Pancreas

Question 1

Exocrine portion?

Endocrine portion?

Answer 1

Exocrine portion: Acini by releasing their secretion into a set of ducts coming out of your major and minor ducts of the pancreas (Santorini and Wirsung)

Endocrine: Islets of Langerhans which are associated with capillaries bc their secretion will always go directly into the blood

Question 2

Cells of islets vs secretion

Answer 2

Alpha - glucagon
Beta - insulin
Delta - somatostatin
F cell - pancreatic polypeptide

Question 3

F cell secretion importance?

Answer 3

Pancreatic polypeptide: marker of tumors of the pancreas

Normally, it is VERY LOW but if it goes up, it means you have pancreatic tumor

Importance: Tells us the person has cancer (one of the cancers you don’t want have because by the time it’s symptomatic, it’s v far advance na and px has a few months to live

The location of the organ has something to do w/ it unless the cancer’s in the head causing obstruction in duodenum then maaga ka magkakasymptoms. Pero kung nasa body and tail, wala
Retroperitoneal pos niya so the most you’ll have is unexplainable back pain
So by the time madetect siya, advanced na

Question 4

Insulin
1. Structure

2. Message is in which chromosome?
3. What gives its conformation structure?
4. In order to work, it has to?
5. Release of insulin is via?
6. Once in the blood, what happens to it?

Answer 4

1. Structure: 2 chains: alpha and beta and C peptide which is actually inert
2. Chr 11
3. Position of the disulfide bonds
4. It has to form microcrystals around zinc ions especially within secretory granules so you have hexamers on release
5. Via exocytosis
6. Rapidly degraded by insulinase which is found in most of the target tissues and has a half-life of 4-6 minutes
   >Insulin degraded is cleared in the liver and excreted mostly through the kidney

Question 5

How do you measure insulin levels?

Answer 5

By measuring the C peptide because it is the one that is NOT metabolized

Question 6

Insulin synthesis

Answer 6

Protein so message comes from gene, you make your mature RNA after splicing and then you synthesize the molecule together w/ your signal peptide then it goes to GA that causes the correct conformation. You now cleave the C peptide and in the vesicle, you have equimolar amts of the insulin and the C peptide.

Question 7

GLUT-2 and GLUT-4
>Primary tissue distribution
>Function

Answer 7

GLUT-2
>Primary Tissue distribution: Kidney & small intestinal epithelial cells, liver, pancreatic Beta cells

> Function: Low-affinity transporter, Basal-lateral transporter in kidney and gut to facilitate glucose entry into the blood; hepatic glucose output; part of the glucose sensor in islets and liver

GLUT-4
>Primary tissue distribution: Skeletal ms, brown & white adipose tissue, heart
>Function: Mediate insulin-regulated glucose transport

Question 8

What happens when the beta cell detects that it has a lot of glucose around?

Answer 8

It will now pick up the Glucose
The enzyme that conv Glu -> Glu-6-P (RLS for glycolysis)
GK: for fat and muscle cells
HK: for liver
If there’s high amt, maddriveyung passage/transport of the glucose and it’s conv immed to Glu-6-P then goes to glycolysis then Krebs -> produces ATP
ATP now, in amt, will be greater than ADP
And when you inc ATP/ADP ratio -> you close K+ channel
So papasok yung arrow
Normally, bc of the Na/K pump, you have higher conc of K in cells so there’s high amt of K here and the normal flux of K through this channel is going out
But if we close it due to change in ATP/ADP ratio -> you retain K+ inside
When this happens, the membrane potential inside is relatively positive than the outside then you have depolarization (dumami positive charges)
Once this happens, you now open voltage-gated calcium channel, causing Ca to come in and ca2+ will interact with microtubules (w/c have actin and myosin so they start moving now your vesicles from a readily releasable pool going to the CM and that’s how exocytosis happens)
Note: May ready releasable pool
Meaning may nagaabang to be sent out
Other thing Ca will do -> will activate insulin gene expression
Bc Ca will interact with CREB which is a TF so other than secreting stored pool, you’re going to start synthesis of more insulin

Question 9

Phases of Insulin Secretion

1. Phases
   >include period of onset
2. What happens when you have Type II DM?

Answer 9

1.
Phase 1: due to stored insulin that’s in the readily releasable pool
>rapid onset

Phase 2: Slower in rise because you’re going to synthesize new insulin
>slow onset

2. You lose the 1st phase because the px does produce insulin but not adequate or not working well. Those with type II diabetes usually eat all the time so there’s no readily releasable pool kasi palaging nirerelease so you just rely on newly synthesized.

Question 10

What is the triggering pathway? Amplifiers?

Answer 10

Triggering pathway is when glucose comes in -> ATP/ADP ratio goes up -> K+ channels close -> depolarization -> VGCC open -> Inc [Ca2+]i -> insulin secretion

Amplifiers: other things that can cause the release of more stored insulin
>partly responsible for the 2nd phase
>NADPH, GTP, Malonyl-CoA, cAMP, LC Acyl-CoA, Glutamate

Question 11

What causes the amplifying pathway?

Answer 11

GLP-1 (a molecule normally produced) binds to its receptor, a GPCR -> AC activation -> inc cAMP -> inc Ca2+ intracellularly -> more release over and beyond the triggering pathway of insulin

Question 12

What is the incretin effect?

Answer 12

> Intestinal hormones modulate insulin secretion
Glucointegrins (Postprandial glucose homeostasis)
-GIP (Gastric inhibitory peptide)
-GLP-1 (Glucagon-like peptide 1)

Question 13

Enzyme that degrades GLP-1?

Answer 13

DPP4

Question 14

What happens to your insulin release if these are involved?

1. Give sulfonylurea
2. GLP-1 activation
3. ACh release
4. Fatty acids
5. Epinephrine

Answer 14

1. Give sulfonylurea:
   >SUr is the receptor for SU and K channel that is closed by the trigger pathway (one and the same)
   >So give a px SU -> you trigger more insulin release
2. GLP-1 activation -> inc AC -> inc cAMP -> inc Ca2+ -> More exocytosis
3. ACh release -> binds to muscarinic receptors (GPCR) -> activate PLC -> inc IP3 -> inc Ca2+ -> more insulin secretion
4. FA same as #3
5. Epinephrine
   >If alpha-adrenergic receptor stimulation -> you stimulate GPCR (Gi) -> inhibit AC -> less secretion

> If beta -> opposite -> more secretion

Question 15

Regulators of insulin release
1. Strongest stimulus of insulin?

2. Effect of the ff on insulin release
A. Mannose
B. Gastrin
C. Alpha-adrenergic stimulation
D. Beta-adrenergic stimulation
E. CCK
F. Vagal stimulation
G. GLP-1
H. GLP-2
I. Diazoxide
J. Sulfonylurea
K. Secretin
L. Somatostatin
M. Phenytoin
N. GIP

Answer 15

1. Glucose

2.
A. Mannose: Stimulant
B. Gastrin: Amplifier
C. Alpha-adrenergic stimulation: Inhibitor
D. Beta-adrenergic stimulation: Amplifier
E. CCK: Amplifier
F. Vagal stimulation: Stimulant
G. GLP-1: Amplifier
H. GLP-2: Amplifier
I. Diazoxide: Inhibitor
J. Sulfonylurea: Stimulant
K. Secretin: Amplifier
L. Somatostatin: Inhibitor
M. Phenytoin: Inhibitor
N. GIP: Amplifier

Question 16

Insulin Receptor

1. Type of receptor
2. Structure
3. Message is in which chromosome?
4. Held in place by?
5. Mechanism

Answer 16

1. Tyrosine kinase receptor (Catalytic receptor)
2. Heterotetramer receptor: 2 alpha, 2 beta
3. Message is in Chr 19
4. Held in place by covalent disulfide bonds
   Why? In the CM, all of them are actually mobile (reassemble, disassemble). The movement of molecules is horizontal hindi across so recognition of the insulin molecules is the responsibility of the alpha; and the beta subunit that traverses the CM has the enzymatic part (so you call it a catalytic receptor specifically TKR) and the kinase causes a phosphorylation rxn
5. Mechanism:
   Insulin bound to alpha -> conformational change -> autophosphorylation of tyrosine residues -> eventually phosphorylate insulin response substrates (IRS)

Question 17

IRS

1. What is an IRS?
2. How many IRS are there?
3. What happens when they are activated?

Answer 17

1. IRS = “Insulin Response Substrates”
2. There are 5 IRS.
   >3 function the same way (converting message from outside to inside the cell)
   >IRS 4 & 5 - unknown pa
3. 2 possibilities:
   A. IRS will activate PI3K -> Convert PIP2 to PIP3 -> PIP3 activates Akt (aka PKB) -> Translocation of GLUT-4 transporters to be inserted to the membrane -> More entry of glucose via facilitated diffusion
   -> PKB also activates glycogen synthase and mTOR (mammalian target of rapamycin that will cause more transcription and translation of proteins/enzymes)

> Pathway responsible for most metabolic effects of insulin
Connected exclusively through IRS

B. IRS can activate RAS/MAP pathway
>MAP (Mitogen activating protein) -> More mitosis -> more cells -> You grow
>So we need insulin to grow
>From both IRS and Shc unlike PI3K pathway that is connected exclusively through IRS
>Regulation of gene expression and, in cooperation with PI3K pathway, control of cell growth and dx

Question 18

Four of the critical downstream substrates of AKT/PKB?

Answer 18

1. Increased amino acid uptake and protein synthesis
   >via mTOR which increases enzymes needed for translation
2. Increased glycogen synthesis
   >By inhibiting glycogen synthase kinase 3 (GSK3) which inhibits glycogen synthase via phosphorylation
3. Decreased gluconeogenesis
   >By inhibiting FoxO (especially FoxO1)
4. Increased glucose transport
   >By AS160 (Akt Substrate of 160 kDa) which translocates transporter

Question 19

Action of insulin in the:

1. Liver
2. Fat/Adipose tissue
3. Muscle

Answer 19

1. Liver
   >Decreased glucose production (Glycogenolysis inhibited)
   >Increased glucose utilization and FA, Protein & Glycogen synthesis
2. Fat
   >Inc glucose uptake and TG synthesis
   >Dec Lipolysis
3. Muscle
   >Inc glucose uptake, protein synthesis, and muscle mass

Question 20

Effect of exercise on glucose uptake?

Answer 20

In exercising muscles, you cause more transporters of glucose (GLUT-4) to be on the surface.

How? Transporters recycle from surface pabalik via endocytosis then palabas via exocytosis.

SO tell px to lower blood sugar over and above what you normally have in effect due to meds

Question 21

Relationship of alpha, beta, and delta cells of the pancreas if the glucose level is high?

Answer 21

Beta and delta will secrete something that will inhibit the alpha cell from producing glucagon.

Beta: produces insulin, GABA, zinc

Delta: produces somatostain

Question 22

Mechanism of glucagon?

Answer 22

Polypeptide that binds to a GPCR -> activate AC -> inc cAMP -> stimulate PKA -> activate PK (that activates glycogen phosphorylase, an enzyme that degrades glycogen to Glu-1-P) -> elevation of blood glucose

Question 23

Effect of glucagon on:

1. Fat cells
2. Glucose production
3. Glycogen
4. FA and Ketone Body production

Answer 23

1. Glucagon increases lipolysis in fat cells -> inc FFAs -> FFAs once oxidized will produce ketone bodies
2. Activate PFK-2 which converts the two 3C to one 6C responsible for GLUCONEOGENESIS
3. Increases Glycogenolysis (bc it phosphorylates Phosphorylase B) -> Inc glucose -> once high, will turn off glucagon secretion
4. Increases (thus, inhibits anabolism)
   >You use these two to spare glucose and make the cell use more FA and KB as fuel
   >Net effect: Blood sugar elevation

Question 24

Somatostatin
1. Identified as/aka

2. Effect on:
A. Gastric emptying
B. GIT blood flow and nutrient absorption
C. Growth
D. Insulin and glucagon secretion
E. Blood flow

Answer 24

Somatostatin:
1. Aka GHIH (Growth Hormone-Inhibiting Hormone)

2. Effects:
   A. Decreased gastric emptying (release of chyme from stomach to small intestine)
   B. Decreased GIT blood flow and nutrient absorption, and C. Dec Growth
   >By causing vasoconstriction in splanchnic vasculature
   >Less blood flow -> less to digest and absorb in GI -> lower nutrient absorption -> di lalaki (so dec growth)
   D. Decreased insulin and glucagon secretion
   >Paracrine signaling in Islets of Langerhans
   E. Less blood flow

Question 25

Normal vs. Prediabetic vs. Diabetic px:
A. HbA1c (in %)
B. Fasting Plasma Glucose/FBS (mg/dL)
C. OGTT (mg/dL)

Answer 25

A. HbA1c (%)
Normal: ~5.7
Prediabetic: 5.7-6.4
Diabetic: x >/ 6.5

B. FBS (mg/dL)
Normal: x < 99
Prediabetic: 100-125
Diabetic: x >/ 126

C. OGTT (mg/dL)
Normal: x < 139
Prediabetic: 140-199
Diabetic: x >/ 200

Question 26

Diabetic Ketoacidosis (DKA)
1. Insulin and glucagon secretion?
2. Due to?
3. Effects on:
A. Glycogenolysis
B. Proteolysis
C. Blood sugar level
D. FA oxidation
E. Gluconeogenesis
F. Bicarbonate levels

4. DKA triad
   - Explain
5. Why do px have lactic acidosis?

6. Explain the ff symptoms:
A. Confusion/Coma
B. Tachycardia and hypotension
C. Fever
D. Polydipsia and polyuria
E. Kussmaul respiration/Tachypnea
F. Abdominal pain and tenderness
G. Nausea and vomiting
H. “Sweet odor”

Answer 26

1. low insulin and HIGH GLUCAGON
2. Due to viral infection (Destroyed beta cells) or genetic

3. Effects:
A. Inc Glycogenolysis
B. Inc Proteolysis
C. Inc Blood sugar level
D. Inc FA oxidation
-You’re going to produce KBs
E. Inc Gluconeogenesis
F. Dec Bicarbonate levels

4. DKA triad: Hyperglycemia, acidemia, ketonemia
   >No insulin so body produces glucose -> elevated blood glucose lvls
   >One way to inc blood glucose lvls is to inc FA oxidation leading to inc ketone body production (ketonemia and acidic)
5. Lactic Acidosis
   >Poor perfusion due to hypovolemia can lead to lactic acidosis
   >Why? Poor perfusion -> Poor O2 delivery to cells -> Cells undergo anaerobic metabolism -> Produce lactic acid
6. Signs and Symptoms vs. Cause
   A. Confusion/Coma
   >Hyperosmolar px so water leaves brain cells/neurons (dehydration)
   >Acidemia

B. Tachycardia and hypotension
>Severe intravascular volume depletion from osmotic diuresis, vomiting, and ketoacidosis

C. Fever
>Usually DKA is brought abt by infection

D. Polydipsia and polyuria
>Due to osmotic diuresis & resulting hypovolemia which increases thirst

E. Kussmaul respiration & tachypnea
>Kussmaul respiration aka deep laboured breathing
>Because you have acidosis, respiratory system will try to compensate

F. Abdominal pain and tenderness
>No clear explanation yet

G. Nausea and vomiting
>Due to KBs

H. “Sweet odor”
>Due to KBs

Question 27

HONK

1. Meaning?
2. More seen in?
3. Symptoms

Answer 27

1. HONK = Hyperosmolar Hyperglycemic Non Ketotic Coma
2. Px with Type II DM
3. Hyperglycemia, hyperosmolarity, dehydration, no severe metabolic acidosis, pH is usually greater than 7.30, NO ketonemia, less common than DKA (but still common)