Endocrinology (4) - insulin and glucagon Flashcards
central regulated H regulates
anabolism - cell growth
catabolism - breakdown component for energy
in hunger - neurological changes
motor neurones - triggered - trembling
<40 = lethargy and <20 - permanent neurological damage
liver function
BG buffer system and ketone body formed - glycogen store, glycogenesis centre
largest store = muscle
2H work antagonistically e.g. insulin and glucagon
decrease BG = decrease insulin and increase glucagon
opposite when increase BG
fedstate
insulin dominate
glucose oxidised - stored as glycogen = fat and protein due to neurological trigger
fast state
glucagon dominate - increase glycogenolysis , gluconeogenesis
pathway - glycogen to glucose -
glycogen (glycogen phosphorylase) make 2 glucose
using ATP and going downstream
produce pyruvates which is modified by using CoA-SH and NAD+ -> NADH +CO2 to form acetyl CoA
citric acid cycle - TCA cycle - intermediates
burn out 2 C on acetyl CoA = Co2 and remove e- - energy
are induced and used for different functions as well
TCA cycle - from producing NADH
goes to e- transport chain = more ATP
TCA cycle - acetyl CoA from
breakdown of lipid as well
at low BG - triglyceride
broken down by adipocytes and FA - sent out to liver
oxidised = acetyl Co-A - transferred back into metabolism tissue
problem of acetyl Co-A
with CoA attached - liver cannot send out therefore broken down = acetoacetate - transferred
beta hydroxybutyrate is also produced and sent to tissues
take 2c in acetyl CoA put into acetoacetate and beta hydroxybutyrate
problem of acetone
cannot be used therefore excreted
so ketone bodies carried to metabolism tissues and reconvert acetoacetate and beta hydroxybutyrate back to acetyl-CoA put back to TCA
by product ketone body - not converted
acidic - COOH therefore dissociate = decrease pH
short term - very low BG - keto
lipid - converted to ketone bodies by liver - at normal ketosis
more energy with exception of acetone - excreted via urine/ breath
too much ketone - ketoacidosis - >7.1 - metabolic acidosis
forced by by keto diet - filter ketone out with water = osmotic diuresis
short term - too high BG
lose glucose in renal filtrate (reabsorbed) but too much (>180mg)
reabsorption overwhelmed and lost through urine = osmotic diuresis - denatured
long term - change in vascular cells
lining BV of endothelia - change ECM - it’s glycated (glucose + surface) = protein glycated
turnover> than normal - build up abnormal ECM - get cholesterol in deposited matrix = vascular disease
long term - increase in blood sugar - renal disease
different vascular disease - cardiac, renal fibrotic, retinal as retinal capillaries and peripheral vascular damage
all relates to same thing - abnormal , glycated ECM
how insulin in produced
as single preproprotein - cleaved C-peptide but A and B chains bind by disulphide bonds = mature insulin
beta cells for insulin secretion
consists of
has GLUT2 in membrane
high levels of ATP close it s gated K+ channels but Na - able to get in
effect membrane charge - more +ve
process of beta cells for insulin secretion as membrane charge becomes +ve
Ca2+ channel opens by cellular depolarisation - once charge becomes close to -30 millivolt (set point) - Ca+ allowed in cell and released from ER = insulin granule stored in vesicle - brought to cell surface and secreted
rapid insulin secretion - due to
GLUT2 use
monitoring amount of glucose in blood
need GLUT2 transporter for pathway to work and produce insulin
increase in insulin secretion caused by
increase BG, free FA and blood a.a.
gastrointestinal H - food ingested ( gastrin, cholecystokinin, secretin)
decrease in insulin secretion caused by
decrease BG - fasting
alpha-adrenergic activation - acute stress - low insulin save uptake for CNS
insulin receptor
class 2 RTKs - disulphide linked tetramer, remain together class 1 RTKs - come together on ligand binds
2alpha and 2beta subunits form ad function when insulin binds
heterotetramer
2 insulin bind to alpha subunits
2 beta subunits - brought together and kinase and auto phosphorylates each other - active autophosphorylation sites
kinase region and phosphorylates down stream molecules
effect of insulin signalling (output)
- v. rapid fusion of intracellular vacuoles with cell surface carry GLUT4 and a.a. transport in membrane
- activate intracellular E
- increase gene expression
fast transfer of glucose of a.a. transporters to membrane
modifying vesicles
insulin receptor activated - look for IRS-1 phosphorylase - binds to kinase in membrane - PI-3K take Pi(4,5)P2 and add phosphate - increase charge - kinase attachment (PDK-1) bind to PkB = vesicle modification has lots of intermediate step - can be amplified
some signalling cascade goes down to PkB - phosphorylation of GSK3
active - remain glycogen synthase alpha in active state - inactivating the activator
increase activity of glycogen synthase - store glycogen - muscle and liver cell
decrease activity of glycogen phosphorylation - decrease glycogen use
increase glucokinase, PFK-1, pyruvate dehydrogenase - use glucose - breakdown
IRS-1
insulin receptor S1
PI-3K
phospho-Inositol - 3-kinase
PkB
phosphokinase beta
increasing gene expression - slowest
kinase amplification chain - ERK
MAPK goes into nucleus and turns on transcription factor
results for carbohydrate from effects of insulin signalling
glucose used/stored, excess glycogen converted to FA
inhibits gluconeogenesis but glucose used as energy source/ store
results for protein from effects of insulin signalling
insulin works with growth H
increase protein formation and storage and uptake of a.a.
decrease breakdown
increase gene transcription/ translation - inhibiting protein catabolism - gluconeogenesis
results for lipid from effects of insulin signalling
excess glucose - convert to acetyl CoA to FA in liver
stops lipid breakdown - FA released as VLDL absorbed by adipocytes - inhibits H sensitive lipase - increase storage
glucagon - glucose agonist - alpha cells - glycaemia - increase blood sugar level
due to decrease in BG - its secretion
has BLUT1 - allow glucose in cell and broken down in TCA cycle = ATP
decrease in BG in glucagon-glucose agonist
decrease ATP:ADP ratio
K+ channel activated by ATP means
in terms of Ca2+ etc
decrease ATP - close channel but Na+ channel open due to depolarisation = increase polarity in membrane
voltage gated Ca2+ channel opens - Ca2+ enter = vesicles and H fuses with membrane - release glucagon into EC space into blood
glucagon function - amplification of making glucose
bind to G protein-linked receptor - splits and activated
alpha unit bind to adenyl cyclase - activated
=ATP convert to CAMP binds to Pka - activated
phosphorylase - cleaves glycogen = glucose-1 phosphate = glucose
highly amplified - 5-10 ug of glucagon = x2 BG in mins
glucagon causes
glycogenolysis and gluconeogenesis = increase BG - opposing insulin
increase a.a. uptake for energy
regulation of glucagon expression and release
decrease blood sugar
induce glucagon (ATP gated) - before meal
regulation of glucagon expression and release
increase blood sugar
inhibit glucagon expression - after meal
paradoxically - v. high serum a.a.
increase glucagon release = glucose
diabetes
failure of water reabsorption of kidney collecting duct
2 flavour - insipidus(no taste) and Meletus(sweet) - increase glucose and ketone body
2 forms - type 1 and 2 - both lack utilisation of glucose - mobilise of lipid and protein = energy
type 1 diabetes
lack insulin secretion due to AI destruction of beta cell
combo of genetic and environmental factor
type 2 diabetes
body cannot respond to insulin (non-insulin dependent)
osmotic diuresis
in adrenal diabetes and insulin failure
cause cushing’s disease or gestation diabetes
signs - high BG - >180mg/100ml
urine contains glucose - osmotic diuresis - polyuria - dehydration - increase thirst
use protein and lipids as metabolic fuels
increase appetite and wasting and metabolic acidosis
metabolic acidosis
lipid convert to ketone bodies
therefore more osmotic diuresis, acetone breath
fibrosis
long term hyperglycaemia - change in endothelial cell
ECM caused by glycation
= damage to peripheral nerve due to insufficient blood supply
signs of diseases
vascular damage, hypertension and cardiovascular disease
abnormal (glycation) matrix shown
laid down and cholesterol being placed in this
getting glycated protein cross linked ECM - break down - BV start packing up
eye - diabetic retinopathy
BV close up
BV pack and ulcer - in what tissue
peripheral tissue
if v. bad - lose limb
incidence / prevalence - type 1
1-30 new case
highest - Scandinavia
incidence / prevalence - type 2
3800000 in UK
