diabetes Flashcards
4 hormones involved in glucose homeostasis
Insulin
Glucagon
Adrenaline
Glucocorticoids ( esp cortisol )
Fasting vs fed state
Fed = insulin - glucose to glycogen Fasting = glucagon
insulin
Signals the fed state
Secreted in response to high blood glucose from B cells of the pancreas
Glucagon
Signals the fasting state
Secreted in response to low blood glucose from the alpha cells of the pancreas
Adrenalin
Secreted from adrenal medulla in response to low blood glucose an fear, stimualates fuel mobilisation, especially in muscle and adipose tissue
Glucocorticoids - cortisol
Secreted in response to stress and starvation
Long term effects on the expression of enzymes involved in fat and carb metabolism
HYDROPHOBIC - cross membranes
Hormones derived from cholesterol
Cortisol Aldosterone Testosterone Estrogen Progesterone
2 types of molecule interaction receptor
Cell surface receptors
Intracellular receptors
How do steroid hormones enter the cell
Transported in the blood bound to transporter proteins
Inside cell membrane. they bind to members of the nuclear receptor family
Nuclear receptor signal complexes bind specific DNA sequences and regulate gene expression
As these responses require protein synthesis, timescale is slow
Cortisol in central metabolism
Increases fuel supply
Released in response to stress
Stimulates breakdown of non essential muscle tissue into AA for GNG
stress adaptation
Elevates blood pressure, increases NA+ uptake by kidney
Increases expression of hormone sensitive lipase = triglyceride mobilisation
Cortisol acts on..
Liver, muscle and adipose tissue
synthesised in fasciculate
Prolonged cortisol …
LOOSES positive effect
Causes damage
Where are insulin, glucagon and other peptide hormones released from
PANCREAS
alpha cells - glucagon
beta cells- insulin
delta cells - somatostatin
What are the pancreatic cells that secrete insulin and glucagon
ISLETS OF LANGERHANS
Insulin function and formation
Lowers blood glucose synthesised as preproinsulin Signal sequence directs it to ER A and B peptides are linked by disulphide bonds and the proinsulin is cleaved twice by a protease INsulin - secretory vesicle
Glucagon, cortisol and adrenaline - blood glucose
RAISES
Secretory granules
Insulin released
2 phases of insulin secretin - BIPHASIC
1st phase = fusion of granules with plasma membrane
2nd phase = synthesis and translocation of granules to the membrane
Factors affecting insulin secretion
Adrenaline - inhibitory
Amino acids - stimulatory
fatty acids - stimulatory
How does insulin enter cells
Insulin binds to RTK coupled receptor, which activates RTK and auto phosphorylates tyrosines
Phosphorylated receptor can now bind IRS1 allowing PIP2 to be converted into PIP3 ( both embedded in membrane)
PIP3 activates PDK1 which activates Akt
akt activates responses - cells update glucose
Pip3
Can be cleaved to become IP3 and DAG - which are also second messengers
Insulin signalling pathway
Primary transduction relay Transduction and amplification Feedback Distribute Altered metabolism
Muscle cells and glucose
Have a low Km
if there’s high glucose conc and kM is lower - CANT UPTAKE
Muscle and adipose uptake of glucose
GLUT4 trasnporters in vesicles in cell
When insulin binds, Akt activates- vesicles fuse with plasma membrane
Rate of glucose uptake increase 15x more
How does glucose regulate insulin secretion from B cells
Glucose enters B cells via GLUT 2 transporter
Glycolysis leads to ATP increase
ATP binds to ATp gated k+ channels and they close, depolarising the plasma membrane
Triggers the opening of voltage gated ca2+ channel s
Increased cytosolic triggers more ca2+ release Fromm the ER and this wave of calcium inside the cell triggers insulin secretion by exocytosis
ATP gated K+ channels and diabetes
Aolfonylurea drugs such as tolbutamide bind to SUR1 subunits closing the K+ channel stimulating insulin release
Diazoxide opens the channel and is used to treat low blood pressure caused by pancreatic tutors over releasing insulin
Insulin binding activates
Glucose uptake Glycogen synthesis Glycolysis - PSK and PSK2 Pyruvate oxidation Fatty acid synthesis
Glucagon and adrenaline binds to ..
GPRCs on cell surface
Work via adenyl cyclase and cAMP
Activate glycogen breakdown
Glucagon acts on
Liver, adrenaline on muscle and adipose tissue
Adrenaline function
Stimulates glucagon secretion
Inhibits insulin secretion
Lactate formation
Fight or flight
Glucagon effect
Glycolysis inhibits Gluconeogenesis Protein and fatty acid synthesis inhibited Glycogen breakdown in liver Ketone body synthesis activated
2 types of diabetes
type I- can’t produce or secrete insulin, destruction of beta cells - insulin injection
type II- can’t respond to insulin - diet and drugs
Diagnosis of diabetes
Urine glucose analysis
Oral glucose tolerance test
Glycated haemoglobin
Measurement of plasma insulin
HOW DOES THE BRAIN respond to diabetes
Starving state
Body Assumes theres no glucose in the blood
Gluconeogenesis produces glucose for brain
Proteins are broken down and glycogenic aa yield glucose as fuel from brain.
NH3 – urea and excreted
Fatty acids produce acetyl CoA used for ketone body production
Acetone ( ketone body) exhaled
Conc of ketone bodies increases and compounds appear in the urine
Diabetes symptoms - both forms
Blood sugar elevated
Body tries to dilute glucose= excessive urine and thirst
TYPE I diabetes symptoms
Fat breakdown is accelerated which leads to high production of ketone bodies
Some of ketones are ketoacids which raise blood H+ leading to ketoacids
Bicarbonate buffering sustem is activated, leading to altered breathing
Acetone expelled via breath
Untreated diabetes leads to dramatic weight loss
What happens when blood sugar levels are elevated
Haemoglobin becomes glaciated
Compromises o2 delivery
Increases risk of CVD, renal failure and damage to blood vessels
Early symptoms of diabetes
Urination, thirst, blurred vision, fatigue, headache
Later symtoms od diabetes
Pear drop breath ( acetone) Nausea and vomiting Shortness of breath Dry mouth Abdominal pain Weakness Confusion Coma
Measuring blood glucose
Pinprick monitors
Urine test strips - shouldn’t be seen in urine if you’re well
mM concentrated
Oral glucose tolerance test
75g of glucose
See how the blood glucose conc changes
Starts at 5mm, then increases then reduces
Diabetic - higher than normal at rest, then goes increasingly higher, slowly slowly decreases
Impaired glucose tolerance
Increase then slow decrease
BETWEEN diabetes
Measuring insulin
Enzyme linked immunosorbent assay ( ELISA)
Insulin is an antigen
, coat surface of well with plasma sample , block unoccupied sites with non specific protein, incubate with primary antibody against antiegen and secondary antibody, add substrate, formation of coloured product = insulin , more yellow = more antibody = more insulin
