal gland and cortisol
TSH: thyroid stimulating hormone, affects T4 secretion
GH: growth hromone, affects metabolism
LH: luteinising hormone, affects ovary and testis function
FSH: follicle stimulating hormone, affects ovary and testis function
Prolactin: affects breast development and milk production
How do releasing or inhibiting hormones control hormone secretions?
Examples?
Come from nerve cells in the hypothalamus
Travel to anterior pituitary via the hypophyseal portal vessels
Allows brain to control hormone secretion
Thyrotrophin releasing hormone, TRH
Corticotrophin releasing hormone, CRH
Somatotrophin releasing hormone, SRH, stimulated GH release
Somatostatin, inhibits GH release
How are hormones inactivated?
Occurs in liver and kidney and sometimes target tissues
Steroid hormones are inactivated by increasing their water solubility, can be excreted in urine or bile
Protein hormones need extensive chemical changes and are degraded to amino acids which are recycled
Where is the centre of the control of appetite?
What neurones are involved?
What do they do?
Arcuate nucleus in the hypothalamus
Group of neurones consisting of two types
Primary neurones: sense metabolite leves in blood, respond to hormones.
Secondary neurones: synthesise input from primary neurones and synthesise a response via the vagus nerve
Describe the types of primary neurones and their actions.
Excitatory: stimulate appetite via neuropeptide Y and agouti related peptide
Inhibitory: suppress appetite by releasing pro-opiomelanocortin (POMC)
What is POMC cleaved into?
Beta endorphin, reward system, euphoria and tiredness
ACTH, stimulate cortisol
Alpha melanocyte stimulating hormone: a-MSH, acts on melanocortin 4 receptors which suppress appetite
What hormones are involved in the control of appetite?
Expain how they work
GHRELIN: peptide released from the wall of the empty stomach, activates stimulatory neurones in the arcuate nucleus and appetite. Stretch of stomach caused by food intake inhibits Ghrelin.
LEPTIN: Peptide released by adipocytes, levels correlate to fat stores. Stimulates inhibitory and inhibits stimulatory neurones in arcuate nucleus, suppresses appetite. Lack of leptin can cause obesity. Induces expressionof UCP in mitochondria, lose heat rather than get ATP
PYY: released from small intestine wall, suppressed appetite.
INSULIN: same mechanism as leptin but less important.
AMYLIN: peptide from B cells in pancreas, supresses appetite, decrease glucagon secretion and slow gastric emptying
What is metabolic syndrome?
Group of symptoms commonly found in obese peopl
Insulin resistance, dyslipidaemia, glucose intolerance, hypertension
Associated with central adiposity, sedentary lifestyle
CVS risk factors
Controversial
WHO criteria: BMI above 30, blood pressure 140/90, high TAGs, HDLs low, high fasting glucose etc
Explain the deevlopmental origins of health and disease theory, and epigenetics
David barker showed that rhw strongest association of adult disease like CHS, hypertension and T2DM is low birth weight.
Suggests experience of foetus in utero determines future health.
Biochemical adaptation by foetus according to nutrient supply in uterus, programmed in for adult life
Switching on and off genes at critical times in development
EPIGENETICS: stably inherited phenotype resulting from changes in chromosome without alterations in the DNA sequence, methylations and changes in histone structure, supressing transcription, targeting promotor regions.
How is body water controlled?
Osmolality and concentration of Na+ ions monitored by OSMORECEPTORS inthe hypothalamus (supraoptic/paraventricular nuclei)
If osmolality increases
ADH released from posterior pituitary
Increase in collecting duct permeability to water, more absorbed into blood, more concentrated urine, lower volume.
Osmolality decreases
How are polypeptide hormones stored in glands?
How are steroid hormones stored in glands?
How are thyroid hormones stored?
Polypeptides, inside storage vesicles inside cells
Steroids stored as precursor cholesterol esters as lipid droplets
Thyroid hormones stored outside cell in the form of protein colloid
What is diabetes mellitus?
A group of disorders characterised by chronic hyperglycaemia due to insulin deficiency, insulin resistance, or both
A state of hyperglycaemia leading to small and large vessel damage, in which there is premature death from cardiovascular diseases
Why does blood glucose rise in diabetes? (both types)
An inability to produce insulin due to B cell failure, autoimmune destruction in the B islet cells in the tail of the pancreas
Insulin produced adequately, but insulin resistance prevents insulin working effectively, receptors don’y work properly, especially in patients with central adiposity, many free fatty acids interfere
When does type 1 diabetes typically present?
What causes it?
Usually in the teenage years, strong seasonal variation suggesting a link with a viral infection as a trigger
Likely that a genetic predisposition interacts with an environmental triggere to produce immune activation.
Production of killer lymphocytes, macrophages and antibodies that attack and progressively destroy bta cells.
Associated with genetic markers HLA DR3 and HLA DR4
What symptoms will a lean young person with a recent viral infection with type 1 diabetes typically present with?
Triad of symptoms
Polyuria: excess urine production. Large quantities of glucose in the blood are filtered by the kidney, exceed renal threshold, so not all is reabsorbed. Has osmotic effect of drawing more water into the urine.
Polydipsia: thirst and drinking a lot, due to polyuria
Weight loss: as fat and proteinare metabolised because insulin is absent
What does a lack of insulin cause?
Decreased glucose uptake into adipose and skeletal muscle
Descreased storage of glucose as glycogen in the muscle and liver
Increased gluconeogenesis in the liver
What does high blood glucose cause to appear in the urine?
Glucose
Glycosuria
In what populations is type 2 diabetes common?
All populations enjoying a affluent lifestyle
Usually older
Overweight
What are the main differences between type 1 and type 2 diabetes?
1: commonest type in the young. 2: affects large numbers of older individuals
1: characterised by progressive loss of all or most pancreatic B cells. 2: characterised by slow progressive loss of B cells bu with disorders of insulin secretion and tissue resistance
1: is rapidly fatal if not treated. 2: may be present for a long time before diagnosis
1: must be treated with insulin. 2: may not initially need treatment with insulin but all do eventually
What are typical symptoms of hyperglycaemia?
Polyuria
Polydipsia
Blurring of vision
Urogenital infections eg thrush
Symptoms of inadequate energy utilisation
Tiredness
Weakness
Lethargy
Weight loss
How might type 1 diabetes develop?
May be found with relevant HLA markers and auto antibodies but without glucose or insulin abnormalities
THey may then develop impaired glucose tolerance
Then diabetes which may be initially diet controlled
Before becoming totally insulin dependant
How is type 2 diabetes managed progressively?
Diet and exercise
Tablets
Then insulin
How does type 2 diabetes develop?
Insulin resistance
Insulin production falls
Impaired glucose tolerance
What is hypoglycaemia?
What can cause it?
When can it become fatal?
What are the symptoms?
When plasma glucose is less than 3mM
Insulin/sulphonylurea treatment with activity, missed meal, accidental or non accidental overdose
Can be fatal when blood glucose is less than 3mM as CNS and glucose dependant tissues need a constant supply
Sweating, anxiety, hunger, tremor, palpitations, confusion, drowsiness, seizures, coma
What is hyperglycaemia?
What are the symptoms?
Blood glucose is more than 10mM
Symptoms: polydipsia, polyuria, weight loss, fatigue, blurred vision, dry or itchy skin, poor wound healing.
Plasma proteins become glycosylated affecting their function
Ketoacidosis in T1DM
Hyperosmolar non-ketotic syndrome in T2DM
Explainhow ketoacidosis arises in the uncontrolled diabetic
How can it be diagnosed?
What symptoms does it cause?
How is it treated?
High rates of beta oxidation of fats in the liver
Low insulin to anti insulin ratio
Production of huge amounts of ketone bodies
Acetone can be breathed out and smelt on the patient’s breath
Test for ketones in the urine, ketostik
The H+ associated with the ketones produces a metabolic acidosis
Prostration, hyperventilation, nausea, vomiting, dehydration, abdominal pain
Treated with fluids to rehydrate, and insulin
How is diabetes diagnosed?
Triad of symptoms
Random venous plasma glucose concentration of more than 11.1mM
Fasting plasma glucose concentration of more than 7mM
Plasma glucose concentration of more than 11.1mM, 2 hours after 75g anhydrous glucose in an oral glucose tolerance test
With no symptoms must have two of the tests to confirm, with an additional test on another day with a value in the diabetic range.
Important to be correct: medicolegal
How is type 1 diabetes managed?
Can not be cured
Insulin is used to treat
Must be injected subcutaneously
As is a peptide hormone that can be digested in the stomach
Appropriate doses at appropriate times to mimic normal islet behaviour
May need to increase insulin with infection, trauma to reduce ketoacidosis risk
Frequent test for blood glucose, finger prick, BM stick and reader
Need to be aware of hypoglycaemic effects
Social and psychological implications
Education
How is diabetes monitored?
Well being
Glucose control (capillary blood glucose)
HbA1c
vascular risk factors: BP, lipids, smoking, exercise, diet
Surveillance for chronic comlications
How is type 2 diabetes managed?
Sometime managed by diet
Sulphonylureas such as glicazide increase insulin release from remaining beta cells SPANK THE PANC, acts of K ATPase pumps
Biguanides such as metformin increase insulin sensitivity
Insulin may be needed if cells are lost
Why is persistent hyperglycaemia harmful?
Produces potentially harmful products
Uptake to cells of peripheral nerves, the eye and kidney does not need insulin, is determined by concentration of glucose in ECF
So in hyperglycaemia ICF in these tissues increases
Glucose is metabolised via aldose reductase catalysing:
Glucose + NADPH + H+ to Sorbitol + NADP+
This depletes NADPH, leading to increased disulphide formation in cellular proteins altering structure and function. Accumulation of sorbitol causes osmotic damage to cells.
Describe non enzymatic glycosylation
Hyperglycaemia can cause this
Plasma proteins are glycosylated
Leads to disturbances in function
Glucose reacts with free amino groups in proteins to form stable covalent linkages
Changes net charge of the protein and 3D structure
Describe the basis and interpretation of the HbA1c test
Glucose reacts with terminal valin of Hb to produce HbA1c, glycosylated Hb
% HbA1c is a good indicator of how effective blood glucose control has been
RBCs usually in circulation for 3 months
%HbA1c shows the average blood glucose concentration over last 2 to 3 months
Above 6.5% is undesirable. Poor control above 10%
Normal value between 4 and 6%
What are some long term macrovascular effects of diabetes?
Risk of stroke
Risk of myocardial infarction
Poor circulation to periphery: feet
Intermittent claudication: muscle pain in calf
Gangrene (poor blood circulation)
What are some long term microvascular complications of diabetes?
Diabetic eye disease: changes in lens due to osmotic effects of glucose (glaucoma) and possibly cataracts. Diabetic retinopathy: damage to blood vessels in the retina which can cause blindness. Blood vessels may leak and form protein exudates on retina, may rupture and bleed. New vessels may form and easily bleed
Diabetic kidney disease, nephropathy: due to damage to the glomeruli, poor blood supply due to change in kidney blood vessels, or damage from urinary tract infections. Early sign is microalbuminuria, protein in urine
Diabetic neuropathy: damage to peripheral nerves which directly absorb glucose, changes or loss of sensation, and also changes due to alteration in autonomic nervous system function
Diabetic feet: poor blood supply, damage to nerves, increased risk of infection. Gangrene.
How is insulin stored and transported?
What are its target tissues?
How does it act on cells?
Stored in beta cell storage granules as a crystalline zinc complex in vesicles
Dissolves in the plasma and circulates as a free hormone
Targets liver, skeletal muscle, adipose
Interacts with cell surface receptors, a dimer. Spans the membrane, alpha chains move together, fold around insulin. Moves beta chains together, active tyrosine kinase. Initiates phosphorylation cascade and GLUT 4 expression so cells can take up more glucose.
Where is glucagon secreted from?
What is its structure?
How is it synthesised?
How does it act on cells?
Alpha cells in the islets of the pancreas
SIngle chain polypeptide, flexible
Synthesised as a large precursor molecule which is cleaved in post translational processing from preproglucagon
Takes up active conformation when it binds to receptors on the surface of the cell.
G protein coupled receptor
Increases cyclic AMP in cells, which activate protein kinase A which posphorylates and activates important enzymes in cells
What are the properties of alpha and beta cells?
Lots of rough ER
Golgi
Mitochondria
Defined microtubule/ filament system
What signal stimulates insulin?
What signal stimulates glucagon?
Feeding
Fasting
What is the general affect of insulin?
ANABOLIC
Affects metabolism of carbohydrates, lipids and amino acids
Short term, clears absorbed nutrients from the blood following a meal
Long term, effects on cell growth and division relate to its ability to stimulate protein synthesis and DNA replication
What are the major actions of insulin?
Increased:
Glucose uptake into tissues
Glycogenesis in liver and muscle
Glycolysis in liver/adipose
Lipogenesis and esterification of fatty acids in liver/adipose
Lipoprotein lipase activity
Amino acid uptake and protein synthesis
Decreased:
Glycogenolysis in liver and muscle
Gluconeogenesis in liver
Lipolysis in adipose
Ketogenesis
Proteolysis
Describe the major actions of glucagon
Increased:
Glycogenolysis in liver
Gluconeogenesis in liver
Ketogenesis in liver
Lipolysis in adipose
Decreased:
Glycogenesis in liver
Describe the structure of insulin?
Large peptide
2 chains, alpha and beta
2 disulphide bridges for stability
How is insulin synthesised?
mRNA translated as preproinsulin on ribosomes of RER
Signal peptide removed on insertion to ER, creating proinsulin
In ER, proinsulin folds, disulphide bridges form
In the trans glogi packaged into storage vesicles
Proteolysis in vesicles to remove C peptide forming 2 chains
Secretory vesicles accumulate in cytoplasm. Margination to cell surface
Released by exocytosis
What is the C peptide a good marker for?
Endogenous insulin levels
As released along with the insulin
Cleaved inside the storage vesicles
How do glucose levels stimulate insulin release?
Increased glucose levels in the ECF
Glucose into cell by facilitated diffusion through GLUT 2
Leads to membrane depolarisation, influx of calcium ions
Triggers exocytosis of insulin
What are the key features of the pancreas?
Exocrine and endocrine, mixed gland
Fish shaped
Adjacent to the duodenum
Sits behind the stomach
Develops embryologically as an outgrowth of the foregut
Hormones produced in the Islets of Langerhans
1% endocrine tissue
Islets are adjacent to capillaries
What are the 5 polypeptide hormones produces in the islets of the pancreas?
Insulin: B cells
Glucagon: a cells
Somatostatin: d cells
Pancreatic polypeptide: f cells
Ghrelin: new cell type
What are the three zones of the adrenal cortex?
Which type of steroid hormone is produced in each?
Zona glomerulosa: mineralocorticoids such as aldosterone
Zona fasciculata: glucocoticoids such as cortisol
Zona reticularis: androgens such as testosterone
Salt, sugar, sex
What hormone is produced in the adrenal medulla?
Adrenaline/epinephrine
What does TSH do?
Where is it produced?
Stimulates the thyroid follicular cells to produce T3 and T4
Produced in the thyrotrophs of the anterior pituitary gland
What does ACTH do?
Where is it produced?
Controls the release of cortisol
Produced in the corticotrophs of the anterior pituitary
What does growth hormone do?
Where is it produced?
Important for growth of all tissues and metabolism
Counteracts insulin preventing glucose uptake
Stimulates IGF1 production in the liver
Produced in somatotrophs
What does prolactin do?
Where is it produced?
How is it controlled?
Initiates and maintains lactation
Acts on peripheral tissues, the breast
No target gland
High levels, lactation and menstrual disturbance
Stimulates production not release
Produced in the lactotrophs
Tonic inhibitory control by dopamine
Minor positive control by TRH
Oestrogen increases prolactin
What is the mechanism of action of ACTH?
Hydrophilic
Hihgh affinty receptors on cell surface of zona fasiculata and reticularis. Melanocortin receptor, cAMP as secondary messenger.
Leads to activation of cholesterol esterase increasing conversion of esters to free cholesterol
Also stimulates other steps in cortisol synthesis
Describe the action of cortisol
Stress response
Increases proteolysis, lipolysis and gluconeogenesis
What does aldosterone do?
Stimulates uptake of sodium ions in the kidney in exchange for potassium ions
Over secretion increases sodium and water retention causing hypertension and muscle weakness
Undersecretion causes hypotension
What do androgens do?
Stimulate growth and development of male gential tract
Development of secondary male characteristics
Anabolic actions on muscle protein
Produce male effects in females
What do oestrogens do?
Stimulate growth and development of female genital tractl breasts and female secondary characteristics
Weakly anabolic
Decrease circulating cholesterol
Describe the action of cortisol
Stress response
Affects availability of all substrates increasing proteolysis, lipolysis and gluconeogenesis
Decreased amino acid uptake + reduced protein synthesis + more proteolysis = MORE AMINO ACIDS
More hepatic gluconeogenesis + more glycogenolysis = MORE GLUCOSE
More lipolysis in adipose = MORE FATTY ACIDS
Decreased peripheral uptake of glucose = ANTI INSULIN
Direct effects on cardiac muscle, bone and the immune system
What is the general structure of steroid hormones?
eg cortisol
Derived from cholesterol which is tetracyclic with an OH group
Cortisol is a member of the C21 steroid family
Differs from other steroids in terms of
Number of C atoms
Number of C=C double bonds
Presence of functional groups
Synthesised via progesterone with enzymes
All are lipophilic and must be transported by plasma proteins like transcortin
Other examples: vit D/calciferol, glucorticoids, mineralocorticoids, progestins, androgens, oestrogens
How is adrenaline synthesised?
How are they stored?
What type of substance are dopamine, noradrenaline and adrenaline?
Enzyme catalysed
Tyrosine to Dopa to Dopamine to Noradrenaline to Adrenaline
Noradrenaline to adrenaline by methylation
They are stored in vesicles in the medullary cells
Catecholamines
What is synthesised in the adrenal medulla?
What type of tissue is it modified from?
Adrenaline, noradrenaline, some dopamine
Modified sympathetic ganglion
Describe the chemical properties of adrenaline?
When is it secreted?
Amine
Cyclic
-OH groups
Secreted in response to stress
Fight or flight response
What are the effects of adrenaline on various boduly systems?
CVS: increase cardiac output and increase muscle blood supply
CNS: increase mental alertness
CARBOHYDRATE METABOLISM: increase glycogenolysis in liver and muscle
LIPID METABOLISM: increase lipolysis in adipose
What are the clinical consequences of oversecretion of adrenaline?
What usually causes it? Give clinical name
Hypertension
Palpitations
Sweating
Anxiety
Pallor
Glucose intolerance
Usually caused by a tumour in the adrenal medulla
PHAEMOCHROMOCYTOMA
How do steroid hormones such as cortisol work on their target tissues?
Lipid soluble so can cross plasma membranes
Binds to cytoplasmic receptor
Hormone receptor complex travels to nucleus
Interacts with specific regions of DNA
Changes the rate of transcription of specific genes
May take some time to act
How does adrenaline act on its target cells?
Does not cross the cell membrane
Binds to adrenoreceptor on the outside of the cell
Secondary messenger affects cell activity
How is cortisol secretion controlled by CRH and ACTH?
Positive hypothalamic control from CRH
Secreted in response to chemical, physical and emotional stress
Stimulates release of ACTH from corticotrophs in the anterior pituitary
Both secreted in a pulsatile fashion
Increased activity in the morning, reduced at night
ACTH binds to cell surface receptors, zona fas. and ret.
Activated cholesterol esterase to free cholesterol
Negative feedback on both ACTH and CRH
Why does ACTH cause pigmentation in some parts of the body?
ACTH is a single chain polypeptide
Precursor is a large protein POMC
Post translational processing of POMC makes ACTH, a-MSH and endorphins
MSH sequence is inside ACTH
So some MSH activity when produced in excess, eg lack of negative feedback
Stimulates melanocytes to produce melanin, buccal cavity, scars, palmar creases
In Addisons or ACTH related Cushings
Describe how Cushing’s (syndrome or disease) is caused?
Increased activity of the adrenal cortex due to a tumour, adenoma
Tumour of the anterior pituitary secreting excess ACTH
Excess CRH
Ectopic secretion of ACTH
Compare the effects of high and low cotrisol
Deficiency: low glucose. Excess: High glucose
D: Weight loss. E: Weight gain
D: Nausea. E: Increased appetite
D: Hypotension. E: Hypertension
What are the clinical effects of Cushings?
Increased muscle proteolysis
Hepatic gluconeogenesis
Associated glucose increase in blood, polyuria and polydipsia - ‘steroid diabetes’
Prooximal muscle wasting, thin weak arms and legs
Purple straie on lower abdomen, catabolic effects on protein in skin. Easy bruising
Lipogenesis in adipose, deposition of fat in neck, abdomen and face, weight gain. Moon shaped face, cushingoid shape
Increased susceptibility to bacterial infections, acne, due to immunosuppressive, anti inflammatory and anti allergenic actions of cortisol
Back pain and rib collapse, osteroporosis, loss of bone matrix protein
Minveralocorticoid effects, retention of sodium and water producing hypertension
Describe how Addisons is caused
Diseases of the adrenal cortex, such as auto immune destruction, this reduces glucocorticoids and mineralocorticoids
Disorders in the pituitary or hypothalamus that lead to decreased ACTH or CRH secretion, only affects glucocorticoids
How are ACTH and cortisol levels measured?
Measurement of plasma cortisol and ACTH
MUST NOTE TIMING - circadian rhythm
Breakdown products measurement: 17 hydroxysteroids
24 hour urinary excretion of cortisol
What are the clinical effects of too little cortisol production (Addison’s) ?
Acute emergency (crisis) or chronic debalitating disorder (disease)
Loss of mineralocorticoids, hypotension due to sodium and fluid depletion, especially postural
Insidious onset with non specific symptoms of tiredness, extreme muscular weakness, anorexia, vague abdominal pain, weight loss, dehydration and dizziness
Increased pigmentation, more ACTH due to lack of negative feedback
Hypoglycaemia especially on fasting, decreased cortisol so decreased catabolism
Crisis can be caused by stress such as trauma, infection, leading to nausea, vomiting, extreme dehydration, hypotension, confusion, fever and even coma
Clinical emergency that must be treated with IV cortisol and fluid replacement, dextrose in saline to avoid death
What is the dexamethasone suppression test?
What disease does it test for?
Potent synthetic steroid
Normally when given orally, would suppress ACTH secretion and therefore cortisol
Supression of 50% is characteristic of Cushing’s, as although the diseased pituitary is relatively insensitve to cortisol it does respond somewhat to potent steroids
Does not suppress adrenal tumours or ectopic ACTH production
What is the synacthen test?
What disease does it test for?
What does stressing of the pituitary test for and how does it work?
Synthetic ACTH
Tests for primary adrenal addisons
Would usually increase plasma cortisol by more than 200ml
Normal response usually excludes Addisons
Tests for Addison’s by stress test, give insulin to induce hypoglycaemia. ACTH should increase.
Describe how cortisol can have week mineralocorticoid and androgen effects.
Steroid receptors form part of a family of nuclear DNA binding proteins that include thyroid and vit D receptors
They all have 3 main regions: hydrophobic hormone binding region, DNA binding region rich in cysteine and basic AAs, a variable region
Sequence homology in hormone binding region between glucocorticoids, mineralocorticoids, androgens, oestrogen, thyroid
Low affinity binding to other receptors
Significant when cortisol concentration is high
Stimulate fluid and sodium reabsorption in kidney, hypernatraemia, hypokalaemia
Stimulation of male genital tract and male characteristics, ANABOLIC
How is an insulin tolerance test used to test for growth hormone deficiency?
What about excess?
Insulin tolerance test
Stops somatostatin
GH increases if normal
Glucose tolerance test
Somatostatin up
GH decreases if normal
How is pituitary disease treated?
Surgery: transcranial or transphenoidal
Radiotherapy: external beam, gamma knife, protects vision but possible pituitary damage, increased stroke risk
Medical: dopamine agonists reduce prolactin.
Somatostatin analogues for acromegaly
GH receptor analogues stimulate IGF1
What is the embryological origin of the posterior pituitary gland?
What does it produce?
Neuroectoderm
Anti-diuretic hormone
Oxytocin
Describe the condition of diabetes insipidus
ADH deficiency or resistance
Water not reabsorbed by the kidney
Polyuria and polydipsia
High serum osmolality, low urine osmolality
Cranial - disease of the hypothalamus or pituitary stalk
How can a pituitary tumour present?
Visual disturbance: up growth compressing the optic chiasm
Lateral Carvernous sinus invasion affects cranial nerves
Secreting tumour:
More GH, acromegaly, coarse features, hypertension, headaches, diabetes, gigantism if before puberty
Prolactinoma: menstrual disturbance, galactorrhoea, infertility
ACTH: Cushings
Non secreting tumour: Posterior, no ADH, Diabetes insipidus. Anterior, low GH, LH, FSH< TSH, ACTH, more prolactin.
What are the causes of high prolactin?
5 Ps
Pregnancy
Physiological
Pharmacological
Pituitary: prolactinoma
Polycystic ovaries
Where are hormones produced and stored in the posterior pituitary?
Produced at the top
Stored at the bottom
What is growth hormone needed for?
What occurs if GH is
Deficient?
In excess?
Needed for skeletal growth, metabolism, muscle strength, bone density, cardiac function, quality of life
Deficient: short stature, in adult cause osteopenia, more fat, less muscle
Excess: acromegaly in adults, gigantism before puberty, can be abused in sport
Describe the condition of congenital adrenal hyperplasia
Enzyme deficiency
Build up of androgens
Less mineralocorticoids and glucocorticoids
Autosomal recessive
Virilisation of female baby, clitiromegaly
Neonatal salt losing crisis
Hypotension, hypoglycaemia, hyponatraemia
How are glucocorticoids replaced in Addison’s?
Hydro/flurocortisone
What are the causes of Addisons?
TB
Surgical removal
Haemorrhage
Infarction
Infiltration
Adrenal leukodystrophy
What advice is given to sufferers of addisons?
Increase steroids in incurrent illness
Steroid card, medic alert bracelet
Emergency 1M hydrocortisone ampoule
Describe the location of the thyroid gland
Neck
Anterior to lower larynx and upper trachae
Inferior to the thyroid cartilage
Recurrent laryngeal and external branch of superior laryngeal nerves lie close
Describe the structure of the thyroid gland
Highly vascularised, 3 arteries and veins, superior, middle and inferior
2 lateral lobes connected by a central isthmus
2 - 3 cm across, normally weighs 20g
2 major cell types: follicular and parafollicular
Abundant sympathetic and parasympathetic nervous system, stimulation by them increases thyroid hormone
Describe the follicular cells of the thyroid and how they are arranged
Arranged in units called follicles, seperated by connective tissue
Follicles are spherical
Lined by epithelial cells (follicular cells) surrounding a lumen
The lumen contains protein: colloid
Where are parafollicular cells found in the thyroid?
What are they also known as?
In the connective tissue around follicles
C cells
What hormones are produced in the thyroid?
Where?
In the follicular cells
T4: Thyroxine
T3: Triiodothyronine
In the parafollicular/C cells
Calcitonin
What are the general actions of thyroid hormones?
Needed to modulate metabolism
Role in growth and development
Needed for nervous development
What are the thyroid hormones derived from?
What are they soluble in?
Derived from tyrosine
With addition of iodine, the number refers to the number or iodine atoms
Soluble in fat
Compare the stability of T3 and T4
Which is released more?
What are their half lifes?
T4 is much more stable than T3
T4 is produced in large quantities then converted to T3 in the peripheral tissues
T3 has a shorter half life
How are T3 and T4 synthesised in the follicular cells of the thyroid gland?
(REGULATED BY TSH)
Transport of iodide actively into epithelial cells
With 2 Na+ ions (Sodium Iodide transporter, Na/K pump creates a Na gradient)
Synthesis of tyrosine rich protein THYROGLOBULIN in the epithelial cells
Exocytosis of thyroglobulin into the lumen of the follicle
Oxidation of iodide by peroxidase to create iodinating species
iodination of side chains of tyrosine residues to produce MIT and DIT
Coupling of MIT + DIT = T3
DIT + DIT = t4
How are thyroid hormones stored?
How long would the stores last for?
Stored extracellularly
In the lumen of the follicles
As part of the thyroglobulin molecules
Will last several months at the normal rate of secretion
How are the thyroid hormones secreted?
Thyroglobulin taken up into epithelial cells
By endocytosis
Proteolytic cleavage
Releases T3 and T4
Diffuse from epithelial cells
Into circulation
How are the thyroid hormones transported?
99% bound to proteins
Hydrophobic
TBG: Thyroid Binding Globulin
Pre albumin
Albumin
Only free hormone is active
T3 lower affinity for proteins so more is free and a shorter half life
What is the half life of
T3?
T4?
T3: 2 days
T4: 8 days
How is the activity of the thyroid gland controlled?
Hypthalamic and anterior pituitary control
TRH: tri peptide from dorsomedial nucleus of hypothalamus. Stress and decrease in temp increase secretion
Travels via hypophyseal portal system to anterior pituitary to stimulate TSH from thyrotrophs
TSH in blood to follicular cells
Negative feedback from thyroid hormones
How does TSH stimulate the release of the thyroid?
Action mechanism
Glycoprotein consisting of 2 non covalently linked subunits, alpha and beta
Released in low amplitude pulses
Circadian rhythm
Interacts with surface receptors
Stimulates synthesis and secretion of T3 and T4
Trophic effects increasing vascularity, size and number of follicular cells
Trophic effect can cause goitre which can be over or underactive
What is the effect of thyroid hormones on cells and the body as a whole?
Increase metabolic rate
Increased uptake of glucose and metabolism of it
Stimulate mobilisation and oxidation of fatty acids
Stimulate protein metabolism
Mainly catabolic so highger BMR, increased heat UCPs, increased o2 consumption
Response can occur slowly
How are T3 are T4 important for normal growth and development?
Affects on heart? Neurotransmitters? GI? Ovulation?
Bone mineralisation
Increase heart muscle protein synthesis
CNS development: cellualr processes of nerve cells hyperplasia of cortical neurones, myelination
Indirect hormone and neurotransmitter interaction: stimulate receptor synthesis
Tachycardia in heart muscle. Increased motility in GI tract
Permissive role in FSH and LH actions, ovulation fails in absence
Turnover of proteins and glycoproteins in skin and hair and nails
Describe how cretinism arise in the newborn and its reversibility
How is lack of thyroid hormone characterised in adult behaviour?
Absence of thyroid hormone from birth, hypo
Severe physical and mental retardation
Lack of CNS development
Coarse features, diminished linear growth, delayed sexual development
Must be corrected in a few weeks to reverse, all newborns are tested with T4/TSH assays
Hypo in adults”poor concentration, memory, lack of initiative
What is the mechanism of action of thyroid hormones?
Cross plasma membrane
Interact with high affinity receptors in the nucleus or possibly mitochondria
Binding of T3 to hormone binding domain
Unmasks DNA binding domain
Interaction of hormone receptor complex with DNA
Increases rate of transcription of specific genes that are translated into proteins
Stimulates oxidative energy metabolism
How is T4 converted to T3?
Why does this conversion happen?
How is reverse T3 produced and what are its properties
Removal of the 5’ iodide
Helps to regulate the amount of free hormone in the cells as T3 is 10x more active than T4
Removal of 3’ iodide produces rT3 which is inactive
What are the causes of hypothyroidism?
How is it treated?
Hashimotos: autoimmun destruction of follicles or production of an antibody that blocks the TSH receptor on follicular cells
Post surgery
Radioactive iodine
Anti thyroid drugs
Secondary: lack of TSH
Congenital
Iodine deficiency
Treated with oral thyroxine T4, measure TSH levels to stabilise.
What are the signs and symptoms of hypothyroidism?
Weight gain
Brady cardia
Cold intolerance
Dry and flaky skin
Alopecia
Tiredness
Deep husky voice due to goitre, trophic effect of more TSH
Neuromuscular: weakness, muscle cramps and cerebella ataxia (clumsiness)
Poor concentration/memory loss
Constipation
What are the causes of hyperthyroidism?
Grave’s disease: autoimmune, antibodies are produced which stimulate TSH receptors on follicle cells, resulting in increased T3 and T4 secretion
Toxic overproducing T3/4, multinodular goitre
Exessive T3/4 therapy
THyroid carcinoma, but 99% don’t cause hypo/hyperthyroidism
Ectopic thyroid tissue
How is Grave’s disease treated?
Carbimazole
Inhibits the addition of iodine into thyroglobulin
What are the symptoms of hyperthyroidism?
Heat intolerance
Weight loss
Tachycardia
Physical and mental hyperactivity
Intestinal hyperactivity
Increase appetite
Exopthalmos
Skeletal and cardiac myopathy, causing tiredness, weakness, breathlessness
Osteoporosis due to increased bone turnover and preferential reabsorption
Hyperreflexive
Increased perspiration
How is hyperthyroidism treated?
Carbimazole for graves
Thyroidectomy, complete or partial
Radioactive iodine
Then manage hypo
Important to be aware of parathyroids
Compare the signs and symptoms of hyperthyroidism and hypothyroidism
BMR and catabolic activity:
Hyper: increase. Hypo: Decrease
Sympathetic and CNS activity, GI tract, CNA:
Hyper: increase. Hypo: Decrease
Direct effect on tissues:
Hyper: CVS. Hypo: CVS, subcutaneous
Describe interpretation of thyroid function tests
Euthyroid: Normal free T4, Normal TSH
Hypothyroid: Low free T4, high TSH
Hyperthyroid: High free T4, low TSH
What is the variation like in thyroid function tests?
In a population
In an individual
Large variation in the population
Small variation in the inividual
How are oestrogen and thyroid binding globulin linked?
In pregnance
More oestrogen, more TBG synthesis
Fall in free T3/4
Removes negative inhibitory feedback
More TRH and TSH, so more T3 and T4
Free T3 and T4 back to normal
Total amount of thyroid hormones in the blood increases
How are the thyroid hormones inactivated?
T3 and T4 are degraded by removal of iodine
Liver and kidney
What is the incidence of thyroid disease?
More females than males
1-2% of women
Give some examples of cellualr process in which calcium plays a critical role
Hormone secretion
Nerve conduction
Inactivation/activation of enzymes
Muscle contraction
Exocytosis
intracellular secondary messenger
What level range is biologically free active calcium usually regulated to?
Calcium ions
between 1.0 to 1.3 mM
How does calcium exist in the plasma?
Free ionised species
Bound to proteins such as albumin
Complexed with organic anions like citrate and oxaloate
Why is phosphate important?
Is it controlled?
Part of adenosine triphosphate molecule
Crucial role in cellular energy metabolism
Activation and inactivation of enzymes
Not strictly regulated
Fluctuates during the day, e.g. after meals
Why are calcium and phosphate homeostasis linked?
Both are major components of calcium hydroxyapatit crystals which mineralise bone
They are regulated by the same hormones, parathyroid horomones, 1,25-dihydroxyvitaminD/calcitriol, and to a lesser extent calcitonin
These hormones act on bone, the kidneys, the GI tract to control levels of these ions in plasma
Differing effects on levels of each ion
What are the two main hormones involved in serum calcium control?
What do they do?
Parathyroid hormone
Calcitriol
They both raise serum calcium concentrations, but by different mechanisms and time scales
What is calcitonin thought to do?
In animals lowers serum calcium
In humans suggested to only preserve the maternal skeleton
Lowers serum calcium
Increase osteoclast activity
What tissues to PTH and calcitriol act on?
Bone: act on calcium hydroxyapatite store within collagen fibrils
Kidneys: filter, reabsorbed, most in PCT, then loop of Henle, hormonal control in DCT
Gut: in through diet and egest through faeces, taken up in duodenum and jejunum, secretions are rich in calciu. Energy dependant uptake
How is calcium in the serum regulated in the short term?
Where is the hormone secreted from?
Parathyroid hormone, PTH
Polypeptide hormone
Secreted from the parathyroid glands, typiaclly 2 pairs, by CHIEF CELLS
Describe how PTH regulates serum calcium
Changes in calcium ion concentration alter PTH by negative feedback
Chief cells have unique G protein calcium receptors on the cell surface
Increased calcium binding to G protein binding receptors
stimulates Phospholipase C
inhibiting adenylate cyclase
This leads to reduced cAMP
and reduced PTH release
Reverse occurs when calcium is low
What is the effect of PTH on
Bone?
Kidneys?
Gut?
Bone: osteolysis within 1 to 2 hours. Osteoblast synthesis. Cytokines secreted which expose the bone surface. Decrease osteoblast activity, which usualy protect bony surface. Protect osteoclasts from apoptosis. Reabsorption of mineralised bone, release of Pi and calcium into ECF
Kidney: Affects tubular cells. In DCT, increases calcium ion reabsorption, therefore decreasing excretion. Supresses reabsorption of Pi, which prevents calcium stone formation.
Gut: stimulates conversion of vitamin D to active form. Increased uptake of caclium from the cut, less egested.
How does vitamin D work to control serum calcium?
Long term action
Increase calcium and Pi absorption in gut, active uptake
Mobilise calcium stores in bone
Stimulate reabsorption in the kidney
Explain the interaction of parathyroid and vitamin D
Vitamin D is formed in the skin or absorbed in the gut from the diet
Has a short half life
So is converted to calciferol (25-hydroxyvitamin D) in the liver, which has a 2 week half life
Vitamin D is not regulated
Final conversion is in the kidney to calcitriol, regulated by PTH
Hydroxylation of C1
Explain regulation of PTH
Transcriptional and post transcriptional level
Low serum calcium up regulates transcription and prolongs mRNA survival
High serum calcium down regulates transcription
Contrinually synthesised but little store
Chief cells degrade and synthesise
Increased PTH cleavage in cheif cells, increased by high serum calcium
Released PTH cleaved in liver
Negative feedback
Explain regulation of vitamin D
Two forms vitamin D2 (gut) and D3 (sunlight) both form calcitriol and are equipotent
Needs 2 hydroxylations
In liver at c25, not regulated
In kidney at C1, regulated by PTH
Explain the significance of renal function on calcium metabolism
PTH affects tubular cells in the kidney
Increase calcium reabsorption in the DCT
Pi is removed from circulation by inhibition of reabsorption in PCT
Prevents calcium stone formation
What is hypocalcaemia?
Decrease in plasma calcium
Leads to parathesia - tingling
Tetany: involuntary muscular contraction
Paralysis, even convulsions
Due to low amount of calcium bound to the NMJ membrane, allowing Na+ to depolarise it much more easily, lowers threshold
More PTH, can cause rickets
What is hypercalcaemia?
High serum calcium levels
MOANS GROANS AND STONES
May result in formation of kidney stones, renal calculi
Constipation
Dehydration (treat with fluids lost in urine)
Kidney damage
Tiredness and depression
Could be primary hyperparathyroidism, remove benign tumour
What can cause PTH deficiency?
Effects?
Accidental surgical removal
Life threatening hypocalcaemia
Describe how an ectopic tumour can produce hypercalcaemia
Breast/ prostate/ sometimes myeloma etc
Parathyroid hormone related peptide (PTHrp) is a peptide hormone produced by these
Leads to humeralhypercalcaemia of malignancy
Similar structure to PTH
Increased calcium release from bone, less calcium excreted, less phosphate reabsorption
Does not increase C1 hydroxylasse activity in the kidney so does not increase calcitriol concentration
How much weight will a woman typically gain in pregnancy?
Why?
8kg
As the mother has to supply everything required for the growth of the foetus: nutrients, vitamins, minerals, oxygen and water
How are nutrients transferred to the foetus from the maternal circulation?
Mainly diffusion, facilitated diffusion
Placental exchange
Some active transport
What metabolic changes occur in the first half of pregnancy?
Preparatory increase in maternal nutrient stores
Especially adipose
Bigger apetite
Ready for more rapid growth of foetus, birth and lactation
Increasing levels of insulin promote anabolism
Increased beta cell glucose sensitivity, hyperplasia and hypertrophy
More glycogen
Increased insulin action on storage tissues
Less insulin action on energy using tissues
Which hormones are involved in the adaptive responses of maternal metabolism?
What do they do?
Maternal insulin: concentration in maternal circulation increases.
Acts to promote the uptake and storage of nutrients, largely as fat in adipose
Foetal-placental hormones: more imporant as pregnancy processd
Largely oppose the actions of insulin: anti-insulin
Maintain the glucose gradient to ensure it is in constant supply
What are the main maternal adaptations to metabolism in pregnancy?
Adjust maternal blood concentrations
Modify nutrient stores to cope with demands, highest in late pregnancy and lactation
Minimal disturbance to maternal homeostasis
Fat stores accumulate in first half
Increase in blood volume
Placenta supersedes HPA axis
What metabolic changes occur in the second half of pregnancy?
Marked increased in growth of the placenta and foetus
Adapts to increased demand
Foetal placental demands are met by keep concentration of nutrients high (glucose above 5mM) in maternal circulation by:
Reduce maternal utilisation of glucose, switch to fatty acids
Delay maternal disposal of nutrients after meals
Relase FAs from stores
Maternal levels of insulin still increase, but anti insulins at a faster rate (oestrogen, progesterone, human placental lactogen)
Why does maternal ketogenesis occur in the second half of pregnancy?
Marked decrease in insulin to anti insulin ratio
More fatty acids to the liver
Ketone bodies fuel for the fetal brain
Why do some women develop gestational diabetes?
What are the consequences?
B cells in the endocrine pancreas unable to response to the metabolic demand of pregnancy
Fails to release the amount of insulin required
loss of control of metabolim, blood glucose increases, diabetes results
Consequences: effects of hyperglycaemia, excess fetal growth, macrosomia, fat baby with lots of liver and muscle glycogen, difficult delivery
Usually corrects after birth
Women may be more likely to develop type 2 diabetes later in life
Treat with insulin short term if severe
What does the metabolic response to exercise in the body ensure?
Energy demands of cardiac and skeletal muscle are met by fuel mobilisation from stores
Minimal disturbances to homeostasis keep rate of mobilisation equal to rate of utilisation
Glucose supply to brain is maintained, prevent hypoglycaemia
Waste products removed as quickly as possible
Oxygen supply maintained
Adaptations to temperature, CVS and resp. system
What does the nature and extent of the metabolic response depend on?
Type of exercise, muscles used
Intensity and duration of exercise
Physical and nutritional status of individual
What are the energy requirements during exercise?
ATP needed to detach myosin from actin in muscle contraction
Energy from hydrolysis
ADP must be converted back by coupling to oxidation of fuel molecules
Glycogen and TAGs
How is glycogen used in exercise?
Aerobic, last for long periods, 1 hr
Anaerobic, very quick, 2 mins
Liver helps to prevent hypoglycaemia and keep up CNS
Muscle advantageous as availability not affected by blood supply, no need for membrane transport into muscle cells, G 6 P produced without ATP
Can’t produce glucose as no G 6 P phosphatase
What is the issue with glycogen metabolism in anaerobic exercise?
Build up of lactate and H+
H+ exceeds buffering capacity
Produces fatigue as function is impaired
Inhibits glycolysis by H+
H+ interferes with actin and myosin
H+ causes sarcoplasmic reticulum to bind calcium which inhibits contraction
What limits the use of fatty acids from TAGs in muscle during exercise
Rate of fatty acid release, lipolysis
Limited carrying capacity in blood: albumin
Raate of fatty acid uptake into cells and mitochondria, cartinine shuttle in B oxidation
More oxygen needed per mole to metabolise FAs than glucose
Can only be metabolised aerobically
What hormones are needed to mobilise reserves?
Insulin needed to express GLUT4 channels to take up glucose
Glucagon stimulates glycogenolysis in lover
Adrenaline causes glycogenolysis in muscle
Explain the benefits of exercise
Body composition changes: more muscle, less adipose
Glucose tolerance improves, muscle glycogenesis increases
More GLUT 4 channels
Insulin sensitivity of muscles increases
Blood lipids decrease, VLDL and LDL down, HDL up
Blood pressure falls
Psych effects: well being
Explain the body’s response to training
Muscle
and
CVS
Skeletal muscle changes:
More and bigger fibres
More GLUT4
More capillaries
Better B oxidation capacity, more mitochondria
More myoglobin
More glycogen storage
CVS changes:
Lower heart rate for same output
Hypertrophy of let ventricle
Lower BPM
More 2,3-BPG in blood, lowers Hb affinity
Describe the metabolic response to short duration high intensity exercise?
Confined to skeletal muscle that works anaerobically
Controlled by nervous system, noradrenaline, with some input endocrine, adrenaline
Muscle ATP and creatine phosphate used first
Muscle glycogen mobilised to provide G 6 P
G 6 P mobilised via glycolysis
Anaerobic glycolysis oxygen supply inadequate
Produces lactate and H+, acidotic effecct, cramp as H+ stimulate nerve ends
Describe the metabolic response to medium intensity exercise
Regenerates ATP 60% aerobic, 40% anaerobic metabolism of glycogen
Must eliminate lots of CO2 but no major problem with H+, can be buffered
Initial sprint: ATP and C P used, anaerobic glycogenolysis
Long middle phase, ATP aerobically from glycogen in muscle, some lipolysis
Finishing burst with anaerobic glycogenolysis producing lactate
Describe the metabolic response to long duration low intensity exercise
Carbohydrate stores insufficient to complete distance so fatty acids must be oxidised by muscle cells
Mostly aerobic, use all fuel types
Muscle glycogen used in a few mins
Glucose from liver glycogen
Gluconeogenesis
FA beta oxidation
Control is mainly hormonal: insulin levels fall. Adrenaline noradrenaline and growth hormone rise rapidly to promote lipolysis. Cortisol and glucagon levels rise gradually, mobilise fats and gluconeogenesis
