case 6 - glucose and insulin physiology Flashcards
where is delivery of glucose critical to
the CNS - it cannot substitute glucose
what is the stored reservoir of glucose
glycogen
what is normoglycaemia
4-6mmol/L
8mmol/L post-prandial (2 hrs after eating)
what is hypoglycaemia
<3mmol/L
what is hyperglycaemia
> 10mmol/L
what decreases blood glucose
glucose utilisation
energy expenditure
glucose loss <0.3g/day
what increases blood glucose
food intake - 160g/day
glucose uptake
glucose production
glucose reabsorption
what is insulin secreted by
the beta cells which are situated in the islets of Langerhans in the endocrine pancreas
what does insulin serve to do
decrease blood glucose levelds
what is glucagon secreted by
the alpha cells in the islets of langerhans
what is glucagon secreted in response to
low glucose levels and increase blood glucose levels
what are the glucagon sensitive tissues
liver
fat (adipocytes)
muscle
what are the insulin sensitive tissues
liver
fat (adipocytes)
muscle
what happens to our glucose levels when we have fasted
they are often quite low
what does low glucose levels trigger
the release of glucagon from the alpha cells
what also happens at low glucose levels
beta cells are not stimulated
what happens once the glucagon is released
it will act upon the liver to stimulate endogenous glucose production from its glycogen stores
where does this glucose go
into the blood stream
what are glucose levels like in the fed state and what does this stimulate
relatively high glucose levels, this stimulates the beta cells
what do these beta cells do
they secrete insulin
what does this insulin do
turns off glucagon production
acts on muscle and fat to increase their uptake of glucose - thus lowering blood glucose levels
it also acts upon the liver to switch of endogenous glucose production
what else happens when we are in the fed state
there are endocrine cells located within the small and large intestine called enteroednocrine cells and they are stimulated to produce hormones
what is the main hormone they produce and wha does it do
they produce GLP1. it is secreted in response to glucose load. it is an incretin hormone. GLP1 receptors are on the beta cells and this stimulated insulin secretion
what is T1DM
autoimmune destruction of beta cells
what is T2DM
defects in insulin release, sensing and/or signalling
what is common in patients with diabetes receiving insulin
hypoglycaemia is common and there is a huge lack of awareness of it
what is hyperinsulinism caused by
congenital defects in insulin release or insulin signalling
insulinoma
pancreatic tumours can produce too much insulin too - insulinomas
what are the main transporters in glucose homeostasis
passive glucose transporters - GLUTs
sodium coupled/linked transporters - SGLTs
what are the SGLTs
family of insulin insensitive transporters
what are the two important SGLTs
Two are important:
- SGLT1 (SLC5A1) (2 sodiums per 1 glucose molecule per transport)
- SGLT2 (SLC5A2) (uniporter)
what transporter has the highest affinity for glucose
SLGT2
can SGLT inhibitors be used to treat diabetes
are approved for mono- and combination therapy of T2DM
what mutations cause glucose-galactose malabsorption
SLC5A1
what mutations cause familial glucosuria
SLC5A2
what passive transporters have major functional roles
GLUT1, GLUT2, GLUT4
which of these are insulin insensitive
GLUT1 and GLUT2 are insulin insensitive ; critical to glucose absorption and glucose signalling
what are some features of GLUT4
it is insulin sensitive
found in adipose tissues, striated muscle and heart
what are the Km values of the GLUTs
GLUT 4 and GLUT1 have similar Km for glucose (approx 5mM), lower than GLUT2 (17mM)
how many transporters are in the GLUT family
13
what do the GLUTs do
not only take glucose into the cell but also out of it aswell
how does SGLT1 take glucose into the cell
takes glucose into the cells across the membrane by using 2 sodium ions
how does glucose leave the enterocyte
via the passive transporters GLUT2
what happens next to the glucose
it goes into the blood stream and goes into erythrocytes using the GLUT1 transporters
what happens in the early primal tubule
in the early primal tubule >90% of glucose is absorbed by SGLT2
what happens in the late proximal tubule
In the late proximal tubule, almost all of the remaining glucose os absorbed by SGLT1
in healthy conditions, how much filtered glucose is reabsorbed
> 99%
what happens in people with diabetes to this level
the absorptive capacity of glucose transporters is overwhelmed in people with diabetes
what do SGLT2 inhibitors promote
insulin loss and are used as diabetes therapy, pass out much more glucose in the urine
what are two different diabetes therapy
K channel inhibitor
enhance insulin secreiton
describe the uptake of glucose into the beta cells
Uptake via the GLUT1 and GLUT2
Metabolism
Leads to generation of signalling molecules such as ATP which stimulates the closure of potassium channels - located within the cell membrane
When these potassium channels are closed, this leads to depolarisation of the beta cell which leads to an influx of sodium and calcium into the cell via calcium channels
This influx of calcium leads to exocytosis - insulin release from the beta cell and into the blood stream
what is the class of drugs used to counteract this
sulphinurias
describe the GLP-1 mediated insulin release cascade
Activation of GLP-1 receptor
G protein stimulation
Stimulation of adenylate cyclase
Elevation of cAMP
Exocytosis
Activation of PKA and Epac2
what diabetes therapies are used for this
incretin minetics
enhance insulin secretion
what is the mechanism of action of the beta cells
Uptake
Metabolism
K ATP channel closure
Activation of GLP1 receptor
G protein stimulation
Stimulation of adenylate cyclase
Elevation of cAMP
Exocytosis
Activation of PKA and Epac2
Insulin release
describe the process of insulin sensitive glucose transport
GLUT 4 :
Insulin binding to receptors
Tyrosine kinase actiivation
Signalling molecules: PRS, P13K, PDK1, AKT, AS160 etc
Translocate GLUT4 transporters
Glucose uptake
what therapies are given for this signalling pathway
enhance insulin signalling e.g metformin
where are the immediate effects of insulin
in the cytoplasm
what does lower insulin lead to
increase glucose production and lowered peripheral glucose uptake
this leads to hyperglycaemia
what is the short term complications of hyperglycaemia
Glucosuria leading to dehydration, polydipsia, osmotic diuresis
This short term problem leads to ketoacidosis
what are the long term effects of hyperglycaemia
leads to diabetes complications
where does glucotoxicity take place
capillary endothelial cells; mesangial cells; neurones and Schwann cells in peripheral nerve
