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AC1 > Endocrinology > Flashcards

Endocrinology Flashcards

1
Q

What molecule monitors the energy status of a cell?

A

AMP-activated protein kinase (AMPK)
Part of a nutrient/energy sensing system
Activated by a low ATP/AMP ratio
This shuts off energy requiring processes (lipid synthesis) and activates pathways of ATP formation (fatty acid oxidation)

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2
Q

What is the Warburg effect?

A

Cancer cells are adapted to form ATP anaerobically continuously even when oxygen is available
Inefficient process, they need to use glucose at a very high rate

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3
Q

What do catabolism and anabolism do to ATP levels?

A

Catabolic processes produce ATP

Anabolic processes consume ATP

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4
Q

What are the different pathways by which Acetyl co A can be formed?

A

Carbs: sugars -> glucose -> glycolysis to pyruvate -> pyruvate dehydrogenase -> Acetyl co A
Triglycerides: glycerol -> glycolysis to pyruvate. Fatty acids -> beta oxidation to Acetyl co A
Protein: amino acids -> pyruvate, Acetyl co A and citric acid cycle

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5
Q

What are the products of glycolysis?

A

2 molecules of pyruvate
2 molecules of ATP
2 NADH (high energy electron carrying molecules)

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6
Q

Where does ATP synthesis occur in mitochondria?

A

ATP synthase is at inner membrane

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7
Q

How is most ATP produced?

A

In mitochondria via oxidation of NADH (and FADH2)

When oxygen is present and mitochondria is active/present

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8
Q

How is NADH generated?

A

Glycolysis in cytosol (mechanisms needed to transfer NADH into mitochondria)
Fatty acid oxidation (also FADH2)
Tricarboxylic Acid Cycle (citric cycle) (FADH2)
Amino acid utilisation

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9
Q

How does glucose get into cells?

A

Transported into cells through facilitated diffusion (requires transporters)
GLUT transporters

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10
Q

Which GLUT transporters are insulin sensitive and insensitive?

A

GLUT4: main insulin sensitive, adipose and skeletal muscle
GLUT1/3: not sensitive, CNS and skeletal muscle
GLUT2: not sensitive, liver and pancreatic beta cells

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11
Q

What are the 3 important regulated steps of glycolysis?

A

Hexokinase (1st step): glucose to glucose-6-p (uses 1 ATP)
Phosphofructokinase (3rd): fructose-6-p to Fructose-1,6-bP (uses 1 ATP)
Pyruvate kinase (last step): Phosphoenolpyruvate to pyruvate (makes 2 ATP)

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12
Q

What does lactate dehdrogenase do to pyruvate?

A

Forms lactic acid

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13
Q

What happens during phase 1 and phase 2 of glycolysis?

A

Phase 1: investment phase, consume 2 molecules ATP

Phase 2: production phase, makes 4 ATP and 2 NADH

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14
Q

What different Hexokinase isoforms are present in tissues?

A

Isoforms differ in affinity for glucose, depending on cell-type
Tissues with low affinity GLUTs express low affinity Hexokinases
HK1: (high affinity) ubiquitously expressed including brain
HK2: restricted to insulin-sensitive tissues (adipose tissue, skeletal muscle,heart) but is also highly expressed in cancer cells
HK1 and 2 are inhibited by Glucose-6-p
HK4: Glucokinase expressed in liver, low affinity, not inhibited by G6P

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15
Q

What enzyme converts pyruvate into Acetyl co A?

A

Pyruvate dehydrogenase

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16
Q

What are the mechanisms of transferring reducing power across mitochondrial inner membrane?

A

Inner membrane of mitochondria is impermeable to NADH Glycerol Phosphate Shuttle: regenerates NAD+ from NADH. Allows NADH synthesised in cytosol by glycolysis to contribute to oxidative phosphorylation via Glycerol-3-P then FADH2
Malate-Aspartate shuttle: translocating electrons across inner membrane of mitochondria for oxidative phosphorylation
Oxoglutarate and aspartate carriers move malate and H across the membrane

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17
Q

Which molecule by product of glycolysis can go on to participate in lipogenesis?

A

Glycerol-3-p

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18
Q

How do fatty acids get into mitochondria? And then how do they contribute to energy release?

A

Carnitine shuttle: fatty acid converted to Acyl co A which in turn is converted to acylcarnitine
Carnitine-acylcarnitine carrier moves it into mitochondria
Then converted back to Acyl co A and Carnitine is moved back via carrier out of mitochondria
Acyl co A undergoes beta oxidation to become Acetyl co A and FADH2 and NADH is released in the process

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19
Q

How do fatty acids and glucose inhibit each other’s utilisation?

A 
Acetyl co A as end product 
Citrate release (first step of TCA cycle) provides negative feedback to utilisation
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20
Q

Describe slow twitch muscle fibres

A

Oxidative, high capacity for oxidising glucose and fatty acids
Depends on oxygen availability and glycogen store of muscle fibre
Used for regular, long term contraction (postural muscles, running)
Highly vascularised, high mitochondrial content
Can switch to fatty acids as main source of energy especially when glycogen exhausted
Can use ketones during fasting

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21
Q

Describe type 2 fast twitch muscle fibres

A

Less oxidative, generate enough ATP from glycolysis for short periods
Relies on rapid glycogen breakdown
Used for short bursts of activity (sprinting)
Anaerobic glycolysis produces lactate, lowering intracellular pH (causing cramp)
Can also rely on creatine phosphate breakdown for very short bursts of contraction

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22
Q

Are cardiac and diaphragm muscles slow or fast twitch?

A

Same as Type-1 fibres
Heart depends 75% of its energy needs on fatty acid oxidation under normal conditions, and an even greater extent in diabetes
Problems during ischaemia – reperfusion

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23
Q

How is AMP produced?

A

Hydrolysis of ADP: ADP –> AMP + Pi

Hydrolysis of ATP: ATP –> AMP + PPi

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24
Q

Where does the TCA cycle happen?

A

Matrix of the mitochondria

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25
Q

What is the purpose of the TCA cycle?

A

Oxidation of Acetyl-CoA as a source of NADH and FADH2 (electron carriers)

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26
Q

What is combined with Acetyl co A to start the TCA cycle?

A

Oxaloacetate

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27
Q

What are products of the TCA cycle?

A

3 NADH
FADH2
GTP
2 CO2

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28
Q

What is the electron transport chain?

A

Energy of electrons from NADH and FADH2 is used to pump protons across the mitochondrial inner membrane across their concentration gradient

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29
Q

What are the sources of NADH for the electron transport chain?

A

TCA cycle
Fatty acid β-Oxidation
Malate shuttle (glycolysis)

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30
Q

What are the sources of FADH2 for the electron transport chain?

A

TCA cycle
Fatty acid β-Oxidation
G-3-P shuttle (glycolysis)

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31
Q

How does the electron transport chain lead to ATP production?

A

Protons pumped out of the mitochondria to form a concentration gradient
Chemiosmosis: ATP synthase re-pumps H+ and allows the synthesis of ATP

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32
Q

How is ATP transported out of the mitochondria?

A

ATP-ADP carrier
ATP synthase requires 3 protons flowing down concentration gradient to synthesise one ATP molecule, the fourth proton is symported with each ATP out across the i.m. in exchange for one ADP

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33
Q

What is uncoupling?

A

Proton influx can be uncoupled from ATP synthesis by UCP1 (Uncoupling Protein 1)
Dissipation of the proton gradient results in the release of heat

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34
Q

Where does production of heat resulting in non-shivering thermogenesis occur?

A

Brown adipose tissue

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35
Q

What is DNP and why does it make you lose weight?

A

Blocks ATP synthase and increases uncoupling reaction
Results: increased body temperature, resulting in dramatic weight loss
Lack of ATP leading to death

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36
Q

What are amino acids required for?

A

Synthesis of proteins (structural, catalytic, signalling)

Synthesis of peptides (intra- and inter-cellular communication)

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37
Q

When are amino acids an important source of carbohydrates?

A

Fasting, trauma, sepsis

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38
Q

What needs to happen to amino acids before they can be used for glucose/lipid synthesis?

A

Deamination

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39
Q

How are amino acids metabolised?

A

Series of transamination reactions before urea formation
Branched chain amino acids require branched chain ketoacid dehydrogenase complex to be converted to -CoA derivatives
Dysfunction results in branched chain ketoaciduria (Maple syrup urine disease)

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40
Q

What is the main nitrogen-containing compound that is excreted through the kidneys?

A

Urea

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41
Q

How is urea formed from amino acid metabolism?

A

Glutamate + Oxaloacetate -> Aspartate aminotransferase -> aspartate + urea

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42
Q

How is glutamine formed from ammonia?

A

NH3 + α-Ketoglutarate -> Aminotransferase -> glutamate -> Glutamine

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43
Q

What is anaplerosis?

A

Replenishing TCA cycle intermediates using amino acids

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44
Q

What is the glucose-alanine cycle?

A

In muscle, glucose -> pyruvate -> alanine (transaminase enzyme)
Alanine transported to liver
Alanine -> pyruvate -> gluconeogenesis or Acetyl co A
By product is NH3 production which is converted to urea to be excreted

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45
Q

What factors are required for the urea cycle to work? What product feeds back into the TCA cycle?

A

NH3 and HCO3
Aspartate from TCA cycle
Fumarate formed which goes back into TCA cycle

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46
Q

Which tissues use glucose for fuel?

A

Most tissues

Obligatory for brain and erythrocytes

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47
Q

Which tissues use fatty acids for fuel?

A

Most tissues

Minimal in neurons as a source of energy

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48
Q

Which tissues use ketones for fuel?

A

Not liver (where they are synthesised)
Can be used by most tissues
Important for brain as a partial substitute for glucose when this is less available

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49
Q

Which cells use amino acids as fuel?

A

Not many cell types

Used (particularly glutamine) in fast-dividing cells e.g. enterocytes and cancer cells

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50
Q

Where can glucose taken up by the gut end up?

A 
Red blood cells
Liver
Brain
Adipose tissue
Skeletal/cardiac muscle
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51
Q

Where do triglycerides absorbed from the gut end up?

A

Transported in chylomicrons to adipose tissue
Broken down by lipoprotein lipase into fatty acids which can be transported to liver or skeletal muscle
Liver breaks them down to ketone bodies which can be used to supply the brain and skeletal muscle

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52
Q

Describe the interaction between glucose and fatty acids when glucose is in excess

A

Fatty acids can be formed from glucose
Glucose excess can be stored as lipid (triglycerides) but this can only be mobilised/metabolised as fatty acids
Depots of white adipose tissue (internal or subcutaneous) are
specialised for triglycerides storage
Spill over of triglycerides storage into ectopic tissues: muscle
(skeletal and cardiac) and liver has pathological consequences

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53
Q

What type of bond holds 2 monosaccharides together to form a disaccharide?

A

Glycosidic bond

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54
Q

What are Sucrose, Maltose and Lactose formed from?

A

Sucrose: glucose + fructose
Maltose: glucose + glucose
Lactose: glucose + galactose

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55
Q

What happens to disaccharides for them to be absorbed?

A

Disaccharides are soluble in water but do not cross cell membrane by diffusion
Must be broken down in small intestine during digestion: hydrolysis reaction which releases energy

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56
Q

What is glycogen?

A

Branched polysaccharide with 1-4-alpha-glycosidic linkages in chains and 1-6-glycosidic linkages for branches
Each glycogen granule has a core glycogenin protein

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57
Q

What are roles of lipids?

A

Energy storage
Components of cell membrane (phospholipids and cholesterol)
Chemical messengers

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58
Q

What is white adipose tissue specialised for?

A

Store large amounts of triglyceride in lipid droplets

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59
Q

What are triglycerides synthesised from?

A

Glycerol and Fatty Acids

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60
Q

What is glycerol?

A

Type of alcohol – contains hydroxyl group (OH)

Glycerol has 3 hydroxyl groups, which will be linked to 3 Fatty Acids

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61
Q

Describe the structure of fatty acids

A

Long fatty or hydrophobic chain and an acidic COOH group at end
Some are Saturated (all C-C bonds are single covalent bonds)
Some are Unsaturated (some of C-C bonds are double)

62
Q

How do fatty acids form phospholipids?

A

One of the fatty acids of a triglyceride is substituted by a phosphate group and a head group

63
Q

What is special about cholesterol which makes it good for membrane structure?

A

Planar structure that makes membranes more rigid

64
Q

What are sphingolipids?

A

Fatty acids can form ceramides which are important components of membranes and are also important in cell signalling

65
Q

What happens to fatty acids when they are in intracellular compartments?

A

Fatty acids are very rapidly linked to a Coenzyme A molecule which traps them in specific intracellular compartments, as CoA and its derivatives are not membrane permeable

66
Q

What are ketone bodies and when are they produced?

A

3 molecules: acetone, acetoacetic acid, beta-hydroxybutyric acid
Produced from fatty acids during fasting (low food intake) or carbohydrate restriction
Produced in liver
Can be used for energy (more important for the brain)

67
Q

Which are the essential amino acids which are obtained from the diet?

A 
Leucine
Methionine
Isoleucine        
Phenylalanine
Valine
Threonine
Histidine            
Tryptophan
Lysine
68
Q

Describe the levels of organisation of protein structure

A

Primary structure: sequence of amino acids
Secondary structure: arrangement of protein chains
Tertiary structure: folding into a globular shape (enzymes, immunoglobins)
Quaternary structure: more than one protein chain (Insulin and hemoglobin)

69
Q

What is endocrine secretion?

A

Secretion of a hormone into the blood stream to act on a distal tissue

70
Q

How do the symptoms of endocrine disease correlate with the mode of secretion?

A

Multi organ manifestations
Generalised nonspecific symptoms such as weakness, difficulty
concentrating, lack of energy, and change in appetite
Constellation of symptoms

71
Q

What is the only example of positive feedback in the body?

A

Oestrogen causing LH surge

72
Q

What can cause excess hormone secretion?

A

Neoplasm
Hyperplasia
Ectopic production

73
Q

What can cause too little hormone production?

A 
Gland destruction (trauma, disease, autoimmune) 
Not developed
74
Q

What can cause hormone resistance?

A

Receptor problems

Intracellular signalling defects

75
Q

What are primary and secondary endocrine problems?

A

Primary: too much of effector hormone from endocrine organ
Secondary: overstimulation of effector endocrine organ by excessive trophic hormone

76
Q

What changes in endocrine tissues would increase secretion?

A

Cellular adaptations: Hyperplasia and hypertrophy
Inflammation: Transiently
Neoplasms: Benign (histologically resemble tissue differentiating towards)

77
Q

What causes hyperplasia or hypertrophy?

A

Increased functional demand driven by growth factors

Hormonal stimulation e.g. trophic hormones

78
Q

What are stimuli for changes leading to tissue changes and therefore increased hormone secretion?

A

Increased trophic hormones: Neoplasms in trophic organ, Ectopic hormone production e.g. small cell lung cancer
Increased secretion without trophic hormone: Mimics of trophic hormone i.e. antibodies to the receptor, Loss of normal feedback control
i.e. neoplasms

79
Q

What changes in endocrine tissues would decrease hormone secretion?

A

Cellular adaptations: Atrophy e.g. lack of stimulation or lack of necessary metabolites e.g. iodine
Cell injury or death: ischaemia or toxic injury
Chronic inflammation: sarcoidosis
Adjacent neoplasm

80
Q

What are stimuli for changes leading to tissue changes and therefore decreased hormone secretion?

A

Decreased trophic hormones: Neoplasms in trophic organ, Lack of metabolites, Infarction of organs
Decreased secretion despite trophic hormone: Lack of metabolites, Lack of functional tissue e.g. infarction or inflammation, Loss of sensitivity to trophic hormones

81
Q

What is a dynamic function test?

A

Measure serum levels of a hormone
Stimulate axis and observe response
Suppress axis and observe response

82
Q

What TSH and T4 level results would you expect in someone with primary and secondary hypothyroidism?

A

Primary: high TSH, low T4
Secondary: low TSH, low T4

83
Q

What techniques can be used to image endocrine problems?

A

Ultrasound/CT/MRI

Nuclear imaging: Use injectable substances that localise to tissue, Useful in identifying ectopics

84
Q

What are principles of management for hypo endocrinism?

A

Replace effector hormone

Treat symptoms

85
Q

What are principles of management for hyper endocrinism?

A

Primary: Symptomatic, Surgery, Radiotherapy
Secondary: Symptomatic, Surgery, Radiotherapy, Block receptors on downstream organs

86
Q

What factors are associated with the development and progression of peripheral neuropathy?

A

Poorly controlled hyperglycaemia
Uncontrolled hypertension
Dyslipidaemia

87
Q

If a patient on metformin presents with a neuropathy, what may be causing it?

A

B12 deficiency

88
Q

What autonomic neuropathies can occur as a result of poorly controlled diabetes?

A 
Postural hypotension
Gustatory sweating
Autonomic diarrhoea 
Diabetic gastroparesis 
Erectile dysfunction
89
Q

What is sildenafil?

A

Viagra - Phosphodiesterase inhibitor

90
Q

What is the leading cause of blindness in under 65s in industrialised countries?

A

Diabetic retinopathy

91
Q

When should diabetic retinopathy screening occur? What is it?

A

At diagnosis
Annually thereafter
Bilateral digital photography of fundi after pupil dilatation

92
Q

What causes diabetic retinopathy?

A

Microvascular disease, basement membrane of small vessels
Damage leads to leakage of blood or plasma into extravascular space with secondary thickening of basement membrane
Blood supply disruption causes tissue hypoxia triggering vascular growth factor release -> proliferation of vessels in retina and vitreous humour
Vascular insufficiency due to atheroma of large vessels or micro emboli from carotid artery disease can worsen problem

93
Q

What do you see on fundoscopy of a patient with diabetic retinopathy?

A

Micro aneurysms - dot haemorrhages, vessel dilation
Blot haemorrhages - leakage of blood
Cotton wool spots - ischaemic areas
Venous beading
Intra-retinal microvascular abnormalities
Exudative maculopathy
Neovasscularisation - new vessels are friable and bleed easily

94
Q

What should be offered to patients with diabetic nephropathy with any degree of albuminuria?

A

ACE inhibitors

95
Q

What factors promote the development and progression of nephropathy?

A 
High blood pressure
Poor glycemic control
Dyslipidaemia 
Smoking
High protein intake
Small kidneys 
Genetic factors
96
Q

What are signs and symptoms of uraemia?

A 
Malaise 
Nocturia
Pallor
Dyspnoea 
Hiccoughs 
Oedema
Nausea
Confusion
Pruritus
Pericarditis
97
Q

If a diabetic patient has microalbuminuria but their mid stream urine sample shows no sign of infection, what do they have?

A

Stage 2 nephropathy

98
Q

What is nephrotic syndrome?

A

Hypoalbuminaemia

Oedema

99
Q

What histological signs would be seen on renal biopsy of a patient with nephropathy?

A

Diabetic glomerulosclerosis with mesangial expansion and thickening of basement membrane

100
Q

What needs to be done before a renal biopsy?

A

Clotting function tests
Platelet count
Fasted for 6 hours

101
Q

What factors should be controlled to prevent diabetic nephropathy?

A

Glycemic control
Blood pressure control
Smoking cessation
Lipid management

102
Q

What are treatment targets for diabetic nephropathy?

A

Blood pressure

103
Q

What are the minimum surveillance measures for diabetes?

A 
Weight and BMI
Blood pressure measurement 
Serum cholesterol
HBA1C
eGFR
Foot examination
Digital retinal photography
Urinalysis for microalbuminuria 
Depression screening
104
Q

What do you look for in a diabetic foot examination?

A

General foot health: Deformity, Hair loss, Loss of skin integrity, Loss of sweating, Swelling of joints, Callosities, nail health, fungal infection between toes
Vascular sufficiency: temperature of skin, detention of dorsalis pedis, and posterior tibial pulses, capillary refil at toes
Neurological integrity: light touch sensation, vibration sense, Achilles’ tendon reflex

105
Q

What 3 foot complications may occur in poorly controlled diabetes?

A

Vascular disease
Peripheral neuropathy
Raised risk of infection

106
Q

What is an early symptom of vascular insufficiency?

A

Intermittent claudication

107
Q

Why does vascular insufficiency increase risk of infection?

A

Ischaemia reduces immunological response to infection
Delays healing
Raises likelihood of anaerobic infection in deeper tissues

108
Q

Why does neuropathy increase the risk of ulceration of feet?

A

Reduced light touch sensation so unnoticed trauma

Impaired proprioception and denervation of intrinsic foot muscles leads to deformation and swelling of joints

109
Q

Why might a diabetic foot have a bounding pulse?

A

Autonomic denervation leading to arterio venous shunting

110
Q

What is a Charcots joint?

A

Swollen
Disfigured externally
Disorganised internally
Due to loss of proprioceptive function of foot so abnormal weight distribution - neuropathic arthropathy

111
Q

What imaging would you do to investigate venous insufficiency?

A

Doppler assessment to measure ankle brachial pressure index

112
Q

What are the international diabetes federation risk factors for ulcer development?

A 
Previous ulcer/amputation
Lack of social contact
Lack of education
Impaired protective sensation
Impaired vibration perception
Absent Achilles' tendon reflex 
Callus
Foot deformities
Inappropriate footwear
113
Q

What are the five cornerstones of management of the diabetic foot?

A

Regular inspection and examination of foot at risk
Identification of foot at risk
Education of patient, family and healthcare providers
Appropriate footwear
Treatment of non ulcerative pathology

114
Q

What are common triggers for foot ulceration?

A 
Poorly fitting footwear
Unnoticed trauma from foreign body
Burns (hot bath, hot water bottle, radiator)
Heel friction in bed bound patient
Nail infection
Dry skin
Self treatment of callus with corn plasters or sharp instrument 
Callus not effectively treated
115
Q

What should diabetic patients be encouraged to do with their feet?

A

Wear comfortable, properly fitting and supportive footwear
Avoid walking bare foot
Wash feet once a day in warm soapy water
Check for problems every day, report any fissures or loss of integrity
If skin is dry, use regular emollient to prevent fissures
Check visually inside footwear before putting on
Do not warm feet with hot water bottle or direct contact with radiator
Never attempt to self manage calluses
Do not apply any self adherent plasters to feet

116
Q

What are treatment options for an infected diabetic ulcer?

A 
Antibiotics
Topical wound management 
Desloughing of ulcer base 
Debridement of adjacent hyperkeratosis 
Appropriate footwear 
A walking programme
Pressure relief cast
Smoking cessation 
Control of vascular risk
Glycemic control
Nutritional management 
Surgical: debridement of necrosis, drainage of abscess, revascularisation, amputation
117
Q

Where does gluconeogenesis occur?

A

Liver and kidneys

118
Q

What activates and inhibits gluconeogenesis?

A

Activated by glucagon (low glucose signal)

Inhibited by insulin (high glucose signal)

119
Q

To perform gluconeogenesis, the cell needs to “reverse” glycolysis, what are the 3 key steps which need to be bypassed?

A

Hexokinase (glucokinase in liver)
Phosphofructokinase
Pyruvate kinase

120
Q

What glycolitic enzymes are needed for gluconeogenesis to occur?

A 
Phosphoenolpyruvate carboxykinase (PEPCK) Limiting step: bypass pyruvate kinase
Fructose1,6 BisPhosphatase (F1,6BPase): bypass Phosphofructokinase
Glucose 6- Phosphatase (G6Pase): bypass Hexokinase/Glucokinase
121
Q

How does glucagon contribute to gluconeogenesis?

A

Increases cAMP levels, Activates protein kinase a which phosphorylates pyruvate kinase to inactivate it

122
Q

What regulates Glucokinase activity?

A

Glucokinase regulatory protein (GKRP)
In low glucose conditions: GKRP binds to GK (competes with glucose) and inhibits GK (traps it in the nucleus)
In high glucose conditions: GKRP releases GK

123
Q

How are glucose-6-phosphatase and PEPCK regulated?

A

Transcriptional levels

In low glucose, G6Pase and PEPCK mRNA expression are induced/increased

124
Q

What happens to gluconeogenesis when ethanol is metabolised?

A

Gluconeogenesis inhibited by ethanol metabolism as this raises cytosolic NADH
TCA cycle is inhibited
Fatty acid oxidation is inhibited
As a result, can end up hypoglycaemic after drinking alcohol

125
Q

How can excess ethanol lead to hepatic steatosis?

A

Ethanol easily passes through membranes and is mostly taken up by liver, first pass
Metabolised to acetaldehyde (cytoplasm), and then to acetate in mitochondria, releasing NADH at both steps
Raised NADH/NAD ratio inhibits gluconeogenesis, TCA and FAO, whereas acetate is diverted towards lipogenesis (FA and cholesterol). Acetate is lipogenic
Ethanol inhibits Glycerol- 3P dehydrogenase so: DHAP (breakdown product of fructose)/Glycerol-3-P equilibrium will be towards G-3-P (precursor of TG)
Ethanol also activates SREBP1c (transcription factor and activator of lipogenesis)

126
Q

How can excess ethanol lead to cancer?

A

Steatosis -> inflammation -> apoptosis -> fibrosis -> cirrhosis -> cancer
Acetaldehyde -> cancer development, partly through Reactive oxygen species formation

127
Q

What catalyses glyconeogenesis?

A

Glycogen synthase

128
Q

What catalyses glycogenolysis?

A

Glycogen phosphorylase

129
Q

Which enzyme catalyses the conversion of Acetyl co A to cholesterol? And what is the clinical application of this?

A

HMG co A reductase

Statins block this

130
Q

What protein is found on the surface of lipoprotein particles?

A

Apoprotein B 100

131
Q

Describe Packaging of triglyceride in Very Low Density Lipoprotein (VLDL) in Hepatocytes

A

Apo b 100 combined with triglycerides to form Nascent dense particle in endoplasmic reticulum
Endoplasmic reticulum lipid droplets combine with this to form VLDL which also contains cholesterol and is then secreted into the blood

132
Q

Describe Packaging of triglyceride in Chylomicrons in enterocytes

A

Triglycerides combine with apo b 48 which are released into endoplasmic reticulum to form Nascent dense particle
This is combined with ER lipid droplets to form chylomicron which is secreted into intestinal lymphatics

133
Q

What happens to insulin and glucagon levels after food intake?

A

Insulin concentration increases (peak)
Insulin decreases circulating glucose (hypoglycemic action)
Glucagon concentration drops

134
Q

What happens to insulin and glucagon levels in the fasted state?

A

Glucagon concentration increases (constant)

Increases glucose production (liver) (hyperglycemic action)

135
Q

What is CPT -1? What is its significance in diabetes?

A

Carnitine palmitoyltransferase 1
Mitochondrial enzyme, catalyses transfer of Acyl group of from Acyl co A to Acyl Carnitine
Increase levels of malonyl co A caused by hyperglycaemia and hyperinsulinaemia inhibit CPT 1 which causes decrease in transport of long chain fatty acids into muscle and heart mitochondria, decreasing fatty acid oxidation in these cells. This increases free fatty acid levels and accumulation of fat in skeletal muscle

136
Q

What are causes of hypoglycaemia?

A 
Exertion/exercise
Fasting
Insulinoma (excess endogenous insulin)
Alcohol intake
Excess exogenous insulin
137
Q

If blood glucose levels drop below 3mmol/L what starts to occur?

A

2-3: cognitive dysfunction, mild neuroglycopenia
1-2: sweating, tremor, activation of autonomic symptoms
0-1: convulsions, severe neuroglycopenia, coma, death

138
Q

What hormones are released in response to hypoglycaemia?

A 
Glucagon
Vasopressin
Growth hormone
Cortisol
Adrenaline
139
Q

What are causes of hyperglycaemia?

A

Absolute absence of insulin (Type-1 diabetes): pancreatic β-cells are destroyed
Relative insufficiency of insulin (resistance leading to T2DM): Insulin is secreted, but tissues (or pathways) are not sensitive to it
Stress: chronically high cortisol and adrenaline, Both hormones activate glycogenolysis in the liver

140
Q

During hyperglycaemia, which areas undergo non insulin dependent glucose uptake?

A

Retina, lens, kidney, neurons

141
Q

What leads to cataract formation in diabetics?

A

High glucose leads to increased sorbitol and fructose
Impermeable through membranes
Osmotic swelling (lens) -> cataract

142
Q

How does high glucose lead to neuropathy and microvascular injury?

A

High glucose levels leads to increased sorbitol levels which competes with and therefore decreases Myo-inositol uptake
Decreased K ATPase activity+ (involved in the generation of electrical action potentials) and leads to injury

143
Q

What are acute complications arising from chronic hyperglycaemia in poorly controlled diabetes?

A

Ketoacidosis (T1DM)- emergency: Low insulin induces disturbance of fatty acid utilisation, leading to ketone production which decreases blood pH
Increased blood osmolarity: Water drawn out of cells to compensate for high blood glucose levels. Leads to dehydration

144
Q

What are chronic complications arising from chronic hyperglycaemia in poorly controlled diabetes?

A

Peripheral neuropathy, cataract, blindness, impaired kidney function, impaired vasodilation, cardiomyopathy, skin conditions
Non-enzymatic modification of proteins by glucose: glycation of haemoglobin (HbA1c)

145
Q

How long does HBA1C give estimate of glycemic control for?

A

2-3 months

146
Q

What are the actions of insulin?

A

In liver: Increase glycogen synthesis, Decrease gluconeogenesis, Decrease glycogenolysis
In muscle: increase glucose uptake, increase glucose oxidation, increase glycogen synthesis

147
Q

What are the different neuropathies of diabetes?

A

Diabetic symmetrical distal polyneuropathy: glove and stocking
Mononeuropathy and Mononeuropathy multiplex: CN palsies, radiculopathies, median, ulnar
Acute painful neuropathy: paraesthesia
Diabetic amytropathy
Autonomic neuropathy

148
Q

Describe the pathogenesis of diabetic renal hypertension

A

Efferent arteriolar vasoconstriction with mesangial expansion
Glomerular hypertension
Capillary protein leaks: microalbuminuria, Proteinuria, nephrotic syndrome
Sodium retention
Altered lipid handling

149
Q

What are the different mechanisms of action of anti diabetic medications?

A

Metformin: reduce hepatic glucose output and increase uptake in the periphery
Glitazones: bind to PPARy nuclear regulatory protein involved in transcription of genes relating to glucose and fat metabolism, improve glucose usage by cells
Sulfonylureas: inhibit K ATP channel of pancreatic beta cells to trigger insulin release (gliclazide, tolbutamide)
Alpha glucosidase inhibitors: slow digestion of starch in small intestine (miglitol,acarbose)
Injectable glucagon like peptide agonist: increase insulin secretion (exanatide)
DPP4 inhibitors: increase blood concentration of GLP1 so increase insulin secretion, less weight loss than GLP agonists (sitagliptin)
SGLT2 inhibitors: block glucose reuptake in renal tubule so increase excretion (canagliflozin)

150
Q

Describe glucose stimulated insulin secretion in beta cells

A

Glucose enters beta cell via GLUT2
It is metabolised by the cell which increases the ATP/ADP ratio
This closes ATP sensitive k channels and causes depolarisation
This opens voltage gated Ca channels to cause a Ca influx
This causes insulin vesicles to fuse with the cell membrane and cause the release of insulin

AC1 (18 decks)

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