Case 5 Flashcards
What is type 2 diabetes?
Insulin Resistance
Diabetes where the insulin does not interact with the receptor
What is the first stage of treatment for type 2 diabetes?
Lifestyle changes
How do we treat type 1 diabetes?
Exogenous Insulin - insulin from an external source. Could be through a pen, syringe or pump.
What are the benefits of fast acting insulin?
The patient has flexibility in giving the dosage - it can be given easily before or after a meal.
They have a quick onset - act rapidly to lower the blood glucose.
What are examples of fast acting insulin?
Aspart, Lispro, Glulisine
What are examples of short acting insulin?
Soluble Insulin (Regular Insulin)
How is short acting insulin given?
Subcutaneously (Through skin)
Compare short acting insulin to regular insulin
Trick question - they are the same, so act the same
*SAI lasts for 8 hours, peaks around 50-120 minutes
Give an example of intermediate acting insulin
Isophane Insulin
*NPH-neutral protamine Hagedorn (NPH)
What does Pyruvate undergo to become Acetyl CoA?
Oxidative Decarboxylation
What is the end product of glycolysis?
Pyruvate
What does Fructokinase do?
Catalyses the reaction of adding a phosphate group onto Fructose. Fructose then becomes Fructose 1-P.
What does Aldolase B do?
Catalyses the conversion of Fructose 1-P into Glyceraldehyde
What is the cause of Essential Fructosuria?
A lack of fructokinase. Fructose cannot be converted into Fructose 1-P, causing a build up of fructose in the urine.
What is the cause of Hereditary Fructose Intolerance (HFI)?
Lack of Aldolase B. Cannot split Fructose 1-P, so it builds up. There is a reduction in the body’s phosphate groups, as they are still attached to Fructose 1-P. This leads to a reduction of ATP production, thus less glucose.
Overall, hypoglycaemia.
What are the symptoms of HFI?
Nausea
Vomiting
Abdominal Distress
Chronic growth restriction/failure to thrive
What are the symptoms of Essential Fructosuria?
There are no clinical manifestations
What is Type 1 Diabetes?
Insulin Deficiency
Diabetes where there not enough/no insulin to bind to receptor
What is a marker of Type 1 Diabetes?
- Glucose in urine
- Low levels of insulin in blood (*high in Type 2)
- Measure anti-bodies: GADA, which fights against enzymes producing insulin.
- Amount of C-peptide in blood = insulin in blood, so low C-peptide = low insulin.
- Smell ketones on breath/ ketones in urine
What are the types of Diabetes covered in case 5?
Type 1 Type 2 Secondary Inherited/Genetic Gestational
What drug is prescribed to someone with Type 2 Diabetes?
Metformin
What does Metformin do?
Decreases gluconeogenesis (stops liver pumping glucose out) and increases glucose uptake in skeletal muscle.
What is Secondary Diabetes?
Diabetes that happens as a result of something that affects insulin production.
How do steroids cause Secondary Diabetes?
They result in the liver being resistant to insulin, resulting in insulin resistant diabetes. The body’s cells are unable to respond to insulin.
How does Pancreatitis cause Secondary Diabetes?
The Pancreas is inflammed, and cells which produce insulin are damaged.
How does Pancreatic surgery cause Secondary Diabetes?
Parts of the Pancreas are removed, affecting insulin production.
How does Cushing’s Syndrome lead to Secondary Diabetes?
High levels of stress hormone (Cortisol) = Increase in BP and Blood Glucose = Stimulation of gluconeogenesis in liver and inhibition of glucose sensitivity in liver and skeletal muscles.
How does Acromegaly lead to Secondary Diabetes?
Excess growth hormone produced which acts as antagonist for insulin.
How does Pheochromocytoma lead to Secondary Diabetes?
Adrenal gland makes too much adrenaline, which suppresses insulin secretion from Pancreas.
Gluconeogenesis is also induced in liver through alpha-adrenergic receptor stimulation.
What is Monogenic Diabetes?
A rare form of inherited Diabetes
How is Monogenic Diabetes treated?
Through diet and tablets, but do not always need insulin treatment.
What is MODY?
Maturity Onset Diabetes of the Young
Condition where young people have diabetes resembling one in older patients.
What is Gestational Diabetes?
Diabetes during pregnancy
Why does Gestational Diabetes occur?
Pregnancy hormones increase insulin resistance.
Diabetic patients may have a fasting glucose of…
> 7.0 mmol/L
Diabetic patients may have a random glucose of…
> 11.0 mmol/L
How do you confirm if a patient is Type 1 or 2 diabetic?
Check urine for ketones. If present, patient has Type 1 and needs insulin treatment straightaway. If not, then it is type 2 and they need a lifestyle and diet change first.
What is HbA1c?
Proportion of Hb with glucose
Average blood glucose (sugar) levels for the last two to three months.
How much HbA1c is diagnostic of Type 2 diabetes?
> 48.0 (6.5%) mmol/mol
What are the HbA1c levels of someone who is pre diabetic?
42 – 47 mmol/mol
Name the features which make you susceptible to diabetes
- Overweight
- Hypertension
- Over 40
- Previous gestational diabetes
- Vascular disease (disease in blood vessels)
- Pre diabetic states
Describe the oral glucose tolerance test (OGTT)
Fast beforehand
Blood taken
Patient drinks 75g of glucose
Blood taken every 60 minutes after
What do we use the OGTT for?
To test for gestational diabetes
What’s the criteria for having Impaired Glucose Tolerance?
11.1 mmol/L < Blood glucose < 7.8 mmol/L at 120 minutes
AND
need to have taken the tolerance test
What are the microvascular diseases of diabetes?
Retinopathy
Erectile Dysfunction
Nephropathy
Neuropathy
Why does diabetes lead to blood vessel damage?
Patients that are diabetic are usually overweight, have a family history, have hypertension etc.
What is Peripheral Artery Disease (PAD)?
Arteries outside of brain and heart are blocked with fatty deposits.
Name the cardiovascular complications with diabetes
Stroke Cardiovascular Disease Peripheral Vascular Disease Low/poor circulation Hypertension
What is the criteria for Impaired Fasting Glycaemia (IFG)?
Fasting glucose is higher than 6.1 mmol/L but lower than 7.0 mmol/L
What is the next stage if a patient has IFG or IGT?
Measure HbA1c
A woman with gestational diabetes will have a fasting glucose of…
5.6mmol/litre or above
A woman with gestational diabetes will have a 2 hour glucose level of…
7.8mmol/litre or above.
Describe the process of Oxidative Decarboxylation (OD)
Pyruvate enters mitochondria
Binds with CoA and NAD+ to form Acetyl CoA, CO2 and NADH.
Which enzyme catalyses Oxidative Decarboxylation?
Pyruvate dehydrogenase complex
PDH
What is the role of PDH Kinase?
Inhibits PDH when ATP levels are too high
What is the mechanism when ATP levels are too low in cells?
PDH Phosphatase activates PDH by removing a phosphate group.
How is Oxidative Decarboxylation stimulated in skeletal muscle?
The increasing number of Ca+ ions stimulates OD.
What is produced in the Krebs cycle?
3 x NADH, 1 x FADH2, 1 x GTP, 2 x Acetyl CoA (for every one glucose).
How can we make ATP in Krebs cycle?
Through Oxidative Phosphorylation (OP) or Substrate Phosphorylation
*OP is more common
What is Oxidative Phosphorylation?
Electron donation from NADH and FADH2 to O2 via the electron transport chain.
Where does the Krebs cycle take place?
Mitochondrial Matrix
What is Substrate Phosphorylation?
GTP transfers phosphate group onto ADP, producing ATP and GDP
What is the function of the Krebs cycle?
To produce energy to fuel production of ATP
Name the complexes involved in the electron transport chain
Complex I - NADH dehydrogenase Complex II - Succinate dehydrogenase Complex III - Cytochrome bc1 Complex IV - Cytochrome C oxidase Complex V - ATP Synthase
Describe the movement of an electron on NADH in the electron transport chain
- Complex I
- Co Enzyme Q
- Complex III
- Cytochrome C
- Complex IV
- O2
- H2O formed in process and proton gradient established
Describe the movement of an electron on FADH2 in the electron transport chain
- Complex II
- Co Enzyme Q
- Complex III
- Cytochrome C
- Complex IV
- O2
- H2O formed and proton gradient maintained
What is Type 1 Diabetes?
Condition where there is a lack of/ no insulin.
What is the Proton Motive Force (PMF)?
When electron transfer is coupled to the transport of protons across the inner membrane of the mitochondria.
How does the movement of protons aid the production of ATP?
A high concentration of protons in matrix
Protons move through Complex V
Enzyme can add phosphate to ADP
= ATP
What is the theoretical yield of ATP from ATP production?
36 ATP
NADH and FADH2 are strong electron…
donors
O2 is a strong electron…
acceptor
The Krebs cycle is an anaerobic pathway. True/False?
False
It is an aerobic pathway, and requires O2.
The Krebs cycle is stimulated by…
Ca+ and ADP
The Krebs cycle is inhibited by…
NADH and ATP
What substances inhibit the electron transport chain?
CO
CN-
Oligomycin
Dinitriphenol
CO and CN- stops the movement of electrons through Complex IV to O2. True/False?
True
This stops ATP production and leads to cell death
Oligomycin stops the movement of electrons from Cytochrome C to Complex IV. True/False?
False
Oligomycin stops electrons moving through Complex v
How does Dinitriphenol stop ATP production?
It acts as an uncoupling chemical.
Protons pass the inner membrane and bypass Complex V = no ATP production
How do uncoupling proteins work?
Create proton leak in inner membrane
Uncouple proton gradient
Protons bypass complex V
= no ATP
What are Brown Adipocytes?
‘Good’ fats, important in neonates
What is non shivering thermogenesis?
When UCP1/Thermogenin creates heat in Brown Adipocytes (a sympathetic response).
What are the risk factors for diabetes?
obesity old age family history of diabetes gestational diabetes low exercise levels, hypertension depression polycystic ovary syndrome Ethnic backgrounds which are at an increased risk of diabetes include Africans, Native Americans, Southern Asians, Pacific Islanders and South Americans.
What is a side affect of Metformin?
Gastrointestinal upset
Ketogenesis occurs in type 1 and type 2 diabetes. True/False?
False
Am absence of insulin is required for ketogenesis, therefore it only occurs in Type 1.
What is Glycolysis?
Break down of Glucose into Pyruvate, which is later used for ATP.
What is Glycogenesis?
Process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage.
What is Gluconeogenesis?
Production of glucose from non-carbohydrates, such as lactate, glycerol, and glucogenic amino acids.
What is protein production?
Replenishment of cellular proteins
What is protein breakdown?
Breakdown of skeletal muscle
What is cellular glucose uptake?
Glucose in blood
Insulin produced and stimulates GLUT2 transporter in the liver and GLUT4 transporter in the adipocytes
What is ketogenesis?
Ketones produced from the products of fatty acid breakdown
What is TAG production?
Triacylglycerides (fat stores in adipocytes) made from fatty acids and glycerol. What happens when there is an excess of glucose.
What is Lipolysis?
Breakdown of TAG’s into fatty acids and glycerol.
Name the three sources of energy from diet
Protein
Carbohydrates
Fat
What is the calorific value?
The energy in the form of ATP produced after oxidation
Give the main energy stores and their weight within a 70kg male
Fat - 15kg
Protein - 6kg
Liver glycogen - 0.1kg
Glycogen is a polymer of Glucose. True/False?
True
What is Liver Glycogen used for?
To maintain blood glucose in between meals.
What is Muscle Glycogen used for?
Provides energy rapidly during exercise e.g. sprinting requires glycogen
Muscle Glycogen is broken down into glucose and transported all over the body. True/False?
False
Stays in the muscle and is not released into the bloodstream.
Fats are stored in adipose tissue. What are they stored as?
TAGs
*Triacylglycerides
What are the products of TAG breakdown?
Glycerol and fatty acids
Glycerol is converted into Glucose via…
Gluconeogenesis
What are fatty acids used for?
- Oxidised to make energy
- Converted to ketone bodies in the liver
All amino acids can be used to make energy. True/False?
False
Glucogenic amino acids can be used to make glucose
Skeletal muscle is broken down rapidly during the fasting period, while it is broken down slowly after the initial fasting period.
True/False?
True
What is the danger of losing proteins in starvation?
Malfunction of vital organs
What is important in being able to survive a prolonged fast?
Switching from different energy/fuel sources
Describe the body’s source of energy from eating a meal to starvation
- Diet (exogenous)
- Glycogen in Liver
- Products of TAG and protein breakdown (gluconeogenesis)
The brain uses ___ as energy in the fed state.
Glucose
What does the brain use as energy in the fasting state?
- Amino acids
- Ketone Bodies
- Glucose
Which ketones does the brain use in the fasting state?
- Acetoacetate
- 3-Hydroxybutyrate
Where is 3-hydroxybutyrate produced?
Liver
Describe the steps glucose undergoes in the liver in the fed state
-Absorbed
-Undergoes Glycolysis and is converted to Glucose 6-P then finally Pyruvate
-Pyruvate undergoes Oxidative Decarboxylation to produce Acetyl CoA
-Acetyl CoA undergoes fatty acid synthesis to become a TAG
-TAG becomes a VLDL
-VLDL transported to Adipocytes
OR
-Glucose undergoes Glycogenesis and is converted into Glycogen
Describe the steps of glucose in the skeletal muscle during the fed state
-Glucose absorbed via the GLUT4 transporter
-Undergoes Glycolysis and is converted into energy
OR
-Undergoes Glycogenesis and is converted into Glycogen
Describe the steps of glucose in the adipocytes during the fed state
-Glucose absorbed via GLUT4 transporter
-Undergoes Glycolysis and is converted into Pyruvate
-Pyruvate undergoes OD and becomes Acetyl CoA
-Acetyl CoA undergoes FA synthesis and becomes a FA
-FA converted to TAG
-TAG
Also during this, VLDL’s from liver enter and are converted back to TAGs
Describe what happens in the brain during the fed state
-Glucose is absorbed and undergoes Glycolysis to be used as energy
Where is glucose first absorbed in the fed state?
Intestine
During fasting, insulin levels decrease whereas Glucagon increases. This is vice versa during fed state. True/False?
True
Describe what happens in the liver during the fasting state
-Glycogen undergoes Glycogenolysis and becomes Glucose 6-P
-Glucose 6-P undergoes Gluconeogenesis and becomes Glucose
Also,
-Glycerol from TAG breakdown in Adipocytes enter Liver
-These are precursors for Gluconeogenesis, enter liver, become pyruvate and then form Glucose
Describe what happens in the skeletal muscle during the fasting state
-Gylcogen broken down in Glycogenolysis to form Glucose
-Glucose undergoes Glycolysis to form energy
Also, during starvation
-Proteolysis occurs, and amino acids are produced
-Amino acids are gluconeogenic precursors, go to liver and become pyruvate, then glucose.
What are chylomicrons?
Lipoprotein particles which carry fats from the intestine to the liver and adipocytes.
The glucose and ketone bodies produced by the liver are used only by the liver. True/False?
False, they are also used by other tissues.
What happens to fatty acids after TAG breakdown?
- Undergo beta oxidation and provide energy tissues
- Go to liver, become Acetyl CoA, then ketone bodies and then provide tissues with energy
The brain does not use fatty acids for energy. True/False?
True
What happens in the brain during the fasting?
Glucose absorbed from the liver
Undergoes glycolysis and is converted into energy
The liver produces and uses ketone bodies for energy. True/False?
False
Does produce, but does not use, only distributes.
How are ketones used in extra hepatic tissues (tissues surrounding liver)?
- Ketones enter mitochondria
- Converted into ATP during Krebs cycle
What are markers for ketones in the body?
- Ketones in urine
- Acetone in breath (pear drop smell)
What ketones are produced in ketogenesis?
- 3-Hydroxybutyrate (major)
- Acetoacetate
- Acetone (not used)
What ketones are produced in ketogenesis?
- 3-Hydroxybutyrate (major)
- Acetoacetate
- Acetone (not used)
What happens in the adipocyte during fasting?
-TAGs undergo lipolysis and form fatty acids and Glycerol
What is Glycogenesis (production of Glycogen) stimulated by?
Insulin
What is Glycogenolysis (degradation of Glycogen) stimulated by?
Glucagon
Describe the steps of Glucose to Glycogen
mention enzymes
-Glucose
-Glucose 6-P
(Phosphoglucomutase)
-Glucose 1-P
(UDP-glucose Pyrophosphorylase)
-UDP-Glucose
(Glycogen synthase)
-Gycogen
Describe the steps go Glycogen to Glucose
-Glycogen (Glycogen phosphorylase) -Glucose 1-P -Glucose 6-P -Glucose
How do Insulin and Glycogen Synthase work together?
- Insulin promotes dephosphorylation of Glycogen Synthase
- Glycogen Synthase is activated
- Can now convert Glycogen from Glucose
How do Glucagon and Glycogen Phosphorylase work together?
- Glucagon promotes phosphorylation of Glycogen Phosphorylation
- Is now active
- Glycogen is broken down
What are the substrates of Gluconeogenesis?
Oxaloacetate
Glycerol
Lactate
In cells, where does gluconeogenesis happen?
cytosol and mitochondria
liver mainly
Gluconeogenesis requires energy to happen. Where does this energy come from?
FA oxidation
Where are fatty acids synthesised?
In the cytosol of adipocytes and liver
What is Acetyl CoA carboxylase and what does it do?
Enzyme
Carboxylates excess Acetyl CoA into malonyl CoA (3 carbons), needed later in FA synthesis
How is Acetyl CoA carboxylase regulated?
- Activated by insulin and citrate (excess energy)
- Deactivated by fatty acids (end product of fa synthesis, feedback mechanism)
Where does the reducing power for fatty acid synthesis come from?
2 NADPH
Excess Acetyl Coa and malonyl CoA bind together in the presence of ___ to form ___
- FA Synthase, 2 NADPH
- 4 Carbon FA
* CO2, H2O, 2NADP+, 2CoA
How many molecules of NADP+ are there in total by the time Palmitic Acid is formed?
14
What are TAGs made of?
1 Glycerol, 3 Fatty Acids
Draw a TAG
Glycerol backbone with 3 FA’s attached to O groups
Which enzyme is involved in lipolysis?
Hormone Sensitive Lipase (HSL)
HSL is activated by…
Epinephrine, Norepinephrine from sympathetic nerve endings
Also by Glucagon
Name all the types of fatty acids (based on length)
VLCFA (>22 Carbons)
LCFA ( 12-22 Carbons)
MCFA (6>12Carbons)
SCFA (<6 Carbons)
What happens to glycerol after TAG breakdown?
Transported to liver for Gluconeogenesis
What happens to FAs after TAG breakdown?
Released into blood, bind to plasma albumin transported and enter cells. Oxidised to make energy, or gone to liver to make Acetyl CoA then ketone bodies.
Where is insulin produced?
Beta cells in Pancreas
Where is Glucagon produced?
Alpha cells in Pancreas