Lecture 9

Question 1

What is the exocrine pancreas?

Answer 1

The majority of the cells of the pancreas. Acinar cells secrete digestive enzyme juices into the pancreatic duct

Question 2

What part of the pancreas is endocrine?

Answer 2

ductless part

Question 3

What are the three major cell types that make up the exocrine pancreas? What are they clustered in?

Answer 3

Beta: 75% synthesize and secrete insulin
Alpha: 20% synthesize and secrete glucagon
Delta:5% synthesize and secrete somatostatin (SS14)

Clustered in groups called “islets of Langerhans”

Question 4

What are the major pancreatic hormones?

Answer 4

1. Insulin-energy storage (anabolic hormone)

2. Glucagon-energy mobilization (catabolic hormone)

Question 5

What are the minor pancreatic hormones?

Answer 5

Somatostatin (delta cells)
Amylin(secreted with insulin)
Pancreatic polypeptide
Ghrelin

Question 6

What is the arrangement of islets of langerhan in the pancreas?

Answer 6

1. cord arrangement surrounded by fine reticular fiber network
2. about one million in human pancreas
3. plentiful fenestrated capillaries-so hormones can easily pass in and out of them

Question 7

How do alpha and beta cells arrange?

Answer 7

Alpha cells”mantle” line the edges with the beta cells in the middle “core”
-paracrine effects between alpha and beta cells

Question 8

Since arterial feeds the center of the islet cell then blood flows outward how does insulin affect glucagon vs how glucagon affects insulin?

Answer 8

insulin will directly impact glucagon on the way out

glucagon doesn’t have that effect on insulin

Question 9

What is the half life of insulin?

Answer 9

3-8 minutes

Question 10

What is released with insulin?

Answer 10

Insulin and c-peptide are released together

Question 11

What is the half life of C-peptide and what is it a good indicator from? what does the cleave of c peptide from insulin do?

Answer 11

35 minutes
good indicator of pancreatic function(if releasing c, then it is making insulin)
cleavage of c-peptide exposes end of insulin chain that interacts with the receptor

Question 12

What are the five steps to insulin release?

Answer 12

1. glucose outside beta cell
   - Transported into cell by GLUT-2
   - low affinity for glucose-only when glucose is high will it transport
2. Glucose inside beta cell
   - Glucose phosphorylated by glucokinase
   - Glucokinase=”pancreatic glucose sensor”
   - G6P metabolism generates ATP
3. Glucose metabolism
   -Increased ATP closes K+ channels
   K+ channel has a SUR subunit
   -Sulfonylurea drugs also close channel-bypass glucose steps
4. Cell depolarization
   - Closing K+ channels depolarize cell
   - Depolarization opens Ca channels
5. Vesicle Exocytosis
   - Ca influx causes exocytosis of insulin-containing vesicles

Question 13

How do FFAs and amino acids affect insulin release?

Answer 13

can increase ATP

protein alone will not stimulate insulin

Question 14

How do catecholamines affect the release of insulin?

Answer 14

inhibit release via alpha-adrenergic receptors

–>directly at beta cell-need to keep glucose mobilized

Question 15

What does incretins (GLP-1) affect the release of insulin?

Answer 15

potentiate insulin release-still needs glucose –>respond to high carb diets

Question 16

Why is insulin release biphasic?

Answer 16

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

95% are stored or reflect newly synthesized insulin
(this is the phase impaired by diabetes)

Question 17

What type of receptor does insulin bind? What subunit does it bind to? What happens to the other subunit?

Answer 17

Receptor Tyrosine Kinases
Binds alpha subunit
Beta subunit is autophosphorylated
-acts as a scaffold for intracellular signaling pathways

Question 18

What does glucose need to enter the muscle cell?

Answer 18

insulin-glucose does not enter without insulin

Question 19

What does autophosphorylation of insulin receptor recruit?What do these do? What is the result?

Answer 19

IRS-insulin receptor substrates

• activate intracellular cascade
• RESULT: glut-4 inserted into membrane and glucose can enter the cell
• metabolic effects mediated through PKB and TC-10 pathways
• Mitogenic effects mediated through MAPK pathways

Question 20

What is the only glucose transporter that is glucose dependent? What is GLUT4 on?

Answer 20

GLUT 4

• skeletal muscle
• fat

Question 21

What is insulins primary action?

Answer 21

Energy storage

Question 22

What does insulin do in the liver?

Answer 22

promotes glycogen and TG production; reduces glucose production/output

• inhibits Glucose 6 phosphatase
• stimulates glucokinase synthesis

Question 23

What does insulin do in the muscle?

Answer 23

promotes glycogen and TG production, protein synthesis

Question 24

What does insulin do in fat?

Answer 24

promotes TG production, release of FFA from chylomicrons, glycolysis; inhibits lipolysis

Question 25

What is the product of glucagon in the pancreas? what about the intestine?

Answer 25

Pancreas=GLUC active Intestine= GLP-1 and GLP-2 active (intestinal GLP stimulated by carbohydrates) -tissue specific enzymes

Question 26

Glucagon is counterregulatory hormone to insulin, when is it activated, what does it do?

Answer 26

- released in response to low blood glucose levels - aa stimulate release (protein meals) - catecholamines stimulate release (exercise)

Question 27

What is glucagons primary action?

Answer 27

energy metabolism

Question 28

What are glucagons main targets?

Answer 28

Liver and adipose tissue -no glucagon receptors in skeletal muscle Has opposite effect of insulin

Question 29

How does glucagon turn on the phosphatase activity of the bifunctional enzyme?

Answer 29

phosphatase activity by phosphorylase

Question 30

How does insulin turn on the kinase activity of the bifunctional enzyme?

Answer 30

kinase activity by dephosphorylase

Question 31

``` ghrelin where? what does it stimulate? what produces it? what is its action on beta cells ? ```

Answer 31

28aa peptide - most circulating ghrelin produced in the stomach - stimulates food intake at level of hypothalamus-->stimulates GH release-->inverse correlation between circulating ghrelin and obesity (low ghrelin in obese patients) - produced by epsilon cells of islets - paracrine action on beta cells - inhibits insulin release via Galph inhibitor activation (opens) of K+ channels-->decrease intracellular Ca--->decreases insulin release

Question 32

``` What is somatostatin (SS14)? produced by stimulated by inhibited by function? ```

Answer 32

produced by delta cells in pancreatic islets -stimulated by high fat, high carb meals inhibited by insulin suppresses insulin release-used in clinic for management of insulin producing tumors -under normal conditions insulin does not play a role in insulin release

Question 33

What is amylin do? what is it released with? What is circulating amylin increased?

Answer 33

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

Question 34

What are the counter regulators hormones to insulin?

Answer 34

1. glucagon-primary 2. growth hormone and cortisol - permissive effects on gluconeogenesis and lipolysis - delayed response (6 hours) -defense against prolonged hypoglycemia (starvation) 3. catecholamines-epinephrine - like glucagon, raise plasma glucose levels - increased during exercise and stress - inhibits insulin release directly at beta cells. stimulates glucagon in alpha cells - increases hepatic glucose output - decreases glucose uptake in skeletal muscle/ adipose tissue

Question 35

What is secreted in a mixed meal due to carbs, fat, and protein?

Answer 35

Carbs-insulin Fat-insulin Protein-glucagon, insulin (some)

Question 36

What is secreted in a protein only meal?

Answer 36

glucagon only

Question 37

When insulin is present AA from protein will stimulates GH which stimulates what? What does this do?

Answer 37

IGF-I (liver) -stimulates glucose uptake in muscle, proliferation of visceral organ tissue; inhibit proteolysis GH opposes insulin lipogenesis - ratio between insulin and GH will ultimately determine the net amount of fat after eating the meal - eventually IGF-1 will inhibit GH