15. SWG Endocrine Exam 2: Pancreas Physiology - Bi (P900/IC)

Release of insulin occurs in two phases. What are these phases and what is each due to? Which one has a larger capacity?

*Early phase secretion*: The vesicles that are right up against the membrane *Late phase secretion*: The vesicles that need to travel to the membrane before getting released (LARGER CAPACITY, because you can only store so many vesicles by the membrane)

TEST: List the 4 major sites where glucose is used

1) Brain (top priority) 2) Muscle 3) Fat (stores) 4) Liver

Where are the 3 main sites of insulin clearance?

1) Liver - 50% 2) Kidney - 30% 3) Skeletal muscle - remainder

TEST: In terms of GLUCAGON secretion, list whether the following INHIBITS or STIMULATES it: 1) Glucose Defecit 2) Insulin 3) Somatostatin 4) Autonomic NS 5) Incretins 6) Amino acids 7) Free fatty acids and ketones

1) Stimulates 2) Inhibits 3) Inhibits 4) Stimulates 5) Inhibits 6) Stimulates 7) Inhibits

What are some major effects of insulin signal transduction?

1) glucose uptake 2) glycogen synthesis 3) protein synthesis 4) transcriptional upregulation

On which chromosome is the INSULIN gene?

11

What is the basic structure of insulin?

51 amino acids arranged as a TWO-chained molecule, connected by two disulfide bridges - A chain = 21 A.A. - B chain = 30 A.A.

ATP-dependent _____ channels also regulate insulin secretion, so that ____ depletion DECREASES insulin secretion. Why?

ATP-dependent POTASSIUM channels (K+) - K+ depletion results in HYPERPOLARIZATION of the cell, so that it can't open up Ca channels and you don't have enough Ca to cause vesicle fusion and thus no insulin release

Glucose stimulated insulin secretion (GSIS) exhibits a _________ pattern

BIPHASIC (high insulin early, then a drop, then a gradual rise in insulin as time moves on)

TEST: Why does exercising reduce total blood glucose levels?

Because exercise induces GLUT4 upregulation in muscle, as it is insulin INDEPENDENT!!

TEST: Where is C-peptide cleaved from? Via which enzymes? What is the significance of this C-peptide both biologically and clinically?

C-peptide cleaved from PRO-INSULIN via PCSK1 and PCSK2 endopeptidases Significance: - Biologically: Needed to keep STABLE conformation of pro-insulin for biological activity - Clinically: Marker to measure insulin production

TEST: What do we use to measure how much insulin we produce each day? Why can't we directly measure the insulin levels?

C-peptide! (one insulin produces one C-peptide!) Can't use insulin directly because: - Short half-life - Exogenous injections of insulin!

TEST: All stimulus-secretion coupling is ____-dependent

CALCIUM!

Preglucagon can exist in both ______ and _______ cells, but only in the pancreatic islet ________ cells can you actually produce glucagon

Can exist in both ALPHA and L cells, but only in the pancreatic ISLET ALPHA cells can you actually produce glucagon

Why do amino acids stimulate both insulin and glucagon secretion?

During evolution, amino acids are very rare (you don't get them as often). Whenever the body gets AA, which is needed by the body for protein synthesis, the body will stimulate BOTH insulin and glucagon - Insulin helps deposit the excess A.A. - Glucagon will release some of the stored glucose so you can replace the stores with A.A! So instead of using the energy directly from the A.A. which you are trying to save, glucagon allows you to use the stored up glucose!

What are the two divisions of the pancreas? How are they regulated?

EXOCRINE (80%) regulated by GI hormones *ENDOCRINE* (2%) regulated by nutrients, GI hormones, neural

TEST: Excess plasma glucose will stimulate pancreatic (beta/alpha) cells, while plasma glucose deficiency will stimulate pancreatic (beta/alpha) cells

Excess --> pancreatic BETA cells --> insulin Deficiency --> ALPHA cells --> glucagon

TRUE or FALSE: IGF-1 cannot act on insulin receptors

FALSE

What is the function of glucagon-like peptide, and where is it primarily produced?

Function: Potentiates insulin release and INHIBITS glucagon release Site: Intestine

What is believed to be the mechanism why insulin has a negative effect on glucagon?

GABA inhibitory NTs from the beta cells, diffusing to the alpha cells and inhibiting glucagon secretion

Glucose, besides under the regulation of insulin, is also under the control of __________ and ___________, known as the counter-_________ hormones

GLUCAGON and EPINEPHRINE - Known as counter-REGULATORY hormones

RECAP: GLUT2 is expressed on ____ cells, while GLUT4 is expressed on ______ and _______ cells

GLUT2 expressed on BETA cells GLUT4 expressed on FAT and MUSCLE cells

TEST/TEST: Why is GLUT4 upregulated in the muscle after exercise?

GLUT4 expression and insertion into the membrane in MUSCLE = insulin INDEPENDENT!!!!! - This is unlike in adipose, where it is insulin-dependent

TEST: The 2nd phase of glucose stimulated insulin secretion is _______ dependent. What is the function of this?

GLUTAMATE dependent!! - Function: Initiates movement of vesicles so they can go to the membrane!! Remember, the 2nd phase is late because it requires the vesicles to travel to the membrane first.

What is the receptor used by glucagon? How is this different from the receptor used by insulin?

GPCR!! Insulin = TYROSINE kinase

Glucagon has a (positive/negative) effect on insulin release by coupling to (Gs/Gi). Why?

Glucagon has a POSITIVE effect on insulin release by coupling to Gs Why: - You want to keep the glucose level low, and you don't want glucagon to overshoot the amount of glucose release (need a balance) - During evolution, you're always starving so whenever "you have a little bit extra you want to deposit it"

RECAP: Glucagon has a (positive/negative) effect on insulin and somatostatin, while insulin has a (positive/negative) effect on glucagon

Glucagon has a POSITIVE effect on insulin/somatostain Insulin has a NEGATIVE effect on glucagon Somatostatin has a NEGATIVE effect on BOTH glucagon and insulin

TEST: What enzyme, when knocked out or mutated, results in the inability of glucose to induce insulin release?

Glucokinase! (converts glucose --> G6P) - in the pancreatic beta cells

REVIEW: Describe the mechanisms by which the following regulate INSULIN: 1) glucose 2) ACh 3) GLP-1 4) Epi/Nor

Glucose-stimulated insulin secretion: involves GLUT2, glucokinase, TCA cycle>>increase ATP>>ATP-K+ closure>>Ca2+ channel open>>increase [Ca2+]i>> increase secretion Ach binds to M3R-coupled to Gq>> increase [Ca2+]i>> increase secretion GLP-1 binds to GLP1R-coupled to Gs>> increase AC/cAMP >> increase insulin synthesis and secretion Epi/Nor binds to αA2R-coupled to Gi>> decrease AC/cAMP>> decrease insulin synthesis and secretion

TEST: There is a greater response of insulin secretion when glucose is (injected/absorbed through GI)

Greater insulin secretion response to ABSORPTION of glucose from the gut! (G.I. hormones potentiate the release of insulin!)

TEST/TEST: Insulin causes (hypo/hyper)kalemia *High yield!*

HYPOkalemia (since it transports K+ INTO cells)

TEST: IGF-1 has insulin-like activity, and it is produced by a lot of cells, especially by the liver. Why can't IGF-1 replace the role of insulin in diabetic patients?

IGF-1 is too weak, even though it has insulin-like activity! - Also, insulin is regulated by glucose but IGF-1 is NOT! So IGF-1 can't take over the role of insulin, especially when you need it.

TEST: Thyroid hormones can (inhibit/increase) intestine glucose absorption and is considered _________

INCREASE glucose absorption - Considered DIABETOGENIC

What are two GI hormones that influence insulin secretion? What class of hormones do these fall under? What cells are each produced by?

INCRETINS: 1) Glucagon-like Peptide-1 (GLP-1) - Increases GSIS, inhibiting glucagon secretion and suppressing food intake and appetite - Produced by L-cells in ileum and colon 2) Gastric inhibitory peptide (GIP) - Produced by K cells in intestine

What genetic mutation accounts for the majority of genetic risk factors for insulin resistance?

IRS-1 mutations (15%) this makes sense considering that IRS-1 action is central to the signal transduction pathway!

In the Beta-cells, parasympathetic NTs (promote/prevent) insulin storage in the beta-cells, while sympathetic NTs (promote/prevent) insulin storage by predominantly acting through what receptors?

In BETA cells: - Parasympathetics: PREVENT storage of insulin (nutrients are abundant, so they want to release insulin) - Sympathetics: PROMOTE insulin storage via Alpha-adrenergic receptors (nutrients are low, so they want to not release insulin)

TEST: What are the RAPID effects of insulin?

Increased transport of: - Glucose - Amino acids - K+ into insulin-sensitive cells

What is the major regulator of blood glucose concentration?

Insulin!

AGAIN: What is the effect of GLP-1 on appetite?

It slows down gastric emptying, so it reduces food intake and appetite - Increases Glucose-stimulated insulin secretion (GSIS)

GLP-1 is secreted by ___ cells from the (same/different) prepeptide as glucagon and is converted to the active form by __________ _________, then QUICKLY to the inactive form by ________

L-cells from SAME prepeptide as glucagon Active form by PROHORMONE CONVERTASE 1 Inactive form by DPP-4 (Dipeptidyl peptidase-4)

TEST: When glucose is low, __________ is secreted and when glucose is high, __________ is secreted.

LOW glucose = GLUCAGON secretion HIGH glucose = INSULIN secretion

TEST: The 1st phase of glucose stimulated insulin secretion is ________ dependent on what three things?

METABOLIC-dependent: 1) GLUT2 transporter (mediates beta cell uptake) 2) Glucokinase 3) Ca channels and ATP-sensitive K channel (ATP binds, CLOSES the K channel and OPENS the Ca channels, inducing release)

TEST/RECAP: The major regulatory hormone of plasma glucose is ________, while the major counter-regulatory hormone is _________. What are 3 other counter-regulatory hormones that can help out?

Major regulatory = INSULIN Major counter-regulatory = GLUCAGON - Others: Epinephrine, cortisol, growth hormone

The catecholamines and somatostatin have a (positive/negative) effect on insulin release by coupling to (Gs/Gi)

NEGATIVE effect, coupling to Gi

Would you expect sympathetic neurohormones to (promote/prevent) insulin inhibition of glucagon?

PREVENT!! You don't want insulin to inhibit the release of glucose under conditions of fight or flight!!

TEST: What is the major function of Somatostatin? Where is it primarily produced? Also, what are the two SS isoforms (and which one is more potent)?

Paracrine INHIBITION of both α and β pancreatic islet cells, inhibiting the production of both INSULIN and GLUCAGON Site: pancreatic δ cells SS14 and SS28 (more potent)

In the Alpha-cells, parasympathetic NTs (promote/prevent) glucagon from being released, while sympathetic NTs (promote/prevent) insulin storage by predominantly acting through what receptors?

Parasympathetic NTs PROMOTE glucagon release, and as do sympathetic NTs, but unlike in insulin secretion, the sympathetic NTs primarily act on BETA-adrenergic receptors.

TEST: Which is more likely to induce postprandial hypoglycemia: pasta or steak? Why?

Pasta, because that is pure carbohydrates which will induce insulin release and the sequestration of glucose. Steak is full of proteins, which is full of A.A, which induces BOTH glucagon AND insulin secretion (so it balances the glucose uptake)

Glucagon is synthesized as a _____________ which is _____ amino acids long

Preproglucagon, 179 amino acids long

What is pancreatic polypeptide?

Product of F cells (aka PP cells) contains 36 amino acids Released in response to amino acids/protein-rich meal, fasting, exercise, acute hypoglycemia Stimulated by vagus (cholinergic) and serves as indicator of vagal tone Inhibited by somatostatin Slows food absorption in human

Of all the insulin the pancreas secretes in a day, half is secreted into what? What is the benefit of this?

Secretes 40 U/day into the PORTAL VENOUS SYSTEM Benefit: Just as the liver takes up a lot of insulin, it can also take up a lot of glucose! And it can also release a lot of glucose when you need it!

What class of drugs act on the ATP-dependent K channels?

Sulfonylureas

TRUE or FALSE: Glucagon has low effect on muscle, while it has high effects on liver and adipose

TRUE! There is a minimum effect on muscle because of the lack of regulatory response

TRUE or FALSE: Cortisol, growth hormone, and both parasympathetic and sympathetic NTs all can cause increased glucagon release

TRUE!!

What is the function of PCSK1 and PCSK2?

They are proteinases (endopeptidases) that cleaves the C-peptide from the pro-insulin to form mature insulin!

What is the glucose sparing effect?

Under conditions of hypoglycemia, the body spares the glucose produced by the liver for the brain (nervous system) instead, the body relies on alternate energy from lipids and protein

TEST/TEST/TEST: The half-life of GLP-1 is very (long/short), but you can extend the half-life by blocking what? What is the CLINICAL relevance of GLP-1?

Very SHORT Can extend half-life by blocking DPP-4, the enzyme that quickly converts it to INACTIVE form Clinical relevance: GLP-1 acts as a good therapeutic drug for DM II, because it promotes insulin secretion while blocking glucagon release!!!!! It also slows down gastric emptying so you always feel full, which helps control obesity and obesity is a major factor for insulin resistance!!!!

Describe the mechanism by which insulin signal transduction leads to glycogen synthesis.

activated IRS triggers PI3 kinase cascade, leading to upregulation of PKB/AKT PKB/AKT inhibits GSK3; this action thus disinhibits glycogen synthase

Describe the mechanism by which insulin signal transduction leads to glucose uptake.

activated IRS triggers PI3 kinase cascade, leading to upregulation of PKB/AKT PKB/AKT stimulates insertion of GLUT-4 transporter into cell membrane

Describe the mechanism by which insulin signal transduction leads to upregulated protein synthesis.

activated IRS triggers PI3 kinase cascade, leading to upregulation of PKB/AKT PKB/AKT stimulates mTOR, leading to upregulated protein synthesis

Describe the mechanism by which insulin signal transduction leads to upregulated transcription.

activated IRS triggers PI3 kinase cascade, leading to upregulation of PKB/AKT PKB/AKT stimulates mTOR, leading to upregulated transcription activated IRS *ALSO* activates Ras, which triggers the MAP kinase pathway, leading to upregulated transcription

After insulin activates the autophosphorylation of the insulin receptor, the receptor binds which main substrate?

insulin receptor substrate (IRS)

TEST: After C-peptide is removed from pro-insulin, how is mature insulin formed? Via which enzyme?

mature insulin is formed following the removal of two base pairs of basic amino acids by carboxypeptidase E

What is MODY?

maturity onset diabetes of the young B cell dysfunction due to genetic mutations in transcriptional factors, etc

Somatostatin parallels the secretion pattern of which hormone? Also, which hormone stimulates somatostatin release?

parallels secretion of insulin stimulated secretion by glucagon

What are the 3 major types of cells found in the pancreas? What is the major content of each cell type?

α (25%) - glucagon β (55%) - insulin δ (10%) - somatostatin

How do adrenal glucocorticoids affect glucose metabolism?

• Have permissive effects for glucagon and catecholamines • Induce Protein catabolism -> hepatic glucose release • Inhibit peripheral glucose utilization DIABETOGENIC

How do thyroid hormones affect glucose metabolism?

• Increase intestine glucose absorption • Potentiate catecholamine effects • Accelerate insulin degradation • Induce B cell exhaustion DIABETOGENIC

How does growth hormone affect glucose metabolism?

• Induces Lipolysis -> ketogenesis • Decreases glucose peripheral uptake • Increases hepatic glucose release • Induces B cell exhaustion