Insulin Synthesis, secretion and action Flashcards
what is the only way in which the organism can reduce blood glucose concentration?
insulin secretion
What cells produce insulin?
beta islet cells of pancreas
what is the term for excessive secretion of insulin?
hypoglycemia
What is the primary function of the beta cell?
production, storage, and regulation of secretion of insulin
Glucagon is produced by what cells?
alpha cells
normal adult pancrease contains how many islets of langerhans?
1 million islets
what percent of the pancreas mass is made up of the islet of langerhans?
1-2%
Under what circumstances do islets of langerhans grow above average in size?
When the body becomes resistant to Insulin - more is made causing the islets to grow
where are islets mos dense in the body?
most densely in the tail of the parenchyma
do some beta cells exist outside of the islets?
Yes! They are not ALL in the islet
Describe the artery system of the islets
- Arterioles branch to form capillaries which form a tortuous complex which first supplies beta cells and then alpha cells
- Blood draining from islet enters the pancreatic vein and then the portal vein (first stop is the liver)
beef insulin differes from human insulin by what degree?
by 2 amino acids
two insulin AA chains are linked by what?
by disulfide bridges
insulin is synthesized from what precursor?
proinsulin - which is then broken down into insulin, and there is a C-peptide also broken off of it
granules full of insulin/C-peptide are trafficed to cell surface and insulin is exocytosed
where is the pre-proinsulin synthesized?
it is synthesized in the ER of the beta cell
what factors increase the biosynthesis of insulin?
- glucose
- leucine
- pyruvate
- inosine, guanosine and adenosine
- ribose
- glucagon
- pregnancy
what factors decrease insulin?
- epinephrine
- starvation
- aging
what is the half life of insulin?
5 min
what percent of insulin is degraded by the liver and kidneys?
80%
how do we divide the effects of insulin?
rapid, intermediate, and delayed (those that involve gene transcription etc)
describe the rapid effects of insulin
–Increased transport of glucose, AA and Potassium into cells (which is why you need to closely monitor potassium when giving insulin)
what are the intermediate effects of insulin?
–Stimulation of protein synthesis (increased transport of amino acids into liver and muscle and increased number and translational efficiency of ribosomes)
–Inhibition of gluconeogenesis preserves amino acids for synthesis
–Inhibition of protein degradation,
–Activation of glycogen synthase (muscle and liver)
–Inhibition of phosphorylase and gluconeogenic enzymes
–Increased hexokinase and phosphofructokinase activity leads to increased glycolysis (muscle and adipose tissue)
what is the GENERAL effect of insulin?
Storage of precursors for energy utilization
are glucose molecules easily transported across membranes?
no, they require transporters (some tissues do not have these- therefore they do not take up glucose at all)
does all tissue require insulin to transport glucose?
no, the brain doesn’t require insulin to take up glucose as well as the
•Tissues where insulin does not facilitate glucose uptake
•
–Brain
–Kidney tubules
–Intestinal mucosa
–Erythrocytes
what is the rate limiting step of glycolysis?
glucokinase - Glucokinase activity determines the rate of flux through glycolysis in the b-cell, and therefore, plays a key role in generating the metabolic signal that controls insulin secretion
are people with decreased levels of glucokinase able to secrete as much insulin in response to high glucose?
no
- Glucokinase activity determines the rate of flux through glycolysis in the b-cell, and therefore, plays a key role in generating the metabolic signal that controls insulin secretion.
- Thus, people with decreased levels of glucokinase aren’t able to secrete as much insulin in response to their high blood glucose levels as normal people are. This results in “glucokinase diabetes”
what transporter is necessory for insulin transport in skeletal muscle and adipose ?
the GLUT4 transporter
If you need a regular insulin injection, where do you give the injeciton?
subcutaneously b/c it’s given much slower this way
what are some other effects of insulin other than glucose transport?
- •Increases activity of of the Na+-K+ ATPase in cell membrane and thus increases K+ uptake into cells
•Can be used to treat hyperkalemia (elevated serum K+ levels)
Can drop significantly with insulin treatment (eg diabetic ketoacidosis
what effect does insulin have on glucagon?
increased insulin leads to decreased glucagon
do mothers with high blood pressure have large or small babies?
they have big babies
- b/c mtohers with high blood sugar, the glucose crosses the membrane, babie’s pancreas takes up the glucose - very fat baby
insulin receptor is what kind of receptor?
tyrosine kinase receptor
describe how the insulin receptor works
- Both subunits are glycosylated
- The a subunit is extracellular and binds insulin
- The b subunit spans the membrane
- The intracellular end of b subunit contains the tyrosine kinase activity
- Binding of insulin triggers a change in the alpha subunit that enables ATP to bind to the beta subunit
- ATP binding stimulates the kinase activity of the b subunit producing autophosphorylation on tyrosine residues which is necessary for insulin to have its biological effects
- Phosphorylated receptor acts by phosphorylating and dephosphorylating signal proteins in the cell
- Serine and threonine residues
- Insulin receptor substrates
–IRS-1
–IRS-2
high insulin has what efffect on the number of insulin receptors?
high insulin downregulates receptor number and low insulin increases affinity of receptor
in what state are the number of insulin receptors per cell increased? Decreased?
•Number of receptors per cell is increased in starvation and decreased in obesity and acromegaly
what condition increases insulin receptor affinity? how about decreases?
•Receptor affinity is increased in adrenal insufficiency and decreased by excess glucocorticoids
how much insulin is secreted in the basal state?
•about 1 unit per hour
how does insulin concentration change after a meal?
•There is a 5-10-fold increase following meals
if not released, what happens to insulin?
•If not released, insulin is degraded by fusion of lysosomes with insulin granules (crinophagy)
what comprises the first and second phase of insulin release?
phase 1= high peak in insulin secretion, mobilized to outside of the cell
phase 2 - steady insulin secretion making a reserve pool
What is the glucose transporter in the beta cell?
GLUT2 (not GLUT 4 like everywhere else)
beta cell depolarizes, what is the response?
Calcium channels open, rising calcium inside of beta cells, calcium interacts with contractile proteins
calcium can also be released from within the ER doesn’t have to come from extracellularly
*either way they lead to insulin release *
sulfonylurea receptors are targeted in the treatement of what disease?
Type 2 diabetes - by binding to this receptor it closes the KATP channel and thus opens the calcium channels- cascade leads to release of insulin
what levels can insuln secretion be modulated?
•Ion channels that regulate calcium influx
–Protein kinase A
–Protein kinase C
•Influence on mobilization of intra-cellular calcium stores:
–IP3
–cAMP
•Modification of calcium sensitivity of contractile proteins involved in the secretory machinery
–Protein kinase A
–Protein kinase C
what factors stimulate insulin secretion ?
•Nutrient secretagogues
–Glucose
–Amino acids
–Ketoacids
–Fatty acids (at stimulatory glucose concentrations)
•Hormones
–Glucagon (? Relevance in vivo)
–Gastrin-releasing polypeptide (PLC)
–Pituitary adenylate cyclase-activating polypeptide (PACAP - cAMP)
–Vasoactive intestinal peptide (cAMP)
–Vasopressin
–Oxytocin
•Peptides
–ACTH
–GHRH
•Neurotransmitters
–Acetylcholine (parasympathetic innervation, blocked by atropine – M3 receptors)
•Incretin effect
–GLP-1 (cAMP)
–GIP (synthetic GIP is available and used to treat Typ2 diabet)
–(DPP IV inhibitors)
•cAMP (probably PKA activation).
•b-adrenergic stimulators (cAMP)
•Theophylline ( cAMP)
•Insulin secretatogue drugs (sulfonyl ureas)
•Purine nucleotides (ATP, ADP)
what mechanisms inhibit insulin release?
- Receptor linked to Adenylate cyclase by inhibitory G-proteins
- Opening of K channels, KATP or other K channels
- Direct inhibition of calcium channels
- Direct effect on exocytosis
What factors inhibit insulin secretion?
•Hormones
–Insulin
–Somatostatin (28 – released gut during absorption of fat rich meals. Somatostatin 14 released by d cells more important locally for glucagon inhibition)
•Peptides
–Islet amyloid polypeptide
–CRF
–ANP
•Neurotransmitters
–Epinephrine (adrenal medulla)
–Norepinephrine (sympathetic innervation, a adrenergic).
–Net effect of epinephrine and norepinephrine is usually inhibition unless in presence of a adrenergic blocking drugs )
•Adipocyte derived hormones
–Leptin (probably reduces cAMP)
•Galanin (found in some autonomic nerves, activates the KATP channels)
•b-adrenergic blocking drugs
•Diazoxide
•K+ depletion (Conn’s Syndrome)- interfers with potassium chan.
•Thiazide diuretic drugs (K+ depletion)
•Microtubule inhibitors - used to inhibit cell division in cancer, and can effect microtubules involved in insulin release
•Mannoheptulose/2-deoxyglucose
