Insulin Synthesis, secretion and action

Question 1

what is the only way in which the organism can reduce blood glucose concentration?

Answer 1

insulin secretion

Question 2

What cells produce insulin?

Answer 2

beta islet cells of pancreas

Question 3

what is the term for excessive secretion of insulin?

Answer 3

hypoglycemia

Question 4

What is the primary function of the beta cell?

Answer 4

production, storage, and regulation of secretion of insulin

Question 5

Glucagon is produced by what cells?

Answer 5

alpha cells

Question 6

normal adult pancrease contains how many islets of langerhans?

Answer 6

1 million islets

Question 7

what percent of the pancreas mass is made up of the islet of langerhans?

Answer 7

1-2%

Question 8

Under what circumstances do islets of langerhans grow above average in size?

Answer 8

When the body becomes resistant to Insulin - more is made causing the islets to grow

Question 9

where are islets mos dense in the body?

Answer 9

most densely in the tail of the parenchyma

Question 10

do some beta cells exist outside of the islets?

Answer 10

Yes! They are not ALL in the islet

Question 11

Describe the artery system of the islets

Answer 11

• 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)

Question 12

beef insulin differes from human insulin by what degree?

Answer 12

by 2 amino acids

Question 13

two insulin AA chains are linked by what?

Answer 13

by disulfide bridges

Question 14

insulin is synthesized from what precursor?

Answer 14

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

Question 15

where is the pre-proinsulin synthesized?

Answer 15

it is synthesized in the ER of the beta cell

Question 16

what factors increase the biosynthesis of insulin?

Answer 16

• glucose
• leucine
• pyruvate
• inosine, guanosine and adenosine
• ribose
• glucagon
• pregnancy

Question 17

what factors decrease insulin?

Answer 17

• epinephrine
• starvation
• aging

Question 18

what is the half life of insulin?

Answer 18

5 min

Question 19

what percent of insulin is degraded by the liver and kidneys?

Answer 19

80%

Question 20

how do we divide the effects of insulin?

Answer 20

rapid, intermediate, and delayed (those that involve gene transcription etc)

Question 21

describe the rapid effects of insulin

Answer 21

–Increased transport of glucose, AA and Potassium into cells (which is why you need to closely monitor potassium when giving insulin)

Question 22

what are the intermediate effects of insulin?

Answer 22

–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)

Question 23

what is the GENERAL effect of insulin?

Answer 23

Storage of precursors for energy utilization

Question 24

are glucose molecules easily transported across membranes?

Answer 24

no, they require transporters (some tissues do not have these- therefore they do not take up glucose at all)

Question 25

does all tissue require insulin to transport glucose?

Answer 25

no, the brain doesn't require insulin to take up glucose as well as the ## Footnote •Tissues where insulin does not facilitate glucose uptake • –Brain –Kidney tubules –Intestinal mucosa –Erythrocytes

Question 26

what is the rate limiting step of glycolysis?

Answer 26

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

Question 27

are people with decreased levels of glucokinase able to secrete as much insulin in response to high glucose?

Answer 27

no ## Footnote * 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”

Question 28

what transporter is necessory for insulin transport in skeletal muscle and adipose ?

Answer 28

the GLUT4 transporter

Question 29

If you need a regular insulin injection, where do you give the injeciton?

Answer 29

subcutaneously b/c it's given much slower this way

Question 30

what are some other effects of insulin other than glucose transport?

Answer 30

* •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

Question 31

what effect does insulin have on glucagon?

Answer 31

increased insulin leads to decreased glucagon

Question 32

do mothers with high blood pressure have large or small babies?

Answer 32

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

Question 33

insulin receptor is what kind of receptor?

Answer 33

tyrosine kinase receptor

Question 34

describe how the insulin receptor works

Answer 34

* 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

Question 35

high insulin has what efffect on the number of insulin receptors?

Answer 35

high insulin downregulates receptor number and low insulin increases affinity of receptor

Question 36

in what state are the number of insulin receptors per cell increased? Decreased?

Answer 36

•Number of receptors per cell is increased in starvation and decreased in obesity and acromegaly

Question 37

what condition increases insulin receptor affinity? how about decreases?

Answer 37

•Receptor affinity is increased in adrenal insufficiency and decreased by excess glucocorticoids

Question 38

how much insulin is secreted in the basal state?

Answer 38

•about 1 unit per hour

Question 39

how does insulin concentration change after a meal?

Answer 39

•There is a 5-10-fold increase following meals

Question 40

if not released, what happens to insulin?

Answer 40

•If not released, insulin is degraded by fusion of lysosomes with insulin granules (crinophagy)

Question 41

what comprises the first and second phase of insulin release?

Answer 41

phase 1= high peak in insulin secretion, mobilized to outside of the cell phase 2 - steady insulin secretion making a reserve pool

Question 42

What is the glucose transporter in the beta cell?

Answer 42

GLUT2 (not GLUT 4 like everywhere else)

Question 43

beta cell depolarizes, what is the response?

Answer 43

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 \*

Question 44

sulfonylurea receptors are targeted in the treatement of what disease?

Answer 44

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

Question 45

what levels can insuln secretion be modulated?

Answer 45

**•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

Question 46

what factors stimulate insulin secretion ?

Answer 46

**•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)**

Question 47

what mechanisms inhibit insulin release?

Answer 47

* 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

Question 48

What factors inhibit insulin secretion?

Answer 48

**•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**