Endocrinology 10

Question 1

Review the following key metabolic pathways by describing the catabolic path, storage/location and metabolic products.

Carbohydrate
(glucose)

Answer 1

Catabolic path: glycolysis (TCA cycle)

Storage/location: glycogen/muscle, liver

Metabolic byproducts: Reactive oxygen species (ROS), lactate (muscle)

Question 2

Review the following key metabolic pathways by describing the catabolic path, storage/location and metabolic products.

FFAs (lipids)

Answer 2

Catabolic path: TCA cycle (yields more ATP/carbon than glucose

Storage/location: TG/mostly adipose

Metabolic byproducts: Can be used to make ketone bodies in liver

Question 3

Review the following key metabolic pathways by describing the catabolic path, storage/location and metabolic products.

AA
What enzyme must be present to use AA as energy?

Answer 3

Catabolic path: TCA cycle

Storage/location: Protein/muscle

Metabolic byproducts: Ammonia, urea,

Question 4

Review the following key metabolic pathways by describing the catabolic path, storage/location and metabolic products.

Ketone bodies (not dietary)
What enzyme must be present to use as energy?

Answer 4

Catabolic path: TCA cycle – must have thiophorase to use as energy

Storage/location: Made in liver, used by brain

Metabolic byproducts:

Question 5

What can the brain use for energy?

Answer 5

** Brain can only use glucose or ketone bodies as energy source

Question 6

Describe how metabolism is affected in a high caloric diet? (In regards to TG)

Answer 6

** TG can be made from glucose under high caloric intake (obesity).

Large accumulation in organs (fatty liver) can cause cell death.

Question 7

Label the cross section of pancreas on slide 6.

What is the head of the pancreas by?
What does the tail extend over?

Answer 7

7. Tail of pancreas
8. Inferior vena cava
9. Bile duct
10. Stomach
11. Air in stomach
12. Spleen

• head of pancreas by duodenum
• tail extends over spleen

Question 8

Where is exocrine pancreas/endocrine pancreas?

Answer 8

portion that contains the pancreatic duct as well as acinar cells linked to duct is exocrine pancreas

(rest is endocrine pancreas)

Exocrine pancreas Majority of cells. Acinar cells secrete digestive enzymes “pancreatic juice” into the pancreatic duct.

Endocrine pancreas Consists of 3 major cell types clustered in groups “islets of Langerhans”

Question 9

What two major physiological processes does the pancreas regulate?

Answer 9

digestion and glucose metabolism

Question 10

Describe the organization of cells of the exocrine pancreas.

Answer 10

The exocrine pancreas consists of acinar and duct cells. The acinar cells produce digestive enzymes and constitute the bulk of the pancreatic tissue. They are organized into grape-like clusters that are at the smallest termini of the branching duct system. The ducts, which add mucous and bicarbonate to the enzyme mixture, form a network of increasing size, culminating in main and accessory pancreatic ducts that empty into the duodenum.

Question 11

Describe the endocrine pancreas.

Answer 11

The endocrine pancreas, consisting of four specialized cell types that are organized into compact islets embedded within acinar tissue, secretes hormones into the bloodstream. The alpha and beta cells regulate the usage of glucose through the production of glucagon and insulin, respectively.

Pancreatic polypeptide and somatostatin that are produced in the PP and delta cells modulate the secretory properties of the other pancreatic cell types.

Question 12

Describe the 5 endocrine pancreas cell types. Which are most abundant? What do each secrete?

Answer 12

1. Beta cells 73 - 75%. Synthesize and secrete insulin.
2. Alpha cells. 18 - 20%. Synthesize and secrete glucagon.
3. Delta cells. 4 - 6%. Synthesize and secrete somatostatin (SS14).
4. PP cells (less than 1%) secrete pancreatic polypeptide. Inhibit acinar cells via paracrine action.
5. Epsilon cells (newly discovered, less than 1 percent) – synthesize ghrelin

Question 13

What are the major pancreatic hormones? Are they anabolic or catabolic?

Answer 13

Insulin – energy storage (anabolic hormone)

Glucagon – energy mobilization (catabolic hormone)

never zero of insulin or glucagon, there is always balance of the 2 ..insulin/glucagon

Question 14

What are the minor pancreatic hormones? What cells secrete them?

Answer 14

Somatostatin (delta cells)
Amylin
Pancreatic polypeptide (function not well known)
Ghrelin

Question 15

Explain the significance of cellular arrangement and blood flow patterns through the Islets of Langerhans.

Answer 15

blood flow comes into center of islet then flows outward

if flatten thing out and look like sandwich, beta cells in center, alpha cells around edges-mantle. Beta cells clustered in “core”; other cells in “mantle”

most of it is beta cells and alpha you sort of see around edges there. Alpha cells surround beta cells in a sandwich formation

core of beta cells surrounded by alpha cells

Paracrine effects between alpha and beta cells

Islet blood flow:

• arteriole projects to center of islet
• insulin-rich blood flowing from center to periphery of islet
• functionally means insulin made in beta cells, immed. impacts neighboring alpha cells

(but not other way
alpha cells making glucagon do not directly affect insulin
insulin can directly affect glucagon.)

Question 16

Describe the histology of the pancreas; its cellular arrangement.

Answer 16

“cord” arrangement surrounded by fine reticular fiber network

About one million in human pancreas

Plentiful fenestrated capillaries

clusters of cells, about a million, highly vascularized, fenestrated so hormones can be released immed. into circulation

Question 17

Where are glucagon-secreting cells located in pancreas?

Answer 17

Most glucagon-expressing cells were located around vascular channels and at the mantle of islets, independent of their size

Question 18

Describe the synthesis of insulin.

Half life?
How is it released?
What is a critical step for interaction with the receptor?

Answer 18

Half-life = 3 – 8 minutes

Insulin and C-peptide released together

C-peptide half-life = 35 min. Good indicator of pancreatic function.

Cleavage of C-peptide critical exposes end of insulin chain that interacts with the receptor

production, translation of pre-prohormone, signal peptide is made first, add on B, then add C and signal is split, A is added and proinsulin is complete, proinsulin “folded” and S-S bonds formed, converting enzymes cleave C peptide…

(will wrap around self and form disulfide bonds which are then packaged up into the vesicles.) once packaged, have cleavage that occurs and C part of chain is cleaved off, C pep. packaged into same vesicles and is released along w insulin

Question 19

Insulin has a short half-life? How can its levels be measured in the blood?

Answer 19

nice thing about this is C peptide hangs around a long time compared to insulin
so is insulin being released from pancreas? can measure that by measuring C peptide levels. all C peptide HAS to come from same vesicles that insulin was made in, so if had C peptide, also had insulin released.

C-peptide half-life = 35 min. Good indicator of pancreatic function.

Question 20

Describe the steps of insulin release.

Answer 20

Step 1: Glucose outside beta cell (transported by GLUT2)

Step 2: Glucose inside beta cell (phosphorylated by glucokinase-traps it in cell) G6P metabolism generates ATP

Step 3. Glucose metabolism (Increased ATP closes K channels, K channel has SUR subunit)

Step 4: Step 4. Cell depolarization (Closing K+ channels depolarize cell, Depolarization opens Ca++ channel)

Step 5: Vesicle exocytosis (Ca++ influx causes exocytosis of insulin-containing vesicles)

Question 21

Describe GLUT2, what is it involved with? Describe its affinity for glucose.

Answer 21

glucose outside the beta cell is transported into cell by GLUT2

GLUT-2 = LOW affinity for glucose. Only when glucose is high will it transport

normally glucose levels HAVE to increase and be elevated before glucose comes into beta cell

Question 22

How can the SUR subunit be used to treat diabetes?

How about Sulonylurea drugs?

Answer 22

K+ channel has a SUR subunit.

SUR subunit- drug target for early diabetes drugs, targets subunit to close channel and bypass all these steps w glucose. when that channel close K cant leave, build up of positive charge in cell, depolarizes the cell, cause voltage gated Ca channels to open, Ca floods in, cause release of secretory granules from beta cell. so if close that channel then you depolarize the cell and can keep getting insulin to be released. so when have beta cells that don’t function properly but still make insulin can kick start it release more insulin than it would

Sulfonylurea drugs also close channel – bypasses glucose steps.

Question 23

How does ATP affect the K channel inside beta cell?

Answer 23

ATP sensitive K channel and closes when ATP levels high inside cell

Question 24

Describe other modulatory pathways affecting insulin release.

What effect do FFAs, AAs, Incretins, and catecholamines have?

Answer 24

FFAs, Amino Acids ——- can increase ATP (come in and oxidized to ATP so FFA def do that, AA not as much, not much insulin released if ONLY eat protein diet)

Incretins (GLP-1) potentiate insulin release – still needs glucose!

Catecholamines inhibit release via alpha-adrenergic receptors

Question 25

Where are Incretins produced? Describe their action.

Answer 25

Incretins- made in intestine, they respond to high fat and high carb… those act through GPCR,

activate adenyl cyclase pathway, PKA released, potentate Ca signal, get more Ca released from intercellular stores, causes a little more insulin to be released

incretins dont work on own, can’t cause insulin to be released by self without first influx of Ca, still needs glucose to work

Question 26

Describe how catecholamines affect insulin release?

Answer 26

catecholamines increased in response to stress and exercise and they activate inhibitory pathway here, (GI receptor) and shut this pathway down…inhibit release through adrenergic receptors.

inhibit release- which is good… benefits of exercise

Question 27

Describe the basis of the biphasic response of insulin release following ingestion of a meal.

How will this differ for diabetics?

Answer 27

First phase secretion, second phase secretion

glucose infusion coming in, immed. get spike in insulin levels (represents insulin vesicles that are docked at membrane, sitting there ready to be released upon stimulus) but then you have to make more insulin and package more insulin.. second phase rep. what happens later, take stored ones and has to be moved to membrane and be trafficked there so can be released

Slide 25

5% of vesicles are available for immediate release - docked at membrane

95% are “stored” or reflect newly synthesized insulin

Question 28

What type of receptor does insulin interact with?

Answer 28

RECEPTOR TYROSINE KINASES

Insulin binds receptor at alpha subunit (alpha subuint has hormone binding domains)

Beta subunit is autophosphorylated (beta subunit has ATP-binding and tyrosine kinase domains)

tyrosine kinases can autophos. their beta subunit. insulin binds alpha and then beta is phosphorylated. this phosphory. of beta subunit allows it to recruit other proteins inside the cell, one of them being insulin receptor substrates (recruited to receptor and will direct what intracellular signaling pathway will be upon cell seeing insulin is there)

Question 29

Describe Insulin’s action in the muscle cell.

Answer 29

Glucose does not enter cell without insulin

Autophosphorylation of receptor recruits IRSs (insulin receptor substrates).

IRSs activate intracellular signaling cascades

if RAS GTP pathway that activates MAP kinase- get growth effects. insulin promoting growth of tissues and the cells

in muscle cells will activate phos. and activation of PKB/ TC-10 and protein kinase B pathway- GLUT 4 transporter normally seq. inside cell of muscles and activation of this pathway will phos. these and allow them to be trafficked them to membrane so now glucose can come into muscle cell

w/o insulin this doesn’t happen and glucose cannot get into the muscle cells at all bc it has to go through this particular transporter.
these substrates imp. for activating these pathways, defects in these enzymes could contribute to insulin resistant states

RESULT: GLUT-4 inserted in membrane
– glucose can enter cell

Slide 28

Question 30

In regards to insulin action in the muscle cell, metabolic effects are mediated through which pathway? Mitogenic effects mediated through which pathway?

Answer 30

Metabolic effects mediated through PKB and TC-10 pathways.

Mitogenic effects mediated through MAPK pathways

Question 31

Discuss the similarities and differences among the glucose transporters (GLUT1, GLUT2, GLUT3, GLUT4, and GLUT5).

Answer 31

GLUT1- expressed in brain vasculature, erythrocytes, skeletal muscle, fat, heart (minor role), Insulin independent, Uptake under basal conditions

GLUT2- expressed in Pancreatic beta cells, liver, intestine, kidney, Insulin-independent
Low affinity
Uptake when glucose levels are high

GLUT3- expressed in neurons, insulin-independent, major transporter in the brain

GLUT4- expressed in Skeletal muscle, fat
Stored inside cell under basal conditions, Insulin-dependent!

GLUT5- expressed in Spermatozoa, small intestine, fructose transporter

Question 32

Which is GLUT transporter expressed in neurons (major transporter in brain)?

Which is insulin dependent?

Which is a fructose transporter?

Which is expressed in pancreatic beta cells?

Which important in vasculature of brain?

Answer 32

Which is expressed in neurons (major transporter in brain)? GLUT3

Which is insulin dependent? GLUT4

Which is a fructose transporter? GLUT5

Which is expressed in pancreatic beta cells? GLUT2

Which important in vasculature of brain? GLUT1

Question 33

What happens to these transporters in a person with diabetes mellitus?

Answer 33

low affinity transporters (GLUT2) …so when glucose is high that’s when it’ll transport it in (diabetes mellitus, hyperglycolic state..these transporters will be super saturated)

same w GLUT3 -hyperglycemic state brain getting lots of glucose and these will become saturated

Question 34

Describe the major physiological effects of insulin on liver.

What enzymes will it inhibit/stimulate?

Answer 34

Liver – promotes glycogen and TG production; reduces glucose production/output
Inhibits glucose-6 phosphatase
Stimulates glucokinase synthesis

G6P can be made to glycogen or TG to VLDL, cholesterol and phospholipids

Question 35

Describe Describe the major physiological effects of insulin on muscle.

Answer 35

Muscle – promotes glycogen and TG production, protein synthesis

GLUT4 skeletal muscle..

G6P to glycogen, ATP, TG

Question 36

Describe Describe the major physiological effects of insulin on adipose tissue.

Answer 36

Fat – promotes TG production, release of FFAs from chylomicrons, glycolysis; inhibits lipolysis

G6P to ATP or glycerol-3-P which is combined w fatty acyl CoA to produce TG

Question 37

How are GLP1 and 2 produced?

Describe their various actions depending on tissue present in.

Answer 37

Slide 35

Incretins (GLP-1 and GLP-2) – important clinical use

Synthesized from the same prohormone as glucagon

Tissue specific enzymatic activity

Intestinal GLP stimulated by carbohydrates

GLP-1 in the intestine responds to carbohydrates. Then, it will travel to pancreas and potentiate release of insulin. Carbohydrate only meal will only stimulate insulin.

in pancreas get active glucagon- co peptide which doesn’t do anything …GLP - dont do anything in pancreas bc not processed in a form they can be active but processed from same prohormone as glucagon

Question 38

Describe glucagon products from pancreatic A cells vs products from intestinal L cells?

Answer 38

processed differently dep. on what cell type its made in. in pancreas get active glucagon- co peptide which doesn’t do anything …GLP - dont do anything in pancreas bc not processed in a form they can be active but processed from same prohormone as glucagon

glucagon made in alpha cells, in intestine that pathway not cleaved… will be stuck to co peptide and when attached to co-peptide can’t do anything. this complex is “glicentin” but do get syn. of GLP… targeted for treatment of DMII

Question 39

Why does the atkins diet (only protein) work?

Answer 39

this is why atkins diet works bc eating protein so switch ratio and have more glucagon to insulin circulating - catabolic effects…

Slide 36

Question 40

Describe the action of glucagon.

When is it released?
How will its release be affected by AA or catecholamines?

Answer 40

Major counterregulatory hormone to insulin – most things that stimulate insulin will inhibit glucagon

Released in response to low blood glucose levels

AAs stimulate release
(protein meals)

Catecholamines stimulate release (exercise)

Question 41

What is the primary action of glucagon?

What are its main targets?

Answer 41

Primary Action: energy mobilization

Main targets: liver and adipose tissue. No glucagon receptors in skeletal muscle

Opposite effects of insulin

Question 42

How will glucagon affect…

• hepatic glucose production
• glycogen or lipid synthesis
• glucose uptake by adipose and muscle
• hepatic ketogenesis
• release of gluconeogenic substrates from muscle and adipose
• HSL levels and FFA release from adipose

Answer 42

increase hepatic glucose production (glycogenolysis, gluconeogenesis)

decrease glycogen or lipid synthesis

decrease glucose uptake by adipose tissue and muscle

increase hepatic ketogenesis

increase release of gluconeogenic substrates from muscle and adipose

increase HSL levels and release of FFA from adipose

Question 43

Describe hepatic ketogenesis in the presence of insulin.

Answer 43

inhibits hepatic ketogenesis!

any time any insulin circulating you don’t get ketones being made

Question 44

If a patient presented with ketoacidosis, what might you assume about what type of diabetes they had?

Answer 44

DMII- usually have some insulin in blood, not enough to handle all the glucose but is enough to prevent ketogenesis… when ketoacidosis that happens usually restricted to something that happens in type I diabetes

Question 45

What is HSL? How will insulin/glucagon affect levels?

Answer 45

encoded by the LIPE gene. HSL is an intracellular neutral lipase that is capable of hydrolyzing a variety of esters

glucagon- increase HSL
insulin- inhibit HSL

Question 46

How do catecholamines affect beta/alpha cells?

Describe its effect when there is low plasma glucose.

Answer 46

catecholamines stimulate alpha cells but also inhibit secretion of insulin in the beta cells

low glucose, glucagon being prod. catecholamines potentiating this effect (directly at beta cell and directly stimulating the alpha cells) that causes hepatic glucose prod. to increase…get gluconeogenesis, break down of glycogen stores… will decrease hepatic conversion to glycogen stores and to lipids… decrease uptake by adipose and muscle cells, increase hepatic ketogenesis (normally a function of glucagon, but as long as some insulin present that won’t occur) 
activate HSL (hormone sensitive lipase)

Question 47

Describe how insulin and glucagon can have opposite actions on the same pathways?

Answer 47

these are bifunctional enzymes… these enzymes have kinase and phosphates activity dep. on phosphorylated or not

glucagon phosphorylates it, increase phosphatase activity and cause it to go on this pathway…

Slide 39

glucagon phosphorylates enzyme and activates phosphatase activity

insulin de-phosphorylates enzyme and activates kinase activity

Question 48

What enzymes are active if you have decreased Fructose 2,6 P2, increased?

Answer 48

Slide 39

decreased F2,6, P2 - then activate fructose 1,6 bisphosphatase…Fructose6P and glucose prod.

increased levels- activate 6-phosphofructokinase and get fructose 1,6P2 and pyruvate

Question 49

Where is somatostatin (SS14) produced?

What cells produce?
How is it stimulated? Inhibited?
What is its clinical use?

Answer 49

-Produced by delta cells in pancreatic islets

Stimulated by high fat, high carb meals. slows down digestive process

Inhibited by insulin these are inhibited by insulin.. bc of way blood flows. clustered around outside just like alpha cells are

Suppresses insulin release - used in clinic for management of insulin-producing tumors

Question 50

Somatostatin is stimulated by high fat, high carb meals and works to slow down the digestive process. Insulin however, will inhibit it. Why is this a good thing?

Answer 50

why would u want to not slow down process? initial high spike you get in insulin… don’t want to overshoot and cause hypoglycemic situation bc you have a lot of insulin released right away and if this process was slowed down then its possible you could overshoot amount of glucose and cause hypoglycemic situation, if this SS is inhibited… the glucose levels will raise more and more quickly and first spike of insulin can take of it

Question 51

Can somatostatin inhibit insulin release? Why/why not? When?

Answer 51

inhibited by insulin physiologically.. somatostatin will inhibit insulin release - not physiologically. the way cells are arranged, somatostatin is not able to get to beta cells and will not inhibit insulin release
can use large doses of SS to inhibit insulin release from insulin secreting tumors
but under normal conditions SS does not inhibit insulin release

Question 52

What type of cells release amylin? Describe its action.
In what clinical situation might you see higher levels of circulating amylin?

What can it contribute to? Why?

Answer 52

Released with insulin from vesicles in beta cells
Synergistic with insulin in regulation of blood glucose
Circulating amylin increased in obesity, hypertension
Possibly contributes to beta cell destruction by forming amyloid

high prod. of amylin can result in accumulation of amyloid plaques in certain cells - this is one theory why beta cells are pot. destroyed in type II diabetes (now making lots of amylin and excess prod. becoming amyloid which are aggregates of protein and cause toxicity in the cell)
helpful bc acts synergistically w insulin

Question 53

Describe the structure of ghrelin.

Where is most circulating ghrelin produced?

Where does it act?
What does it stimulate?

Where is it produced?
Describe its paracrine action on beta cells.

Answer 53

28 AA peptide

Most circulating ghrelin produced in stomach

• Stimulates food intake at level of hypothalamus
• Stimulates GH release
• Inverse correlation between circulating ghrelin and obesity

Produced in newly described epsilon cells of islets
Paracrine action on beta cells:
- Inhibits insulin release via Galpha(i) activation (opens) of K+ channels
- Decreases intracellular Ca++; decreases insulin release

Question 54

How will growth hormone and cortisol affect gluconeogenesis and lipolysis?

Answer 54

Permissive effects on gluconeogenesis and lipolysis

Delayed response (6 hours) – defense against prolonged hypoglycemia (starvation).

they change receptor levels in these tissues so that the other hormones can work
tends to be considered delayed response bc glucagon will act first
but if don’t eat for long period, then other hormones around longer and they protect against hypoglycemia

Question 55

What hormones might kick in after glucagon if you are not eating for a while?

Answer 55

GH and cortisol

tends to be considered delayed response bc glucagon will act first
but if don’t eat for long period, then other hormones around longer and they protect against hypoglycemia

Question 56

Describe the effect of epinephrine (catecholamines).

How do they affect plasma glucose levels?

When increased?

How does it affect alpha/beta cells?

How is overall hepatic glucose output affected?

Glucose uptake in skeletal muscle/adipose tissue?

Answer 56

Like glucagon, raise plasma glucose levels

Increased during exercise and stress

Inhibits insulin release directly at beta cell, stimulates glucagon in alpha cell

Increases hepatic glucose output

Decreases glucose uptake in skeletal muscle/adipose tissue

brain needs lots of glucose all the time…
they directly inhibit insulin release from pancreatic cells

tissue type- decrease some glucose uptake so glucose can get where it needs to be in times of stress

Question 57

What do the following stimulate?

Carbs
Fat
Protein

Protein only meal?

Answer 57

Mixed meal:
Carbs – insulin
Fat – insulin
Protein – glucagon, insulin (some)

Protein meal:
Glucagon only

carbs and fat primarily stimulate release of insulin
protein primarily glucagon.. but ratio is more insulin to glucagon
(if just ate hamburger then stimulate primarily glucagon and ratio will shift)

Question 58

When insulin is present, what effect will AA from protein have?

Will proteolysis be inhibited or stimulated?

Answer 58

AA from protein stimulate GH which stimulates IGF-I (liver).

IGF-I stimulates glucose uptake in muscle, proliferation of visceral organ tissues; inhibits proteolysis.

GH opposes insulin lipogenesis.

Question 59

How will GH affect lipogenesis?

Answer 59

GH opposes insulin lipogenesis.

GH also will oppose insulin effect on lipogenesis… GH wants to maintain lean body mass.. little bit of fat storage but not a lot.