Case 5 Flashcards
What is Type-1 diabetes characterised by
Insulin deficiency
Auto-immune condition
Destruction of ß-cells in pancreas
What is Type-2 diabetes characterised by
Insulin resistance
Associated with obesity
Most common in certain racial groups
Interplay between genes and environemtn
What is the mode of action fo insulin
Binds to the insulin receptor on the CSM
Intracellular cascade to translocate GLUT4 to the CSM
Glucose is transported into the cell through these transporters
How do you distinguish between Type-1 and 2 diabetes
Measure the insuling levels (type 1 is low 2 is high)
Send a blood sample to the lab that will test for antibodies
What is considered an abnormal blood glucose level and should be investigated further
Fasting >7mmol/L
Random measurement > 11.1 mmol/L
What would show up for Type 1 diabetics in urinalysis
Ketones in the urine
Who should be screened for type 2 diabetes
Overweight individuals Vascular disease sufferers Hypertension Over 40 Previous gestational diabetes Pre-diabetic states
What is HbAC1
This is an indicator of how much glucose is in the blood as the maount fo glucose on its surface can be measured
What reading on HbAC1 is diagnostic of chronic hyperglycaemia
48mmol/mol
How does the impaired glucose tolerance drink work
It’s a drink containing 75% glucose
Blood tests are at 120 minutes and diagnosed as having ‘impaired glucose tolerance’ if blood glucose levels 7.8mmol/l
What level constitutes impaired fasting glycaemia
6.1mmol/L
What are typical diabetic symptoms
Thirst increased urination Tiredness Weight loss Blurred vision
How does Type 1 diabetes present differently to type 2
Much more acute rapid symptom onset
Generally young patients
Clear marked symptoms as opposed to mild symptoms
Mostly no family history
Most present as an emergency instead of complications
What is secondary diabetes
This is after medication, particularly steroids
Can also affect after pancreas conditions or rare endocrine conditions
Is diabetes attributed to one or many genes
It is described as polygenic as it can be attributed to many genes
What may there be a history of in Type 1 diabetes
Other autoimmune diseases such as thyroid disease or inflammatory bowel disease
What are examples of monogenic diabetes and how do these affect patients
Neonatal diabetes and Maturity Onset Diabetes of the Young (MODY)
Strong family history and onset before 25
Often diagnosed with Type 1 diabetes but don’t need to be treated with insulin in general
What are the risk factors for pregnant women of gestational diabetes
Overweight or obese
History of gestational diabetes
Large baby in previous pregnancies
When does gestational diabetes resolve
After delivery of the baby
How does gestational diabetes occur
Some hormones released during pregnancy interfere and cause insulin resistance
What cardiovascular problems can diabetes lead to
Increased risk of Stroke CVD Hypertension PVD Absent foot pulses
What else can diabetes lead to beyond cardiovascular disease
Retinopathy
Nephropathy
Erectile dysfunction
Neuropathy
How do insulin and glucagon react after a meal
Insulin rises and glucagon drops in a response to blood glucose rising
What is ATP important for
Muscle contraction Active transport Biosynthesis Cellular Processes Adaptive thermogenesis
What is metabolism
The chemical processes by which cells produce the substances needed to sustain life
What is catabolism
A degradative process when you produce energy from the breakdown of energy rich molecules
What is anabolism
A biosynthetic process where you combine small molecules to produce complex molecules
What is gluconeogensis
The production of glucose
What is glycogenesis
The production of glycogen from glucose
Where is glucagon secreted
å-cells of the pancreas
Where is GLUT1 found
RBCs
Where is GLUT2 found
The liver and kidney
Where is GLUT3 found
Glucose uptake in neurone
Where is GLUT4 found
Adipose tissues and skeletal muscles
What is the cotransporter for Na+/glucose known as
SLGT
Where does glycolysis occur
In the cytoplasm
What is the end product from one molecule of glucose in glycolysis in aerobic conditions
2 pyruvate
2 ATP
2 NADH
What is the product of glycolysis in anaerobic conditions
2 lactate
2 ATP
What are the two stages of aerobic glycolysis
Stage 1 is the consumption of 2 ATP
Stage 2 produces 2 NADH and 4 ATP
What are the key occurrences in the first stage of glycolysis
Start with a 7-carbon glucose molecule and produce two three-carbon molecules (glyceraldehyde or DHAP)
Requires 2 ATP
DHAP is always converted into glyceraldehyde before stage 2 begins
What is the ATP production in stage 2 of glycolysis known as
Substrate level phosphorylation
What happens to pyruvate after glycolysis
It is transferred to the mitochondria and converrted to Acetyl CoA
What enzyme converts pyruvate into Acetyl CoA
Pyruvate dehydrogenase through oxidative decarboxylation
Why is no NADH produced in anaerobic respiration
Because it is required to convert pyruvate into lactate
Where can lactate be converted back to glucose
In the liver
Why are the enzymes in glycolysis found at key points
Because each reaction they catalyse is irreversible
What are the three key enzymes involved in the regulation of glycolysis and at which points
Hexokinase catalyses reaction 1 (glucose to glucose-6-phosphate)
Phosphofructokinase catalyses the 3rd reaction (Fructose-6-phosphate to fructose-1, 6BP)
Pyruvate Kinase (only in the liver) catalyses the final reaction of phosphoenolpyruvate into pyruvate
What are the characteristics of hexokinase
Has a very high affinity for glucose
Low Vmax of glucose which means it converts it slowly
What inhibits hexokinase
G6P its product
What’s the difference between glucokinase in the liver and hexokinase in other tissues
Has a lower affinity for glucose and a higher Vmax to convert it quickly
Stimulated by glucose and not inhibited by G6P
Why does the lack of inhibition by G6P of glucokinase help with its function
This means it still works well when intracellular glucose levels are high after a meal
What is the characteristics of PFK1 phosphofructorkinase
Inhibited by ATP (high cellular energy levels)
Stimulated by AMP (cell energy low)
Activated by fructose 2,6-biphosphate even when cell energy levels are high
What enzyme is regulated in the liver for glycolysis and why
Pyruvate kinase
Activated by fructose-1,6-BP so linked with PFK1 as this is its product
How does fructose affect insulin levels
It doesnt
Where is fructose processed
In the liver
What is fructose initially converted to in the liver and what can this be used for
glyceraldehyde which is fed into glycolysis
What else can fructose be used to produce beyond glyceraldehyde
It can be used for glycerol production and this can be sued for gluconeogenesis or as a building block for lipids
What does fructokinase catalyse
The conversion of fructose into fructose 1-P
What reaction does Aldolase B catalyse
The conversion of Fructose 1-P into glyceraldehyde or DHAP
What is the lack of fructokinase known as and how does it present
Essential fructosuria with fructose in the urine
What does aldolase B deficiency result in
Hereditary fructose intolerance
What are the symptoms of hereditary fructose intolerance
Nausea Vomiting Abdominal distress Chronic growth restriction Severe liver damage on function tests Hypoglycaemia on blood tests
When does hereditary fructose intolerance present
During weaning (moving onto solid food)
What does oxidative decarboxylation produce
Acetyl CoA from pyruvate
What is created beyond Acetyl CoA during oxidative decarboxylation
CO2 and NADH
What activates pyruvate dehydrogenase
pyruvate dehydrogenase kinase when Acetyl CoA, ATP or NADH levels are high
Where does the krebs cycle occur
In the mitochondrial matrix
What does the Krebs cycle rely on
O2 being present, must be aerobic conditions
What upregulates the Krebs cycle
Ca2+ and ADP
What down regulates the Krebs cycle
NADH and ATP
What does one molecule of Acetyl CoA produce in the Krebs cycle
3 NADH
1 FADH2
GTP + ADP
What transfers electrons from NADH and FADH2 to O2
The electron transport chain
What is the chemiosmotic model
How the transfer of electrons across the electron transport chain generates O2 from ATP
Where does oxidative phosphorylation occur
In the inner mitochondrial membrane
What does membrane protein complex I do
Contains NADH dehydrogenase and NADH transfers electrons to this complex
What does membrane protein complex II do
This is succinate dehydrogenase and FADH2 transfers electrons to this complex
How many membrane protein complexes are there in oxidative phosphorylation
4
What is the final electron acceptor
O2
What is the electrochemical gradient produced by O2 pulling the electrons along the electron transport chain known as
The proton motive force
How many protons does FADH2 move along the membrane and why
2 as it doesn’t come into contact with complex 1
How many protons does NADH move across the membrane
3
How do protons re enter the mitchondrial matrix
Through complex V (ATP synthase) and this phosphorylates ADP to ATP
How much ATP, in perfect conditions, is produced from one glucose molecule
36
How do carbon monoxide and cyanide interfere with oxidative phosphorylation
These inhibit the transfer of electrons from complex IV to O2 and thus the whole system becomes backlogged
Therefore ATP production cannot continue
How does oligomycin stop oxidative phosphorylation
It stops protons from moving through Complex V
How does dinitrophenol stop oxidative phosphorylation
It’s an uncoupling chemical that allows protons to bypass Complex V and move directly through the membrane so ATP isn’t synthesised
What do uncoupling proteins do
These create a proton leak in the mitochondrial membrane so protons can bypass COmplex V
What is an example of an uncoupling protein
UCP1/thermogenin and it generates heat in humans and does this by bypassing Complex V instead
When an amino acid is converted into a carbon skeleton in a cell what is the by product
A nitrogen waste
What happens to the nitrogen waste by product of amino acid break down in cells
It is converted into urea and taken out by the urine
What is the main source of nitrogen in the body
Dietary proteins
What are the three sources of amino acids
Hydrolysis of dietary proteins
De novo synthesis
Degradation of tissue proteins
Where are non essential amino acids sourced from
Metabolic intermediates or from the carbon skeleton of amino acids
Where are essential amino acids obtained
In our diet
What are examples of nitrogen compounds in the body- sourced from amino acids
Cellular proteins Hormones Neurotransmitters Haemoglobin Cytochromes Melanin Nucleotides
What are the three sources for the amino acid pool
Protein biosynthesis
Biosynthesis of other nitrogen containing compounds
Oxidation for energy and excretion of nitrogen atoms
What is your nitrogen balance
The difference between the intake and the excretion of. nitrogen
What is a positive nitrogen balance
It is when nitrogen intake is greater than excretion and occurs in those growing or pregnant
What is a negative nitrogen balance
When nitrogen intake is less than excretion and occurs during times of starvation
What are the two steps in removal of the amine group to form a carbon skeleton
Transamination
Oxidative deamination
What is the main site of amino acid catabolism
The liver
Where does transamination occur
In the cytosol and mitochondria
What occurs in transamination
The amino group is removed and transferred to form glutamate and an å-keto acid
What catalyses transamination
Aminotransferases
What organs does oxidative deamination occur in
The kidney and liver
What reactions occur in oxidative deamination
The amino group of glutamate is released to form å-ketoglutarate and ammonia alongside NADH
What enzyme catalyses oxidative deamination
Glutamate dehydrogenase
What can glucogenic acids be converted to
Pyruvate or Krebs cycle intermediates
What can ketogenic acids be converted to
Acetoacetate or Acetyl CoA or acetoacetate CoA
What occurs to the free ammonia produced in oxidative deamination
It is immediately converted to non-toxic urea in the liver
What reaction occurs in normal tissues when ammonia is produced
It combines with glutamate to form glutamine
What enzyme catalyses the reaction between glutamate and glutamine
Glutamine synthase
How is ammonia processed in a skeletal muscle
It combines with pyruvate to form alanine, a gluconeogenic precursor
What can defects in liver function cause if the urea cycle cannot be processed as efficiently
Hyperammonia
What are symptoms of hyperammonia
CNS based as neurotoxin Slurring Tremors Drowsiness Coma
How does epinephrine affect insulin function
It inhibits the function as it is making sure there is energy readily available to be used in the fight or flight mechanism
What is glycogensis
The production of glycogen when there is excess glucose
What is glycogenolysis
The breakdown of glycogen from glucose in the liver and skeletal muscle
How much energy is in the fat of a typical 70KG male
~15KG which equates to about 135,000Kcal
How much energy is in proteins in the body of a 70KG male
6Kg for around 24,000Kcal
How much glycogen is in the body fo a typical 70KG male
0.1KG at about 800Kcal
How much glycogen can be found in the muscle
around 400g
What is fat stored as as an energy source
Triacyl glycerides or TAGs
What can TAGs be broken down into to generate energy
Glycerol and fatty acids
What can glycerol be used to generate in the body
glucose
What can fatty acids be converted to for energy
Ketone bodies in the liver
Where is the main protein store
Skeletal muscles
When there is not enough glucose through gluconeogensis or diet what must be used as an energy source
Ketone bodies and fatty acids
What is an example of a key ketone body that the body generates and uses
3-hydroxybutyrate
Where is 3-hydroxybutyrate generated and from what subatnce
In the liver from fatty acids
How do fatty acids travel to adipocytes where they are stored
In VLDL packages that act as vesicles
What organ can fatty acids not be used directly by and what do they need to be converted into before they can be used
The brain requires ketone bodies instead of fatty acids
Why do Type 1 diabetics produce an excess of ketone bodies- even in a fed state
Because their insulin is completely inactive the body thinks they are in a state of starvation and thus produces the chemical compounds required during a state of starvation
Why do Type 2 diabetics not normally show an uncontrolled breakdown of TAGs in adipocytes
They still give off a small amount of insulin normally and this is enough to suppress this
How are ketone bodies formed
Excess Acetyl CoA produced by fatty acid oxidation is converted into ketone bodies
What are the three main ketone bodies
3-hydroxybutyrate
Acetoacetate
Acetone
What occurs to ketone bodies to produce energy
They are oxidised by the Krebs cycle to produce ATP
What does the liver use as an energy source instead of ketone bodies
Fatty acids
How can you tell a person is breaking down ketone bodies as an energy source
They will have acetone in their breath that smells like pear drops
What is the main enzyme that is involved in converting glucose into glycogen
Glycogen synthase
What is glycogen synthase promoted and activated by
It is activated when it is dephosphorylated and promoted by insulin
What enzyme converts glycogen back into glucose
Glycogen phosphorylase
What is glycogen phosphorylase promoted by
Glucagon
What are fatty acids synthesised from
Excess Acetyl CoA from excess carbohydrate catabolism
What happens to the excess Acetyl CoA transported to the cytoplasm from the mitochondria
It forms malonyl CoA by Acetyl CoA carboxylase
How is Acetyl CoA carboxylase regulated
Activated by high insulin levels
Activated by citrate
Inhibited by fatty acids
What enzyme catalyses malonyl CoA to fatty acids
fatty acid synthase
how many carbons does the main product of fatty acid synthesis have
16
How is fatty acid synthesis powered
The oxidation of NADPH to form NADP
What pathway produces NADPH
Hexose monophosphate pathway
What is the first step of fatty acid synthesis after malonyl CoA is formed
Malonyl CoA (3C) is combined with Acetyl CoA (2C) to form a 4C compound as one carbon is cleaved off
What is the by-product of fatty acid synthesis and what is the reaction powered by
CO2 and H2O are by-products alongside two CoA molecules
This reaction is powered by NADPH which is oxidised to NADP+ to provide reducing power
What does the product of each fatty acid reaction combine with to form the next product
Malonyl CoA under the same conditions
What is the difference in products between the first fatty acid synthesis reaction and subsequent ones
The carbon chain increases in number each time
Only 1 CoA enzyme is subsequently produced as a by-product
How are the fatty acids processed so they can be transported around the body as an energy store
They are combined with glycerol to form TAGs
Why are TAGs the chosen energy storage unit instead of FA
They are insoluble which means they can be packed into the cell whereas FA are soluble
What enzyme breaks down TAGs to extract energy from them
Hormone sensitive lipase
What does hormone sensitive lipase break down fatty acids into
Fatty acids and glycerol
What activates hormone sensitive lipase
Epinephrine, norepinephrine and glucagon
What happens to the products in the break down of TAGs
Glycerol is transported to the liver
FAs bind to plasma albumin and are transported in the blood to enter cells
FAs have variable lengths
What does ß-oxidation of fatty acids produce
Acetyl CoA
How are long chain fatty acids transported into the mitochondrial matrix and how long are they
12-22Cs and transported via the carnitine shuttle
How are medium and short chain fatty acids transported into the mitochondrial matrix and how long are they
<12Cs and diffuse through mitochondrial membranes
What are fatty acids activated to in the mitochondrial matrix
Fatty Acidcyl CoAs
What is different about VLCFAs in the mitochondrial matrix when they are initially transported
They need to be degraded in the peroxisome
What is the first stage of ß-oxidation
The removal of two carbons to form a 14C substance and Acetly CoA
What are by products of ß-oxidation
NADH and FADH2
What is Acetyl CoA produced in ß-oxidation used for
In normal tissues the Krebs cycle however in the liver ketogenesis
How much ATP do you get from one 16C fatty acid
131
What enzyme varies based on the chain length of each fatty acid in ß-oxidation
Acyl CoA dehydrogenase
In the fed state what are amino acids converted to in skeletal muscles
Proteins
In the fed state what are amino acids converted to in the liver
Pyruvate, Acetyl CoA and then TAGs
What happens to amino acids in the fasting state
They are moved from the skeletal muscles and converted into ketone bodies through Acetyl CoA or glucose via Pyruvate
What does an absence of insulin mean for protein metabolism
This results in increased protein breakdown, gluconeogenesis and glyocogenolysis
What does the complete absence of insulin mean for the breakdown of lipids
Lipolysis is increased so there are increased blood FAs and ketogensis which can lead to ketoacidosis
What are the three main substrates for gluconeogenesis
Lactate
Glycerol
å-ketoacids
What is glycerol converted to in the liver in order to undergo gluconeogenesis
DHAP
Where is the energy for gluconeogenesis sourced from
FA oxidation
What enzyme converts pyruvate to oxaloacetate to bypass pyruvate kinase
Pyruvate carboxylase
What enzyme converts oxaloacetate into 2-phisphoenolpyruvate
PEP carboxykinase
What enzyme converts fructose 1,6-bis phosphate into fructose 6-P by bypassing phosphofructokinase
Fructose 1,6-bis phosphatase
What enzyme catalyses the conversion of glucose 6-phosphate into glucose to bypass hexokinase
Glucose 6-phosphatase
To produce one glucose molecule from two oxaloacetate what energy sources are needed
4 ATP
2 GTP
2 NADH
Which demographics does obesity affect more prominently
Women from deprived areas
Older age groups
Black and ethnic minority groups
People with disabilities
What is a key question when discussing weight with a patient if they have acknowledged they are overweight
Do you want to take action?
How much physical activity should a child be doing a day
60 minutes
What is insulin resistance
The decreased ability of target tissues to respond normally to circulating insulin
What consequences can insulin resistance result in for bodily functions
Uncontrolled hepatic glucose production and decreased glucose uptake by target tissues
at what point does Type 2 diabetes officially develop
When insulin resistant individuals develop impaired ß-cell function so that insulin resistance cannot be compensated by increased insulin production
What is the intial advice to those who have been diagnosed with Type 2 diabetes
Healthy diet
Increase exercise and physical activity
Decrease alcohol intake
Avoid smoking and substance misuse
What is the name for the group of hormones that are key appetite suppressing hormones
Anorexigenics
What is leptin and what is its role
This is secreted by adipocytes and is secreted when fat stores are high and, when it decreases it increases appetite levels
How does insulin secretion affect appetite
It decreases it
What is Choleystokinin and where is it released
Released from the duodenum and jejenum and has a local effect of reducing gastric emptying and reduces appetite
What is GLP-1
Glucagon like peptide released from the small intestine and colonic L-cells in proportion to ingested calories local effect of reducing gastric emptying
What is PYY
peptide YY released from the small intestine and colonic L-cells in proportion to ingested calories local effect of reducing gastric emptying
What is ghrelin
Ghrelin is secreted from the gut and stomach in absence of food to stimulate appetite
What is the role of Metformin as an anti-diabetic drug
It inhibits liver gluconeogensis and helps insulin to move glucose into cells
What are advantages of Metformin (4)
It can promote weight loss
It is very cheap and has a long track record
It improves Type 2 diabetes mortality
It rarely causes hyperglycaemia
What are disadvantages of Metformin (4)
GI upset
Advised to take with food
Lactic acidosis is rare but can be fatal
With caution when impaired renal function/ heart failure/ liver disease
What is the first line of treatment for Type 2 diabetes
Biguanides such as Metformin
What is the mode of action of sulphonylureas
Bind to sulphonylurea receptors on the beta cells of the pancreas and block the K+ channel
This results in insulin secretion
What is the suffix of sulphonylureas
-ide
What are side effects of sulphonylureas
May stimulate hypoglycaemia, hyperinsulinaemia and weight gain as insulin can be in excess
What is the suffix of Thiazolidinediones
-zone
What is the mode of action of Thiazolidinediones
Activate transcription factor PPARy which activates genes in the lipid and glucose metabolism pathways
Peripheral lipogenesis increases
Lipolysis decreases
Decreases plasma fatty acid levels
What are the negative and side effects of Thiazolidinediones
Slow onset of action Fluid retention Cardiac failure Weight gain Liver dysfunction Long term effects if withdrawn and may lead to cardiovascular events
What are the two main groups of incretins
Glucagon like Peptide 1 and Gastric inhibitory polypeptide
What role do incretins have in the body
Secreted by intestinal endocrinal cells
Help to produce more insulin when it is needed and reduce the amount of glucose produced by the liver when it is not needed
What is the role of GLP1 in the body (6)
Secreted from L cells upon food ingestion
Reduces appetite in the brain
Suppresses glucagon secretion
Enhances insulin production and secretion
reduces hepatic gluconeogenesis
Slows the rate of stomach gastric emptying
What is DPP-IV
An enzyme that rapidly degrades GLP-1
Why should GLP-1 be given with enzyme inhibitors of DPP-IV
Because it rapidly degenerates GLP-1 so should be inhibited to counteract this
What is the suffix of GLP-1 inhibitors
-liptin
How are DPP-IV inhibitors taken
Orally
What is the suffix of GLP-1 mimetics
-tide
What is the function of rapid acting secretagogues
Non sulphonylurea beta cell stimulators
Rapid onset of action and short duration of activity so taken shortly before a main meal
What are the disadvantages of secretagogues
Associated with weight gain and hypoglycaemia
Require multiple doses
What is the mode of action of SGLT2 inhibitors
Inhibit SGLT2 in the proximal tubule to prevent reabsorption of glucose and present glucosuria
What side effects can SGLT2 inhibitors present
Weight loss
low risk of hypoglycaemia
Can cause UTIs
What is the NICE guidance for patient management for those with Type 1 DM
Multiple daily injection basal-bolus insulin regimens and guidance on how to use them
What are the 4 types of insulin
Rapid acting
Short acting
Intermediate acting
Long lasting
What is basal insulin
this provides a constant supply of insulin to bring down resting blood glucose levels
Intermediate or long lasting insulin
What is bolus insulin
Has a short lived effect on blood sugar and is taken at meal times
Has characteristics of short or rapid acting insulin
When in the day should you take a basal-bolus insulin regimen
Two times a day at breakfast and before dinner
What are the characteristics of rapid acting insulin
5-15 minute onset
work for 4-5 hours
What are examples of rapid acting insulin
NovoRapid
Humalog
What are the characteristics of short acting insulins
30-60 minute onset
peak at 2-4 hours
duration of 8-10 hours
When should you inject short acting insulin
20-30 mins before a meal
What are some examples of short acting insulin
Actrapid and HumulinS
What are the characteristics of intermediate acting insulin
1-2 hour onset
5-7 hour peak
13-18 hour action
How frequently should you take intermediate acting insulins
twice daily
What is an example of intermediate acting insulin
HumulinI
What are exmaples of long acting insulin
Lantus
Levemir
Tresiba
What are the characteristics of long lasting insulin
Onset: Lantus 1-2 hours Levemir 2-4 hours Peak: Lantus flat Levemir ~8-12 hours Last around 24 hours
How many days a week should adults be improving their muscle strength
2
What constitutes moderate exercise
Fast breathing and increased heart rate
What constitutes vigorous exercise
This should lead a person to be unable to maintain conversation at the time
How long in a day should those 5 and under be active for
180 minutes
What are the main benefits of physical activity
Decreased blood pressure
Cancer prevention
Large impact with diabetes
