PBL 1 : T1DM Flashcards
What is the Islet of Langerhans and what does it secrete?
Cluster of endocrine cells in the pancreas which secrete endocrine hormones
what do alpha cells secrete? where are they found? and how much secretion do they contribute ?
Glucagon
Found around outer edge
around 20%
What cells secrete insulin? Where are they found in the islet of Langerhans? how much secretion do they contribute?
Beta cells
Found in the middle
about 70%
what do delta cells secrete? how much secretion do they contribute ?
what do PP cells secrete and how much secretion do they contribute
Somatostatin
About 10%
secretes pancreatic polypeptide (2%)
What is insulin? Describe what it is made up of
Insulin is a polypeptide hormone
It consists of 2 short chains- alpha and beta linked by disulphide bonds
Describe the steps int he synthesis of insulin
Insulin is synthesised as a pro-hormone:
Insulin mRNA is translated as a single chain precursor called Preproinsulin
Signal sequence is cleaved off to generate Proinsulin
Endopeptidases cleave off the C-peptide to generate mature form of Insulin
what is also packaged into granules along with insulin?
C peptide
Describe the process of insulin release in response to post-prandial rise in glucose
1) Glucose enters the beta cells via GLUT2 transporter through facilitated diffusion
2) Glucose is then phosphorylated by glucokinase to generate glucose-6-phosphate, which is then metabolised via oxidative phosphorylation to produce ATP
3) Elevated ATP levels cause the ATP-dependant K+ channels to close, resulting in depolarisation (inside cell becomes more +ve since no K+ leaving)
4) Influx of Ca2+ ions into the cell via voltage-gates Ca channels
5) Ca2+ entry stimulates the vesicles containing insulin to fuse with plasma membrane and release insulin into the extracellular fluid by exocytosis.
which chemicals/factors stimulate insulin secretion?
Amino acids e.g. arginine and leucine Parasympathetic innervation sulfonylurea gastrointestinal tract peptides e.g. cholecystokinin Incretins
which chemicals/factors inhibit insulin secretion?
noradrenaline
sympathetic innervation
somatostatin
what happens to remaining insulin which is not taken up by receptors on target cells?
remaining insulin is degraded by the enzyme insulinase
where are insulin receptors primarily found?
found on most tissues but primarily located in the liver, striated muscle and adipocytes
Describe the binding of insulin to insulin receptors
The receptor is a tyrosine kinase which is made of 2 alpha and 2 beta units and phosphorylates itself.
When insulin binds to the extracellular alpha subunits, the beta subunits become activated and undergo a conformational change.
The Beta-subunit receptors auto phosphorylate themselves on tyrosine residues.
Receptor tyrosine kinase activity begins an intercellular cascade of phosphorylation:
o The phosphorylated receptor forms a complex with and phosphorylates Insulin Receptor Substrate-1 (IRS)
(cascade of phosphorylation occurs)
Eventually, this leads to translocation of GLUT4 transporters
is insulin an anabolic or catabolic hormone?
anabolic
Describe the actions of insulin - what it stimulates and inhibits
Stimulates:
• Glucose uptake (Muscle, adipocytes)
• Glycogen synthesis – (Muscle, liver)
• Fatty acid synthesis – glucose storage in form of lipids (Liver, adipocytes
Inhibits:
• Lipolysis – breakdown of lipids (adipose tissue)
• Gluconeogenesis – production of glucose from non-carbohydrate source
is glucagon an anabolic or catabolic hormone?
Catabolic hormone
describe the synthesis of glucagon and where it occurs
Glucagon is synthesised as preproglucagon which is proteolytically cleaved in the alpha cell to produce proglucagon and then glucagon.
where is the primary site of glucagon action in the body?
Liver
which chemicals/factors stimulate glucagon secretion?
Drop in blood glucose
Adrenaline
Amino acids
Parasympathetic and sympathetic innervation
which chemicals/factors inhibit glucagon secretion?
insulin
Somatostatin
Fatty acids
Ketones
what type of receptors are glucagon receptors? where are they mostly found?
GPCRs, in liver
describe the binding of glucagon to GPCR
Glucagon binds to GPCR and causes a conformational change which activates G protein
The G protein undergoes a conformational change which replaces GDP with a GTP
This causes the activation of adenylyl cyclase which goes onto make cAMP
cAMP acts as a second messenger to initiate a phosphorylation cascade
Describe the actions of glucagon
- Stimulates glycogenolysis (muscle, liver)
- Stimulates gluconeogenesis (liver)
- Enhances hepatic ketone production by promoting fatty acid conversion to ketone bodies (liver)
- Promotes lipolysis (adipose tissue)Inhibits glucose uptake (muscle)
• Inhibits glycolysis (muscle)
• Inhibits fatty acid synthesis (adipose tissue)
in response to which hormone do fatty acids and ketone levels increase?
Glucagon
what percentage of diabetes does T1DM account for?
10%
Describe the pathophysiology of T1DM
o In T1DM there is a genetic abnormality which causes a loss of self-tolerance among T cells which specifically target beta cell antigens.
o Loss of tolerance means these T cells can recruit other immune cells and coordinate a cell-mediated immune attack on beta cells.
o Losing beta cells means less insulin is made and glucose levels increase in blood
This results in autoimmune destruction of Beta-islet cells
what are the normal fasting blood glucose levels ?
below or equal to 6 mmol/l
What are Impaired fasting blood glucose levels ?
between 6.1 and 6.9 mmol/l
What are diabetic fasting blood glucose levels ?
above or equal to 7 mmol/l
An increased frequency of which HLA alleles is associated with T1DM?
DR3 and DR4
problems with which genetic component increase susceptibility to T1DM?
MHC on chromsome 6
List the risk factors of T1DM
Presence of other autoimmune diseases
Certain viruses
Environmental factors (COw’s milk, wheat proteins)
Insulin resistance (occurs transiently in puberty)
Increased age
Family history
what are the 3 main autoantibodies found in T1DM and which is most prevalent?
o GAD65 (Glutamic acid decarboxylase 65) – most prevalent o ICA (Islet Cell Antibody) o I-A2 (Insulinoma-associated antigen 2)
What are symptoms of T1DM?
thirst (polydipsia) increased urge to urinate (Polyuria) Tiredness Unintentional weight loss Wounds that don't heal/prone to infections
List the diagnostic tests for t1DM + explain them
o Fasting blood glucose test (blood test taken after fasting overnight)
o Oral glucose tolerance test (blood is taken after fasting overnight. Patient has sugary drink and blood sugar levels are tested 2 hours after drinking)
o Random blood glucose test (Blood sugar levels measured at any time of day)
o Haemoglobin A1C test -measures the average glucose level for the past three months. It measures what percentage of haemoglobin is coated with glucose.
What are the 2 main treatment options for T1DM?
Insulin injections
Insulin pumps
Describe what type of insulin a pump provides and the 2 types of pump treatments
provides rapid acting insulin through needle under the skin
Bolus = taken when you need to eat or to give a correction dose if glucose too high Basal = insulin is continually given throughout the day and night. Can be altered according to how active you are. (still rapid acting, just small amount)
What is someone with T1Dm at risk of if they take too much/little insulin or forget to eat/eat too much?
If a person takes too much insulin relative to their dietary intake, or if they forget to eat = dangerous hypoglycaemia.
If they take too little insulin, or eat too much, they can develop ketoacidosis
list the 3 acute complications of t1DM
hypoglycaemia
Hyperglycaemia
Diabetic Ketoacidosis
Describe the causes and treatments of hypoglycaemia
Due to: Low carbohydrate intake (e.g. missed meal) Unexpected exercise Insulin overdose Malabsorption
Treatment:
Keep a sugary snack close by in case they feel it coming on
Glucagon pen
Severe hypoglycaemia can result in a coma – this is treated with IV infusion of 5% dextrose and sugary drinks.
Describe the causes and treatments of hyperglycaemia
causes: Missed insulin High carbohydrate intake Stressed Have over treated hypoglycaemia
Treatment:
Drink plenty of sugar free drinks
Take extra insulin
Describe the causes and treatments of DKA
Due to:
Being ill from chest infection, flu, UTI
High blood sugar levels due to puberty/growth spurt
Not taking insulin
High blood sugar due to having your period
Surgery or an injury
Treatment: IV infusion of NaCl IV infusion of KCl IV glucose IV insulin
list the chronic complications of T1DM
retinopathy
peripheral neuropathy
nephropathy
Heart attack/CAD/stroke
