PBL 6 Flashcards
What are the 5 types of cell present in the islets of langerhans and what do they secrete?
Alpha cells - secrete glucagon Beta cells - secrete insulin Delta cells - secrete somatostatin Epsilon cells - secrete ghrelins PP cells - secrete pancreatic polypeptide
What is the function of pancreatic polypeptide?
Promotes GI fluid secretion
Promotes satiety signals (feeling full)
What effect does somatostatin have on insulin and glucagon?
It inhibits their secretions
What is the normal range for glucose levels in the body?
3.5 - 8.0mmol/L
Which transporter is responsible for glucose uptake in the brain?
GLUT-3
How is insulin synthesised from preprohormone?
Where is it packaged?
Preprohomrone is cleaved in the endoplasmic reticulum to form proinsulin
Proinsulin is further cleaved in the Golgi apparatus to form insulin
Packaged in secretory vesicle granules
How is insulin secreted in response to high glucose levels?
Glucose is taken into beta cells though GLUT2 transporters
Glucose is phosphorylated to glucose-6-phosphate
Glucose-6-phosphate is oxidised to form ATP
ATP inhibits the ATP sensitive K+ channels of the beta cell
This depolarises the beta cell membrane
Depolarisation of the cell opens voltage gated calcium channels
An influx of calcium stimulates the fusion of vesicles containing insulin with the cell membrane
Insulin is secreted by exocytosis
What effect does the action of noradrenaline have on insulin secretion?
It inhibits secretion of insulin
Apart from high glucose levels, what other factors can stimulate insulin secretion?
Amino acids
Incretins
Growth hormone
What is the plasma half life of unbound insulin?
6 minutes
What is the structure of the insulin receptor?
Four subunits held together by disulphide linkages:
Two alpha subunits - outside the membrane where insulin binds
Two beta subunits - lie inside the membrane and protrude into the cytoplasm
Where does insulin bind to on its receptor?
To the alpha subunits
What happens when insulin binds to its receptor?
Autophosphorylation of the intracellular beta subunits
This activates local tyrosine kinase
Tyrosine kinase causes phosphorylation of IRS
IRS signalling causes fusion of GLUT4 transport protein vesicles with cell membrane
This facilitates glucose uptake into the cell
What is the only organ in the body that doesn’t require insulin for glucose uptake?
The brain
How does citrate activate fatty acid synthesis?
By activation of acetyl coA carboxylase which converts acetyl coA to malonyl co A
How can insulin deficiency lead to the development of atherosclerosis?
In the absence of insulin, fat breakdown for energy is enhanced
Conversion of fatty acids into phospholipids and cholesterol
These are discharged into the blood as lipoproteins
These can lead to the development of atherosclerosis
What are the two incretins (gut hormones) released following a meal which stimulate insulin release
Glucagon like peptide (GLP-1)
Glucose dependant insulinotropic polypeptide (GIP)
What effect do incretins have on insulin release?
They promote insulin release
How does glucose reabsoption at the proximal tubule occur?
Na+K+ pump sets up sodium gradient at the basolateral membrane
Na+ brings glucose into cell via SGLT1/2
Glucose diffuses out at basolateral membrane through GLUT1/2
What are the typical acute symptoms of diabetes?
Polyuria
Thirst
Feeling very tired
Weight loss
What is the overall prevalence of type II diabetes in the UK?
2-3%
In which ethnicities is type II diabetes more likely?
South Asian
African
Caribbean
What happens in an oral glucose tolerance test?
You give the patient glucose and then measure glucose concentration 2 hours afterwards
What happens in a fasting plasma glucose test?
Patient doesn’t eat or drink anything but water for 8-10 hours
Why is measured glycated Hb a more accurate measure of glucose concentration?
Can get an overall picture of the last 3/4 months
What is the difference between type I and II diabetes?
Type I - inability to produce insulin
Type II - resistance to insulin
How do fatty acids lead to insulin resistance?
Fatty acid infusion into cells cause production of DAG
DAG activates protein kinase C in the presence of Ca2+
PKC causes phosphorylation of serines instead of tyrosines on IRS
This suppresses the action of IRS
How does beta cell dysfunction occur due to ERstess?
Beta cells componsate for insulin resistance by increased insulin secretion
This excess protein production can lead to ER stress
This leads to protein misfolding and stress signalling
This can lead to apoptosis and death of beta cells
What is polydipsia?
Thirst
How can diabetes cause neuropathy?
Excess sugar can damage the walls of capillaries that nourish nerves
This can cause tingling, numbness, burning or pain that usually beings at the tips of toes and fingers
How can diabetes cause diabetic retinopathy?
High sugar levels cause damage to the blood vessels of the retina
This can potentially lead to blindness
What is a balantis?
Why is it more common in diabetic patients?
Skin irritation on the head of the penis
High glucose on penis allows bacteria to multiply more
Diabetes patients have reduced immunity so are more prone to infections anyway
What is the major consequence of hypoglycaemia?
Cognitive impairment
Convulsions
Coma
What type of drug is metformin?
Biguanide (insulin sensitiser)
What is the mechanism of action of metformin?
Activates AMP-kinase
AMPK is involved in GLUT4 metabolism and fatty acid oxidation
Reduced hepatic glucose production
Increases insulin sensitivity
What are the disadvantages of metformin?
GI side effects (diarrhoea, abdominal cramping)
Vit B12 deficiency
What is PPAR-gama?
Peroxisome proliferator activated receptor
It is a nuclear hormone receptor - dimerises with retinoid X
Acts to induce transcription to increase the differentiation of adipocytes, so they go from a poorly differentiated state to fully differentiated state
This stimulates metabolism to take up and dispose of fat
This increases insulin receptor function
What kind of drug is pioglitazone?
A thizaolinedione
What is the mechanism of action of thizaolinediones?
They increase the action of PPAR-gamma
This reduces central adipose tissue -
Reduces hepatic glucose production
Increases insulin receptor function
What are the two classes of drugs which help to increase insulin sensitivity?
Biguanides (metformin)
Thizaolinediones
Give some examples of drugs used in type II diabetes which help to secrete insulin?
Sulphonylureas
Incretins (GLP-1 receptor agonist)
DPP4 inhibitors (increase GLP-1 levels)
What is the mechanism of action of sulfonylureas?
Bind to sulfonylurea receptor on beta cell membrane
Closes the ATP sensitive K+ channel
This depolarises the cell, promoting calcium influx
This is a signal for insulin release from vesicles
How is DDP-4 inhibitors used to treat type II diabetes?
DDP-4 is an inactivator of GLP-1
GLP-1 is an incretin hormone which activates insulin release
Therefore by inhibiting DDP-4 you can increase insulin release from beta cells
How are SGLT2 inhibitors used to treat diabetes?
They block SGLT2 which usually reabsorbs glucose at the proximal tubule in the kidney
More glucose is excreted
This lowers blood glucose levels
What BMI is classed as obese?
> 25
Name the different molecules that adipose tissues secretes?
Adiponectin (Acrp30) Interleukin 6 (IL-6) Resistin TNF-alpha Leptin
What is Leptin released in response to?
High concentrations of lipids
What effect does leptin have on the hypothalamus?
It inhibits the hypothalamus to inhibit the feeling of hunger (causes you to feel full)
Explain the concept of Neel’s Thrifty Genotype?
Genes that were once useful for storage of energy are now detrimental and can lead to obesity
Explain the concept of Barker and Hales Thrifty Phenotype?
Mistmatch to what the fetus experiences during development and to what they experience after brith
In fetus, mother is starving to the fetus is born to the wrong Production of a life of starvation
How does DNA methylation effect the transcription of genes?
Methylation suppresses transcription and therefore causes gene inactivation
How does histone acetylation effect genes?
Causes gene activation
How can microRNA effect genes?
Causes suppression of transcription
What are diabetogens and obesogens?
Compounds in the environment that disrupt gene expression which can lead to altered hormone control of weight
What is PDX-1?
A homeobox transcription factor which binds to insulin and activates it
What is a MODY gene?
A gene which has a defect causing beta cell dysfunction - leading to maturity onset diabetes of the young (MODY)
How is PDX-1 a MODY gene?
PDX-1 is a gene which can be methylated
This causes it to be knocked out
It therefore is no longer able to bind and activate insulin
This leads to a decrease in insulin and an increase in glucose
This can cause diabetes
What is orlistat and how does it work?
Orlisat is a weight management drug
It acts as a lipase inhibitor which reduces the absorption of fat from the diet
What is the major side effect of orlistat and why?
Steatorrhoea
Due to unabsorbed fats
What are the 3 types of bariatric surgery?
Gastric banding
Roux-en-Y gastric bypass
Sleeve gastrectomy
What happens in gastric banding?
A band is created in the stomach which limits the amount of food you can eat by making you feel full quicker
How is a gastric bypass carried out?
Pouch created connecting oesophagus to small intestine
What lifelong supplements must you have to take if you have a gastric band?
B12
Iron
Calcium
What is a sleeve gastrectomy?
Removal of the greater curvature of the stomach
This reduces the stomach to about 15% of original size
How can excess TNF-alpha lead to diabetes?
TNF-alpha has a direct effect on the insulin receptor
TNF-alpha causes insulin resistance
This leads to diabetes
What forces urine out of the kidneys into the ureters?
Pacemaker cells in renal calyces
