Metabolism Flashcards

Question

What are the fates of nutrients in the body?

Answer 1

Degraded to release energy in all tissue Synthesis of cell components in all tissues except RBCs Storage in liver muscle or adipose tissue

Answer 2

``` Break down of large molecules into smaller molecules Exergonic Oxidative Produces intermediate cell metabolites Stimulated by low energy signals ```

Answer 3

``` Synthesis of large molecules from smaller molecules Endergonic Reductive Uses metabolites from catabolism Stimulated by high energy signals ```

Answer 4

``` Mechanical (muscle contraction) Electrical (nerves) Transport (active) Biosynthesis (e.g. Protein) Osmosis (kidneys, large intestine etc) ``` If insufficient energy intake- body uses stores

Answer 5

Synthesis of ATP is anabolic/ endergonic Breakdown of ATP is catabolic/ exergonic (used by cells) Terminal phosphate bond contains large amount of energy- which is released in hydrolysis Adenine and three phosphates

Answer 6

Creatine + ATP = creatine phosphate + ADP So ATP can be quickly regenerated when required CREATINE KINASE

Answer 7

Measured of muscle mass Determinant for kidney function Comparison for other nutrient measurements

Answer 8

``` NAD+ (niacin) FAD (flavin) NADP (niacin) CARRIERS OF BIOSYNTHETIC REDUCING POWER Change between oxidised and reduced form ``` Obtained from vitamin B ()

Answer 9

By the addition of 2 H

Answer 10

Remains constant

Answer 11

Loss of electrons and H+ | Exergonic

Answer 12

Gain of electrons and H+ | Endergonic

Answer 13

ATP, NADPH, NADH, FADH2 | activates anabolism

Answer 14

AMP, ADP, NADP, FAD, NAD+

Answer 15

C H O Polysaccharide chain made up of monosaccharides joined together by glycosidic bonds in condensation reactions Contain aldehyde or ketone groups

Answer 16

Monomer unit for carbohydrates Asymmetric carbon atom (stereoisomers) Natural form = d form (not l) Usually 3-9 carbon atoms

Answer 17

Two monosaccharides units joined by a glycosidic bond

Answer 18

Lactose (galactose and glucose) Sucrose (fructose and glucose) Maltose (glucose and glucose)

Answer 19

Carbohydrates with 3-12 monosaccharide units

Answer 20

Carbohydrates with 10-100 monosaccharide units

Answer 21

Glycogen-polymer of glucose, animals, alpha 1,4 and 1,6 bonds, highly branched Starch-polymer of glucose, plants, mixture of amylose and amylopectin, alpha 1,4 and 1,6 bonds, less branched than glycogen, broken down to glucose and maltose by GI tract enzymes Cellulose- structural polymer of glucose, plants, beta 1,4 bonds, no GI enzymes exist to digest these bonds, dietary fibre important for normal GI function

Answer 22

``` Salivary amylase (digest alpha 1,4) Pancreatic amylase (digest alpha 1,4) Maltase Lactase Sucrase Isomaltase (digest alpha 1,6) ```

Answer 23

Actively transported into the intestinal epithelial cells | Facilitated diffusion out of epithelial cells into the blood (using GLUT1-5 transport proteins)

Answer 24

Glucose transport proteins which alter their affinity for glucose according to the differences in requirements of tissues for glucose E.g glut 4 sensitive to presence of insulin in skeletal muscle and adipose tissue (high insulin increases glucose uptake by these cells by increasing number of transport proteins in plasma membrane)

Answer 25

Some tissues have an absolute requirement of glucose and the amount of glucose uptake by these tissues is dependent on the concentration in the blood RBCs, kidney medulla, lens of eye, WBCs, peripheral nerves Brain and CNS prefers glucose

Answer 26

180g/day 40g/day by RBCs WBCs kidney medulla lens of eye 140g/day by CNS Various amounts required by tissues for specialised functions (e.g. Synthesis of tags in adipose tissue requires glucose as it needs glycerol phosphate)

Answer 27

Glycolysis Link reaction Krebs cycle Oxidative phosphorylation

Answer 28

Amino group is removed by deamination Amino group goes to urea cycle or undergoes ammonia detoxification Carbon skeleton- -- glucogenic: glycolysis (pyruvate) or Krebs cycle (oxaloacetate, fumerate or alpha ketoglutarate) -- ketogenic: ketone body synthesis (acetyl coA) Amino group is transferred to a keto acid using amino transferase enzymes Keto acid generated can be metabolised in the Krebs cycle (glucogenic and ketogenic as above) aa1 + ka2 --> ka1 + aa2

Answer 29

Alanine + alpha ketoglutarate = pyruvate + glutamate

Answer 30

Alanine amino transferase

Answer 31

Aspartate + alpha ketoglutarate = oxaloacetate + glutamate

Answer 32

Aspartate amino transferase

Answer 33

Step 1 hexokinase and glucokinase (exclusively found in the liver) Step 3 phosphofructokinase 1 Step 10 pyruvate kinase

Answer 34

Pyruvate dehydrogenase

Answer 35

Isocitrate dehydrogenase

Answer 36

Glucose 6-phosphate product inhibition

Answer 37

Muscle : By allosteric regulation Simulated by AMP, ADP, citrate Inhibited by ATP Liver : By hormonal regulation Stimulated by high insulin: glucagon Inhibited by low insulin: glucagon

Answer 38

Dephosphorylation- covalent modification Stimulated by high insulin: glucagon ratio Inhibited by low insulin: glucagon ratio

Answer 39

Cytoplasm of all body cells

Answer 40

Oxidise glucose, produce 2 NADH Synthesise 2 ATP (net) Produces c6 and c3 intermediates (glycerol phosphate (for fatty acid synthesis) and 2-3BPG)

Answer 41

``` Exergonic, oxidative (catabolism) C6--> 2C3 no loss of C Operates anaerobic ally Cytoplasm of all cells Irreversible ```

Answer 42

Fructose --> Fructose-1-Phosphate --> Glyceraldehyde --> Glyceraldehyde-3-Phosphate --> GLYCOLYSIS Fructose --> Fructose-1-Phosphate --> Dihydroxyacetone phosphate (DHAP) --> Glyceraldehyde-3-Phosphate --> GLYCOLYSIS

Answer 43

``` Fructose kinase (F to F-1-P) Aldolase (F-1-P to glyceraldehyde) ```

Answer 44

Essential fructosuria

Answer 45

Fructose intolerance | Fructose-1-Phosphate accumulates in liver = liver damage

Answer 46

Galactokinase (Gal to Gal-1-P) | Galactose-1-Phosphate uridyl transferase (Gal-1-P to G-1-P)

Answer 47

Build up of galactose Increased conversion of galactose into galactitol using aldose reductase and NADPH Depletes levels of NADPH (normally prevents formation of SS bonds) in lens Formation of disulphide bonds between cysteine residues on proteins in lens= cataracts

Answer 48

Build up of galactose Increased conversion of galactose into galactitol using aldose reductase and NADPH Depletes levels of NADPH (normally prevents formation of SS bonds) in lens Formation of disulphide bonds between cysteine residues on proteins in lens= cataracts Build up of galactose-1-phosphate Damage to liver kidney and brain Toxic to hepatocytes = liver damage Bilirubin (which is produced from haem in breakdown of RBCs in the spleen) can't be conjugated by liver and so is released in to the blood = jaundice

Answer 49

Glycolysis would stop due to accumulation of NADH inhibiting some steps (Normally NAD+ is regenerated in oxidative phosphorylation but in anaerobic conditions this cannot occur)

Answer 50

Oxygen is the final acceptor in the electron transport chain Lack of oxygen means electron transport chain will stop- oxidative phosphorylation cannot occur - as no free energy is being produced and so no pmf is produced Therefore no NAD+ is being regenerated

Answer 51

Glycolysis (anaerobic) + | Pyruvate--> lactate (using lactate dehydrogenase) = reduction reaction

Answer 52

They lack mitochondria which are the site of aerobic catabolism

Answer 53

By RBCs all the time and by skeletal muscle under anaerobic conditions

Answer 54

Released in the blood Normally metabolised by LIVER and HEART via LDH back to pyruvate (since liver and heart are generally well supplied with oxygen and so can quickly perform the reaction when anaerobic conditions cease)

Answer 55

Plasma conc 2-5 mM Below renal threshold No change in blood pH (buffering capacity)

Answer 56

Above 5mM Above renal threshold- lactosuria Blood pH lowered (lactate itself does not cause the lowering of pH- the fact that H+ ions, which are released in ATP hydrolysis, are not being reincorporated back into ATP synthesis in oxidative phosphorylation means that H+ concentration increases) Cramps, pains

Answer 57

40-50g/day

Answer 58

Normally metabolised by LIVER and HEART via LDH back to pyruvate (since liver and heart are generally well supplied with oxygen and so can quickly perform the reaction when anaerobic conditions cease) Heart--> CO2 Liver --> glucose (gluconeogenesis) ------ impaired in liver disease, thiamine vitamin B1 deficiency, alcohol consumption (NAD+ --> NADH), enzyme deficiencies

Answer 59

Low activity of lactase Lactose can't be broken down in the gut so remains and lowers wp in the large intestine so increased water loss = diarrhoea and dehydration Bacteria colonise indigested lactose and ferment it to produce organic acids that irritate the GI= stomach cramps

Answer 60

2 stage (multistep) pathway, break from glycolysis! - oxidative decarboxylation of G-6-P by G-6-P dehydrogenase G-6-P + NADP+ --> C5 sugar + CO2 + NADPH -rearrangement back to glycolytic intermediates 3C5 sugars ~~~~> 2-fructose-6-phosphate + 1-glyceraldehyde-3-phosphate

Answer 61

No ATP production Loss of CO2 therefore irreversible Controlled by NADP+/NADPH ratio at G-6-P dehydrogenase

Answer 62

Glucose-6-Phosphate dehydrogenase

Answer 63

Produces NADPH in cytoplasm- Biosynthetic reducing power (for fatty acid synthesis so high activity in liver and apipose) and maintain free S-H on cysteine residues in certain proteins/ prevent oxidation to S-S (disulphide bond) Produces C5 sugars for nucleotides needed for nucleic acid synthesis (so high activity in dividing tissues e.g. Bone marrow)

Answer 64

Liver and adipose tissue- fatty acid synthesis Dividing tissues (bone marrow)- c5 nucleotides RBC and lens of eyes- need NADPH to prevent formation of S-S bonds

Answer 65

``` NADPH C5 sugars (ribose) ```

Answer 66

Cataracts | Galactosuria

Answer 67

Cataracts Galactosuria Liver damage Jaundice

Answer 68

Galactose --> Galactose-1-Phosphate --> Glucose-1-Phosphate --> Glucose-6-Phosphate --> GLYCOLYSIS

Answer 69

Reduction in NADPH causes: Reduction in fatty acid synthesis Less maintenance of SH residues in lens of eyes= formation of disulphide bonds= CATARACTS in lens of eye Less maintenance of SH residues in RBCs= formation of disulphide binds between haemoglobin molecules= Heinz bodies= increased breakdown of RBCs by spleen= ANAEMIA = increased amount of bilirubin in liver= liver can't conjugate all the bilirubin= some released back into blood= JAUNDICE Oxidised form of glutathione (with disulphide bonds) stabilised= so reduced glutathione is not available to detoxify/ reduce hydrogen peroxide and other ROS's = oxidative stress

Answer 70

Anti malarials have the side effect of oxidising glutathione (disulphide bridges formed) Reduced Glutathione (and NADPH) both prevent the formation of disulphide bonds between haemoglobin molecules So when an anti malarial oxidises glutathione, it is no longer able to present formation of disulphide bonds- which consequently form = Heinz bodies

Answer 71

Occurs in anorexic patients, cancer patients, post surgery, alcoholics Unclear cause- occurs from reintroduction of calories to malnourished Metabolic disturbance due to shift away from predominantly fat metabolism Need to closely monitor electrolytes and treat disturbances carefully Risks include confusion, coma, convulsions and death

Answer 72

In the mitochondrial matrix

Answer 73

Pyruvate dehydrogenase

Answer 74

5 enzyme complex- different enzymes require different cofactors (FAD, thiamine pyrophosphate, lipoic acid= all provided by vitamin B) Pyruvate --> acetyl coA

Answer 75

Pyruvate + NAD+ + coA --> acetyl coA + NADH + CO2 Irreversible! Using PDH

Answer 76

IRREVERIBLE AS CO2 IS LOST = key regulatory step

Answer 77

Stimulated by coA, NAD+, ADP, (pyruvate and insulin) | Inhibited by acetyl coA, NADH, ATP

Answer 78

Vitamin B1 (thiamine) - provides the cofactors (FAD, thiamine pyrophosphate and lipoid acid) needed by the different enzymes in the PDH enzyme complex

Answer 79

Lactic acidosis as lactate dehydrogenase pathway is stimulated

Answer 80

Mitochondrial Single pathway- central pathway in catabolism of sugars, fatty acids, ketone bodies amino acids and alcohol Acetyl converted to 2CO2 Oxidative/exergonic/ requires NAD+ and FAD Produces lots of NADH FADH2 - used to drive ATP synthesis in ox phos Some energy produced as ATP/GTP Produces precursors for biosynthesis (amino acids, haem, glucose and fatty acids) Occurs twice for every molecule of glucose entering glycolysis Only functions in presence of oxygen

Answer 81

Isocitrate dehydrogenase

Answer 82

Regulated by energy availability ATP/ADP ratio and NADH/ NAD+ ratio Stimulated by ADP (low energy signals) Inhibited by NADH (high energy signals)

Answer 83

Electron transport- electrons in NADH and FAD2H transferred through a series if carrier molecules to oxygen; releases energy in steps ATP synthesis by Oxidative phosphorylation- free energy released used to drive ATP synthesis

Answer 84

Inner mitochondrial membrane

Answer 85

NADH and FAD2H carriers transfer their electrons to carrier molecules in the mitochondrial membrane, which transfer electrons to molecular oxygen and are organised into a series of 4 highly specialised protein complexes spanning the entire mitochondrial membrane 3 complexes (I, III AND IV) act as proton translocation complexes Free energy from electron transport is used to move protons from the inside to the outside of the inner mitochondrial membrane via the proton translocation complexes The mitochondrial membrane itself is impermeable to protons and as electron transport continues, concentration of protons outside the inner mitochondrial membrane increased Proton translocation complexes transform chemical bond energy of electrons into an electrochemical gradient of protons across the membrane = proton motive force ATP synthesis requires 31kJ/mol energy from pmf to drive the reaction Protons renter the mitochondrial matrix bis ATP synthase complex (V) driving the synthesis of ATP from ADP and Pi Oxygen acts as the final electron acceptor of the electron transport chain

Answer 86

NADH uses 3 whereas FAD2H uses 2 | Because electrons in NADH have more energy than in FAD2H

Answer 87

The greater the pmf the more ATP synthesis

Answer 88

2.5 ATP/ mole of NADH

Answer 89

1.5 ATP / mole FAD2H

Answer 90

Mitochondrial concentration of ATP

Answer 91

Tightly Coupled

Answer 92

When ATP: ADP ratio is high = no substrate for ATP synthase = inward flow of protons stops = increase in conc of protons in inner mitochondrial space= prevents further pumping of protons= stops electron transport

Answer 93

Dinitrophenol Dinitrocresol Fatty acids

Answer 94

Uncouplers work by uncoupling electron transport and ATP synthesis Uncouplers penetrate the inner mitochondrial membrane Uncouplers increase permeability of inner mitochondria membrane for protons Protons reenter the mitochondrial matrix ATP synthase not activated so no ATP synthesis Pmf is dissipated as heat Electron transport and thus NADH/FAD2H oxidation continues Free energy is released as heat Respiration continues to bring more NADH and FAD2H to mitochondria and uses up fuel molecules (fatty acids, glucose etc) More and more heat production

Answer 95

``` Cyanide and carbon monoxide Binds to IV (ptc) Stops electron transport Blocks NADH and FAD2H oxidation No free energy is produced No pmf No ATP synthesis Cell death ```

Answer 96

Genetic defects in proteins encoded by mtDNA (some subunits of the PTCs and ATP synthase) which cause a decrease in electron transport and ATP synthesis

Answer 97

Transamination

Answer 98

Alpha keto glutarate- always produces glutamate when an amino group is added

Answer 99

Important intermediate in the synthesis of urea

Answer 100

L and D amino acid oxidases in the liver (D has a higher activity)

Answer 101

Glutamine is converted into glutamate and ammonia by glutaminase Glutamine --> glutamate + NH3 (glutaminase) Produced glutamate is then converted to alpha ketoglutarate and an ammonium ion by glutamate dehydrogenase Glutamate + NAD + H2O --> alpha ketoglutarate + NADH + H+ + NH4+ (glutamate dehydrogenase)

Answer 102

There are no known defects in Krebs and ureas cycle that allow life to be sustained as a lack in any enzyme would result in DEATH

Answer 103

Phenylalanine--> tyrosine (phenylalanine hydroxylase) Inherited recessive condition = Defective enzyme: phenylalanine hydroxylase Phenylalanine accumulates in tissues and is metabolised by their pathways Phenylketones (phenylpyruvate) are produced in an alternative pathway: Phenylalanine--> phenylketones

Answer 104

Hypopigmentation If not picked up- it can cause mental retardation as phenylalanine inhibits brain development Lack of tyrosine (usually involved in synthesis of neurotransmitters, hormones, noradrenaline, adrenaline) leads to decrease in neurotransmitters Phenyl pyruvate prevents pyruvate uptake into mitochondria- brain energy metabolism

Answer 105

Transamination reaction | Phenylalanine + alpha ketoglutarate --> phenyl pyruvate + alpha glutamic acid

Answer 106

Phenylalanine is a large neutral amino acid (LNAA) and so competes with other LNAA's for transport across the brain blood barrier via LNAAT (transporter) If excess phenylalanine is present (in the case of PKU) this saturates the LNAAT thereby decreasing the levels of other LNAA's (essential for neurotransmitters and protein synthesis) entering the brain As a result phenylalanine builds up hindering the development of the brain and causing MENTAL RETARDATION

Answer 107

Heel prick test at birth

Answer 108

Phenylalanine hydroxylase

Answer 109

Homocysteine--> cystathione --> cysteine (cystathione beta synthase) (vitamin B6 and folate) Inherited recessive condition = Defective enzyme: cystathione beta synthase Homocysteine accumulates in tissues and is metabolised by other pathways Methionine is produced in an alternative pathway: Homocysteine --> methionine (vitamin B12)

Answer 110

Cystathione beta synthase

Answer 111

Affects muscles, CNS and CVS | Fibrillin 1 protein is affected- unstretchy skin

Answer 112

Homocystine (oxidised form of homocysteine) Methionine is not found in the urine because kidneys have a higher renal threshold for methionine than for homocystine and so methionine is reabsorbed into the blood whereas homocystine is not)

Answer 113

Vitamin b12

Answer 114

Avoiding phenylalanine in diet

Answer 115

Homocysteine affects fibrillin1 production much like in Marfan's Results in tall stature, less stretchy skin due to this effect on connective tissue

Answer 116

Supplement vitamin b6 and folate (increase activity of CBS) Low methionine diet Supplements of cysteine Medication to reduce levels of homocysteine

Answer 117

Disease in which there is lack of expression of fibrillin 1 protein- affects connective tissues

Answer 118

Arms length versus height

Answer 119

Renal threshold for methionine is much higher than it is for homocystine - so methionine is reabsorbed into the blood whereas homocystine remains in urine

Answer 120

Homocysteine is a sulphur containing compound which increases its potential for oxidative stress This results in increased atheroma formation in coronary arteries a a younger age High risk of artery rupture due to defective fibrillin 1 formation (elastin) so high pressure in arteries OR oxidative stress (high sulphur content)

Answer 121

Example of uncoupling process BAT in babies and mice In response to cold noradrenaline activates lipase to release fatty acids from TAGs Fatty acids activate UCP1 and themselves undergo oxidation to produce NADH and FAD2H for electron transport UCP1 transports H+ back into mitochondria So electron transport and ATP synthesis are uncoupled and pmf is captured as extra heat

Answer 122

Broken down into fatty acid and glycerol (breakdown and recombination occurs a lot throughout) Fatty acid undergoes beta oxidation- combined with coA using fatty acyl coA synthase to make fatty acyl coA; taken into mitochondria using the carnitine shuttle; beta oxidation then occurs- 2 C lost in every cycle, using FAD/NAD+ and H2O Acetyl coA is formed as a result--> Krebs cycle or ketone body synthesis Glycerol--> glycerol phosphate (glycerol kinase) - -> Dihydroxyacetone phosphate (DHAP) - -> 2-Glyceraldehyde-3-phosphate - -> GLYCOLYSIS

Answer 123

``` A Acetyl coA molecule is converted into Malonyl coA: Acetyl coA(2) + CO2 + ATP ---> Malonyl coA(3) + ADP + Pi (acetyl coA carboxylase) Malonyl coA(3) is combined with another acetyl coA(2) using NADPH in repeat cycles- in each cycle a CO2(1) is lost - so at the end if each cycle a molecule is produced with 2 more carbons than the original eventually producing fatty acyl coA (~C16) (fatty acid synthase) Fatty acyl coA is elongated and desaturated in the ER and combined with glycerol 3 phosphate to produce a TAG ```

Answer 124

Triacylglycerols- three fatty acids and one glycerol

Answer 125

Esterification of glycerol and 3 fatty acids

Answer 126

Lipolysis of TAG with 3 water molecules

Answer 127

* Fatty acid derivatives- TAGs (storage and insulation), phospholipids (cell membrane and plasma lipoproteins), eicosanoids (local mediators) * Hydroxy-methyl-glutaric acid derivatives- ketone bodies (water soluble fuel molecules- can cross blood brain barrier; substitute for glucose can be made from fatty acids), cholesterol (membranes and steroid hormone synthesis), cholesterol esters (storage of cholesterol), bile acid and salts (lipid digestion) * Vitamins- DAKE

Answer 128

NO as it requires NAD+ and FAD which need to be regenerated in the aerobic stage 4 of metabolism- so without oxygen fatty acid metabolism CANNOT OCCUR

Answer 129

Acetoacetate Acetone Beta hydroxy butyrate

Answer 130

In the liver under conditions of starvation or type 1 diabetes TAGs (storage)--> Fatty acids --> Acetyl coA--(HMGcoA synthase)--> HMG coA --(HMG coA lyase)--> acetoacetate --> acetone (spontaneous decarboxylation of acetoacetate) OR beta hydroxy butyrate

Answer 131

TAGs (storage)--> Fatty acids --> Acetyl coA--(HMGcoA synthase)--> HMG coA --(HMG coA reductase)--> mevalonate --> cholesterol

Answer 132

Statins inhibit cholesterol synthesis by inhibiting the enzyme HMG coA reductase

Answer 133

``` Ketone bodies are produced in conditions of starvation or in type 1 diabetes when an alternative source of fuel is required for organs like the brain! Lyase enzyme Hormone regulation Stimulated by glucagon Inhibited by insulin ``` Regulated by the availability of carbohydrates for the body cells - so when no carbohydrates are available in starvation and type 1 diabetes- ketogenesis occurs

Answer 134

HMG coA synthase and lyase

Answer 135

HMG coA synthase and reductase

Answer 136

Alcohol--(alcohols dehydrogenase and CYP2E1)--> acetaldehyde --(aldehyde dehydrogenase)--> acetic acid/ acetate Alcohol --> acetaldehyde step requires NAD+ so can only occur in aerobic conditions (since NAD+ has to be regenerated in stage 4 of metabolism which can only occur in the presence of oxygen)

Answer 137

Alcohol dehydrogenase CYP2E1 (form of cyp450) Aldehyde dehydrogenase

Answer 138

The intermediate metabolite of alcohol metabolism, acetaldehyde, is toxic to liver cells. The increased availability of acetyl-CoA affects liver metabolism. The conversion of alcohol to acetaldehyde by alcohol dehydrogenase also produces NADH. The decreased NAD+/NADH ratio favours the formation of triacylglycerols which accumulate in the liver cells, leading to ‘fatty liver’.

Answer 139

Desulfiram - inhibits aldehyde dehydrogenase leading to an accumulation of acetaldehyde which gives symptoms of a long lasting headache PUTS YOU OFF ALCOHOL FOR GOOD! Danger is it could cause liver damage

Answer 140

What the drug does to the body - the effect of the drug on the body

Answer 141

What the body does to the drug- how the body metabolises the drug

Answer 142

Absorption Distribution Metabolism Elimination of a drug

Answer 143

Phase 1 - hydrolysis, oxidation and reduction; make drug more reactive before it enters phase 2; CYP450; sometimes NADPH Phase 2 - glucuronidation, glutathione conjugation, sulphate conjugation; attaches a water soluble group to the drug so that the whole drug molecule is made water soluble, so that it can be excreted in the urine; cytosolic enzymes in liver

Answer 144

Hydrolysis reduction and oxidation

Answer 145

Glucuronidation Glutathione conjugation Sulphate conjugation

Answer 146

Paracetamol is a reactive enough drug so it normally directly enters phase 2 of metabolism Undergoes glucuronidation or sulphation

Answer 147

Phase 2 of metabolism (glucuronidation and sulphation) tries to happen but it becomes a saturated situation whereby glucuronic acid and sulphate run out, SO: Toxic paracetamol overdose enters phase 1 Paracetamol --> N-acetyl-p-benzo-quinine-imine (NAPQI) NAPQI then enters phase 2 with GLUTATHIONE (as opposed to sulphate or glucuronic acid as normal) NAPQI--> conjugated with glutathione

Answer 148

Glucose + ATP --(glucokinase/hexokinase)--> glucose-6-phosphate + ADP Glucose-6-phosphate --(phosphogluco mutase)--> glucose-1-phosphate Glucose-1-phosphate +UTP + H2O --> UDP-glucose + 2Pi UDP-glucose + glycogen (n) --(glycogen synthase/branching enzyme)--> glycogen (n+1) + UDP

Answer 149

Hexokinase/ glucokinase Phosphogluco mutase Glycogen synthase (rate limiting) Branching enzyme

Answer 150

Glycogen(n) + Pi --(glycogen phosphorylase/debranching enzyme)--> glycogen(n-1) + glucose-1-phosphate Glucose-1-phosphate --(phosphogluco mutase)--> glucose-6- phosphate (GLYCOLYSIS IN Muscle)

Answer 151

Glycogen(n) + Pi --(glycogen phosphorylase/debranching enzyme)--> glycogen(n-1) + glucose-1-phosphate Glucose-1-phosphate --(phosphogluco mutase)--> glucose-6- phosphate Glucose-6-phosphate --(glucose-6-phosphatase)--> glucose + Pi

Answer 152

Glycogen phosphorylase (rate limiting) Debranching enzyme Phosphogluco mutase (Glucose-6-phosphatase)

Answer 153

Glycogen phosphorylase (stimulated in low glucose conditions) Hormones Stimulated by Glucagon/ adrenaline Inhibited by insulin

Answer 154

Glycogen synthase (stimulated in high glucose conditions) Hormones Stimulated by insulin Inhibited by glucagon/adrenaline

Answer 155

(Lactate) Pyruvate --(pyruvate carboxylase)--> Oxaloacetate --(phosphoenol pyruvate carboxykinase PEPCK)--> PHOSPHOENOLPYRUVATE --> 2-PHOSPHOGLYCERATE --> 3-PHOSPHOGLYCERATE --> 1,3-BISPHOSPHOGLYCERATE --> (Glycerol, DHAP/ Fructose) GLYCERALDEHYDE-3-PHOSPHATE --> FRUCTOSE-1,6-BISPHOSPHATE --(fructose-1,6-bisphosphatase)--> FRUCTOSE-6-PHOSPHATE --> (galactose) GLUCOSE-6-PHOSPHATE --(glucose-6-phosphatase)--> GLUCOSE

Answer 156

Pyruvate carboxylase Phosphenol pyruvate carboxykinase (PEPCK) Fructose-1,6-bisphosphotase Glucose-6-phosphatase

Answer 157

Phosphoenol pyruvate carboxykinase (PEPCK) | Fructose-1,6-bisphosphatase

Answer 158

``` Phosphoenol pyruvate carboxykinase (PEPCK) Fructose-1,6-bisphosphatase Hormone Stimulated by glucagon/ cortisol Inhibited by insulin ```

Answer 159

``` Ketone bodies are produced in conditions of starvation and in type 1 diabetes In starvation (no glucose) and in type 1 diabetes (no insulin is being produced so body thinks there is no glucose) and so lipolysis and fatty acid oxidation occur (to provide acetyl coA by an alternative route) and ketone bodies (water soluble) are produced as an alternative fuel for the brain cells as ketone bodies can cross the blood brain barrier ```

Answer 160

2% with albumin (FFA or NEFA) | 98% lipoprotein

Answer 161

3 fatty acids and 1 glycerol | Non polar

Answer 162

Carbon chain and a tetracyclic structure (can be cleaved and be made into STEROID HORMONES and BILE SALTS) Polar Can be esterified at a hydroxy group with a fatty acid and made into cholesterol ester (completely non polar)

Answer 163

2 fatty acids 1 glycerol 1 phosphate group | Polar due to phosphate

Answer 164

Lipids are not soluble in water and so cannot travel freely in the blood Lipids however can pass through cell membranes without assistance

Answer 165

Chylomicrons VLDL LDL HDL

Answer 166

Chylomicrons transport dietary TAGs from intestines to adipose tissue for storage Produced in epithelial cells in small intestine Present in blood 4-6 hours after meal and are released into the kid via the LYMPHATIC SYSTEM

Answer 167

VLDLs transport TAGs made in the liver to adipose tissue for storage Produced in the liver

Answer 168

LDLs transport cholesterol made in the liver to tissues Made in liver Specific apolipoprotein APB100 - very important (signaller for cholesterol to be endocytosed)

Answer 169

HDLs transport excess tissue cholesterol to the liver where it can be disposed of as bile salts or used to produce steroid hormones

Answer 170

Raised plasma concentrations of one or more lipoprotein classes due to overproduction or under removal due to defective enzymes, receptors and apolipoprotein Type 1- chylomicrons- defective lipoprotein lipase Type 2-LDL- CAD- defective LDL receptor Type 2b- LDL and VLDL- CAD- unknown defect Type 3- IDL and chylomicrons- CAD- defective apolipoprotein E Type 4-VLDL- CAD- unknown defect Type 5- chylomicrons and VLDL-CAD- unknown defect

Answer 171

Absence (homozygous) or deficiency (heterozygous) of functional LDL receptors Type 2a of hyperlipoproteinaemia Raised LDLs CAD- develops earlier in homozygous and later in heterozygous Due to defective LDL receptor

Answer 172

Lipoprotein lipase on endothelial cells of capillaries, binds chylomicrons and VLDLs Lipoprotein lipase cleaves TAGs into glycerol and fatty acids which enter the adipose tissue and are reassembled for storage Remnants of chylomicrons and VLDLs are removed by liver/ converted to other lipoproteins

Answer 173

HDL and LDL receptors present on cells; endocytosis

Answer 174

Xanthelasma - lipid deposit on eyelids Tendon xanthoma - lipid deposits on tendon Corneal arcus - lipid deposits on iris of eye Atheroma- oxidised LDL - macrophage - foam cell - accumulate in intima of blood vessel artery walls - fatty streak - atheroma CAD

Answer 175

Fasting plasma concentration of glucose Total cholesterol and TAG concentration Examination of results of plasma lipoprotein separation by electrophoresis

Answer 176

Diet lifestyle drugs

Answer 177

Restores stability of lipoproteins by conversion of surface lipid into core lipid Converts cholesterol into cholesterol ester using the fatty acid derivative from lecithin (phosphatidylcholine)

Answer 178

Restores stability of lipoproteins by conversion of surface lipid into core lipid Converts cholesterol into cholesterol ester using the fatty acid derivative from lecithin (phosphatidylcholine) Deficiency of LCAT results in unstable lipoproteins of abnormal structure and therefore general failure of lipid transport (can occur in protein deficiency- kwashiorkors) Lipid deposits occur in many tissues and atherosclerosis is a serious potential problem

Answer 179

Reactive oxygen species Highly reactive Powerful oxidising agents

Answer 180

``` Superoxide radical (*O2-) Hydroxyl radical (*OH) Nitric oxide (NO*) Peroxynitrate (ONOO-) Drugs- anti malarials Toxins- Paraguay ```

Answer 181

In the electron transport chain not all electrons reach the oxygen molecule (final electron acceptor) at complex IV (incomplete reduction of oxygen to water) These electron drop out of the etc and react with split molecular oxygen to form the free radical *O2- (superoxide)

Answer 182

Produced in all cells from superoxide radicals or hydrogen peroxide Can be produced using ionising radiation- (X and gamma rays- high energy penetration of skin and UV light- skin surface penetration) Very damaging to cell membrane Cannot be rid of by enzymes

Answer 183

Free radicals and gas Arginine --(inducible nitric oxide synthase)--> NO* NO* can be produced in large amounts by the body= inflammation

Answer 184

NO* + O2 --> ONOO- Very oxidising Damage to cells

Answer 185

*Superoxide dismutase (SOD) - converts superoxide radicals into hydrogen peroxide (less oxidising than SOR) *Catalase - converts hydrogen peroxide into water and oxygen *Glutathione - 3 amino acids (glutamate, cysteine (SH), glycine) SH of cysteine can donate its hydrogen- so glutathione is a good reducing agent/ antioxidant; becomes oxidised when it reduces a ROS and so disulphide bond forms between 2 glutathione molecules (GSSG) *Antioxidant vitamins A, C, E *Antioxidant flavonoids polyphenols and Beta carotene *Antioxidant minerals selenium and zinc *N acetyl cysteine- very good reducing agent (used to replace glutathione in metabolism of overdose of paracetamol)

Answer 186

Damage to DNA and proteins Lipid peroxidation Oxidative stress

Answer 187

When antioxidant levels are too low to deal with ROS levels When production of ROS is high and antioxidant levels are low= oxidative burst Rapid release of SOR and HP from cells (leukocytes- neutrophils and monocytes) NADPH oxidase (membrane bound enzyme in the cell membrane and membrane of phagosomes) transfers electrons across membrane to couple these to molecular oxygen to generate SOR; enzyme important in development of atherosclerosis; rapid production of ROS kills pathogens in the locality There are man conditions associated with oxidative stress Often linked to SOD, catalase, G-6-PD deficiencies

Answer 188

``` Cancer Emphysema Pancreatitis Cardiovascular disease Crowns disease Rheumatoid arthritis Type 1 diabetes mellitus Alzheimer's disease Ischaemia/ reperfusion injury (cells adjust to low oxygen blood flow, so when O2 is reperfusion its causes lots of oxidative stress - reperfusion injury) ```

Answer 189

Foreign to body, potentially toxic | Lipid soluble

Answer 190

Reaction of unsaturated lipids with ROS to form lipid peroxides Unsaturated lipid + *OH -->(loss of H2O) lipid radical + O2 --> lipid peroxyl radical --> lipid peroxide --> lipid radical (continues in cycle) Causes damage to cell membranes Involved in early stages of cardiovascular disease

Answer 191

Acetyl coA carboxylase and fatty acid synthase Allosteric regulation Stimulated by citrate Inhibited by AMP Covalent modification Stimulated by insulin (dephosphorylation) Inhibited by glucagon/ adrenaline

Answer 192

How glucose can be converted into acetyl coA and then fatty acids and then stored as TAGs in adipose tissue Hence it occurs in high energy/ glucose conditions as a storage mechanism

Answer 193

Acetyl coA carboxylase | Fatty acid synthase

Answer 194

It can be used to make the digestive acid bile

Answer 195

The levels of bile

Answer 196

Cytochrome P450 CYP450

Answer 197

``` Fatty acid oxidation Cycle of reactions that remove C2 C2 atoms removed as acetyl coA Occurs in mitochondria Enzymes separate in mitochondrial matrix Oxidative (produces NADH and FAD2H) Requires small amounts of ATP to activate the fatty acid Intermediates are linked to coA Regulated indirectly by availability of fatty acids in mitochondria Glucagon and adrenaline stimulates Insulin inhibits Only in aerobic conditions ``` Fatty acid synthesis Cycle of reactions that add C2 C2 atoms added as Malonyl coA Consumes acetyl coA Occurs in cytoplasm Reductive- requires NADPH Requires large amount of ATP to drive process Intermediates are linked to fatty acid synthase by carrier protein Regulated directly by activity of acetyl coA carboxylase Glucagon and adrenaline inhibit Insulin stimulates

Answer 198

Substrate level phosphorylation Requires soluble enzymes (cytoplasmic and mitochondrial matrix) Energy coupling occurs directly through the formation of a high energy of hydrolysis bond (in phosphorylation group transfer) Can occur to a limited extent in absence of oxygen Minor processes for ATP synthesis in cells require large amounts of energy Oxidative phosphorylation Requires membrane associated complexes (inner mitochondrial membrane) Energy coupling occurs indirectly through the generation and subsequent utilisation of a protein gradient pmf Cannot occur in the absence of oxygen Major processes for ATP synthesis in cells that require large amounts of energy

Answer 199

Drugs are more often deactivated by the body in the two have process

Answer 200

Codeine ----> morphine | Where the enzyme that converts codeine to morphine is deficient codeine does not work for the patient

Answer 201

Acetylation enzymes in liver (phase 1) Plasma cholinesterase enzymes Alkylation enzymes in liver (phase 2)

Answer 202

Genetic factors- polymorphism (individual variation in the expression of metabolic enzymes; normal distribution curve; some individuals may lack the allele that codes for a specific enzyme) Environmental factors-(if two drugs are given simultaneously, then the metabolism of one drug may affect the metabolism of the other by activating or inhibiting enzymes in the cyp450 system)- enzyme induction and inhibition

Answer 203

When one drug increases the metabolism of another drug Alcohol Nicotine Barbiturate --- increase number of enzymes in liver

Answer 204

When one drug decreases the metabolism of another drug Cimetidine used to reduce stomach acid Grapefruit and cranberry juice

Answer 205

Found in blood plasma Affect drugs containing ester bonds (e.g. Suxamethonium) Act by hydrolysis in phase 1 of metabolism

Answer 206

The effect of the drug on the body lasts much longer than expected

Answer 207

Produces NAPQI which is a toxic metabolite to the liver Glutathione is used in conjugation instead of glucuronic acid and sulphate (which will have been used up) Use of glutathione means that glutathione is no longer available to protect against ROS- so exposure to oxidative stress Liver failure (oxidative stress and NAPQI) Liver transplant required in severe cases Nausea, sweating, liver damage, kidney failure, pain in right upper quadrant due to hepatic necrosis Toxic dose is 10g or 200mg per Kg.

Answer 208

Can be treated with N-acetyl cysteine (SH) (NAC) which donates Hydrogen and acts as an antioxidant / very good reducing agent Prevents liver from oxidation and replaces the function of glutathione Treatment: stomach pumping, replenish glutathione by giving Nacetylcysteine, liver transplant.

Answer 209

Reductase enzyme Hormone regulation Stimulated by insulin Inhibited by glucagon

Answer 210

Hydrophilic molecules on outside: apolipoproteins, phospholipids, cholesterol Hydrophobic molecules on inside: triacylglycrides, cholesterol ester

Answer 211

Communication Control centre Receptor Effector

Answer 212

Nervous- action potential Endocrine- hormones Paracrine- local hormones Autocrine- hormones which affect the cells that release them

Answer 213

CNS Determines set point Analyses input Determines an appropriate response

Answer 214

Detect stimuli and transfer the stimuli to control centre via the signal AFFERENT pathway

Answer 215

Generate an effect and receive stimuli from the control centre via the signal EFFERENT pathway

Answer 216

Where the effector produces an effect which opposes the stimulus Occurs in most homeostasis control systems

Answer 217

Where the effector produces a response which increases its effect System ales out of control Rare

Answer 218

Set point is not fixed- set point can vary

Answer 219

24hour change in set point

Answer 220

Temperature Cortisol levels - highest in morning (hence time at which bloods were taken should ALWAYS be recorded) Menstrual cycle - woman's core body temp varies in cycle- sudden increase in temp is a marker for ovulation Time- biological clock in hypothalamus of brain (superchiasmatic nucleus) Body water homeostasis- osmoreceptors in hypothalamus, ADH

Answer 221

Biological clock = superchiasmatic nucleus in hypothalamus When we travel across time zones, out biological clock will tell us one time and zeitgeibers (clues around us) will tell us a different time = JET LAG Melatonin produced from the pineal gland is involved in setting the biological clock- released at night- light/dark cycle

Answer 222

70kg male 42L water 28l IC 9.4l EC and 4.6lblood plasma Osmolality and sodium concentration monitored by osmoreceptors in the hypothalamus Increase in osmolality (high conc of solvent in solute) in the blood plasma -> release of ADH from posterior pituitary gland (urine is made more concentrated) -> increased reabsorption of H2O from urine into the blood in collecting ducts in the kidney -> decrease in osmolality of blood plasma

Answer 223

Chemical signals produced in endocrine glands or tissues that travel in the blood stream to cause an effect on other tissues

Answer 224

Released from endocrine glands Travel in blood stream Only affect certain cells Only interact where there are receptors Specific hormones have specific receptors Can have an effect in small amounts Its secretion is usually controlled by a negative feedback system Long-lasting effects Circulate in very low concentrations Take about 30 seconds to reach all parts of the body

Answer 225

Polypeptide Glycoproteins Amino acid derivatives Steroids

Answer 226

Largest group Single chain peptides Some organised in closely related families GH (191aa) Insulin (51aa in 2 chains) Thyrotrophin releasing hormone (3aa) Gut hormones

Answer 227

All have 2 polypeptide chains with carbohydrate side chains (alpha and beta) Related families Thyroid stimulating hormone follicle stimulating hormones Luteinising hormones Human chorionic gonadotrophin

Answer 228

``` All derived from cholesterol C27 calciferols (vitamin D) C21 corticosteroids (gluco/mineralo corticoids and C19 androgens and C18 oestrogens) ```

Answer 229

``` Some form tyrosine Thyroid hormone (T4 and T3) Adrenaline Histamine from histidine 5 hydroxytryptamine from tryptophan ```

Answer 230

Polypeptide glycoprotein hormones and adrenaline (amino acid derivatives) Water soluble => travel freely in blood plasma Hormones cannot cross cell membranes on their own Hormones bind to receptors on cell membrane surface which activates a second messenger pathway- second internal messenger exerts metabolic effects often modifying the action of enzymes Faster

Answer 231

Steroid hormones and thyroid hormones (amino acid derivative) Not water soluble => travel in blood plasma bound to binding proteins Dynamic equilibrium exists between bound and free forms of hormones in blood plasma Only the free form is biologically active Carrier proteins increase the solubility of hormone in plasma, increase the half life of hormone and act as a readily accessible reserve Hormones can cross cell membrane as they are lipid soluble Hormones bind to receptors on the inner membrane, in the cytoplasm or on the nucleus forming a dimer Binds to hormone response element of DNA Switches transcription on or off Particular protein production is switched on or off Alters gene expression- slower and longer lasting

Answer 232

Polypeptide

Answer 233

Glycoprotein

Answer 234

Amino acid derivative

Answer 235

Glycoprotein

Answer 236

Amino acid derivative

Answer 237

Hypothalamus --(releasing factors)--> anterior pituitary gland --(tropic hormones)--> endocrine glands --> produce a hormone --> transported in blood (freely or bound to binding protein) --> target cells (receptors and response)--> eventual inactivation of chemical by liver kidney or target tissues

Answer 238

Appetite (satiety) centre- arcuate the nucleus in hypothalamus (primary and secondary neurones) Different hormones stimulate or inhibit a primary neurone ``` PRIMARY NEURONES (sense metabolite levels and respond to hormones) Excitatory neurones- release Neuropeptide Y (NPY) and Agouti related peptide (AgRP) which stimulate secondary neurone- stimulate appetite Inhibitory neurones- release proopiomelanocortin (POMC) which is enzymatically cleaved to produce alpha melanocytes stimulating hormone (alpha MSH) which bind to MC4 receptors on secondary neurone and inhibit the secondary neurone -suppressing appetite and beta endorphins which gives a feeling of euphoria/tiredness ``` SECONDARY NEURONES (synthesise input from primary neurones and coordinate a response via the vagus nerve)

Answer 239

``` Ghrelin PYY Leptin Insulin Amylin ```

Answer 240

Peptide hormone Released from wall of the stomach when it's empty Stimulates the excitatory primary neurone STIMULATION OF APPETITE

Answer 241

Peptide hormone Released from wall of small intestine Inhibits the excitatory primary neurone SUPPRESSION OF APPETITE

Answer 242

``` Peptide hormone Released from adipocytes Inhibits excitatory primary neurone Stimulates inhibitory primary neurone SUPPRESSION OF APPETITE Effect from secondary neurone- induced the expression of uncoupling proteins in the mitochondria, dissipating pmf energy as heat ```

Answer 243

``` Peptide hormone Released from beta cells of pancreas Inhibits excitatory primary neurone Stimulates inhibitory primary neurone SUPPRESSION OF APPETITE ```

Answer 244

``` Peptide hormone Released by beta cells of pancreas Inhibits excitatory primary neurone Stimulates inhibitory primary neurone SUPPRESSION OF APPETITE ``` Effect from secondary neurone- decreases glucagon secretion and slows gastric emptying

Answer 245

Co occurrence in the same individual of a number of cardiovascular risk factors such as dyslipidaemia, hypertension, insulin resistance and glucose intolerance, usually in association with overweight or obesity and a sedentary lifestyle

Answer 246

``` Waist: hip ratio >0.9(men) ; >0.8(women) BMI > 30 kg/m(squared) BP > 140/90 mmHg Triacylglycrides >1.7 mM HDL < 0.9mM(men) ; 0.8mM(women) Glucose uptake in lowest quartile ```

Answer 247

Not yet universally accepted by medical profession

Answer 248

Barker hypothesis- Several health surveys of large cohorts of adult males; Statistical analysis showed the strongest association between incidence of adult disease (CHD, hypertension, T2 diabetes) and low birth and placenta weight Fetal programming- biochemical adaptation took place in the foetus according to the supply of nutrients via the placenta ; these adaptations were programmed in for adult life and predisposed the individual to developing chronic diseases throughout life; adaptations which appeared to be heritable- passed through the mother

Answer 249

A stably inherited phenotype resulting from changes in a chromosome without alterations in the DNA sequences; mechanism appears to involve methylation of DNA and changes to histone structure which causes suppression of gene transcription

Answer 250

Biochemical adaptations which are programmed in for the predisposing individuals to chronic conditions

Answer 251

Blood glucose level < 3.0 mM Rapidly can be fatal- glucose is essential for CNS function (without it CNS will starve and die) Often mistaken for drunkenness- slurred speech, reduced coordination, dizziness, headache, coma and then death

Answer 252

``` Random blood glucose level > 11.1mM Fasting blood glucose level > 7mM Glucose in urine- above renal threshold Polyuria and polydipsia due to osmosis Non enzymatic glycosylation of proteins- haemoglobin - HbA1c ```

Answer 253

Chronic condition/ State of hyperglycaemia due to insulin deficiency and or resistance, leading to small and large vessel damage in which there is premature death (of vessels) from cardiovascular disease

Answer 254

Type 1- insulin deficiency (loss of all or most of B cells); develops in young; can be rapidly fatal; must be treated with insulin; ketone bodies are produced Type 2- insulin resistance (body not able to use insulin that is produced) and insulin deficiency (develops with slow progressive loss of B cells); develops in older individuals; may be present for a long time before diagnosis; may not initially need treatment with insulin- but eventually will; ketone bodies are not produced

Answer 255

It’s likely that a genetic predisposition to the disease interacts with an environmental trigger to produce immune activation. This leads to the production of killer lymphocytes and macrophages and antibodies that attack and progressively destroy b-cells (an auto-immune process). The genetic predisposition is associated with the genetic markers HLA DR3 and HLA DR4.

Answer 256

Typically for type 1 - a lean young person with a recent history of viral infection who present a triad of symptoms: - Polyuria – excess urine production. Large quantities of glucose in the blood are filtered by the kidney, so not all of it is reabsorbed. The extra glucose in the nephron places an extra osmotic load on it, meaning that less water is reabsorbed to maintain osmotic pressure. - Polydipsia – thirst and drinking a lot, due to polyuria. - Weight loss - as fat and protein are metabolised because insulin is absent Ketoacidosis may also be apparent- nausea, vomit, coma, death (Due to increased amount of fatty acid in liver) Dehydration, tiredness, weakness, lethargy, blurring of vision

Answer 257

People can be found with the relevant HLA markers and auto-antibodies but without glucose or insulin abnormalities. They may then develop impaired glucose tolerance, then diabetes (sometimes initially diet controlled) before becoming totally insulin dependant.

Answer 258

Type 1 can be diagnosed by measurement of plasma glucose levels. Blood glucose is elevated because of the lack of insulin. Diabetes is diagnosed in the presence of symptoms i.e. polyuria, polydipsia and unexplained weight loss plus: - A random venous plasma glucose concentration > 11.1 mmol/l or - A fasting plasma glucose concentration > 7.0 mmol/l (whole blood > 6.1 mmol/l) or - Plasma glucose concentration > 11.1 mmol/l 2 hours after 75g anhydrous glucose in a oral glucose tolerance test (OGTT) - smell of acetone on breath

Answer 259

The lack of insulin causes: - decrease in the uptake of glucose into adipose tissue and skeletal muscle - decrease in the storage of glucose as glycogen in muscle and liver - Gluconeogenesis in liver The high blood glucose will lead to the appearance of glucose in the urine (glycosuria) as glucose exceeds the renal threshold of the kidney, and if not dealt with rapidly the individual will progress to a life-threatening crisis (diabetic ketoacidosis)

Answer 260

High rates of b-oxidation of fats in the liver coupled to the low insulin/anti-insulin ratio leads to the production of huge amounts of ketone bodies (such as acetoacetone, acetone and b-hydroxybutyrate). Acetone, which is volatile may be breathed out, and smelt on the patient’s breath. The H+ associated with ketones produce a metabolic acidosis – ketoacidosis. The features of ketoacidosis are: prostration, hyperventilation, nausea, vomiting, dehydration and abdominal pain. Ketoacidosis is a very dangerous condition. It is most important to test for ketones in the urine when assessing diabetes control.

Answer 261

Acetone, which is volatile may be breathed out, and smelt on the patient’s breath Test for ketones in the urine Ketone plasma conc (normally 10mM

Answer 262

Lipolysis Glycogenesis Gluconeogenesis

Answer 263

Genetic predisposition- only manifested with the influence of the environment- OBESITY Impaired glucose intolerance for example with pregnancy (ie, body cannot produce extra insulin to deal with demands of pregnancy)

Answer 264

Elderly individual with weight related problems (obesity) Slower onset of symptoms (triad of polyuria, polydipsia and weight loss) Tiredness, thrush, blurring of vision etc. Can be asymptomatic depending on progress stage Ketoacidosis is never apparent in type 2 (as some insulin is present and so lipolysis not activated and hence fewer fas available to make ketone bodies)

Answer 265

People can be found with insulin resistance then as insulin production fails they develop impaired glucose tolerance. Finally they will develop diabetes that can initially be controlled by diet, then tablets, then insulin. If the process continues long enough they may lose all insulin production.

Answer 266

Type 1 can be diagnosed by measurement of plasma glucose levels. Blood glucose is elevated because of the lack of insulin. Diabetes is diagnosed in the presence of symptoms i.e. polyuria, polydipsia and unexplained weight loss plus: - A random venous plasma glucose concentration > 11.1 mmol/l or - A fasting plasma glucose concentration > 7.0 mmol/l (whole blood > 6.1 mmol/l) or - Plasma glucose concentration > 11.1 mmol/l 2 hours after 75g anhydrous glucose in a oral glucose tolerance test (OGTT)

Answer 267

With no symptoms diagnosis should not be based on a single glucose determination but requires confirmatory venous plasma glucose determination. At least one additional glucose test result on another day with a value in the diabetic range is essential, either fasting, from a random sample or from the two hour post glucose load.

Answer 268

A diabetic can become hypoglycaemic with an excess of insulin, coupled with less than usual glucose in diet and/or excess exercise compared to usual (plasma glucose <3mmol/l) This can become fatal as the CNS and other glucose dependant tissues require a constant supply of glucose. The patient may experience sweating, anxiety, hunger, tremor, palpitations, confusion, drowsiness, seizures, coma. The severe consequences of hypoglycaemia are a reason why a diabetic is more likely to maintain a higher blood glucose level.

Answer 269

High intake of glucose, and wrong (too low) dosage of insulin Blood glucose >11 mmol/l. Symptoms include polyuria, polydipsia, weight loss, fatigue, blurred vision, dry or itchy skin, poor wound healing. Plasma proteins may become glycosylated, affecting their functions

Answer 270

Exogenous insulin by subcutaneous injections (directly below epidermis and dermis) several times a day Patients must be educated to treat themselves at appropriate times with appropriate doses so as to mimic as closely as possible the behaviour of pancreatic islets in controlling blood glucose. On occasion, if the patient has an infection or suffered a trauma, insulin dosage needs to be increased or there is a risk of ketoacidosis. The social and psychological implications are huge, and the degree of control achieved by patients can be very variable. Dietary management and regular exercise are vital components of the treatment regime. The management of blood glucose requires frequent blood glucose measurement. A small amount of blood from a finger prick is sufficient to measure blood glucose using the BM stick and reader. There is always a risk that blood glucose will fall too low – hypoglycaemia – so both patients and their associates need to be aware of the signs and symptoms of hypoglycaemia, which can occasionally be fatal unless treated with glucose either my mouth or by infusion.

Answer 271

It is a peptide hormone that can be digested in the stomach

Answer 272

Education Lifestyle: diet and exercise Non insulin therapies: “oral hypoglycaemic” drugs such as sulphonylureas that increase insulin release from the remaining b-cells, and reduce insulin resistance and particularly metformin that reduces gluconeogenesis Insulin can be given when all B cells have become damaged and no more insulin is produced

Answer 273

Not by insulin | By the extracellular glucose concentration

Answer 274

During hyperglycaemia the intracellular concentration of glucose in these tissues increases and glucose is metabolised via the enzyme aldose reductase which catalyses the reaction: Glucose + NADPH + H+ --> Sorbitol + NADP This reaction depletes NADPH and leads to increased disulphide bond formation in cellular proteins altering their structure and function. The accumulation of sorbitol causes osmotic damage to cells.

Answer 275

Glucose in the blood will react with the terminal valine of the haemoglobin molecule to produce glycosylated haemoglobin (HbA1c).

Answer 276

Hyperglycaemia is also associated with increased non-enzymatic glycosylation of plasma proteins (e.g. lipoproteins) that leads to disturbances in their function. Glucose reacts with free amino groups in proteins to form stable covalent linkages. The extent of glycosylation depends on the glucose concentration and the half-life of the protein. Glycosylation changes the net charge on the protein and the 3D structure of the protein, therefore affects the function of the protein.

Answer 277

The percentage of HBA1c is a good indicator of how effective blood glucose control has been. As RBCs normally spend ~3 months in the circulation the %HbA1c is related to the average blood glucose concentration over the preceding 2-3 months Glucose reacts non-enzymatically with the terminal valine of haemoglobin to form glycosylated haemoglobin (HbA1c). Extent of glycosylation depends on blood glucose concentration and half-life of haemoglobin (~60days). Poor glycaemic control = high blood glucose = high HbA1c. Good glycaemic control = normal blood glucose = normal HbA1c (~5%).

Answer 278

risk of stroke risk of myocardial infarction Poor circulation to the periphery – particularly the feet

Answer 279

Diabetic eye disease: Changes in the lens due to osmotic effects of glucose (glaucoma) and possibly cataracts. More important problem is diabetic retinopathy – damage to blood vessels in the retina, which can lead to blindness. Damages blood vessels may leak and form protein exudates on the retina or they can rupture and cause bleeding in the eye. New vessels may form (proliferative retinopathy) - these are weak and can easily bleed. Diabetic kidney disease (nephropathy): This is due to damage to the glomeruli, poor blood supply because of change in kidney blood vessels, or damage from infections of the urinary tract (more common in diabetics – excess glucose for bacteria to thrive). An early sign of nephropathy is a protein in the urine (microalbuminuria). Diabetic neuropathy: Damage to the peripheral nerves which directly absorb glucose causing changes of or loss of sensation, and changes due to alteration in the function of the autonomic nervous system. Diabetic feet: Poor blood supply, damage to nerves and increase risk of infection all sum up to make the feet of a diabetic vulnerable. In the past, loss of feet through gangrene was not uncommon. Care is needed to keep feet in good condition.

Answer 280

Large mixed exocrine/endocrine gland Adjacent to duodenum Exocrine: acinar (99%); produces digestive enzymes; secreted directly into the duodenum; alkaline secretions through pancreatic duct into the duodenum Endocrine: islet cells (1%) near to capillaries for direct secretion; hormone production

Answer 281

B cells - insulin (regulation of metabolism of carbohydrates, proteins and fats) A cells - glucagon (regulation of metabolism of carbohydrates, proteins and fats) D cells - somatostatin (inhibits release of hormones from islet cells) F cells - pancreatic polypeptide (GI function) 5th cell - ghrelin (appetitie- also secreted by wall of stomach)

Answer 282

Anabolic- glucose storage Released by B cells of pancreas when blood glucose levels are high Targets liver, adipose tissue and skeletal muscle Causes glycogenesis, lipogenesis, (protein synthesis)

Answer 283

2 unbranched peptide chains which a connected by 2 disulphide bridges- ensures stability 51 amino acids (A= 21, B=30)

Answer 284

Catabolic- glucose release Released by A cells of pancreas when blood glucose is low Targets liver and adipose mainly Causes glycogenolysis, gluconeogenesis, lipolysis, ketone body synthesis

Answer 285

29 amino acids in 1 polypeptide chain | No disulphide bridges = flexible

Answer 286

Simpler synthesis than insulin Synthesised in RER Transported to Golgi Packaged into granules Margination- movement of storage vesicles to cell surface Exocytosis- fusion of vesicle membrane with plasma membrane with release of vesicle contents

Answer 287

Pre- pro insulin produced on RER ribosomes and enters the RER Cleavage of pre signal = pro insulin Pro insulin folds to ensure correct alignment of cysteine residues so that correct disulphide bonds form Pro insulin is transported from the ER, through the golgi and packaged into vesicles Proteolysis in the storage vesicles by endopeptidases results in the excision of the C peptide in the middle of the chain Results in two single chains held together by two disulphide bonds (Storage vesicles contain equimolar amounts of mature insulin, 4 basic amino acids and C peptide) These are all secreted together in exocytosis from the cell

Answer 288

Measurement of plasma C peptide levels in patients receiving insulin can be used to monitor any endogenous insulin secretion

Answer 289

Movement of storage vesicles towards the cell membrane

Answer 290

An increase in glucose in the ECF is a stimulus for insulin release Glucose enters B cells by facilitated diffusion through Glut2, resulting in an increase in ICF concentration of glucose in B cells This causes an increase in glycolysis which leads to an increase in ATP High ATP causes an inactivation of ATP sensitive potassium ion channel (so no more potassium can enter the cell) which causes a depolarisation of the membrane As a result the voltage gated calcium channels open, and there is an influx of calcium into the cell Increase in ICF calcium triggers the exocytosis of insulin containing secretory granules

Answer 291

Insulin is stored in the B cell storage granules as a crystalline zinc- insulin complex

Answer 292

Freely- it is a water soluble polypeptide hormone so does not require a binding protein

Answer 293

Insulin receptor is a dimer (2 subunits each made up of 1B chain (which spans the membrane) and protruding 1A chain- 1A and 1B are connected via a single disulphide bond) When insulin detected A chains move together and fold around the insulin B chains then move together making the B chains an active tyrosine kinase This initiates a phosphorylation cascade - which results in an increase in Glut4 expression (increase in uptake of glucose into cells) So cell takes up more glucose

Answer 294

It takes up its active conformation on binding to its receptor on the surface of target cells. Binds to a specific glucagon receptor in the cell membrane, a type of receptor termed a G protein-coupled receptor (GPCR). Binding to the receptor activates the enzyme adenylate cyclase, which increases cyclic AMP (cAMP) intracellularly High levels of cAMP activate protein kinase A (PKA), which phosphorylates and :. activates important enzymes within the target cell.

Answer 295

ACTH- acts on adrenal gland to release cortisol (initiates bodies response to stress) (corticotrophs) GH- acts on liver to release IGF1 (growth, muscle strength metabolism, bone density) (somatotrophs) TSH- acts on thyroid to release T3 and T4 (metabolism) (thyrotrophs) Prolactin-acts on mammary glands to release milk (initiates and maintains lactation) (lactotrophs) FSH/LH- acts on ovaries or testes (FSH- sperm production (m) and release of follicle from ovaries and oestrogen stimulation (f) / LH- testosterone secretion (m) and oestrogen and progesterone release (ovulation) (f)) (gonadotrophs)

Answer 296

Oxytocin ADH osmolality and Na+ concentration of blood plasma is constantly monitored by osmoreceptors in the hypothalamus- monitor release of ADH- which has effect on the kidney of causing an increase in permeability of the collecting ducts to water thus n reseeding the reabsorption of water from urine into the blood

Answer 297

Mineralocorticoids- aldosterone- regulates body Na+ and K+ levels Glucocorticoids- cortisol- regulate carbohydrate metabolism Androgens- sex hormones- dehydroepiandrosterone Adrenaline- epinephrine

Answer 298

Cortex and medulla

Answer 299

Zona glomerulosa- mineralocorticoids Zona fasisculata- glucocorticoids Zona reticularis- glucocorticoids and androgens

Answer 300

The catecholamines are synthesised in a series of enzyme-catalysed steps. The catecholamines are stored in the medullary cells in vesicles. Tyrosine --> Dopa --> Dopamine --> Noradrenaline -->(methylation)--> Adrenaline

Answer 301

Adrenaline is released as part of the fright, flight or fight response in man and it is secreted in response to stress situations. It has effects on: - Cardiovascular System (Cardiac Output, Blood supply to muscle) - Central Nervous System (Mental alertness) - Carbohydrate Metabolism (Glycogenolysis in liver and muscle) - Lipid Metabolism (Lipolysis in adipose tissue)

Answer 302

``` Overproduction by the adrenal medulla, usually due to a tumour (Phaemochromocytoma), may be associated with: o Hypertension o Palpitations o Sweating o Anxiety o Pallor o Glucose intolerance ```

Answer 303

Produced from cholesterol via progesterone ina series of enzyme catalysed reactions All steroid hormones are hydrophobic and must be transported in the blood bound to proteins (90% with transcortin/ or with corticosteroid binding globulin) Steroid hormones differ from each other in number of C atoms, essence of functional groups and distribution of C=C bonds Cortisol is part of C21 steroid family

Answer 304

Corticosteroids are hydrophobic and so can cross the cell membrane of target cells and bind to cytoplasmic receptors The hormone/receptor complex then enters the nucleus to interact with specific regions of DNA This interaction changes the rate of transcription of specific genes and may take some time Affects gene expression

Answer 305

Physical (temperature/pain), chemical (hypoglycaemia) and emotional stressors stimulate release of CRH CRH (corticotropin releasing hormone) released from hypothalamus and travels via hypophyseal portal vessels to anterior pituitary CRH stimulates the release of ACTH (adrenocorticotropic hormone) from the corticotrophins of the anterior pituitary ACTH stimulates adrenal gland to secrete cortisol Negative feedback - cortisol on the hypothalamus and anterior pituitary gland

Answer 306

Proopiomelanocortin (POMC) is a biosynthetic precursor molecule which is cleaved to produce ACTH and alpha MSH (melanocyte stimulating hormone) (and other molecules- like endorphins in control of appetite) Alpha MSH is contained within the ACTH sequence in POMC giving ACTH some MSH like activity when present in excess Therefore increased ACTH => increased alpha MSH => increased production of melanin from melanocytes => pigmentation

Answer 307

ACTH is a hydrophilic peptide hormone and so interacts with high affinity MC2 receptors on the cell membrane of cells in the zona fasisculata and reticularis in cortex Binding of ACTH to mc2 receptors stimulates cAMP inside the cell to act as a secondary messenger This causes the activation of cholesterol esterase and conversion of cholesterol esters into free cholesterol and stimulates other steps in the synthesis of cortisol from cholesterol =release of cortisol

Answer 308

Cortisol is a hydrophobic steroid hormone and so is transported in the blood bound to plasma proteins (transcortin/ corticosteroid binding globulin) Cortisol can cross cell membranes of target cells and bind to cytoplasmic receptors The hormone receptor complex then enters the nucleus and interacts with specific regions of DNA This interaction changes the rate of transcription of that specific gene/portion of DNA and may take some time to occur Cortisol- stress response => affects metabolism - decrease in aa uptake and protein synthesis, increase in proteolysis - increase in hepatic gluconeogenesis and glycogenolysis - increase in lipolysis in adipose tissue (to really high levels of cortisol can lead to an increase in lipogenesis in adipose tissue) -decrease in peripheral uptake of glucose (anti insulin hormones increase) OVERALL EFFECT increase in blood glucose, aa and fatty acids

Answer 309

Located in base of brain Suspended from hypothalamus by a stalk Blood supply via hypophyseal portal vessels as well as arterial supply from superior and inferior hypophyseal arteries Anterior pituitary derived from up growth of primitive pharynx Posterior pituitary derived from down growth of neural tissue from hypothalamus

Answer 310

Endocrine glands which cap the upper lobes of the kidney and lie against the diaphragm Contain the outer cortex (mineralocorticoids, glucocorticoids and androgens) and inner medulla (adrenaline)

Answer 311

``` Prolactinoma Gonadotrophinoma GH adenoma ACTH adenoma TSHoma ```

Answer 312

``` Pregnancy Physiological Pharmalogical Pituitary Poly cystic ovaries ```

Answer 313

Dopamine agonist (capergoline/ quinagolide)

Answer 314

``` Hair growth Acne Menstrual problems Virilisation Increased muscle bulk Deepening of voice ``` More obvious in females than males

Answer 315

Growth and development of male genital tract, height, body shape and hair Lower voice pitch

Answer 316

``` Acromegaly = Growth of hands and feet Coarse features Sweating Headaches Hypertension Diabetes Gigantism ```

Answer 317

Cushings disease

Answer 318

``` Rounded/ plethoric face Central obesity with striae Easy bruising Proximal myopathy Hypertension Diabetes ```

Answer 319

Compression of structures by adenoma -optic chiasm (upwards) and cavernous sinus (laterally) can cause visual defects

Answer 320

GH LH FSH TSH ACTH all decrease | Prolactin increases

Answer 321

1. basal test when suspecting adrenocortical disease- stable hormone levels at any time of the day ; 24hr urinary excretion 2. dynamic test in differential diagnosis of adrenocortical disease- (e.g dexamethasone suppression tests and ACTH stimulation test)

Answer 322

Control or removal of tumour- surgery (transphenoidal or transcranial) / radiotherapy (external beam gamma knife) / medical therapy Reduction of excess hormone secretion Replacement of hormone deficiencies

Answer 323

Prevention of tumour growth | Protection of vision

Answer 324

Damage to normal pituitary gland | Increased risk of stroke

Answer 325

Hyperactivity Hypoactivity Congenital adrenal hyperplasia

Answer 326

Cushing's syndrome- excess secretion of cortisol

Answer 327

Pituitary adenoma (Cushing's disease) Adrenal adenoma Ectopic secretion of ACTH (cancer) Use of exogenous steroids

Answer 328

Moon face and fat deposition on face, neck, abdomen Apple on a stick body shape (central obesity with wasted skinny arms and legs) Purple striae on lower abdomen Easy bruising High blood pressure Polyuria Polydipsia Back pain and collapse of ribs- osteoporosis

Answer 329

Increase in cortisol Increase in hepatic gluconeogenesis and glycogenolysis- hyperglycaemia Increase in proteolysis- muscle wastage and purple striae (protein structures affected) Increase in lipogenesis in adipose tissue (at v high cortisol levels)- fat ********* Disturbances in calcium metabolism and loss of bone matrix protein - back pain and osteoporosis Cortisol binds to mineralocorticoid receptors- increased retention of sodium and water in kidney and increased wasting of potassium- hypertension

Answer 330

Consumer of excess alcohol = pseudo Cushing's

Answer 331

MRI - size and site of adenoma/ carcinoma - adrenal or pituitary? Plasma concentrations of ACTH and cortisol 24hour urinary cortisol excretion Dexamethasone suppression test

Answer 332

Dexamethasone suppression test

Answer 333

Normally DMS increases the negative feedback effect which decreases CRH and ACTH secretion and hence a decrease in cortisol secretion = Normal pituitary and adrenal function cortisol secretion is suppressed In a patient with a pituitary ACTH tumour (Cushing's disease) DMS at low doses will increase the negative feedback effect a little bit which decreases CRH secretion but ACTH secretion will still be high and so will cortisol. At high doses CRH secretion will decrease, and so will ACTH secretion as suppression will occur since diseased pituitary still has some sensitivity to the effect of the dexamethasone and thus cortisol secretion will also decrease = suggests Cushing's disease In a patient with an Ectopic secretion of ACTH, DMS will increase the negative feedback effect which decreases CRH secretion but ACTH secretion will still be high and thus so will cortisol secretion = suggests Ectopic secretion of ACTH In a patient with an adrenal tumour, DMS will increase the negative feedback effect which decreases CRH and ACTH secretion but cortisol secretion will still be high = suggests problem with adrenal gland

Answer 334

Dexamethasone test - low and high doses

Answer 335

Addison's disease - deficient secretion of cortisol

Answer 336

Diseases of adrenal cortex (autoimmune destruction) -reduces glucocorticoids, androgens and mineralocorticoids Disorders in pituitary or hypothalamus that lead to decreased secretion of ACTH or CRH which only affects glucocorticoids

Answer 337

``` Tiredness Extreme muscular weakness Weight loss and anorexia Occasional dizziness Dehydration Hypotension Increased pigmentation ```

Answer 338

Decrease in cortisol Decrease in gluconeogenesis- hypoglycaemia Decrease in glycogenolysis- hypoglycaemia Decrease in proteolysis- weight loss Decrease in lipogenesis- maybe some lipolysis (at low cortisol levels) - weight loss Less binding of cortisol to mineralocorticoid receptors- so decreased retention of Na and water in kidney and so hypotension Increase in levels of alpha MSH (due to less negative feedback) and so hyperpigmentation Reduced appetite - weight loss

Answer 339

Glucocorticoids- decreased production- less gluconeogenesis, less preoteolysis, less lipogenesis =dizziness and tiredness (hypoglycaemic on fasting) Mineralocorticoids- under secretion of aldosterone, Na+ not reabsorbed in kidney so increased water loss (increased retention of K+) = dehydration and low blood pressure (hypotension) Androgens= less facial and body hair

Answer 340

``` Glucocorticoids= increase in cortisol, increase in gluconeogenesis, proteolysis and lipogenesis (= fat, muscle wastage, energy burst) Mineralocorticoids= increased reabsorption of Na+ in kidneys and hence increased retention of water (loss of K+) ( hyper tension) Androgens= over secretion means increased growth a development of male genital tract and male and female secondary characteristics (hair, deeper voice, body shape) ```

Answer 341

Yes as pigmentation is related to an increase in ACTH production (as alpha MSH is contained within ACTH from POMC) Cushing's- increased ACTH due to pituitary tumour or ectopic secretion (won't get pigmentation with adrenal tumour causing Cushing's) Addison's- decreased secretion of cortisol means there is less negative feedback on ACTH, so increase in ACTH production

Answer 342

In trauma or sever infection- effects of addisonian crisis can be exacerbated

Answer 343

``` Nausea Vomiting Extreme dehydration Hypotension Confusion Fever Coma CLINICAL EMERGENCY ```

Answer 344

Must be treated with IV cortisol and fluid replacement (dextrose in normal saline) to avoid death

Answer 345

Plasma concentrations of ACTH and cortisol 24hour urinary cortisol excretion Synacthen stimulation test Insulin tolerance test- normal ppl would secrete cortisol due to the stress response of starvation/fasting which would stimulate gluconeogenesis but this doesn’t happen in hypoadrenalism.

Answer 346

Synacthen stimulation test (synthetic analogue of ACTH) | Insulin tolerance test (not on individuals with ischaemic heart disease or epilepsy)

Answer 347

Synacthen is an analogue of ACTH Normally synacthen (intramuscularly) would cause there to be an increase in cortisol secretion by > 200nmol/l = excludes Addison's and secondary cause of hypoadrenalism In an Addison's patient- administration of synacthen has no effect on cortisol levels which still remain low = hypoactivity of adrenal gland (primary)

Answer 348

Where there is a suspected hormone deficiency in production by a gland => stimulation test should be carried out Where there is a suspected hormone excess in production by a gland => suppression test should be carried out

Answer 349

Transphenoidal surgery Pituitary irradication Medical treatment Bilateral adrenalectomy

Answer 350

``` Nelsons syndrome Lack of negative feedback Uncontrolled pituitary growth Very high secretion of ACTH Pigmentation Difficult to treat ```

Answer 351

Hydrocortisone (increases cortisol) Fludrocortisone (increased mineralocorticoids) REPLACEMENT

Answer 352

The steroid receptors form part of a family of nuclear DNA-binding proteins (steroids pass through the cell membrane acting in the cell) that include the thyroid and vitamin D receptors. They all have three main regions: - A hydrophobic hormone-binding region - A DNA-binding region rich in cysteine and basic amino acids - A variable region There is sequence homology in the hormone-binding region of the receptors. The percentage homology of the hormone-binding region of the glucocorticoid receptor with receptors is: - Mineralocorticoid is ~64% - Androgen is ~62% - Oestrogen is ~31% - Thyroid is ~24% Therefore, cortisol will bind to the mineralocorticoid and androgen receptors with low affinity. This binding may become significant when high levels of the hormone are present. The actions of cortisol on target tissues are mediated by binding to receptors in the cytoplasm/nucleus. All steroid hormone receptors have similar basic structure with hormone and DNA binding domains. The hormone binding domains of the mineralocorticoid and androgen receptors have over 60% sequence homology with the hormone-binding domain of the glucocorticoid receptor. Thus, cortisol can bind to these receptors to a limited extent causing their partial activation

Answer 353

In the neck in front of the lower larynx and upper trachea

Answer 354

Two major cells types are found in the gland: - Follicular cells - arranged in units called follicles separated by connective tissue. The follicles are spherical and are lined with epithelial columnar/ cuboidal (follicular) cells surrounding a central space (lumen) containing protein - colloid. - Parafollicular (C-cells) - found in the connective tissue.

Answer 355

Lumen in thyroid gland which is lined by follicular cells | Where t3 and t4 are stored

Answer 356

Thyroxine (T4) | Triiodothyronine (T3)

Answer 357

Amino acid derivative hormones Derived from tyrosine (aa found on thyroglobulin) Attached to iodine (3 or 4) Fat soluble/ hydrophobic/ bind to proteins to be transported in blood/ can cross cell membranes and bind to cytoplasmic/ nuclear receptors

Answer 358

Calcitonin- believed to be involved in lowering plasma calcium levels in calcium metabolism

Answer 359

Active transport of iodide into epithelial cells using ATP Thyroglobulin synthesis (tyrosine rich) in epithelial cells Exocytosis of thyroglobulin into colloid (in prep for storage of hormones) Oxidation of iodine to produce iodinating species Iodination of side chains of tyrosine residues on thyroglobulin Formation of DIT and MIT Coupling of DIT and DIT= T4 and coupling of DIT and MIT = T3

Answer 360

Butterfly shape with two lateral lobes joined by a central isthmus 15-20g weight (largest endocrine gland in the body) Highly vascularised with 3 supplying arteries and 3 draining veins (superior, middle and inferior) Two nerves lie close to the gland - recurrent laryngeal, external branch of superior laryngeal

Answer 361

Stored extracellularly in the colloid as part of the thyroglobulin Storage amounts T3= 0.4 micro moles ; T4= 6 micro moles Can last for several months with normal amounts of secretion

Answer 362

Thyroglobulin is taken into the epithelia (follicular cells) from the colloid by endocytosis Proteolytic cleavage then occurs releasing T3 and T4 from thyroglobulin which diffuse from epithelial cells into circulation

Answer 363

Hydrophobic/ not water soluble Bound to thyronine binding globulin (TBG) Bound to albumin or pro albumin 1% free in plasma = biologically active

Answer 364

T4 has a greater affinity for TBG than T3 and so is more commonly found bound to TBG

Answer 365

T3 (2days) because it has a lesser affinity for TBG and so is found free more greatly T4 (8 days)

Answer 366

In pregnancy an increase in oestrogen causes an increase in TBG- meaning that there is less free T3/4 in the blood = less negative feedback on hypothalamus and pituitary gland = more TRH and TSH and hence there is an increase in secretion of T3/4 and thus more active free T3 and T4 circulating in the blood

Answer 367

No only free hormones in the blood can have a negative feedback!

Answer 368

T3 & T4 act within the target cell, interacting with high-affinity (10x greater affinity for T3) receptors located in the nucleus and possibly mitochondria. - Binding of T3 to the hormone-binding domain (is thought to) produce a conformational change in the receptor that unmasks the DNA-binding domain. - Interaction of the hormone-receptor complex with DNA increases the rate of transcription of specific genes that are then translated into proteins. - The increase in rate of protein synthesis stimulates oxidative energy metabolism in the target cells to provide the extra energy required for protein synthesis. - Also, protein synthesis produces more specific functional proteins, therefore increases cell activity and demand for energy.

Answer 369

T3 and T4 increase the metabolic rate of many tissues: - Increased Glucose uptake and metabolism - Stimulate mobilization and oxidation of fatty acids - Stimulate protein metabolism Since the metabolic effects of T3 and T4 are mainly catabolic, this leads to: - Increased BMR- increase in number and size of mitochondria, increase in oxygen consumption and heat production (UCPs), increase in nutrient utilisation - Stimulate most metabolic pathways- Catabolic>Anabolic (lipolysis, glycolysis, glycogenolysis, proteolysis) - promote normal growth and development of tissues- increase in synthesis of specific proteins - Increase responsiveness of tissues to SNS (adrenaline) and various metabolic and reproductive hormones

Answer 370

T3 and T4 are important for normal growth/development - T3 and T4 directly affect bone mineralisation and increase the synthesis of heart muscle protein. - The CNS is sensitive to T3/T4, especially during development as they’re required for the development of cellular processes of nerve cells, hyperplasia of cortical neurons and myelination of nerve fibres. In the absence of thyroid hormone from birth-puberty the child remains mentally & physically retarded (cretinism). If the deficiency isn’t corrected within a few weeks of birth there’s irreversible damage. All newborns have their thyroid function assessed soon after birth. In adults lack of thyroid hormones is characterised by poor concentration and memory, lack of initiative. - T3 and T4 are also indirectly related to interactions with hormones and neurotransmitters. T3/T4 stimulate hormone and neurotransmitter receptor synthesis in tissues (i.e. heart muscle, GI) that can increase responsiveness of these tissues to regulatory factors. - In heart muscle – tachycardia. In the GI tract – increased motility. - T3 and T4 have a permissive role in the actions of hormones such as FSH and LH. - Ovulation fails to occur in the absence of thyroid hormones.

Answer 371

T4 can be converted to T3 by the removal of the 5’-iodide. This helps to regulate the amount the amount of active (free) hormone in cells, as T3 is 10x more active than T4. Removal of the 3’-iodide produces the inactive reverse T3 (rT3)

Answer 372

Hypothalamus --(Thyrotrophin releasing hormone, TRH- tripeptide released from cells in dermomedial nucleus of hypothalamus)--> anterior pituitary gland--(thyroid stimulating hormone-released by thyrotrophs)--> follicular cells of thyroid gland --> T3 and T4

Answer 373

Thyroid stimulating hormone! Glycoprotein consisting of 2 non covalently linked subunits (alpha and beta) Released in low amplitude pulses following an a diurnal rhythm: high at night, low in morning

Answer 374

TSH interacts with receptors on the surface of the follicle cells and stimulates all aspects of the synthesis and secretion of T3 and T4 Also TSH has trophic effects on the gland that result in increased vascularity, increase in size and number of follicle cells --> enlarged thyroid gland (GOITRE) with an over and under active thyroid

Answer 375

Development (birth --> puberty) and functioning (adults) Increased myelination of nerve fibres and neurone development Increased speed of reflexes Increased mental activity (alertness, emotional tone, memory) Development of cellular processes of nerve cells Hyperplasia of cortical neurons Myelination of nerve fibres

Answer 376

Increases responsiveness of heart to SNS and catecholamines | Increases synthesis in heart muscle protein

Answer 377

Increases turnover of proteins and glycoprotein (mucopolysaccharides)

Answer 378

Over activity of the thyroid gland leading to over secretion of thyroid hormones

Answer 379

HUGE EYES Heat intolerance, Increased oxygen consumption, Increased BMR Weight loss Physical and mental hyperactivity Tachycardia Intestinal hyper mobility Skeletal and cardiac myopathy= tiredness, weakness, breathlessness Osteoporosis- increased turnover of bone and preferential resorption Common signs and symptoms: • Weight loss • Heat intolerance, sweating, warm vasodilated hands. • Irritability, emotional lability • Tachycardia (noticeable heart beat) often irregular. • Fatigue and weakness • Increased bowel movements - increased appetite • Menstrual dysfunction • Hyper-reflexive • Possible tremor of outstretched hands

Answer 380

Graves' disease Others include: thyroid adenoma, pituitary or hypothalamus cause, drugs

Answer 381

Affects ~1% of population- mostly women Autoimmune disease in which antibodies are produced to stimulate TSH receptors on follicle cells, resulting in increased production and release of T3/4

Answer 382

``` TSH Low (due to negative feedback from high T3/4) T3/4 High ```

Answer 383

TSH and T4 levels in blood Technetium scan- diagnostic scanning using technetium 99m and a gamma camera; picks up radioactivity produced by iodine producing thyroids Normal= some iodine lights up Diseased= dark

Answer 384

Using an anti thyroid drug- carbimazole Surgical removal of thyroid and then treat for hypothyroidism Radioactive iodine- following surgery that didn't remove the entire gland- destroys the remaining diseased portion of the thyroid gland

Answer 385

Inhibits the enzyme thyroid peroxidase and so prevents coupling and iodination of tyrosine residues on thyroglobulin Inhibits incorporation of iodine into thyroglobulin

Answer 386

Risk of causing consequential hypothyroidism

Answer 387

Underactivity of thyroid gland leading to under secretion of thyroid hormones

Answer 388

``` Cold intolerance and reduced BMR Weight gain Tiredness and lethargy Bradycardia Neuromuscular system- weakness, muscle cramps and cerebella ataxia (clumsiness of movement) Skin dry and flaky Alopecia (hair loss) Voice is deep and husky ``` If it occurs in embryo/ new born = cretinism (failure in CNS development, protruding tongue and delayed sex development) Weight gain due to reduced BMR. • Cold intolerance due to reduced BMR. • Lethargy/tiredness due to reduced uptake of nutrients by muscle. • Bradycardia – slow heart rate due to reduced responsiveness to catecholamines and reduced heart muscle protein synthesis. • Dry skin and hair loss due to reduced synthesis of proteins. • Slow reflexes and clumsiness due to reduced sensitivity to catecholamines. • Constipation due to reduced responsiveness of GI tract • Hoarse voice.

Answer 389

Hashimotos Others include a pituitary or hypothalamus cause, or iodine deficiency

Answer 390

Affects 1% of population- mostly women Autoimmune disease that results in either the destruction of thyroid follicles or the production of an antibody that blocks the TSH receptor on follicle cells preventing them from responding to TSH

Answer 391

``` T3/4 LOW TSH HIGH (due to less negative feedback from low T3/4) ```

Answer 392

Oral T4/ thyroxine Dose adjusted according to patients signs, symptoms and TSH levels Increased latke of iodine if cause is iodine deficiency

Answer 393

Can be converted to more active T3 | Replaces the T3/4 lost and reinstates negative feedback on TSH

Answer 394

Risk of it causing hyperthyroidism

Answer 395

Don't need to know but just know that they are formed

Answer 396

In hypothyroidism there is low T3/4 and hence less negative feedback on TSH- therefore TSH levels increase which causes there to be an increase in trophic effects on follicular cells - increase in size and number of follicular cells = GOITRE

Answer 397

Swelling of the thyroid gland Lump on throat of varying sizes Caused by hypo/hyper thyroidism

Answer 398

Calcium plays a critical role in many cellular processes: - Hormone secretion - In/activation of enzymes - Muscle contraction - Exocytosis -Nerve conduction Therefore, the body very carefully regulates the plasma concentration of free ionised calcium ([Ca2+]), the physiologically active form of the metal, and maintains free plasma [Ca2+] within a narrow range (1.0 to 1.3mM, or 4.0 to 5.2mg/dl). Other things: can calcify the osteoid of bone- more rigid structure (main storage of calcium in body)

Answer 399

1.0 to 1.3mM, or 4.0 to 5.2mg/dl

Answer 400

Parathyroid hormone Vitamin D (calcitriol) Calcitonin

Answer 401

Produced in the parathyroid gland in the chief cells Regulated by negative feedback Raises Ca2+ concentration of blood- short term regulation Straight chain polypeptide hormone (water soluble) Pre hormone = 115 aa and hormone = 84 aa Half life = 4 mins

Answer 402

High [Ca2+] = increase in binding of Ca2+ to G receptors on surface of chief cells = * stimulates Phospholipase C = inhibits adenylate cyclase = decrease in cAMP = decrease in release of PTH * = down regulation of gene transcription = accelerated cleavage and degradation of PTH in chief cells (already released PTH cleaved in liver) = decrease in synthesis of PTH

Answer 403

Low [Ca2+] = decrease in binding of Ca2+ to G receptors on surface of chief cells = * inhibits Phospholipase C = stimulates adenylate cyclase = increase in cAMP = increase in release of PTH * = up regulation of gene transcription = less cleavage and degradation of PTH in chief cells = increase in synthesis of PTH * prolonged survival of mRNA

Answer 404

Activated vitamin D, 1,25dihydroxyvitaminD Vitamin D- 25 hydroxyvitamin D -1,25dihydroxyvitaminD (calcitriol) Raises [Ca2+] of serum- long term regulation Vitamin D is made in skin when exposed to UVB in sun Vitamin D is sourced in cheese, butter, margarine, fortified milk, fish, fortified cereals Steroid hormone (not water soluble) Vitamin D has a very short half life whereas the half life of calciferol (2weeks) and calcitriol (few hours) is much higher

Answer 405

Pro vitamin D used UVB to be converted into pre vitamin D, which is cleaved to form vitamin D3 (cholecalciferol) and D2 (ergocalciferol) These undergo a hydroxylation in the liver = 25 hydroxyvitamin D (calciferol) This undergoes a further hydroxylation In the kidney = 1,25 dihydroxyvitamin D (calcitriol) Calcitriol raises serum [Ca2+]

Answer 406

Vitamin D / PTH stimulate osteoblast cells on bony surface to secrete cytokines which stimulate the differentiation of osteoblasts and stem cells into osteoclasts which results in stimulated activity of osteoclasts and consequential decrease in activity of osteoblasts (also inhibited by PTH) Bony surface is then exposed to osteoclast action Resorption of mineralised bone Release of phosphate and calcium into ECF INCREASE IN serum conc of Ca2+ and Pi

Answer 407

Vitamin D/ PTH affect the tubular cells in the kidney: - increases the reabsorption of Ca2+ in the dct, thus reducing excretion of Ca2+ - increase P filtration in kidney- Pi removed from circulation bu inhibition of kidney reabsorption This has the effect of preventing kidney stone for action as their wise calcium and phosphate stones (hydroxyapatite crystals) would form causing blockages INCREASE IN serum conc of Ca2+ DECREASE IN serum conc of Pi

Answer 408

Vitamin D --(1st hydroxylation in LIVER)--> calciferol --(2!pnd hydroxylation in KIDNEY- requires PTH)--> calcitriol Calcitriol increase the uptake of Ca2+ from the gut (active uptake and extrusion, transcellular transport, endocytosis and exocytosis using CaBP complex) Increased serum calcium concentrations means that there can be increased calcification of osteoid (organic matrix) in bone INCREASE IN serum conc of Ca2+

Answer 409

``` Kidney stones and damage Constipation Dehydration Tiredness and depression Moans(depression), groans(abdominal pain), stones (kidney) ```

Answer 410

Raised serum concentration of Ca2+

Answer 411

Hyper excitability of neuromuscular junction (low Ca2+ in ECF slightly depolarises cells such that they have a reduced firing threshold) Paraesthesia (pins and needles) Tetanic contraction of muscles Convulsions and if respiratory muscles are involved = DEATH

Answer 412

Low serum concentration of Ca2+

Answer 413

Excess PTH due to hyperparathyroidism Parathyroid hormone related peptide from Cancers Excess calcitriol

Answer 414

Replace fluid as less calcium and water is reabsorbed in the kidneys Remove tumour from parathyroid gland

Answer 415

Hypoparathyroidism (very rare) PTH deficiency- uncommon, normal serum Ca2+ conc can't be maintained, can be caused by removal of pt, symptoms w/i 48 hrs Removal of parathyroid gland Vitamin D and calcium deficiency

Answer 416

Supplements of vitamin D and or calcium | Normally fixes itself

Answer 417

At the expense of bone

Answer 418

Increase dietary intake of calcium

Answer 419

Failure to mineralise long bones as a result of a vitamin d deficiency Symptoms include- bowed legs, big lumpy joints, curved bone, bony necklace, slow closing soft spot on baby head

Answer 420

Lower Ca2+ levels in animals In humans it lacks pathology associated with either hyper/hypo secretion; removal or destruction of thyroid- lack of calcitonin has no effect on homeostasis May be important in pregnancy, may serve to preserve the fetal skeleton

Answer 421

Chief cells of parathyroid gland

Answer 422

Parafollicular cells of thyroid gland

Answer 423

During pregnancy the rate of insulin secretion and synthesis normally increases When the pancreas fails to respond to the demands if pregnancy less insulin than is required is released Loss of metabolic control and rise in blood glucose, leads to diabetes Normally reverses after birth of child Increase chance of future diabetes

Answer 424

Diabetes insipidus

Answer 425

It's used for synthesis of the cell membrane | It's used for steroidogenesis- adrenal cortex

Answer 426

Converted to bile salts

Answer 427

Increase in the concentration of ammonia in the blood Due to high protein diet, urea cycle defect, amino acid metabolism defect, refeeding syndrome with kwashiorkors Toxic to CNS - tremors slurred speech, coma and death Increased pH of blood - basic ammonia Reaction with alpha ketoglutarate removes TCA substrate and so leads to reduction or energy supply

Answer 428

Both contain acidic groups

Answer 429

Hydrophobic - so not associated with lots of water | More reduced than glycogen so yield more energy when oxidised

Answer 430

Increase permeability of mitochondrial membrane for protons Reduces pmf so that energy is dissipated as heat rather than being used in ATP synthesis Expressed as bat and involved in thermogenesis

Answer 431

Any condition in which, after a 12 hour fast, the plasma cholesterol and/or plasma triglyceride is raised.

Answer 432

Tissues obtain the cholesterol they need from LDLs by the process of receptor-medicated endocytosis. LDL particles are taken up by the cell and the cholesterol released inside the cell. All cells (except erythrocytes) are able to synthesise cholesterol from acetyl~CoA and could satisfy their requirements by biosynthesis. In practice, all cells appear to prefer the uptake of pre-formed cholesterol circulating in plasma lipoproteins. o Cells requiring cholesterol synthesise LDL receptors that are exposed on the cell surface. o These receptors recognise and bind to specific apoproteins (Apo B100) on the surface of the LDL. o The LDL receptor with its bound LDL is then endocytosed by the cell and subjected to lysosomal digestion. o Cholesterol esters are converted to free cholesterol that is released within the cell. o The cholesterol can be stored (as cholesterol esters) or used by the cell o This also inhibits the synthesis of cholesterol by the cell and reduces the synthesis and exposure of LDL receptors. This prevents the cell from accumulating too much cholesterol.

Answer 433

Diet and lifestyle modifications (e.g. increase in exercise) are considered first to treat hyperlipoproteinaemia. Aiming to reduce/eliminate cholesterol from the diet and reduce the intake of triacylglycerols (especially those with saturated fatty acids). In some patients this will have little effect. Drug therapy – statins (e.g. simvastin) are a group of drugs that may lower plasma cholesterol by reducing the synthesis of cholesterol in tissues. The liver can dispose of cholesterol by converting it into bile salts and secreting a small amount directly in the bile. The bile salt sequestrants (e.g. cholestyramine) lower plasma cholesterol by increasing its disposal from the body. They act by binding to bile salts in the GI tract preventing them from being reabsorbed into the hepatic-portal circulation and promoting their loss in the faeces.

Answer 434

Increase in insulin (affects glucose, fas, aas) Increase in: Glycolysis and oxidation by skeletal muscle and adipose tissue Glycogenesis Protein synthesis Lipogenesis

Answer 435

``` Increase in glucagon (affects glucose and fas- not aas) Increase in: Glycogenolysis Gluconeogenesis Lipolysis ```

Answer 436

``` Even more glucagon than in fasting Increase in: Gluconeogenesis Lipolysis Ketogenesis Protein breakdown ```

Answer 437

Cold weather Release of norepinephrine Increase in lipolysis Fatty acids activate the uncoupling protein thermogenin in mitochondrial membrane Increase in permeability of inner mitochondria membrane for protons Protons reenter the mitochondrial matrix ATP synthase not activated so no ATP synthesis Pmf is dissipated as heat Electron transport and thus NADH/FAD2H oxidation continues Free energy is released as heat Respiration continues to bring more NADH and FAD2H to mitochondria and uses up fuel molecules (fatty acids, glucose etc) More and more heat production

Answer 438

Severe obesity can result due to loss of control of the balance between energy intake and energy expenditure

Answer 439

Stimulated by: fatty acids, glucose, amino acids in high conc; gut hormones in readiness for absorption of raw materials Inhibited by: The catecholamines adrenaline and noradrenaline inhibit insulin secretion. This enables the catecholamines released during stress to raise the blood glucose concentration and for the concentration to be maintained while the stress is dealt with. If insulin secretion was not inhibited the increase in blood glucose caused by the catecholamines would stimulate insulin secretion and the blood glucose concentration would fall prematurely.

Metabolism Flashcards

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