Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

ESA 1 Revision > Metabolism > Flashcards

Metabolism Flashcards

1
Q

Define Catabolism

A

Break down molecules to release energy and reducing power

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Define Anabolism

A

Uses energy, reducing power and raw materials to make molecules for growth and maintenance.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the main components of daily energy expenditure?

A

Basal Metabolic Rate

Voluntary Physical Exercise

Diet induced thermogenesis, processing the food we eat. (+10% of BMR and VPE)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the average daily expenditure for males and females?

A

M: 70kg. 12,000 kJ.

F: 58kg, 9500kJ.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Why are fats essential in the diet?

A

Produce 2.2 times the amount of energy as same mass of protein and carbs. But not essential for energy source.

Needed to absorb fat soluble vitamins.

Essential fatty acids, linoleic acids are structural components of cell membranes and precursors of important regulatory molecules.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the fat soluble vitamins?

A

A

D

E

K

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Why are proteins essential in the diet?

A

Needed to synthesise essential N containing compounds: creatine, nucleotides, haem

Needed to provide essential amino acids which can not be synthesised in the body.

Needed to maintain nitrogen balance, 35g excreted as urea per day.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Why are carbohydrates essential in the diet?

A

The major energy containing component in the diet. Glucose required constantly by tissues such as the brain and RBCs.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Why is water essential in the diet?

A

Body weight is 50-60% water.

2.5l of water is lost per day in the urine, expired air, faeces.

Some water is produced by cellular metabolism, the rest is replaced by drinking.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Why is dietary fibre essential?

A

Non digestible plant material is needed for normal bowel function, for example cellulose.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Why are minerals and vitamins essential in the diet?

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is malnutrition?

A

Any condition caused by an inbalance between what an individual eats, and what an individual requires to maintain health

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What causes weight loss?

A

Loss of subcutaeous fat and muscle wasting

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are common effects of starvation?

A

Cold

Weakness

Infections of the GI tract and lungs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What is marasmus caused by?

A

Protein energy deficiency

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are some signs of marasmus?

A

Emaciated, muscle wasting, loss of body fat, NO OEDEMA, thin dry hair, diarrhoea, anaemia possibly

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What is kwashiokor caused by?

A

Protein deficiency but enough carbohydrate in the diet

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What are some signs of kwashiokor?

A

Lethargic, anorexic

Distended abdomen: hepatomegaly, ascites (accumulation of fluid in peritoneum), oedema

Low serum albumin

Anaemia

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Why is oedema present in Kwashiokor sufferers?

A

Protein deficiency but enough carbohydrate for energy, so no proteolysis for gluconeogenesis. Therefore protein not replaced in the blood, low serum albumin creating a low oncotic pressure. Draws water out into tissues.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

How is BMI calculated?

A

weight (kg) / height2 (M)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How are BMI values interpreted?

A

Underweight: <18.5

Desirable: 18.5 - 24.9

Overweight: 25- 29.9

Obese: 30- 34.9

Severely obese: >35

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What is an alternative to BMI?

A

Waist hip ratio, circumference

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Define Obesity

A

Excess body fat has accumulated to the extent that it may have an adverse effect on health. BMI is greater than 30

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What factors contribute to obesity?

A

Mainly: difference between energy intake and expenditure

Genetics

Drug therapy

Endocrine disorders

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What are the increased health risks associated with obesity?

A

Hypertension

Heart disease

Stroke

Type 2 Diabetes Mellitus

Some cancers

Gall bladder disease

Osteoarthiritis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What is homeostasis?

A

The maintenance of a stable internal environment within set limits, in a dynamic equilibrium.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Generally, what causes disease?

A

A failure to maintain homeostasis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What is cell metabolism?

A

A highly integrated network of chemical reactions that occur within cells.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What do cells metabolise nutrients to provide? 4 key things

A
  • Energy for cell function and biosynthesis
  • Building block molecules
  • Organic precursor molecules
  • Biosynthetic reducing power
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What are 3 origins of cell nutrients?

A

The diet

Synthesis in the body from precursors

Body tissue storage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

What are 5 fates of cell nutrients?

A

Degradation to release energy in all tissues

Synthesis of cell components, all except RBCs

Storage: liver, adipose, skeletal muscle

Interconversion to other nutrients

Excretion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What is catabolism?

A

The breakdown of larger molecules into smaller ones

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What are features of catabolism?

A

Exergonic, oxidative (releases H atoms and reducing power), produces intermediary metabolites

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What is anabolism?

A

Smaller molecules being built up into larger ones from intermediary metabolites

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What are features of anabolism?

A

Uses energy released from catabolism (endergonic), reductive (uses H released in catabolism, uses intermediary metabolites.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

Why do cells need a continuous supply of energy?

A

The ATP/ADP cycle releases energy by oxidation for

movement

membrane transport

biosynthesis

growth and repair

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

Why are phosphorylated compounds good for providing energy?

A

Many of them have a high energy of hydrolysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

When [ATP] is high, what pathways are activated?

A

Anabolic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

When [ATP] is low, and [ADP] and [AMP] are high, what pathways are activated?

A

Catabolic

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

What is creatine phosphate used for?

When is it created?

What is it important for?

A

A high energy fuel store that can be used immediately when ATP is low

It is created when ATP levels are high

Sudden vigorous muscle activity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

What enzyme catalyses the formation of creatine phosphate from creatine and ATP?

A

Creatine Kinase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

What is the daily excretion of creatinine proportional to?

A

Skeletal muscle mass

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q
A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

What is an oxidative reaction?

What are the products transferred to?

A

When electrons are removed (hydrogen atoms - H+ and e-)

The products are transferred to carrier molecules

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

What are carriers?

A

Complex molecules derived from vitamins (B), which are reduced by the addition of 2 H atoms

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

What are the reduced forms of these oxidised carriers?

NAD+

NADP+

FAD

A

NADH + H+

NADPH + H+

FAD2H

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

Catabolic pathways are generally activated when…

A

The concentration of ATP falls and the concentration of ADP and AMP increases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
48
Q

Anabolic pathways tend to be activated when…

A

The concentration of ATP rises

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
49
Q

What are two important properties of sugars? explain

A

Hydrophilic: do not readily cross cell membranes

Partially oxidised: need less oxygen thsn fatty acids for complete oxidation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
50
Q

What sort of signal is ATP and why?

A

A high energy signal

It signifies that the cell has adequate energy for its immediate needs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
51
Q

What sort of signal is ADP and AMP.

A

Low energy, need more

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
52
Q

Give 3 high energy signals (not ATP)

A

NADPH, NADH, FAD2H

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
53
Q

Give 3 low energy signals (not AMP/ADP)

A

NAD+. NADP+ and FAD

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
54
Q

What is the general formula of a carbohydrate?

A

C(H20)n

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
55
Q

What sort of chemical groups do they contain?

A

Keto C=O

Aldehyde -CHO

Hydroxyl -OH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
56
Q

What are the most common forms of monosaccharides?

How many C atoms can a monosaccharide have?

A

Triose, pentose, hexose

3Cs to 9Cs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
57
Q

Why do monosaccharides exist mainly as rings?

A

The aldehyde or ketone group reacts with a hydroxyl group

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
58
Q

What is the structure of alpha glucose?

What is different in beta glucose?

A
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
59
Q

What is the chiral carbon in an isomer of aldose (C1) or of a ketose (C2) called?

A

Anomeric C atom

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
60
Q

What is a dissacharide?

A

Two monosaccharides joined together by a condensation reaction eliminating a molecule of water and forming an O-glycosidic bond.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
61
Q

What are the major dietary dissacharides and what monosaccharides are they made from?

A

Lactose: galactose and glucose

Maltose: glucose and glucose

Sucrose: fructose and glucose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
62
Q

When is a dissacharide non reducing?

A

If the aldo and keto groups from both molecules are involved in forming the glycosidic bond

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
63
Q

What is a polysccharide?

A

A polymer of monosaccharide units linked by glycosidic bonds

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
64
Q

What type of polysaccharide are most?

A

Homo polymers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
65
Q

What are 3 glucose polysaccharides?

A

Glycogen

Starch

Cellulose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
66
Q

Properties of glycogen

A

Glucose polymer

Animals

Alpha 1,4 and alpha 1.6 glycosidic bonds

Highly branched

Stored in the liver and skeletal muscle

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
67
Q

Properties of Starch

A

Glucose polymer

Found in plants

Amylose, alpha 1, 4 links

Amylopectin, alpha 1,4 and alpha 1.6

Hydrolysed to maltose and glucose in GI system

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
68
Q

Properties of cellulose

A

Glucose polymer

Plant cell walls, structural role

Beta 1,4 linkages

Linear polymer

Needed in human diet as fibre for good GI function

Humans can not digest, as they do not have the required enzymes to process the beta 1,4 links

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
69
Q

What are the dietary polysaccharides and how are they broken down?

What products are they broken down to?

A

Glycogen and starch, by glycosidase enzymes

Glucose, maltose, dextrins (smaller polysaccharides)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
70
Q

What enzymes break down dietary polysaccharides and where?

A

Salivary amylase in the buccal cavity

Pancreatic amylase in the duodenum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
71
Q

Where does digestion of dietary disaccharides and dextrins occur?

A

The duodenum and jejunum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
72
Q

Where are glycosidase enzymes found that break down dissacharides, and what are they made from?

A

Found on brushborder membrane of epthelial cells of duodenum and jejunum

They are large glycoprotein complexes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
73
Q

What are the main glycosidase enzymes which break down dietary dissacharides?

A

Lactase

Isomaltase/sucrase

Glycoamylase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
74
Q

What condition is low lactase activity associated with?

A

Lactose intolerance

Can not digest the lactose in milk products properly

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
75
Q

Explain the symptoms of lactose intolerance and why they occur.

A

Lactose persists in the colon

As lactase activity is low

Lactose has an osmotic effect drawing water into the lumen

This causes diarrhoea

Bacteria in the colon break down lactose

This produces gases such as CO2, H2, and CH4

This causes bloating and discomfort

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
76
Q

How are monosaccharides transported into the blood from the GI tract?

A

Active transport into the epithelial cells of the intestine

Facilitated diffusion from epithelium to blood

Uses GLUT transport proteins, which can be hormonally controlled

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
77
Q

What monosaccharide to all tissues metabolise?

A

Glucose

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
78
Q

Where is the main site of galactose and fructose metabolism?

A

Liver

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
79
Q

What is the concentration of glucose in the blood regulated at?

A

5mM

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
80
Q

What is the glucose requirement of the body per day?

A

180g per day

40g in tissues with an absolute requirement

140g per day in the CNS

Variable amounts needed in other tissues for specific functions, eg glycerol phosphate for TAGs in adipose is provided by glucose metabolism

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
81
Q

What tissues have an absolute requirement for glucose?

A

Red blood cells

White blood cells

Kidney medulla

Lens of the eye

CNS prefers glucose but can use ketone bodies too

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
82
Q

Describe features of glycolysis

A

Central pathway in sugar catabolism, exergonic

10 enzyme catalysed steps

Cytoplasm

Active in all tissues

Can be anaerobic

Start and end products either C3 or C6

No loss of CO2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
83
Q

What are the functions of glycoslysis?

A

Generate ATP, 2 net (4 produced, 2 used)

Generate NADH from NAD+, reduce

Building block molecules for anabolism

Useful C3 intermediates

Produce pyruvate by oxidising glucose

Substrate level phosphorylation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
84
Q

Which steps of glycolysis are irreversible?

Which enzymes catalyse each step?

A

1, 3 and 10

Step 1: Hexokinase in muscle, Glucokinase in the liver

Step 3: Phosphofructakinase

Step 10: Pyruvate Kinase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
85
Q

What reaction does hexokinase catalyse?

A

Glucose to glucose 6 phosphate.

Uses ATP

Makes the sugar ionic so it can not cross the plasma membrane, increases reactivity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
86
Q

What reaction does phosphofructokinase catalyse?

A

Conversion of fructose 6 phosphate, to fructose 1, 6 bisphosphate

Committing step, irreversible

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
87
Q

Which steps of glycolysis make ATP?

A

7 and 10

through substrate level phosphorylation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
88
Q

Which step of glycolysis makes NADH?

A

6

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
89
Q

What reaction does pyruvate kinase catalyse?

A

Phosphoenolpyruvate to pyruvate, producing ATP x2

irreversible

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
90
Q

What are important intermediates from glycolysis?

A

Glycerol phosphate: from DHAP, needed for glycerol synthesis

2, 3 BPG: Hb regulator, from 1, 3 BPG in glycolysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
91
Q

What is produced in glycolysis in anaerobic conditions?

In anaerobic or cells without mitochondria

A

Pyruvate is reduced to lactate by lactate dehyrdogenase

Produces NAD+

Produces ATP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
92
Q

How is lactate disposed of?

A

Released into circulation

Converted back to pyruvate and oxidised to CO2 in heart

Or converted to glucose in the liver

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
93
Q

What are the levels of lactate in the plasma?

A

1mM

Lactate production = utilisation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
94
Q

Describe the differences between hyperlactaemia and lactic acidosis

A

Hyperlactaemia: 2mM - 5mM in the blood. Below renal threshold, no change in blood pH, within buffering capacity.

Lactic acidosis: above 5mM, above renal threshold, blood pH lowered.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
95
Q

Where does galactose metabolism take place?

What sort of enzymes?

A

Liver

Soluble enzymes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
96
Q

How is fructose metabolised?

A

By soluble enzymes in the liver

Fructose to fructose 1 phosphate

then to 2 glyceraldehyde 3 phosphate/DHAP which feeds into glycolysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
97
Q

Clinical problems with fructose metabolism

A

Fructokinase missing, causes fructose to build up in urine, essential fructosuria, no clinical signs

Frctos intolerance, aldolase missing, fructose 1 phosphate accumulated inliver, damage, treatment, remove fructose from diet

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
98
Q

What enzymes are involved in galactose metabolism, and what to they do?

A

Galactokinase, galactose to galactose 1 phosphate

Galactose 1 phosphate uridyl transferase, to glucose 1 phosphate, which can transfer into glycolysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
99
Q

What is galactosaemia?

A

Individuals are unable to utrilise galactose obtained in the diet because of a lack of galactokinase of glactose 1 phosphate uridyl transferase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
100
Q

What are the two types of galactosaemia, how common are they and which is more serious?

A

Either galactokinase or galactose 1 phospahte uridyl transferse can be deficient.

Loss of transferase is more common

Loss of transferase is more serious because galactose 1 phosphate accumulates which is toxic to the liver, kidney, brain as does galactose.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
101
Q

What happens when galactose builds up in tissues?

A

Galactose is reduced to galactitol by aldose reductase, which depletes some tissues of NADPH.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
102
Q

Explain why lack of NADPH caused by galactosaemia causes problems in the lense of the eye.

A

NADPH is needed in the eye to keep cysteine residues in proteins reduced.

If there is a lack of NADPH, S-S bonds form, cross linking proteins, damaging the len structure and causing cataracts.

Non enzymatic glycosylation of lens proteins due to high galactose concentration - may also contribute to cataracts

Accumulation of galactose and galactitol in the eye leads to increased intraocular pressure, may cause glaucoma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
103
Q

What is the treatment for galactosaemia?

A

No lactose in diet

Should be detected early for effective management. Heel prick test

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
104
Q

What are the main functions of the pentose phosphate pathway?

A

PRODUCE NADPH IN THE CYTOPLASM

PRODUCE C5 SUGARS FOR NUCLEOTIDES

Reducing power for anabolic processes like lipid synthesis

In RBCs maintain free -SH groups on cysteine residues

Detoxification

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
105
Q

In what tissues is the pentose phosphate pathway important?

A

Liver

Red blood cells

Adipose

Dividing tissues

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
106
Q

What are the enzymes in the pentose phosphate pathway and what do they do?

A

Glucose 6 phosphate to 5C sugar phosphates by glucose 6 phosphate dehydrogenase and 6 phosphogluconte dehydrogenase. This reaction produces NADPH and CO2.

Any unused C5 sugar phosphates back to glycolysis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
107
Q

What occurs in glucose 6 phosphate dehydrogenase deficiency?

What sort of inheritance?

A

Reduced activity of this rate limiting enzyme. Low levels of NADPH.

X linked recessive , point mutation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
108
Q

What occurs in red blood cells in an individual with G6PDH deficiency?

A

Lack of NADPH in cells

Can not maintain free -SH cysteine residues

Disulphide bridges form.

Hb and other proteins cross linked

Heinz bodies, insoluble aggregates. GSSG (glutathione)

Premature destruction of RBCs, haemolysis. Jaundice etc complications

Acute haemolytic episodes from antimalarials, oxidants

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
109
Q

What enzyme converts pyruvate to Acetyl - CoA?

A

Pyruvate dehyrdogenase, a multi enxume complex.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
110
Q

Where does pyruvate dehyrdrogenase work?

A

Mitochondrial matrix

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
111
Q

What are features of the pyruvate dehydrogenase reaction?

A

Irreversible, can’t convert acetyl coA back to pyruvate for gluconeogenesis

Loss of CO2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
112
Q

What are some control mechanisms that PDH reaction is subject to?

A

Under certain conditions acetyl coA from B oxidation of FAs is used rather than from glucose in stage 3 catabolism, acetyl coA allosterically inhibits PDH

Reaction is energy sensitive: ATP/NADH inhibit, ADP promotes allosterically

Activated when there is a lot of glucose, insulin activates by dephosphorylating PDH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
113
Q

What is the TCA cycle?

A

A central pathway in the metabolism of sugars, fatty acids, ketone bodies, alcohol and aminoacids.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
114
Q

What are the anabolic functions of the TCA cycle?

A

C4 intermediates: Haem and glucose synthesis, non essential amino acids (from succinate, fumarate, oxaloacetate)

C5 intermediates: non essential amino acids (from alpha ketoglutarate)

C6 intermediates: fatty acids (from citrate)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
115
Q

What are the key features of the TCA cycle?

A

Oxidative

Produces NADH and FAD2H

Needs NAD+, FAD and oxaloacetate

Main function is to break C-C bond in acetate and oxidise the C atoms to CO2

Some ATP produced directly by substrate level phosphorylation

Produces C4 acids that are interconvertible

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
116
Q

What is produced by the TCA cycle per molecule of glucose?

A

2 turns

6 NADH

2 FAD2H

2 GTP

(after ETC 32 ATP)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
117
Q

How is the TCA cycle regulated?

A

ATP/ADP ratio

NADH/NAD+ ratio

Activated by low energy, inhibited by low energy

Irreversible step, isocitrate dehydrogenase, activated by ADP, inhibited by NADPH

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
118
Q

Explain where all the energy is at the end of the TCA cycle.

A

All C-C bonds have been broken, and C atoms oxidised to CO2.

All C-H bonds have been broken and H atoms have been transferred to NAD+ and FAD.

The energy is either in ATP/GTP formation, 2 in each of glycolysis and TCA cycle

Chemical bond energy is in the e- in NADH and FAD2H.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
119
Q

What are the key features of oxidative phosphorylation?

A

Takes place on the inner mitochondrial membrane

Electron transport is coupled with ATP synthesis

NADH and FAD2H are reoxidised

O2 is required, it is reduced to water

Large amounts of ATP are produced

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
120
Q

What are the 2 processes of oxidative phosphorylation? Explain

A

NADH and FAD2H contain high energy electrons that can be transferred to oxygen through a series of carrier molecules with the release of large amounts of free energy.

The free energy released in ETC drives ATP synthesis from ADP and Pi

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
121
Q

Which of the inner and outer mitochondrial membranes are permeable to H+ ions?

A

Outer

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
122
Q

Describe electron transport

A

Carrier molecules transferring electrons to molecular oxygen are in a series of 4 specialised protein complexes

Spanning inner mitochondrial membrane

Electrons are transferred from NADH and FAD2H through the complexes releasing free energy

Three of the complexes are proton translocating complexes.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
123
Q

Describe how the proton motive force is created

A

Free energy from electron transport is used to pump H+ ions across the membrane

into the intermembrane space

Inner membrance impermeable

H + Concentration outside inner membrance increases

Creates electrochemical gradient

Which is known as the proton motive force

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
124
Q

How many ptcs do NADH and FAD2H use?

A

NADH : 3

FAD2H: 2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
125
Q

Describe ATP synthesis

A

Energetically favourable for protons to move back to matrix due to pmf

Can only return through ATP synthase, inner mitochondrial membrane impermeable to H+ ions

Energy from movement drives the synthesis of ATP from ADP and Pi

Greater PMF more ATP made

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
126
Q

How much ATP is produced by :

2 moles of NADH

2 moles of FAD2H

A

5 moles of ATP from 2 NADH

3 moles of ATP from 2 FAD2H

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
127
Q

Describe the coupling of the ETC and ATP synthesis.

Explain how concentration of ATP in the mitochondria regulates both processes

A

ET and ATP synthesis do not occur without each other.

When [ATP] is high, ATP synthesis stops as [ADP] is low, a lack of substrate. This stops H+ transport back to mitochondria.

H+ concentration outside increases so that more can not be pumped out.

In absence of proton pumping, ETC stops.

REVERSE OCCURS WHEN ATP IS LOW

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
128
Q

What do inhibitors of oxidative phosphorylation do?

What are some examples?

A

They block electron transport by preventing oxygen accepting electrons.

Examples are cyanice, carbon monoxide. They have a higher affinity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
129
Q

What are some examples of uncoupling proteins and what do they do?

A

Function is to uncouple ET from ATP synthesis to produce heat

Proteins in the inner mitochondrial membrane

UCPs 1 - 5 (first 3 most important)

UCP1: thermogenin, brown adipose tissue, non shivering thermogenesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
130
Q

What do uncoupling substances do?

A

Increase the permeability of the inner mitochondrial membrane to protons

Protons being pumped out by ET can re enter without the synthesis of ATP.

Pmf is dissapated as heat

Makes up 20-25% of BMR

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
131
Q

Name 2 substances which act as uncouplers in mitochondria

A

Dinitrophenol

Dinitrocresol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
132
Q

In response to cold what does noradrenaline do?

A

Sympathetic nervous system

Stimulates lipolysis releasing FAs for oxidation in brown adipose

NADH and FAD2H produced

Drive electron transport and produce pmf

Noradrenalin activates UCP1

Pmf dissapated as heat

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
133
Q

Compare oxidative and substrate level phosphorylation

A

O: membrane associated complexes. SL: soluble enzymes

O: inner mitochondrial membrane. SL: cytoplasm and mitochondrial matrix

O:Indirect energy coupling, generation and usage of a pmf. SL: Direct energy coupling through formation of a high energy of hydrolysis bond

O: Can not occur without oxygen. SL: can occur to limited extent with oxygen.

O: Major process ATP synthesis. SL: Minor process for ATP synthesis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
134
Q

Give some properties of lipids

A

Generally insoluble in water, hydrophobic

Soluble in organic solvents

No general formula

Most contain C, H and O (phospholipids P and N too)

More reduced than carbohydrates (less O and more H per C atom)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
135
Q

What are the classes of lipids?

Give examples of each

A
  1. FATTY ACID DERIVATIVES: fatty acids (fuel molecules), triacylglycerols (fuel storage and insulation), phospholipids (components of membranes and plasma lipoproteins), eicosanoids (local mediators)
  2. HYDROXY-METHYL-GLUTARIC ACID DERIVATIVES (C6 compound): ketone bodies (C4, water soluble fuel molecule), cholesterol (C27, membranes and steroid hormone synthesis), cholesterol esters (cholesterol storage), bile acids and salts (C24, lipid digestion)
  3. FAT SOLUBLE VITAMINS: A, D, E, K
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
136
Q

Describe how TAGs are hydrolysed in the small intestine

A

By pancreatic lipase

To release glycerol and fatty acids

Complex process

Needs bile salts

Needs protein factor: colipase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
137
Q

How is glycerol metabolised?

A

Enters the blood stream

Transported to liver

Phosphorylated by glycerol kinase

Either goes to TAG synthesis

Or oxidised to DHAP which enters glycolysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
138
Q

Describe properties of fatty acids

A

Long chain molecules

Even no of C atoms

Hydrophobic

Highly reduced - so ideal for energy storage

Saturated or unsaturated

Saturated are non essential, can be synthesised

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
139
Q

How are TAGs stored and what for?

A

Stored anhydrously in adipose tissue

Store of fuel for prolonged aerobic exercise, starvation and pregnancy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
140
Q

Which hormones promote TAG storage?

Which hormones reduce TAG storage?

A

Insulin

Glucagon, adrenaline, growth hormone, thyroxine, cortisol

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
141
Q

How are fatty acids transported in the blood?

A

Bound to albumin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
142
Q

Which tissues can metabolise fatty acids for energy?

A

Heart muscle

liver

skeletal muscle

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
143
Q

How are fatty acids activated for beta oxidation?

A

Links to coenzyme A outside the mitochondrion

Linked via S atom in free -SH group

Forms a high energy of hydrolysis bond

This process needs ATP and Fatty acyl coA synthase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
144
Q

How are fatty acids transported across the mitochondrial membrane?

What does a defect in the transport cause?

A

Cartinine transport shuttle- also helps to regulate the rate of FA oxidation

Converted to acyl cartinine and back

Inhibited by malonyl coA which is an intermediate in FA synthesis

Defect in transport causes poor exercise tolerance, lipid droplets in muscle

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
145
Q

Describe beta oxidation

A

Sequence of reactions that oxidises the fatty acid

Removes an acetate

Cucled repeatedly until only 2 carbons remain

Needs NAD+ and FAD

Needs oxygen for ETC to reoxidise NADH and FAD2H

No direct ATP synthesis

All intermediates linked to co A.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
146
Q

What are the three ketone bodies produced in the body?

How are they produced?

A

Acetoacetate

B-hydroxybutarate

(synthesised in the liver from acetyl coA)

Acetone: spontaneous non enzymatic decarboylation of acetoacetate

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
147
Q

What are normal and abnormal levels of ketones in the blood?

What can cause abnormal levels?

A

Usually ketones less than 1mM in the blood

Increases in starvation: 2mM to 10mM (physiological ketosis)

In untreated type 1 diabetes, bove 10mM

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
148
Q

Properties of ketone bodies

A

Water soluble

So can have high plasma concentration, can cross blood brain barrier, can be excreted in urine

Acetoacetate and b hydroxybutarate are quite strong organic acids so can cause acidosis

Acetone is volatile and can be excreted via the lungs (on breath of untreated type 1 diabetics for example)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
149
Q

What is required for ketone bodies to be produced?

A

Fatty acids for oxidation in the liver: substrate

Plasma insulin:glucagon ratio is low, activates lyase, inhibits reductase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
150
Q

Describe how ketones are produced from acetyl coA

A

Acetyl co A to HMG coA via synthase enzymes

HMG coA to acetoacetate via lyase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
151
Q

What is acetyl coA produced by?

A

Catabolism of

Fatty acids

Sugars

Alcohol

Certain amino acids

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
152
Q

Why is acetyle coA central in metabolism

A

It can be oxidised in stage 3 of catabolism, the TCA cycle

It is an important intermediate in lipid biosynthesis (anabolism), in the liver and some adipose tissue

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
153
Q

What are the major energy stores in a 70kg man?

A

TAGs: 15kg

Glycogen: 400g

Muscle protein: 6kg

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
154
Q

How is glycogen synthesised from glucose?

A
  1. Using ATP is phosphorylated to glucose 6 phosphate by hexokinase/glucokinase
  2. Glucose 6 phosphate to glucose 1 phosphate by phosphoglucomutase
  3. Glucose 1 phosphate + UTP + water makes UDP glucose (high energy) and 2 Pi
  4. Glycogen (n residues) + UDP glucose makes glucogen (n+1 residues_ and UDP. Step 4 is catalysed by glycogen synthase which adds alpha 1,4 links, and branching enzyme which adds alpha 1,6 links about every 10 units
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
155
Q

What is glycogen degraded in response to?

A

Exercise in skeletal muscle.

Fasting in the liver, or stress response

Never degraded fully, a small amount of primer is preserved

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
156
Q

How is glycogen degraded?

A

Glycogen phosphorylase creates glucose 1 phosphate by attacking the alpha 1,4 bonds. Debranching enzyme attacks the alpha 1,6 bonds and releases glucose.

Phosphoglucomutase moves the phosphate from carbon 1 to carbon six producing glucose 6 phosphate. This enters glycolysis in skeletal muscle.

In the liver, the addition of water to glucose 6 phosphate by glucose 6 phosphatase makes glucose and Pi. Therefore glycogen in the liver supplies glucose for all tissues through the blood stream.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
157
Q

Compare the functions of liver and muscle glycogen.

A

LIVER: glucose store for all tissues of the body, in response to fasting or stress. Glucose 6 phosphate to glucose by glucose 6 phosphatase.

MUSCLE: glucose 6 phosphate store, can only be used by muscle as it enters glycolysis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
158
Q

Abnormalities in which enzymes can cause glycogen storage diseases?

What are the consequences?

A
  • Glycogen phosphorylase
  • Phosphoglucomutase

Glucose 6-phosphatase in liver

Increase or decreased amounts of glycogen.

Tissue damage if too much storage

Fasting hypoglycaemia

Poor exercise tolerance

Abnormal structure of glycogen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
159
Q

Describe regulation of glycogen metabolism

A

Allosteric control of glycogenolysis, glycogen phosphorylase: AMP activates

Synthesis: glycogen synthase, activated by insulin dephosphorylating. It is inhibited by glucagon and adrenaline, which phosphorylate.

Glycogen phosphorylase: activated by glucagon and adrenaline phosphorylating. Deactivated by insulin dephosphorylating.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
160
Q

What is gluconeogenesis?

A

The production of glucose when carbohydrates are absent.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
161
Q

What are possible substrates for gluconeogenesis?

What is the main site?

A

Pyruvate, lactate, glycerol

Essential and non essential amino acids whose metabolism involves pyruvate or TCA intermediates

NOT ACETYL COA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
162
Q

Describe the process of gluconeogenesis

A

Uses the reversible steps of glycolysis and bypasses the irreversible ones.

Steps 1 and 3 are bypassed by thermodynamically spontaneous reactions, catalysed by phosphatases. Glucose 6 phosphatase (to make glucose) and fructose 1,6 bisphosphatase (to make fructose 6 phosphate).

Step 10 is bypassed by reactions drived by ATP and GTP hydrolysis. Catalysed by pyruvate carboxylase and phosphoenolpyruvate caroxykinase (PEPCK). This produces oxaloacetate and phosphoenolpyruvate. Link to TCA

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
163
Q

How is gluconeogenesis regulated?

A

Response to starvation, exercise, stress

Glucagon and cortisol stimulate PEPCK and glucagon stimulates Fructose 1,6 bisphosphatase

Insulin inhibits PEPCK and fructose 1,6 bisphosphatase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
164
Q

What reaction converts glycerol and fatty acids to TAGs?

And back again?

A

Esterification

Lipolysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
165
Q

Which hormones promote and deplete TAG storage?

A

Promote: Insulin

Deplete: glucagon, adrenaline, growth hormon, cortisol, thyroxine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
166
Q

How are fatty acids synthesised?

A

From acetyl coA, using ATP and NADPH

Cytoplasm

Carried out by mlti enzyme complex: fatty acid synthase complex

C2 units added as malonyl coA, with loss of CO2

Malonyl coA is made from acetyl coA byt acetyl coA carboxylase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
167
Q

How is glycerol transported in the blood stream to adipose?

A

Chylomicrons to store as TAGs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
168
Q

How is acetyl coA carboxylase regulated?

A

Allosteric regulation: citrate activates and AMP inhibits

Covalent modification:

Insulin activates by dephosphorylation

Glucagon and adrenaline inhibit by promoting phosphorylation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
169
Q

Compare FA oxidation and synthesis

A

O: removes C2. S: adds C2.

O: Removed as acetyl coA. S: Added as malonyl coA with loss of CO2.

O: Produces acetyl coA. S: consumes acetyl coA.

O: In mitochondria. S: in cytoplasm.

O: Oxidative. S: reductive, uses NADPH

O: Seperate enzymes. S: enzyme complex.

O: Needs small amount of ATP to activate the FA. S: needs lots of ATP to drive the process.

O: Regulated indirect by FA availability. S: directly regulated by acetyl coA carboxylase.

170
Q

What are amino acids used for?

A

protein synthesis

synthesis of purines and pyrimidines in DNA and RNA

small amounts of porphyrins (haem), creatine, nerotransmitters, hormones

171
Q

Which amino acids are essential in the diet?

A

PVT. TIM HALL

Phenylalanine

Valine

Tryptophan

Threonine

Isoleucine

Methionine

Histidine (semi)

Arginine (semi)

Leucine

Lysine

Tyrosine and cysteine may become essential

172
Q

How can the amino group of an amino acid be removed?

A

Transamination

Or deamination

173
Q

What can the remaining C skeleton of a deaminated amino acid be converted to?

A

Pyruvate

Oxaloacetate

Fumarate

Alpha ketoglutarate

Succinate

Acetyl coA

174
Q

What is the difference between ketogenic and glucogenic amino acids?

A

Ketogenic amino acids are broke down to acetyl coA which makes ketone bodies by synthase and lyase.

Glucogenic amino acids make the other products which can make glucose by gluconeogenesis.

175
Q

Which amino acids are ketogenic and glucogenic?

A

Isoleucine, threonine, phenylalanine

176
Q

What enzymes carry out transamination?

Write out the equations

A

Aminotransferases

ALT, Alanine aminotransferase: GPT

Alanine+alpha ketoglutarate TO glutamate+pyruvate

AST, Aspartate amino transferase:vGOT

Aspartate+alpha ketoglutarate TO oxaloacetate and glutamate

Most use alpha ketoglutarate as keto acid 2. If oxaloacetate is used, it is converted to aspartate.

177
Q

What are AST and ALT used for in clinical practice?

A

Liver function test

178
Q

Which hormone stimulates transaminase synthesis in the liver?

A

Cortisol

179
Q

Describe the process of deamination

A

L and D amino acid oxidases

Convert amin acids to keto acids and NH3, to ammonium ion

D amino acids from diet, can’t be used for protein synthesis. High activity of D amino acid oxidases in the liver.

Glutaminase converts glutamine to glutamate and NH3.

Glutamate dehydrogease makes alpha ketoglutarate, ammonia and reduced NAD.

180
Q

Which hormones stimulate protein synthesis and breakdown?

A

Synthesis is promoted by insulin and inhibited by glucocorticoids

Breakdown is promoted by glucocorticoids and inhibited by insulin

181
Q

What is phenylketonuria?

A

An inherited autosomal recessive disorder in which the urine contains large amounts of phenylketones produced from phenylalanine.

182
Q

Describe how PKU arises and its effects

A

Phenylalanine hydroxylase enzyme is defective

This oxidises phenylalanine to tyrosine

Excess phenylalanine combines with alpha ketoglutarate to make phenylpyruvate, ketone

Phenylalanine and phenylpyruvate accumulate in the blood.

Phenylalanine saturates transporter LNAAT carrier, this transports amino acids across blood brain barrier. Mental reatrdation due to decreased brain metabolism.

Lack of tyrosine, has to be supplemented in diet. Useful precursor for hormones (thyroid) and neurotransmitters.

183
Q
A
184
Q

Describe homocystinuria

A

A rare inherited autosomal recessive defet

In methionine metabolism

Excess homocystine in urine

Caused by defect in CBS enzyme

cystathionine beta synthase

185
Q

What does cystathionine beta synthase usually do?

A

Converts homocysteine to cystathionine, which is further converted to cysteine.

186
Q

What happens is homocysteine increases in the blood when CBS is deficient?

A

Methionine builds up in the plasma, as does homocystine, oxidised form

Homocysteine causes disorders of connective tissue, muscle, CNS and CVA is elevated in plasma.

Similar to Marfans syndrome, tight joints, intellectual disability, long limbs, near sightedness, arachnodactyly, damages FIBRILLIN

187
Q

How to treat homocystinuria

A

B6 supplement, increases deficient CBS, as cofactor

B12 supplement, more homocysteine to methionine, which can be excreted. Add cysteine to diet.

188
Q

What symptoms are associated with hyperammonaemia?

Why?

What disease is it commonly seen in?

A

Blurred vision

Tremors

Slurred speech

Coma

Death

Removes alpha ketoglurate from the TCA cycle as reacts to form glutamate via glutamate dehydrogenase

Affects the pH in CNS

Interferes with neurotransmitter sunthesis and release.

Commonly seen in liver disease

189
Q

How is ammonia detoxified?

Describe glutamine synthesis and how it is disposed of

A

Either by synthesis of N compounds like glutamine or conversion to urea.

Glutamine can be synthesised from glutamate and ammonis via glutamine synthetase, requiring ATP. It is transported to the liver and kidney where it is hydrolysed to release ammonia.

In the kidney ammonia is excreted and in the liver it is converted to urea.

190
Q

Why is urea a good molecule to excrete?

A

Very soluble in water

Non toxic

Metabolically inert

High nitrogen content

191
Q

How is urea synthesised?

A

NH2 groups of urea come from ammonium and aspartate.

5 enzymes

Occurs in the liver, transported via blood to the kidney for excretion.

Orthinine to citrulline in the mitochondrial matrix. To argininosuccinate and arginine.

192
Q

Describe regulation of urea synthesis

A

Not subject to feedback inhibition

Enzymes are inducible

Refeeding syndrome, hyperammonaemia

193
Q

Describe inherited diseases of the urea cycle and their effects

A

All defects cause hyperammonaemia and accumulation or excretion of urea cycle intermediates

Depends on extent of defect

Vomiting, lethargy, irritability, mental retardation, seizures, coma, death

Treat with low protein diet, replace essential amino acids with ketoacids that use up ammonium when converted to amino acids.

194
Q

What happens to urea?

A

Diffuses from liver cells to blood to kidney where it is filtered and excreted in the urine

Some urea diffuses into the intestine, bacteria break down to release ammonia which is reabsorbed

Kidney failure: urea conc in blood is high, production of ammonia from urea by bacteria in the gut can cause hyperammonaemia.

195
Q

How are lipids transported?

A

98% as lipoprotein particles

2%, mainly fatty acids, bound non covalently to albumin

196
Q

What are the usual maximum fatty acid levels in the blood?

A

3mM

197
Q

What diseases are disorders in plasma lipoprotein metabolism associated with?

A

Atheroschlerosis

Coronary artery disease

198
Q

Describe lipoprotein structure

A

Small assemblies of hydrophobic lipid molecules surrounded by polar molecules (micelles)

Protein components: apoproteins

Spherical particles, surface coat and core

Hydrophobic core: TAGs and cholesterol esters

Surface coat: proteins, phospholipids, cholesterol

Only stable if spherical shape is maintained: ratio of core to surface lipids. LCAT

Non covalent

199
Q

What are the 4 types of lipoproteins and their function?

A

Chylomicrons: dietary TAGs from the intestine to tissue such as adipose.

VLDL:Transport of TAGs synthesised in the liver to adipose for storage.

LDL: Transport of cholesterol synthesised in the liver to the tissues.

HDL: Transport of excess tissue cholesterol to the liver for disposal as bile salts.

200
Q

How are dietary lipids transported for storage?

A

Hydrolysed in small intestine by pancreatic lipase

Fatty acids enter epithelial cells of small intestine

FAs reesterified back to TAGs using glycerol phosphate from glucose metabolism.

Packaged into chylomicrons with other dietary lipids

Released into blood stream via the lymphatic system

Carried to tissues like adipose that express lipoprotein lipase.

Hydrolysed and FAs enter the adipose cells where they are converted to TAGs for storage

201
Q

When are chylmicrons present in the blood?

A

4 to 6 hours after a meal

202
Q

Why are chylomicrons transported in the lymphatic system?

A

They go via the thoracic duct to the left subclavian vein

This bypasses the liver and hepatic portal vein

203
Q

Explain how HDL and LDL levels affect the risk of cardiovascular disease?

A

High LDL levels deposit cholesterol on blood vessel walls.

Plaques.

Risk factor for atheroschlerosis

HDLs remove cholesterol from tissues

Prevent excessive cholesterol build up

Beneficial in blood vessels

204
Q

Describe properties of cholesterol

A

Tetracyclic

Can be esterified with a fatty acid, eliminated the polar OH group

Major membrane component

Precursor of steroid hormones

Precursor of bile acids

Mainly synthesised in the liver, some in the diet

205
Q

Describe properties of phospholipids

A

Diacylglycerol with a phosphate group

Major component of membrances

Phosphate is polar

Amphipathic

Naturally forms micelles

206
Q

Describe the action and control of lipoprotein lipase

A

Removes core TAGs from lipoproteins like chylomicrons and VLDLs

Attached to inner surface of capillaries in tissues such as adipose and muscle

Hydrolyses TAGs to fatty acids and glycerol

Tissues then take up fatty acids, glycerol to the liver

Insulin increases the synthesis of this enzyme

207
Q

What is LCAT?

Describe its action

What happens when it is deficient?

A

Lecitihin: Cholesterol AcylTransferase

Restores the stability of lipoproteins

Converts surface lipid to core lipid

Converts cholesterol to cholesterol ester with FA derived from lecithin

Defiency: unstable lipoproteins of abnormal structure.

Failure of lipid transport

Deposits in tissues

Atheroschlerosis

208
Q

Describe LDL metabolism

(all cells except erthryocytes could in theory synthesise cholesterol, but prefer to take it up pre formed in practice)

A

Receptor mediated endocytosis

Complex proteins on cell surface bind LDL apoprotein B100

LDL receptor with LDL taken in by endocytosis

Subject to lysosomal digestion

Cholesterol released inside the cell from cholesterol esters

Inhibits cholesterol synthesis in cell and reduces synthesis and exposure of LDL receptors, uptake stimulated by need

209
Q

What is Hyperlipoproteinaemia?

How many types are there and what are they called?

Describe the 3 types with known defects

A

Raised levels of one or more of the plasma lipoproteins

There are 6 types, I, IIa, IIb, III, IV, V

Type I: chylomicrons in fasting plasma, no link to coronary artery disease, caused by defective lipoprotein lipase

Type II: raised LDL, associated with CAD may be severe, caused by defective LDL receptor

Type III: Raised IDL and chylomicrons remnants, associated with CAD, caused by defective apoprotein E

210
Q

What is a dyslipoproteinaemia and what are the two main types?

A

Defect in metabolism of plasma lipoproteins

Primary: inborn

Secondary: acquired as a result of diet, drugs, underlying diseases like diabetes.

211
Q

What are clinical signs of hyperlipoproteinaemia?

A

Xanthelasma: lipid deposits by eyelids

Tendon xanthoma

Corneal arcus in iris

212
Q

What is familial hypercholesterolaemia?

Describe it

A

Type II

Absence - homozygous

or

deficiency - heterozygous

of functional LDL receptors

Elevated levels of LDL and cholesterol in the blood

Atheroschlerosis early in life in homozygotes and later in heterozygotes

213
Q

Describe the formation of an atheroma

Clinical significance?

A

Oxidised LDL

Macrophages engulf faulty LDLs

Form foam cells

Accumulate in intima of blood vessel wall lining, swelling

Fatty streak - lighter patch

Atheroma, swelling of vessel

Initially clinically silent

Swelling narrows lumen, if a thrombosis occludes the vessel, myocardial infarction if in coronary vessel.

214
Q

Explain how hyperlipoproteinaemias may be treated

A

Diet and lifestyle modifications first, reduce eliminate cholesterol and TAGs, more exercise

If little effect

Drug therapy: statins. Lower plasma cholesterol by inhibiting HMG co A reductase.

Bile salt sequestrants: dispose of cholesterol by converting to bile salts. This prevents reabsorbtion in GI into hepatic portal circulation, more lost in faeces

215
Q

Describe the production of superoxide radicals in mitochondria

A

Some electrons are leaked for the ETC prematurely at complexes 1 and 3

They reduce oxygen to form superoxide radicals

O2-

Superoxide radicals have an unpaired electron

Free radical

Highly reactive

Know as Reactive Oxygen Species ROS

Constantly leaking out of mirochondria so must be protected against

216
Q

How are ROS protected against in the cell?

How do ROS cause damage?

A

Superoxide radicals converted to hydrogen peroxide by SUPEROXIDE DISMUTASE (SOD)

Hydrrogen peroxide converted to water and oxygen by CATALASE

ROS cause damage to DNA, protein and membranes

217
Q

What are some other examples of ROS and how are they formed?

A

HYDROXYL RADICALS, -OH: produced in all cells. By ionising radiation, from hydrogen peroxide with addition of iron ions. Damage to cells membrane and can’t be eliminated by enzymes.

NITRIC OXIDE, NO: produced from arginine by the inducible enzyme nitric oxide synthase (iNOS).

PEROXYNITRITE, ONOO-: produced when nitric oxide and oxygen react. Involved in inflammation

EXOGENEOUS: Antimalarials like primaquine, powerful oxidants, dangerous in G6PDH. Paracetamol overdose. Paraquat, a herbicide, causes superoxide radical production.

218
Q

Outline other defences against ROS (other than SOD and catalase)

A

Glutathione (GSH), trispeptide, anti oxidant. Free -SH on cysteine are oxidised to GSSG, donate their Hs. Abundant in cells. Recycled by reducing with NADPH, which is produuced by glucose 6 phosphate dehyrdogenase.

Antioxidant vitamins A C and E

Flavenoids: polyphenols, beta carotene

Minerals such as selenium and zinc

219
Q

How do some white blood cells use ROS in an immune response?

A

Neutrophils and monocytes

When stimulated release an oxidative burst

Enzyme: NADPH oxidase

Cell usually destroyed

As is surrounding bacteria/ fungi

220
Q

What is pharmacoDynamics?

What is pharmacokinetics?

A

What a Drug Does to the body

What the body does to the drug

221
Q

Some metabolites of drugs are more pharmacologically active than the pro drug, and are converted in the body.

What are some examples of this?

A

Primidone to phenobarbitone

Pethidine to norpethidine

Codeine to morphine

222
Q

What does pharmokinetics cover? (acronym)

A

ADME

Adsorption

Distribution

Metabolism

Elimination.. of a drug

223
Q

What occurs in phase 1 of drug metabolism?

A

A reactive group is exposed or added to the parent molecule

Generates a reactive intermediate

Most common reactions: reduction, oxidation, hydrolysis

Cytochrome p450, complex enzyme system

High energy cofactor, NADPH

Some bypass phase 1 as they already have a reactive group, for example morphine. Straight to phase 2

224
Q

What occurs in phase 2 of drug metabolism?

A

Conjugation with a water soluble molecule to form a water soluble complex

Glucaronic acid most commonly

Suplhate ions

Glutathione

High energy co factor: UDPGA (uridine diphosphate glucaronic acid)

225
Q

Clinically, what can a lack of cholinesterase enzymes cause?

A

Prolonging of anaesthesia effects

226
Q

What is pharmacology?

A

How chemical agents affect the functioning of living systems

227
Q

What is pharmacoepidemiology?

What is pharmacovigilance?

A

Study of the drug effects in a large population.

Reporting of adverse drug reactions (ADRs) post marketing eg thalidomide

228
Q

Describe the importance of the cytochrome p450 system

A

CYP

Complex enzyme system

50 different haem containing enzymes

Polymorphisms in the population

Isoform CYP3 A4 is most important, 55% of drug metabolism

Co factor is NADPH

229
Q

Explain the variation in drug metabolism in the human population

Genetics and environment

A

GENETICS:

Differences in the level of expression of metabolic enzymes

May lack a gene that codes for an enzyme

Polymorphisms

Different times to metabolise drugs

Gene deletions

Slow acetylators: lack enzyme that acetylates in phase II.

Low levels of pseudocholinesterase enzymes in plasma: affects ability to metabolise drugs with an ester bond, such as some anaesthetics.

ENVIRONMENT:

Inhibition: other drugs: polytherapy, cranberry, grapefruit juice

Induction: increased metabolism of other drugs, ethanol, nicotine, barbiturates, some pesticides

230
Q

Describe the first pass effect

A

Substances absorbed in the lumen of the ileum

Enters venous blood which drains into the hepatic portal vein

Direct to the liver, main site of drug metabolism

All necessary enzyme systems

Any drug absorbed from the ileum may be mostly meatbolised in first pass through liver.

Only small amount passes to the rest of the circulatory system

90% of paracetamol metabolised in first pass, so large dose of 1g is needed.

231
Q

Describe alcohol metabolism

A

Alcohol to acetaldehyde by alcohol dehydrogenase

Acetaldehyde to acetate (to acetyl coA) by aldehyde dehydrogenase

Complete oxidation needs NAD+, forms NADH

Aldehyde dehydrogenase has a low Km so keeps toxic acetaldehyde to a minimum

CYP2E1 also metabolises alcohol via oxidation, and is inducible

232
Q

Alcohol consumption reduces the NAD+/NADH ratio, what are the effects of this?

A

NAD+ is used for fatty acid oxidation, conversion of lactate to pyruvate and glycerol metabolism

So stimulates fat deposition, inadequate amounts for beta oxidaiton

Lactate builds up, could cause lactic acidosis

Reduces ability of the kidney to excrete uric acid, urate may build up in tissues causing gout

Gluconeogenesis cannot be activated. Fasting hypoglycaemia

233
Q

Alcohol consumption increases the amount of acetyl coA. What are the effects of this?

A

Not enough NAD+ to be oxidised

Increase fatty acid and ketone body synthesis

Converts to TAGs: fatty liver as lack of lipoproteins

Can cause ketoacidosis

234
Q

How is the liver damaged by alcohol and what are the effects of this?

A

Toxic acetaldehyde damages liver cells. Alcoholic hepatitis/cirrhosis

Leaky plasma membrane

AST and ALT in blood, liver function test

Reduced liver function can result in:

Decreased:

= uptake of conjugate bilirubin, hyperbilirubinaemia, Jaundice

=urea production, hyoerammonaia and high glutamine

=protein synthesis, low albumin (oedema), clotting factors (slow clotting) and lipoproteins (fatty liver)

235
Q

What are the indirect and direct effects of alcohol on the body?

A

Indirect: likely vitamin and mineral deficiencies, inadequate protein and carbohydrate uptake, CNS

Direct effect: on GI tract

Loss of appetite, diarrhoea, impaired absorption of nutrients due to damage of lining cells (vitamin K, folic acid, haemotological problems, pyridoxine and thiamine, neuro symptoms)

Thiamine deficiency can lead to Wernicke Korsakoff syndrome with mental confusion and unsteady gait

236
Q

How is alcohol dependency treated with drugs?

A

Disulfarim

Aldehyde dehydrogenase inhibitor

If alcohol is consumed, acetaldehyde accumulates in the blood, giving hangover symptoms

237
Q

Describe normal metabolism of paracetamol

A

Straight to phase 2 metabolism

Conjugates with glucaronide or sulphate

238
Q

Describe metabolism of paracetamol in an overdose

How is it treated?

A

Conjugation in phase 2 by glutathione or sulphate is quickly saturated

Undergoes phase 1 metabolism

Produces toxic metabolite NAPQI

Toxic to hepatocytes

Phase II conjugation with glutathione, an important antioxidant, subject to ROS attack

Liver failure over several days

Treatment with N-acetylcysteine, an antioxidant, RAPIDLY

239
Q

What are the major metabolic fuels and their sources in an individual?

A

Glucose/glycogen: glucose used by all cells, preferred fuel. Only 12g in solution can support CNS for 2 hours. Stored as glycogen in liver and muscle. Only liver glycogen can be used by the CNS.

Fatty acids/ketone bodies: many cells except RBCs and CNS can use fatty acids as fuels. Fatty acids from TAGs in adipose can supply fuel for two months, the main fuel reserves. Fatty acids can be converted to ketones for CNS fuel when glucose is low in starvation.

Proteins can be hydrolysed to amino acids that can be converted to glucose, ketone bodies or directly oxidised.

240
Q

What are the communication pathways in humans?

A

Nervous, by action potentional. Afferent to brain, efferent from brain.

Endocrine, by hormones

Paracrine, local hormones via ducts, exocrine

Autocrine, agents being released affect the releasing cell, self control

241
Q

What are the major features of control systems in the human body?

A

Communication

Control centre

Receptor

Effector

242
Q

What is a receptor?

A

Sensors that detect stimuli such as changes to the internal environment

Usually specialised nerve endings such as thermoreceptors and chemoreceptors

Sensors communicate input to the control centre via afferent nerves

243
Q

What is a control centre?

A

Establishes the reference set point

Analyses afferent input

Determines appropriate response

Examples in the brain:

Hypothalamus in the diencephalon: endocrine system

Medulla oblongata in the brain stem: ventilation and CVS control

Trauma to these regions is usually fatal

244
Q

What is an effector?

A

Agents that cause change

The control centre produces an output

Ouput is communicated by the efferent pathway to the effectors

Eg sweat glands are activated to produce more sweat causing heat loss

In paraplegic patients heat loss is affected

245
Q

What is positive feedback?

(feedforward)

A

Stimulus produces a response which increases its effect

Forces system out of ocntrol

Rapid catastrophic change

Exampkes: blood clotting, ovulation

246
Q

What is a feedback loop?

A

When the output/effect affects the control centre

247
Q

What is negative feedback?

A

Output inhibits functino of the control centre

Effector opposes stimulus

Stabilises control systems can control set point in fine limits

In most homeostatic control mechanisms

Tendency to overshoot set point several times, hunting behaviour

Examples: insulin and hyperglycaemia, HPA axis

248
Q

Discuss examples of biological rhythms and what they are

A

Rather than the set point being fixed it can change over time

Cortisol: levels vary throughout the day. Peak at 7am, trough at 7pm. CIRCADIAN RHYTHM. So time should always be noted when taking a cortisol sample, when repeated shouled be at the same time of day, of 24hour urine.

Menstrual cycle: woman’s core body temperature varies in the cycle. Sudden increase in core body temperature is a marker for ovulation.

Biological clock in brain: suprachiasmatic nucleus in hypothalamus, small group of neurones. Natural diurnal cycl. Zeitgabers, keys from the envuronment keep us on 24 hours, long haul flights mismatch. Melatonin hormone in pineal gland helps set clock, no light on retina stimulates melatonin.

249
Q

Define the term hormone

A

chemical signals produced in endocrine glands or tissues, that travel in the blood stream to cause an effect on tissues.

250
Q

Generally how do hormones work?

A

Change in concentration of hormones causes a cell response

About 30 seconds to reach all body parts

Only interact where there are receptors

Can have different effects in differet places

Good for coordinated multiple responses

Path: endocrine tissue releases hormone, transported in blood to target cells, receptors and respsonse, inactivation of chemical by liver or sometimes kidney

251
Q

What are the 4 classes of hormone

Give examples of each

A

Polypeptide: short or long chains of amino acids, largest group, insulin, glucagon, growth hormone, placental lactogen

Steroid: all derived from cholesterol, cortisol, aldosterone, oestrogen, testosterone. Classified by carbon number

Amino acid derivatives: small molecules synthesised from amino acids, thyroid hormones, adrenaline (a catecholamine)

Glycoprotein:large protein molecules with carbohydrate side chains. Anterior pituitary hormones. LH, FSH, TSH

252
Q

How are hormones transported?

A

Polypeptide, glycoprotein and adrenaline: relatively hydrophilic and are transported in the blood by dissolving in the plasma.

Steroid and thyroid hormones are lipophilic and need specialised transport proteins like thyroxine binding globulin or albumin

253
Q

How do hormones act on target cells?

A

Effect of a hormone depends on concentration in the blood stream

Only unbound or free hormones can interact with receptors

Bind to specific high affinity receptors on or in the cell. Hormones that can cross cell membrance and are lipophilic bind to receptors inside the cell. Hydrophilic hormones bind to a receptor on the cell surface.

Then binding hormon triggers a change i the target cells, which may be in enzyme/functional activity (short term) or gene expression (long term). Cell surface receptors often trigger a secondary messenger that influences the cells activity.

Some hormones have one major target tissue whereas others have many.

254
Q

Name ways in which hormones may be controlled

A

Negative feedback

One hormone controlling another

Releasing or inhibiting hormones

Inactivating hormones

255
Q

Describe control of hormones by negative feedback

A

Hormones constantly lost from circulation as they are excreted or broken down

Secretion rate must be adjusted to maintain concentration

Rate of secretion directly affected by blood concentration

If the concentration falls below a critical levels hormone secretion increases until the correct level is acheived again

Example: pancreatic beta cells secrete insulin, are directly sensitive to blood hormone concentration, if it rises abouve 5mM, insulin is secreted until it is brought down to the right level, then it is switched off

256
Q

Describe how one hormone can control another

A

Controlling hormone is a trophic hormone

Secreted from anterior pituitary gland

Example: Secretion of cortisol is controlled by ACTH

negative feedback in some trophic hormones

257
Q

What are the 6 anterior pituitary hormones?

What do they do?

A

ACTH: adrenocorticotrophic hormone, affects the adrenal gland and cortisol

TSH: thyroid stimulating hormone, affects T4 secretion

GH: growth hromone, affects metabolism

LH: luteinising hormone, affects ovary and testis function

FSH: follicle stimulating hormone, affects ovary and testis function

Prolactin: affects breast development and milk production

258
Q

How do releasing or inhibiting hormones control hormone secretions?

Examples?

A

Come from nerve cells in the hypothalamus

Travel to anterior pituitary via the hypophyseal portal vessels

Allows brain to control hormone secretion

Thyrotrophin releasing hormone, TRH

Corticotrophin releasing hormone, CRH

Somatotrophin releasing hormone, SRH, stimulated GH release

Somatostatin, inhibits GH release

259
Q

How are hormones inactivated?

A

Occurs in liver and kidney and sometimes target tissues

Steroid hormones are inactivated by increasing their water solubility, can be excreted in urine or bile

Protein hormones need extensive chemical changes and are degraded to amino acids which are recycled

260
Q

Where is the centre of the control of appetite?

What neurones are involved?

What do they do?

A

Arcuate nucleus in the hypothalamus

Group of neurones consisting of two types

Primary neurones: sense metabolite leves in blood, respond to hormones.

Secondary neurones: synthesise input from primary neurones and synthesise a response via the vagus nerve

261
Q

Describe the types of primary neurones and their actions.

A

Excitatory: stimulate appetite via neuropeptide Y and agouti related peptide

Inhibitory: suppress appetite by releasing pro-opiomelanocortin (POMC)

262
Q

What is POMC cleaved into?

A

Beta endorphin, reward system, euphoria and tiredness

ACTH, stimulate cortisol

Alpha melanocyte stimulating hormone: a-MSH, acts on melanocortin 4 receptors which suppress appetite

263
Q

What hormones are involved in the control of appetite?

Expain how they work

A

GHRELIN: peptide released from the wall of the empty stomach, activates stimulatory neurones in the arcuate nucleus and appetite. Stretch of stomach caused by food intake inhibits Ghrelin.

LEPTIN: Peptide released by adipocytes, levels correlate to fat stores. Stimulates inhibitory and inhibits stimulatory neurones in arcuate nucleus, suppresses appetite. Lack of leptin can cause obesity. Induces expressionof UCP in mitochondria, lose heat rather than get ATP

PYY: released from small intestine wall, suppressed appetite.

INSULIN: same mechanism as leptin but less important.

AMYLIN: peptide from B cells in pancreas, supresses appetite, decrease glucagon secretion and slow gastric emptying

264
Q

What is metabolic syndrome?

A

Group of symptoms commonly found in obese peopl

Insulin resistance, dyslipidaemia, glucose intolerance, hypertension

Associated with central adiposity, sedentary lifestyle

CVS risk factors

Controversial

WHO criteria: BMI above 30, blood pressure 140/90, high TAGs, HDLs low, high fasting glucose etc

265
Q

Explain the deevlopmental origins of health and disease theory, and epigenetics

A

David barker showed that rhw strongest association of adult disease like CHS, hypertension and T2DM is low birth weight.

Suggests experience of foetus in utero determines future health.

Biochemical adaptation by foetus according to nutrient supply in uterus, programmed in for adult life

Switching on and off genes at critical times in development

EPIGENETICS: stably inherited phenotype resulting from changes in chromosome without alterations in the DNA sequence, methylations and changes in histone structure, supressing transcription, targeting promotor regions.

266
Q

How is body water controlled?

A

Osmolality and concentration of Na+ ions monitored by OSMORECEPTORS inthe hypothalamus (supraoptic/paraventricular nuclei)

If osmolality increases

ADH released from posterior pituitary

Increase in collecting duct permeability to water, more absorbed into blood, more concentrated urine, lower volume.

Osmolality decreases

267
Q

How are polypeptide hormones stored in glands?

How are steroid hormones stored in glands?

How are thyroid hormones stored?

A

Polypeptides, inside storage vesicles inside cells

Steroids stored as precursor cholesterol esters as lipid droplets

Thyroid hormones stored outside cell in the form of protein colloid

268
Q

What is diabetes mellitus?

A

A group of disorders characterised by chronic hyperglycaemia due to insulin deficiency, insulin resistance, or both

A state of hyperglycaemia leading to small and large vessel damage, in which there is premature death from cardiovascular diseases

269
Q

Why does blood glucose rise in diabetes? (both types)

A

An inability to produce insulin due to B cell failure, autoimmune destruction in the B islet cells in the tail of the pancreas

Insulin produced adequately, but insulin resistance prevents insulin working effectively, receptors don’y work properly, especially in patients with central adiposity, many free fatty acids interfere

270
Q

When does type 1 diabetes typically present?

What causes it?

A

Usually in the teenage years, strong seasonal variation suggesting a link with a viral infection as a trigger

Likely that a genetic predisposition interacts with an environmental triggere to produce immune activation.

Production of killer lymphocytes, macrophages and antibodies that attack and progressively destroy bta cells.

Associated with genetic markers HLA DR3 and HLA DR4

271
Q

What symptoms will a lean young person with a recent viral infection with type 1 diabetes typically present with?

A

Triad of symptoms

Polyuria: excess urine production. Large quantities of glucose in the blood are filtered by the kidney, exceed renal threshold, so not all is reabsorbed. Has osmotic effect of drawing more water into the urine.

Polydipsia: thirst and drinking a lot, due to polyuria

Weight loss: as fat and proteinare metabolised because insulin is absent

272
Q

What does a lack of insulin cause?

A

Decreased glucose uptake into adipose and skeletal muscle

Descreased storage of glucose as glycogen in the muscle and liver

Increased gluconeogenesis in the liver

273
Q

What does high blood glucose cause to appear in the urine?

A

Glucose

Glycosuria

274
Q

In what populations is type 2 diabetes common?

A

All populations enjoying a affluent lifestyle

Usually older

Overweight

275
Q

What are the main differences between type 1 and type 2 diabetes?

A

1: commonest type in the young. 2: affects large numbers of older individuals
1: characterised by progressive loss of all or most pancreatic B cells. 2: characterised by slow progressive loss of B cells bu with disorders of insulin secretion and tissue resistance
1: is rapidly fatal if not treated. 2: may be present for a long time before diagnosis
1: must be treated with insulin. 2: may not initially need treatment with insulin but all do eventually

276
Q

What are typical symptoms of hyperglycaemia?

A

Polyuria

Polydipsia

Blurring of vision

Urogenital infections eg thrush

Symptoms of inadequate energy utilisation

Tiredness

Weakness

Lethargy

Weight loss

277
Q

How might type 1 diabetes develop?

A

May be found with relevant HLA markers and auto antibodies but without glucose or insulin abnormalities

THey may then develop impaired glucose tolerance

Then diabetes which may be initially diet controlled

Before becoming totally insulin dependant

278
Q

How is type 2 diabetes managed progressively?

A

Diet and exercise

Tablets

Then insulin

279
Q

How does type 2 diabetes develop?

A

Insulin resistance

Insulin production falls

Impaired glucose tolerance

280
Q

What is hypoglycaemia?

What can cause it?

When can it become fatal?

What are the symptoms?

A

When plasma glucose is less than 3mM

Insulin/sulphonylurea treatment with activity, missed meal, accidental or non accidental overdose

Can be fatal when blood glucose is less than 3mM as CNS and glucose dependant tissues need a constant supply

Sweating, anxiety, hunger, tremor, palpitations, confusion, drowsiness, seizures, coma

281
Q

What is hyperglycaemia?

What are the symptoms?

A

Blood glucose is more than 10mM

Symptoms: polydipsia, polyuria, weight loss, fatigue, blurred vision, dry or itchy skin, poor wound healing.

Plasma proteins become glycosylated affecting their function

Ketoacidosis in T1DM

Hyperosmolar non-ketotic syndrome in T2DM

282
Q

Explainhow ketoacidosis arises in the uncontrolled diabetic

How can it be diagnosed?

What symptoms does it cause?

How is it treated?

A

High rates of beta oxidation of fats in the liver

Low insulin to anti insulin ratio

Production of huge amounts of ketone bodies

Acetone can be breathed out and smelt on the patient’s breath

Test for ketones in the urine, ketostik

The H+ associated with the ketones produces a metabolic acidosis

Prostration, hyperventilation, nausea, vomiting, dehydration, abdominal pain

Treated with fluids to rehydrate, and insulin

283
Q

How is diabetes diagnosed?

A

Triad of symptoms

Random venous plasma glucose concentration of more than 11.1mM

Fasting plasma glucose concentration of more than 7mM

Plasma glucose concentration of more than 11.1mM, 2 hours after 75g anhydrous glucose in an oral glucose tolerance test

With no symptoms must have two of the tests to confirm, with an additional test on another day with a value in the diabetic range.

Important to be correct: medicolegal

284
Q

How is type 1 diabetes managed?

A

Can not be cured

Insulin is used to treat

Must be injected subcutaneously

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

Appropriate doses at appropriate times to mimic normal islet behaviour

May need to increase insulin with infection, trauma to reduce ketoacidosis risk

Frequent test for blood glucose, finger prick, BM stick and reader

Need to be aware of hypoglycaemic effects

Social and psychological implications

Education

285
Q

How is diabetes monitored?

A

Well being

Glucose control (capillary blood glucose)

HbA1c

vascular risk factors: BP, lipids, smoking, exercise, diet

Surveillance for chronic comlications

286
Q

How is type 2 diabetes managed?

A

Sometime managed by diet

Sulphonylureas such as glicazide increase insulin release from remaining beta cells SPANK THE PANC, acts of K ATPase pumps

Biguanides such as metformin increase insulin sensitivity

Insulin may be needed if cells are lost

287
Q

Why is persistent hyperglycaemia harmful?

A

Produces potentially harmful products

Uptake to cells of peripheral nerves, the eye and kidney does not need insulin, is determined by concentration of glucose in ECF

So in hyperglycaemia ICF in these tissues increases

Glucose is metabolised via aldose reductase catalysing:

Glucose + NADPH + H+ to Sorbitol + NADP+

This depletes NADPH, leading to increased disulphide formation in cellular proteins altering structure and function. Accumulation of sorbitol causes osmotic damage to cells.

288
Q

Describe non enzymatic glycosylation

A

Hyperglycaemia can cause this

Plasma proteins are glycosylated

Leads to disturbances in function

Glucose reacts with free amino groups in proteins to form stable covalent linkages

Changes net charge of the protein and 3D structure

289
Q

Describe the basis and interpretation of the HbA1c test

A

Glucose reacts with terminal valin of Hb to produce HbA1c, glycosylated Hb

% HbA1c is a good indicator of how effective blood glucose control has been

RBCs usually in circulation for 3 months

%HbA1c shows the average blood glucose concentration over last 2 to 3 months

Above 6.5% is undesirable. Poor control above 10%

Normal value between 4 and 6%

290
Q

What are some long term macrovascular effects of diabetes?

A

Risk of stroke

Risk of myocardial infarction

Poor circulation to periphery: feet

Intermittent claudication: muscle pain in calf

Gangrene (poor blood circulation)

291
Q

What are some long term microvascular complications of diabetes?

A

Diabetic eye disease: changes in lens due to osmotic effects of glucose (glaucoma) and possibly cataracts. Diabetic retinopathy: damage to blood vessels in the retina which can cause blindness. Blood vessels may leak and form protein exudates on retina, may rupture and bleed. New vessels may form and easily bleed

Diabetic kidney disease, nephropathy: due to damage to the glomeruli, poor blood supply due to change in kidney blood vessels, or damage from urinary tract infections. Early sign is microalbuminuria, protein in urine

Diabetic neuropathy: damage to peripheral nerves which directly absorb glucose, changes or loss of sensation, and also changes due to alteration in autonomic nervous system function

Diabetic feet: poor blood supply, damage to nerves, increased risk of infection. Gangrene.

292
Q

How is insulin stored and transported?

What are its target tissues?

How does it act on cells?

A

Stored in beta cell storage granules as a crystalline zinc complex in vesicles

Dissolves in the plasma and circulates as a free hormone

Targets liver, skeletal muscle, adipose

Interacts with cell surface receptors, a dimer. Spans the membrane, alpha chains move together, fold around insulin. Moves beta chains together, active tyrosine kinase. Initiates phosphorylation cascade and GLUT 4 expression so cells can take up more glucose.

293
Q

Where is glucagon secreted from?

What is its structure?

How is it synthesised?

How does it act on cells?

A

Alpha cells in the islets of the pancreas

SIngle chain polypeptide, flexible

Synthesised as a large precursor molecule which is cleaved in post translational processing from preproglucagon

Takes up active conformation when it binds to receptors on the surface of the cell.

G protein coupled receptor

Increases cyclic AMP in cells, which activate protein kinase A which posphorylates and activates important enzymes in cells

294
Q

What are the properties of alpha and beta cells?

A

Lots of rough ER

Golgi

Mitochondria

Defined microtubule/ filament system

295
Q

What signal stimulates insulin?

What signal stimulates glucagon?

A

Feeding

Fasting

296
Q

What is the general affect of insulin?

A

ANABOLIC

Affects metabolism of carbohydrates, lipids and amino acids

Short term, clears absorbed nutrients from the blood following a meal

Long term, effects on cell growth and division relate to its ability to stimulate protein synthesis and DNA replication

297
Q

What are the major actions of insulin?

A

Increased:

Glucose uptake into tissues

Glycogenesis in liver and muscle

Glycolysis in liver/adipose

Lipogenesis and esterification of fatty acids in liver/adipose

Lipoprotein lipase activity

Amino acid uptake and protein synthesis

Decreased:

Glycogenolysis in liver and muscle

Gluconeogenesis in liver

Lipolysis in adipose

Ketogenesis

Proteolysis

298
Q

Describe the major actions of glucagon

A

Increased:

Glycogenolysis in liver

Gluconeogenesis in liver

Ketogenesis in liver

Lipolysis in adipose

Decreased:

Glycogenesis in liver

299
Q

Describe the structure of insulin?

A

Large peptide

2 chains, alpha and beta

2 disulphide bridges for stability

300
Q

How is insulin synthesised?

A

mRNA translated as preproinsulin on ribosomes of RER

Signal peptide removed on insertion to ER, creating proinsulin

In ER, proinsulin folds, disulphide bridges form

In the trans glogi packaged into storage vesicles

Proteolysis in vesicles to remove C peptide forming 2 chains

Secretory vesicles accumulate in cytoplasm. Margination to cell surface

Released by exocytosis

301
Q

What is the C peptide a good marker for?

A

Endogenous insulin levels

As released along with the insulin

Cleaved inside the storage vesicles

302
Q

How do glucose levels stimulate insulin release?

A

Increased glucose levels in the ECF

Glucose into cell by facilitated diffusion through GLUT 2

Leads to membrane depolarisation, influx of calcium ions

Triggers exocytosis of insulin

303
Q

What are the key features of the pancreas?

A

Exocrine and endocrine, mixed gland

Fish shaped

Adjacent to the duodenum

Sits behind the stomach

Develops embryologically as an outgrowth of the foregut

Hormones produced in the Islets of Langerhans

1% endocrine tissue

Islets are adjacent to capillaries

304
Q

What are the 5 polypeptide hormones produces in the islets of the pancreas?

A

Insulin: B cells

Glucagon: a cells

Somatostatin: d cells

Pancreatic polypeptide: f cells

Ghrelin: new cell type

305
Q

What are the three zones of the adrenal cortex?

Which type of steroid hormone is produced in each?

A

Zona glomerulosa: mineralocorticoids such as aldosterone

Zona fasciculata: glucocoticoids such as cortisol

Zona reticularis: androgens such as testosterone

Salt, sugar, sex

306
Q

What hormone is produced in the adrenal medulla?

A

Adrenaline/epinephrine

307
Q

What does TSH do?

Where is it produced?

A

Stimulates the thyroid follicular cells to produce T3 and T4

Produced in the thyrotrophs of the anterior pituitary gland

308
Q

What does ACTH do?

Where is it produced?

A

Controls the release of cortisol

Produced in the corticotrophs of the anterior pituitary

309
Q

What does growth hormone do?

Where is it produced?

A

Important for growth of all tissues and metabolism

Counteracts insulin preventing glucose uptake

Stimulates IGF1 production in the liver

Produced in somatotrophs

310
Q

What does prolactin do?

Where is it produced?

How is it controlled?

A

Initiates and maintains lactation

Acts on peripheral tissues, the breast

No target gland

High levels, lactation and menstrual disturbance

Stimulates production not release

Produced in the lactotrophs

Tonic inhibitory control by dopamine

Minor positive control by TRH

Oestrogen increases prolactin

311
Q

What is the mechanism of action of ACTH?

A

Hydrophilic

Hihgh affinty receptors on cell surface of zona fasiculata and reticularis. Melanocortin receptor, cAMP as secondary messenger.

Leads to activation of cholesterol esterase increasing conversion of esters to free cholesterol

Also stimulates other steps in cortisol synthesis

312
Q

Describe the action of cortisol

A

Stress response

Increases proteolysis, lipolysis and gluconeogenesis

313
Q

What does aldosterone do?

A

Stimulates uptake of sodium ions in the kidney in exchange for potassium ions

Over secretion increases sodium and water retention causing hypertension and muscle weakness

Undersecretion causes hypotension

314
Q

What do androgens do?

A

Stimulate growth and development of male gential tract

Development of secondary male characteristics

Anabolic actions on muscle protein

Produce male effects in females

315
Q

What do oestrogens do?

A

Stimulate growth and development of female genital tractl breasts and female secondary characteristics

Weakly anabolic

Decrease circulating cholesterol

316
Q

Describe the action of cortisol

A

Stress response

Affects availability of all substrates increasing proteolysis, lipolysis and gluconeogenesis

Decreased amino acid uptake + reduced protein synthesis + more proteolysis = MORE AMINO ACIDS

More hepatic gluconeogenesis + more glycogenolysis = MORE GLUCOSE

More lipolysis in adipose = MORE FATTY ACIDS

Decreased peripheral uptake of glucose = ANTI INSULIN

Direct effects on cardiac muscle, bone and the immune system

317
Q

What is the general structure of steroid hormones?

eg cortisol

A

Derived from cholesterol which is tetracyclic with an OH group

Cortisol is a member of the C21 steroid family

Differs from other steroids in terms of

Number of C atoms

Number of C=C double bonds

Presence of functional groups

Synthesised via progesterone with enzymes

All are lipophilic and must be transported by plasma proteins like transcortin

Other examples: vit D/calciferol, glucorticoids, mineralocorticoids, progestins, androgens, oestrogens

318
Q

How is adrenaline synthesised?

How are they stored?

What type of substance are dopamine, noradrenaline and adrenaline?

A

Enzyme catalysed

Tyrosine to Dopa to Dopamine to Noradrenaline to Adrenaline

Noradrenaline to adrenaline by methylation

They are stored in vesicles in the medullary cells

Catecholamines

319
Q

What is synthesised in the adrenal medulla?

What type of tissue is it modified from?

A

Adrenaline, noradrenaline, some dopamine

Modified sympathetic ganglion

320
Q

Describe the chemical properties of adrenaline?

When is it secreted?

A

Amine

Cyclic

-OH groups

Secreted in response to stress

Fight or flight response

321
Q

What are the effects of adrenaline on various boduly systems?

A

CVS: increase cardiac output and increase muscle blood supply

CNS: increase mental alertness

CARBOHYDRATE METABOLISM: increase glycogenolysis in liver and muscle

LIPID METABOLISM: increase lipolysis in adipose

322
Q

What are the clinical consequences of oversecretion of adrenaline?

What usually causes it? Give clinical name

A

Hypertension

Palpitations

Sweating

Anxiety

Pallor

Glucose intolerance

Usually caused by a tumour in the adrenal medulla

PHAEMOCHROMOCYTOMA

323
Q

How do steroid hormones such as cortisol work on their target tissues?

A

Lipid soluble so can cross plasma membranes

Binds to cytoplasmic receptor

Hormone receptor complex travels to nucleus

Interacts with specific regions of DNA

Changes the rate of transcription of specific genes

May take some time to act

324
Q

How does adrenaline act on its target cells?

A

Does not cross the cell membrane

Binds to adrenoreceptor on the outside of the cell

Secondary messenger affects cell activity

325
Q

How is cortisol secretion controlled by CRH and ACTH?

A

Positive hypothalamic control from CRH

Secreted in response to chemical, physical and emotional stress

Stimulates release of ACTH from corticotrophs in the anterior pituitary

Both secreted in a pulsatile fashion

Increased activity in the morning, reduced at night

ACTH binds to cell surface receptors, zona fas. and ret.

Activated cholesterol esterase to free cholesterol

Negative feedback on both ACTH and CRH

326
Q

Why does ACTH cause pigmentation in some parts of the body?

A

ACTH is a single chain polypeptide

Precursor is a large protein POMC

Post translational processing of POMC makes ACTH, a-MSH and endorphins

MSH sequence is inside ACTH

So some MSH activity when produced in excess, eg lack of negative feedback

Stimulates melanocytes to produce melanin, buccal cavity, scars, palmar creases

In Addisons or ACTH related Cushings

327
Q

Describe how Cushing’s (syndrome or disease) is caused?

A

Increased activity of the adrenal cortex due to a tumour, adenoma

Tumour of the anterior pituitary secreting excess ACTH

Excess CRH

Ectopic secretion of ACTH

328
Q

Compare the effects of high and low cotrisol

A

Deficiency: low glucose. Excess: High glucose

D: Weight loss. E: Weight gain

D: Nausea. E: Increased appetite

D: Hypotension. E: Hypertension

329
Q

What are the clinical effects of Cushings?

A

Increased muscle proteolysis

Hepatic gluconeogenesis

Associated glucose increase in blood, polyuria and polydipsia - ‘steroid diabetes’

Prooximal muscle wasting, thin weak arms and legs

Purple straie on lower abdomen, catabolic effects on protein in skin. Easy bruising

Lipogenesis in adipose, deposition of fat in neck, abdomen and face, weight gain. Moon shaped face, cushingoid shape

Increased susceptibility to bacterial infections, acne, due to immunosuppressive, anti inflammatory and anti allergenic actions of cortisol

Back pain and rib collapse, osteroporosis, loss of bone matrix protein

Minveralocorticoid effects, retention of sodium and water producing hypertension

330
Q

Describe how Addisons is caused

A

Diseases of the adrenal cortex, such as auto immune destruction, this reduces glucocorticoids and mineralocorticoids

Disorders in the pituitary or hypothalamus that lead to decreased ACTH or CRH secretion, only affects glucocorticoids

331
Q

How are ACTH and cortisol levels measured?

A

Measurement of plasma cortisol and ACTH

MUST NOTE TIMING - circadian rhythm

Breakdown products measurement: 17 hydroxysteroids

24 hour urinary excretion of cortisol

332
Q

What are the clinical effects of too little cortisol production (Addison’s) ?

A

Acute emergency (crisis) or chronic debalitating disorder (disease)

Loss of mineralocorticoids, hypotension due to sodium and fluid depletion, especially postural

Insidious onset with non specific symptoms of tiredness, extreme muscular weakness, anorexia, vague abdominal pain, weight loss, dehydration and dizziness

Increased pigmentation, more ACTH due to lack of negative feedback

Hypoglycaemia especially on fasting, decreased cortisol so decreased catabolism

Crisis can be caused by stress such as trauma, infection, leading to nausea, vomiting, extreme dehydration, hypotension, confusion, fever and even coma

Clinical emergency that must be treated with IV cortisol and fluid replacement, dextrose in saline to avoid death

333
Q

What is the dexamethasone suppression test?

What disease does it test for?

A

Potent synthetic steroid

Normally when given orally, would suppress ACTH secretion and therefore cortisol

Supression of 50% is characteristic of Cushing’s, as although the diseased pituitary is relatively insensitve to cortisol it does respond somewhat to potent steroids

Does not suppress adrenal tumours or ectopic ACTH production

334
Q

What is the synacthen test?

What disease does it test for?

What does stressing of the pituitary test for and how does it work?

A

Synthetic ACTH

Tests for primary adrenal addisons

Would usually increase plasma cortisol by more than 200ml

Normal response usually excludes Addisons

Tests for Addison’s by stress test, give insulin to induce hypoglycaemia. ACTH should increase.

335
Q

Describe how cortisol can have week mineralocorticoid and androgen effects.

A

Steroid receptors form part of a family of nuclear DNA binding proteins that include thyroid and vit D receptors

They all have 3 main regions: hydrophobic hormone binding region, DNA binding region rich in cysteine and basic AAs, a variable region

Sequence homology in hormone binding region between glucocorticoids, mineralocorticoids, androgens, oestrogen, thyroid

Low affinity binding to other receptors

Significant when cortisol concentration is high

Stimulate fluid and sodium reabsorption in kidney, hypernatraemia, hypokalaemia

Stimulation of male genital tract and male characteristics, ANABOLIC

336
Q
A
337
Q

How is an insulin tolerance test used to test for growth hormone deficiency?

What about excess?

A

Insulin tolerance test

Stops somatostatin

GH increases if normal

Glucose tolerance test

Somatostatin up

GH decreases if normal

338
Q

How is pituitary disease treated?

A

Surgery: transcranial or transphenoidal

Radiotherapy: external beam, gamma knife, protects vision but possible pituitary damage, increased stroke risk

Medical: dopamine agonists reduce prolactin.

Somatostatin analogues for acromegaly

GH receptor analogues stimulate IGF1

339
Q

What is the embryological origin of the posterior pituitary gland?

What does it produce?

A

Neuroectoderm

Anti-diuretic hormone

Oxytocin

340
Q

Describe the condition of diabetes insipidus

A

ADH deficiency or resistance

Water not reabsorbed by the kidney

Polyuria and polydipsia

High serum osmolality, low urine osmolality

Cranial - disease of the hypothalamus or pituitary stalk

341
Q

How can a pituitary tumour present?

A

Visual disturbance: up growth compressing the optic chiasm

Lateral Carvernous sinus invasion affects cranial nerves

Secreting tumour:

More GH, acromegaly, coarse features, hypertension, headaches, diabetes, gigantism if before puberty

Prolactinoma: menstrual disturbance, galactorrhoea, infertility

ACTH: Cushings

Non secreting tumour: Posterior, no ADH, Diabetes insipidus. Anterior, low GH, LH, FSH< TSH, ACTH, more prolactin.

342
Q

What are the causes of high prolactin?

A

5 Ps

Pregnancy

Physiological

Pharmacological

Pituitary: prolactinoma

Polycystic ovaries

343
Q

Where are hormones produced and stored in the posterior pituitary?

A

Produced at the top

Stored at the bottom

344
Q

What is growth hormone needed for?

What occurs if GH is

Deficient?

In excess?

A

Needed for skeletal growth, metabolism, muscle strength, bone density, cardiac function, quality of life

Deficient: short stature, in adult cause osteopenia, more fat, less muscle

Excess: acromegaly in adults, gigantism before puberty, can be abused in sport

345
Q

Describe the condition of congenital adrenal hyperplasia

A

Enzyme deficiency

Build up of androgens

Less mineralocorticoids and glucocorticoids

Autosomal recessive

Virilisation of female baby, clitiromegaly

Neonatal salt losing crisis

Hypotension, hypoglycaemia, hyponatraemia

346
Q

How are glucocorticoids replaced in Addison’s?

A

Hydro/flurocortisone

347
Q

What are the causes of Addisons?

A

TB

Surgical removal

Haemorrhage

Infarction

Infiltration

Adrenal leukodystrophy

348
Q

What advice is given to sufferers of addisons?

A

Increase steroids in incurrent illness

Steroid card, medic alert bracelet

Emergency 1M hydrocortisone ampoule

349
Q

Describe the location of the thyroid gland

A

Neck

Anterior to lower larynx and upper trachae

Inferior to the thyroid cartilage

Recurrent laryngeal and external branch of superior laryngeal nerves lie close

350
Q

Describe the structure of the thyroid gland

A

Highly vascularised, 3 arteries and veins, superior, middle and inferior

2 lateral lobes connected by a central isthmus

2 - 3 cm across, normally weighs 20g

2 major cell types: follicular and parafollicular

Abundant sympathetic and parasympathetic nervous system, stimulation by them increases thyroid hormone

351
Q

Describe the follicular cells of the thyroid and how they are arranged

A

Arranged in units called follicles, seperated by connective tissue

Follicles are spherical

Lined by epithelial cells (follicular cells) surrounding a lumen

The lumen contains protein: colloid

352
Q

Where are parafollicular cells found in the thyroid?

What are they also known as?

A

In the connective tissue around follicles

C cells

353
Q

What hormones are produced in the thyroid?

Where?

A

In the follicular cells

T4: Thyroxine

T3: Triiodothyronine

In the parafollicular/C cells

Calcitonin

354
Q

What are the general actions of thyroid hormones?

A

Needed to modulate metabolism

Role in growth and development

Needed for nervous development

355
Q

What are the thyroid hormones derived from?

What are they soluble in?

A

Derived from tyrosine

With addition of iodine, the number refers to the number or iodine atoms

Soluble in fat

356
Q

Compare the stability of T3 and T4

Which is released more?

What are their half lifes?

A

T4 is much more stable than T3

T4 is produced in large quantities then converted to T3 in the peripheral tissues

T3 has a shorter half life

357
Q

How are T3 and T4 synthesised in the follicular cells of the thyroid gland?

(REGULATED BY TSH)

A

Transport of iodide actively into epithelial cells

With 2 Na+ ions (Sodium Iodide transporter, Na/K pump creates a Na gradient)

Synthesis of tyrosine rich protein THYROGLOBULIN in the epithelial cells

Exocytosis of thyroglobulin into the lumen of the follicle

Oxidation of iodide by peroxidase to create iodinating species

iodination of side chains of tyrosine residues to produce MIT and DIT

Coupling of MIT + DIT = T3

DIT + DIT = t4

358
Q

How are thyroid hormones stored?

How long would the stores last for?

A

Stored extracellularly

In the lumen of the follicles

As part of the thyroglobulin molecules

Will last several months at the normal rate of secretion

359
Q

How are the thyroid hormones secreted?

A

Thyroglobulin taken up into epithelial cells

By endocytosis

Proteolytic cleavage

Releases T3 and T4

Diffuse from epithelial cells

Into circulation

360
Q

How are the thyroid hormones transported?

A

99% bound to proteins

Hydrophobic

TBG: Thyroid Binding Globulin

Pre albumin

Albumin

Only free hormone is active

T3 lower affinity for proteins so more is free and a shorter half life

361
Q

What is the half life of

T3?

T4?

A

T3: 2 days

T4: 8 days

362
Q

How is the activity of the thyroid gland controlled?

A

Hypthalamic and anterior pituitary control

TRH: tri peptide from dorsomedial nucleus of hypothalamus. Stress and decrease in temp increase secretion

Travels via hypophyseal portal system to anterior pituitary to stimulate TSH from thyrotrophs

TSH in blood to follicular cells

Negative feedback from thyroid hormones

363
Q

How does TSH stimulate the release of the thyroid?

Action mechanism

A

Glycoprotein consisting of 2 non covalently linked subunits, alpha and beta

Released in low amplitude pulses

Circadian rhythm

Interacts with surface receptors

Stimulates synthesis and secretion of T3 and T4

Trophic effects increasing vascularity, size and number of follicular cells

Trophic effect can cause goitre which can be over or underactive

364
Q

What is the effect of thyroid hormones on cells and the body as a whole?

A

Increase metabolic rate

Increased uptake of glucose and metabolism of it

Stimulate mobilisation and oxidation of fatty acids

Stimulate protein metabolism

Mainly catabolic so highger BMR, increased heat UCPs, increased o2 consumption

Response can occur slowly

365
Q

How are T3 are T4 important for normal growth and development?

Affects on heart? Neurotransmitters? GI? Ovulation?

A

Bone mineralisation

Increase heart muscle protein synthesis

CNS development: cellualr processes of nerve cells hyperplasia of cortical neurones, myelination

Indirect hormone and neurotransmitter interaction: stimulate receptor synthesis

Tachycardia in heart muscle. Increased motility in GI tract

Permissive role in FSH and LH actions, ovulation fails in absence

Turnover of proteins and glycoproteins in skin and hair and nails

366
Q

Describe how cretinism arise in the newborn and its reversibility

How is lack of thyroid hormone characterised in adult behaviour?

A

Absence of thyroid hormone from birth, hypo

Severe physical and mental retardation

Lack of CNS development

Coarse features, diminished linear growth, delayed sexual development

Must be corrected in a few weeks to reverse, all newborns are tested with T4/TSH assays

Hypo in adults”poor concentration, memory, lack of initiative

367
Q

What is the mechanism of action of thyroid hormones?

A

Cross plasma membrane

Interact with high affinity receptors in the nucleus or possibly mitochondria

Binding of T3 to hormone binding domain

Unmasks DNA binding domain

Interaction of hormone receptor complex with DNA

Increases rate of transcription of specific genes that are translated into proteins

Stimulates oxidative energy metabolism

368
Q

How is T4 converted to T3?

Why does this conversion happen?

How is reverse T3 produced and what are its properties

A

Removal of the 5’ iodide

Helps to regulate the amount of free hormone in the cells as T3 is 10x more active than T4

Removal of 3’ iodide produces rT3 which is inactive

369
Q

What are the causes of hypothyroidism?

How is it treated?

A

Hashimotos: autoimmun destruction of follicles or production of an antibody that blocks the TSH receptor on follicular cells

Post surgery

Radioactive iodine

Anti thyroid drugs

Secondary: lack of TSH

Congenital

Iodine deficiency

Treated with oral thyroxine T4, measure TSH levels to stabilise.

370
Q

What are the signs and symptoms of hypothyroidism?

A

Weight gain

Brady cardia

Cold intolerance

Dry and flaky skin

Alopecia

Tiredness

Deep husky voice due to goitre, trophic effect of more TSH

Neuromuscular: weakness, muscle cramps and cerebella ataxia (clumsiness)

Poor concentration/memory loss

Constipation

371
Q

What are the causes of hyperthyroidism?

A

Grave’s disease: autoimmune, antibodies are produced which stimulate TSH receptors on follicle cells, resulting in increased T3 and T4 secretion

Toxic overproducing T3/4, multinodular goitre

Exessive T3/4 therapy

THyroid carcinoma, but 99% don’t cause hypo/hyperthyroidism

Ectopic thyroid tissue

372
Q

How is Grave’s disease treated?

A

Carbimazole

Inhibits the addition of iodine into thyroglobulin

373
Q

What are the symptoms of hyperthyroidism?

A

Heat intolerance

Weight loss

Tachycardia

Physical and mental hyperactivity

Intestinal hyperactivity

Increase appetite

Exopthalmos

Skeletal and cardiac myopathy, causing tiredness, weakness, breathlessness

Osteoporosis due to increased bone turnover and preferential reabsorption

Hyperreflexive

Increased perspiration

374
Q

How is hyperthyroidism treated?

A

Carbimazole for graves

Thyroidectomy, complete or partial

Radioactive iodine

Then manage hypo

Important to be aware of parathyroids

375
Q

Compare the signs and symptoms of hyperthyroidism and hypothyroidism

A

BMR and catabolic activity:

Hyper: increase. Hypo: Decrease

Sympathetic and CNS activity, GI tract, CNA:

Hyper: increase. Hypo: Decrease

Direct effect on tissues:

Hyper: CVS. Hypo: CVS, subcutaneous

376
Q

Describe interpretation of thyroid function tests

A

Euthyroid: Normal free T4, Normal TSH

Hypothyroid: Low free T4, high TSH

Hyperthyroid: High free T4, low TSH

377
Q

What is the variation like in thyroid function tests?

In a population

In an individual

A

Large variation in the population

Small variation in the inividual

378
Q

How are oestrogen and thyroid binding globulin linked?

A

In pregnance

More oestrogen, more TBG synthesis

Fall in free T3/4

Removes negative inhibitory feedback

More TRH and TSH, so more T3 and T4

Free T3 and T4 back to normal

Total amount of thyroid hormones in the blood increases

379
Q

How are the thyroid hormones inactivated?

A

T3 and T4 are degraded by removal of iodine

Liver and kidney

380
Q

What is the incidence of thyroid disease?

A

More females than males

1-2% of women

381
Q

Give some examples of cellualr process in which calcium plays a critical role

A

Hormone secretion

Nerve conduction

Inactivation/activation of enzymes

Muscle contraction

Exocytosis

intracellular secondary messenger

382
Q

What level range is biologically free active calcium usually regulated to?

A

Calcium ions

between 1.0 to 1.3 mM

383
Q

How does calcium exist in the plasma?

A

Free ionised species

Bound to proteins such as albumin

Complexed with organic anions like citrate and oxaloate

384
Q

Why is phosphate important?

Is it controlled?

A

Part of adenosine triphosphate molecule

Crucial role in cellular energy metabolism

Activation and inactivation of enzymes

Not strictly regulated

Fluctuates during the day, e.g. after meals

385
Q

Why are calcium and phosphate homeostasis linked?

A

Both are major components of calcium hydroxyapatit crystals which mineralise bone

They are regulated by the same hormones, parathyroid horomones, 1,25-dihydroxyvitaminD/calcitriol, and to a lesser extent calcitonin

These hormones act on bone, the kidneys, the GI tract to control levels of these ions in plasma

Differing effects on levels of each ion

386
Q

What are the two main hormones involved in serum calcium control?

What do they do?

A

Parathyroid hormone

Calcitriol

They both raise serum calcium concentrations, but by different mechanisms and time scales

387
Q

What is calcitonin thought to do?

A

In animals lowers serum calcium

In humans suggested to only preserve the maternal skeleton

Lowers serum calcium

Increase osteoclast activity

388
Q

What tissues to PTH and calcitriol act on?

A

Bone: act on calcium hydroxyapatite store within collagen fibrils

Kidneys: filter, reabsorbed, most in PCT, then loop of Henle, hormonal control in DCT

Gut: in through diet and egest through faeces, taken up in duodenum and jejunum, secretions are rich in calciu. Energy dependant uptake

389
Q

How is calcium in the serum regulated in the short term?

Where is the hormone secreted from?

A

Parathyroid hormone, PTH

Polypeptide hormone

Secreted from the parathyroid glands, typiaclly 2 pairs, by CHIEF CELLS

390
Q

Describe how PTH regulates serum calcium

A

Changes in calcium ion concentration alter PTH by negative feedback

Chief cells have unique G protein calcium receptors on the cell surface

Increased calcium binding to G protein binding receptors

stimulates Phospholipase C

inhibiting adenylate cyclase

This leads to reduced cAMP

and reduced PTH release

Reverse occurs when calcium is low

391
Q

What is the effect of PTH on

Bone?

Kidneys?

Gut?

A

Bone: osteolysis within 1 to 2 hours. Osteoblast synthesis. Cytokines secreted which expose the bone surface. Decrease osteoblast activity, which usualy protect bony surface. Protect osteoclasts from apoptosis. Reabsorption of mineralised bone, release of Pi and calcium into ECF

Kidney: Affects tubular cells. In DCT, increases calcium ion reabsorption, therefore decreasing excretion. Supresses reabsorption of Pi, which prevents calcium stone formation.

Gut: stimulates conversion of vitamin D to active form. Increased uptake of caclium from the cut, less egested.

392
Q

How does vitamin D work to control serum calcium?

A

Long term action

Increase calcium and Pi absorption in gut, active uptake

Mobilise calcium stores in bone

Stimulate reabsorption in the kidney

393
Q

Explain the interaction of parathyroid and vitamin D

A

Vitamin D is formed in the skin or absorbed in the gut from the diet

Has a short half life

So is converted to calciferol (25-hydroxyvitamin D) in the liver, which has a 2 week half life

Vitamin D is not regulated

Final conversion is in the kidney to calcitriol, regulated by PTH

Hydroxylation of C1

394
Q

Explain regulation of PTH

A

Transcriptional and post transcriptional level

Low serum calcium up regulates transcription and prolongs mRNA survival

High serum calcium down regulates transcription

Contrinually synthesised but little store

Chief cells degrade and synthesise

Increased PTH cleavage in cheif cells, increased by high serum calcium

Released PTH cleaved in liver

Negative feedback

395
Q

Explain regulation of vitamin D

A

Two forms vitamin D2 (gut) and D3 (sunlight) both form calcitriol and are equipotent

Needs 2 hydroxylations

In liver at c25, not regulated

In kidney at C1, regulated by PTH

396
Q
A
397
Q

Explain the significance of renal function on calcium metabolism

A

PTH affects tubular cells in the kidney

Increase calcium reabsorption in the DCT

Pi is removed from circulation by inhibition of reabsorption in PCT

Prevents calcium stone formation

398
Q

What is hypocalcaemia?

A

Decrease in plasma calcium

Leads to parathesia - tingling

Tetany: involuntary muscular contraction

Paralysis, even convulsions

Due to low amount of calcium bound to the NMJ membrane, allowing Na+ to depolarise it much more easily, lowers threshold

More PTH, can cause rickets

399
Q

What is hypercalcaemia?

A

High serum calcium levels

MOANS GROANS AND STONES

May result in formation of kidney stones, renal calculi

Constipation

Dehydration (treat with fluids lost in urine)

Kidney damage

Tiredness and depression

Could be primary hyperparathyroidism, remove benign tumour

400
Q

What can cause PTH deficiency?

Effects?

A

Accidental surgical removal

Life threatening hypocalcaemia

401
Q

Describe how an ectopic tumour can produce hypercalcaemia

A

Breast/ prostate/ sometimes myeloma etc

Parathyroid hormone related peptide (PTHrp) is a peptide hormone produced by these

Leads to humeralhypercalcaemia of malignancy

Similar structure to PTH

Increased calcium release from bone, less calcium excreted, less phosphate reabsorption

Does not increase C1 hydroxylasse activity in the kidney so does not increase calcitriol concentration

402
Q

How much weight will a woman typically gain in pregnancy?

Why?

A

8kg

As the mother has to supply everything required for the growth of the foetus: nutrients, vitamins, minerals, oxygen and water

403
Q

How are nutrients transferred to the foetus from the maternal circulation?

A

Mainly diffusion, facilitated diffusion

Placental exchange

Some active transport

404
Q

What metabolic changes occur in the first half of pregnancy?

A

Preparatory increase in maternal nutrient stores

Especially adipose

Bigger apetite

Ready for more rapid growth of foetus, birth and lactation

Increasing levels of insulin promote anabolism

Increased beta cell glucose sensitivity, hyperplasia and hypertrophy

More glycogen

Increased insulin action on storage tissues

Less insulin action on energy using tissues

405
Q

Which hormones are involved in the adaptive responses of maternal metabolism?

What do they do?

A

Maternal insulin: concentration in maternal circulation increases.

Acts to promote the uptake and storage of nutrients, largely as fat in adipose

Foetal-placental hormones: more imporant as pregnancy processd

Largely oppose the actions of insulin: anti-insulin

Maintain the glucose gradient to ensure it is in constant supply

406
Q

What are the main maternal adaptations to metabolism in pregnancy?

A

Adjust maternal blood concentrations

Modify nutrient stores to cope with demands, highest in late pregnancy and lactation

Minimal disturbance to maternal homeostasis

Fat stores accumulate in first half

Increase in blood volume

Placenta supersedes HPA axis

407
Q

What metabolic changes occur in the second half of pregnancy?

A

Marked increased in growth of the placenta and foetus

Adapts to increased demand

Foetal placental demands are met by keep concentration of nutrients high (glucose above 5mM) in maternal circulation by:

Reduce maternal utilisation of glucose, switch to fatty acids

Delay maternal disposal of nutrients after meals

Relase FAs from stores

Maternal levels of insulin still increase, but anti insulins at a faster rate (oestrogen, progesterone, human placental lactogen)

408
Q

Why does maternal ketogenesis occur in the second half of pregnancy?

A

Marked decrease in insulin to anti insulin ratio

More fatty acids to the liver

Ketone bodies fuel for the fetal brain

409
Q

Why do some women develop gestational diabetes?

What are the consequences?

A

B cells in the endocrine pancreas unable to response to the metabolic demand of pregnancy

Fails to release the amount of insulin required

loss of control of metabolim, blood glucose increases, diabetes results

Consequences: effects of hyperglycaemia, excess fetal growth, macrosomia, fat baby with lots of liver and muscle glycogen, difficult delivery

Usually corrects after birth

Women may be more likely to develop type 2 diabetes later in life

Treat with insulin short term if severe

410
Q

What does the metabolic response to exercise in the body ensure?

A

Energy demands of cardiac and skeletal muscle are met by fuel mobilisation from stores

Minimal disturbances to homeostasis keep rate of mobilisation equal to rate of utilisation

Glucose supply to brain is maintained, prevent hypoglycaemia

Waste products removed as quickly as possible

Oxygen supply maintained

Adaptations to temperature, CVS and resp. system

411
Q

What does the nature and extent of the metabolic response depend on?

A

Type of exercise, muscles used

Intensity and duration of exercise

Physical and nutritional status of individual

412
Q

What are the energy requirements during exercise?

A

ATP needed to detach myosin from actin in muscle contraction

Energy from hydrolysis

ADP must be converted back by coupling to oxidation of fuel molecules

Glycogen and TAGs

413
Q

How is glycogen used in exercise?

A

Aerobic, last for long periods, 1 hr

Anaerobic, very quick, 2 mins

Liver helps to prevent hypoglycaemia and keep up CNS

Muscle advantageous as availability not affected by blood supply, no need for membrane transport into muscle cells, G 6 P produced without ATP

Can’t produce glucose as no G 6 P phosphatase

414
Q

What is the issue with glycogen metabolism in anaerobic exercise?

A

Build up of lactate and H+

H+ exceeds buffering capacity

Produces fatigue as function is impaired

Inhibits glycolysis by H+

H+ interferes with actin and myosin

H+ causes sarcoplasmic reticulum to bind calcium which inhibits contraction

415
Q

What limits the use of fatty acids from TAGs in muscle during exercise

A

Rate of fatty acid release, lipolysis

Limited carrying capacity in blood: albumin

Raate of fatty acid uptake into cells and mitochondria, cartinine shuttle in B oxidation

More oxygen needed per mole to metabolise FAs than glucose

Can only be metabolised aerobically

416
Q

What hormones are needed to mobilise reserves?

A

Insulin needed to express GLUT4 channels to take up glucose

Glucagon stimulates glycogenolysis in lover

Adrenaline causes glycogenolysis in muscle

417
Q

Explain the benefits of exercise

A

Body composition changes: more muscle, less adipose

Glucose tolerance improves, muscle glycogenesis increases

More GLUT 4 channels

Insulin sensitivity of muscles increases

Blood lipids decrease, VLDL and LDL down, HDL up

Blood pressure falls

Psych effects: well being

418
Q

Explain the body’s response to training

Muscle

and

CVS

A

Skeletal muscle changes:

More and bigger fibres

More GLUT4

More capillaries

Better B oxidation capacity, more mitochondria

More myoglobin

More glycogen storage

CVS changes:

Lower heart rate for same output

Hypertrophy of let ventricle

Lower BPM

More 2,3-BPG in blood, lowers Hb affinity

419
Q

Describe the metabolic response to short duration high intensity exercise?

A

Confined to skeletal muscle that works anaerobically

Controlled by nervous system, noradrenaline, with some input endocrine, adrenaline

Muscle ATP and creatine phosphate used first

Muscle glycogen mobilised to provide G 6 P

G 6 P mobilised via glycolysis

Anaerobic glycolysis oxygen supply inadequate

Produces lactate and H+, acidotic effecct, cramp as H+ stimulate nerve ends

420
Q

Describe the metabolic response to medium intensity exercise

A

Regenerates ATP 60% aerobic, 40% anaerobic metabolism of glycogen

Must eliminate lots of CO2 but no major problem with H+, can be buffered

Initial sprint: ATP and C P used, anaerobic glycogenolysis

Long middle phase, ATP aerobically from glycogen in muscle, some lipolysis

Finishing burst with anaerobic glycogenolysis producing lactate

421
Q

Describe the metabolic response to long duration low intensity exercise

A

Carbohydrate stores insufficient to complete distance so fatty acids must be oxidised by muscle cells

Mostly aerobic, use all fuel types

Muscle glycogen used in a few mins

Glucose from liver glycogen

Gluconeogenesis

FA beta oxidation

Control is mainly hormonal: insulin levels fall. Adrenaline noradrenaline and growth hormone rise rapidly to promote lipolysis. Cortisol and glucagon levels rise gradually, mobilise fats and gluconeogenesis

ESA 1 Revision (8 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions