Diabetes-1 Flashcards
What must blood glucose levels be maintained at?
4-5mM all the time for the benefit of tissues that have an absolute requirement for glucose as an energy source
What cells/tissues rely solely on glucose as an energy source?
BThe brain where glucose is used to generate ATP to drive ion pumps that maintain ion gradients if blood glucose drops below 2Mm nerves start to malfunction causing seizures and even a coma
Red blood cells and immune cells also rely primarily on glucose
How do neurons obtain glucose?
They constitutively make use of the GLUT3 transport protein which rapidly transports glucose down a concentration gradient which is maintained through the actions of hexokinase which phosphorylates the taken up glucose
Where does glucose come from?
Dietary glucose is readily absorbed by the gut through the sodium linked glucose transport protein so that the glucose can enter the gut cell it is then passed onto the blood through the GLUT2 transporter
This however does not allow a stable supply of glucose as we are not constantly eating
Therefore some specialised body cells can produce glucose from glycerol and amino acids via gluconeogenesis however this process must be regulated to prevent the total depletion of fat stores and muscle therefore this is an emergency mechanism
How does uptake of glucose from the gut feed forward regulate metabolism?
Some specialised cells in the small intestine (L and K cells) produce hormones in response to changes in glucose being taken up and these are released into the portal vein and go on to profoundly affect glucose metabolism, these include hormones such as glucagon like peptides 1 and 2 and glucose dependent insulinotropic peptide
Glucose from the epithelial cells is also now in the portal veins which links directly to the liver but along the way passes the pancreas
The islets of the Langerhans in the pancreas play a key role in sensing the glucose as in low glucose the alpha cells produce and secrete glucagon while in high glucose the beta cells produce and secrete insulin
What are Incretins?
These are hormones that are important modulators of insulin secretion and only respond to glucose (rather than fructose) concentrations
They include glucagon like peotide 1 and glucose dependent insulinotropic peptide
What is glucagon-like peptide 1?
This is derived from the transcription product of the proglucagon gene it is produced by the epithelial L cells and secreted in response to nutrients it potentiates insulin secretion in beta cells and blocks glucagon secretion from alpha cells
The active forms is a 30 amino-acid peptide which binds to the GLP-1 receptor which is a GCPR coupled to GalphaS resulting in cAMP production
It has a half life of less than 2 minutes as there is rapid degradation by dipetidyl-peptidase-4 to produce the inactive GLP1 amide which has no affinity for the receptor
Promotion of B cell survival
Regulation of appetite
What is Glucose dependent insulinotropic peptide?
This was formerly known as gastric inhibitory peptide and potnetiaites insulin release it is secreted from K cells in the intestine is response to high glucose and binds to a specific GCPR in target tissues
What is proglucagon?
This is a non-functional peptide which can be broken up into the functional molecules glucagon and GLP 1 and 2
What are the different islets of Langerhans found in the pancreas?
Alpha which secretes glucagon
Beta which secretes Insulin
Delta which secretes somatostatin (capable of shutting down both insulin and glucagon secretion)
PP which produces pancreatic peptide
How is glucagon produced?
It is produced in alpha cells through the cleavage of proglucagon by prohormone convertase 2
How does the beta cell control insulin levels?
Insulin mRNA is expressed only in the beta cells of the pancreas
Expression of the insulin is controlled by a number of agents including extracellular level of glucose and insulin which act as signals to stimulate replenishment of insulin stores
The transcription factor PDX1 plays a key role in regulating insulin expression
Insulin is translated as a pre-prohormone in the endoplasmic recticulum and folds into a 3D shape with 3 disulphide bonds
After initial cleavage produces proinsulin this is then packaged into nascent secretory vesicles
This has very low biological activity and is activated by acidification of the vesicle which leads to activation of prohormone convertases
How are glucose levels sensed?
The Km of GLUT2 and glucokinase is above the physiological range as glucose concentration goes up the amount of glucose trapped in the cell as glucose-6-phosphate will increase not only due to the increase in the amount of substrate but also due to an increase in the rate at which the reaction proceeds
This results in an exponential increase in the flux of glucose to G6P, a huge increase in the glycolysis rate even with only small changes in extracellular glucose concentration
How does insulin perform its action?
The ability of this hormone to maintain glucose homeostasis depends on its effects on hepatic glucose metabolism and its ability to stimulate muscle and fats ability to uptake glucose
In the liver insulin shutdowns glycogenolysis and gluconeogenesis 80-90% of insulin mediated glucose disposal in the periphery is into muscle as they have the GLUT4 transporter which responds to insulin
Lipolysis is suppressed
VLDL secretion from the liver is temporarily suppressed
How does insulin signal?
The insulin receptor is an alpah2beta2 heterotetrameric receptor tyrosine kinase which is highly homologous to the IGF-1 receptor
Insulin binds to the alpha subunit on extracellular surface which activates tyrosine kinase activity in in the intracellular beta subunit
Insulin receptors are present at the highest levels in major insulin responsive tissues like liver, muscle and fat
Insulin phosphorylates IRS-1 on multiple tyrosines with many motifs capable of binding SH2 domain
An important molecule is the class-1 PI 3-kinase this blocks activation of this molecule blocks almost all of insulins effects on cells
