Lecture 15: Endocrine Pancreas

Question 1

What substances do endocrine pancreas cells secrete?

Answer 1

• insulin, glucagon, somatostatin

- from cells that make up the Islets of Langerhans

Question 2

What innervates the cells of the Islet of Langerhans?

Answer 2

-adrenergic, cholinergic and petidergic neurons

Question 3

What cells make up the Islet of Langerhans and what do they produce?

Answer 3

B cells - central, insulin and C peptide
a cells - peripheral, glucagon
delta cells - in between, somatostatin
F/PP cells - pancreatic polypeptide (satiety signal)

Question 4

How do the cells of the Islet communicate with each other?

Answer 4

Gap junctions (between a-a, b-b, a-b) for rapid communication

Question 5

Describe the blood flow to the islet

Answer 5

• first flows to central B cells then to a and delta cells

- B cells “decide” to release insulin first > a and delta cells release glucagon is insulin is not released by B cells

Question 6

What is insulin?

How is it synthesized?

Answer 6

-anabolic hormone, major stimulator is glucose

Preproinsulin (no disulfide) > Proinsulin (has attached C-peptide) > secretory granules (cleaved) > insulin + cleaved C peptide

*final insulin has cleaved off the C-peptide and has a disulfide bridge

Question 7

What is C-peptide and how does it relate to insulin?

Answer 7

• attached to inactive insulin, has to be cleaved off to release active insulin
• secreted together (one won’t exist without the other, so C-peptide in urine is good indicator of insulin levels)

Question 8

Draw the pathway of insulin release

Answer 8

OK

Question 9

What is the significance of the sulfonylurea receptor?

Answer 9

• increases depolarization > increased Ca2+ > increased vesicle fusion and release of insulin

Question 10

What does it mean for insulin release to be biphasic?

Answer 10

Normal: big spike release (phase 1), then gradual release (phase 2)

Diabetics: big spike is absent

Question 11

What happens to the insulin receptor?

Answer 11

-autophosphorylates when insulin binds and is internalized by cell

Question 12

When insulin binds to target cell, what are its intracellular effects?

Answer 12

Metabolic: Glut 4 and 2 translocation on membrane to let glucose in

Growth: activation of mTORC1 & SREBP1c

Question 13

Draw the pathway of insulin leading to expression of Glut 4

Answer 13

Ok

Question 14

How can glucose uptake happen in the absence of insulin?

Answer 14

muscle contractions (exercise) > AMPK translocates GLUT4 to membrane > glucose uptake

Question 15

What are the stimulators of insulin secretion?

What are the inhibitors of insulin secretion?

Answer 15

-K, GIP, Ach from CNX, sulfonylurea, obesity
fed and stressed processes

-NE, hypogly, diazoxide
hungry and active

Question 16

What effects does ….have on Insulin secretion
Ach, CCK, GLP
Somatostatin
Glucagon

Answer 16

• activate release
• inhibit release
• inhibited by insulin, but activates insulin secretion

Question 17

Effects of insulin on…
skeletal muscle

liver

adipocyte

Answer 17

• increased glucose uptake, utilization and storage, increased protein synthesis
• increased glucose utilization and storage, increased lipid storage and protein synthesis, increased hexose shunt and pyruvate oxidation
• increased glucose and FA uptake, glucose utilization

Question 18

What is glucagon?

How is it synthesized?

Answer 18

• straight chain polypeptide with 29 AAs, stored in granules of a-cells
• preproglucgon > proglucagon > glucagon

Question 19

How is glucagon released?

Answer 19

Major stimulator is low glucose

same mechanism of insulin release, but just riggered by low ATP instead of high

Question 20

What inhibits glucagon release?

Answer 20

-Insulin, somatostatin, FAs, ketoacids

Question 21

What are the major effects of glucagon on …
liver
adipose
muscle

Answer 21

Liver: enhance processes that make/release glucose

Adipose: lipolysis, ketoacid production

Muscle: lipolysis

Question 22

Be able to draw he overview of systemic DM effects

Answer 22

Ok

Question 23

Type 1 DM:
Cause
Clinical

Answer 23

• rapid B cell destruction leading to lack of insulin production
• symptoms start appearing when 80% of B cells are destroyed, hyperglycemia, ketoacidosis

Question 24

How does Type 1 DM lead to ….

hyperkalemia

osmotic diuresis/glucosuria

Answer 24

• no insulin = K+ leaks out
• increased filtered load of glucose > lots of glucose filtered and water follows > polyuria, polydipsia (losing lots of water since it’s following the glucose out)

Question 25

What is the main treatment for Type 1 DM?

What is a possible emerging treatment for Type 1 DM:?

Answer 25

Insulin replacement, but takes time, painful, slow and poor glucose control

HEK-B, designed B cell that works like human B cell

Question 26

How does obesity cause Type 2 DM?

Answer 26

obese people have more adipose:

adipose tissue dysfunction > release of adipokines, too much lipolysis, inflammation cause insulin resistance > B cell work harder and hypertrophy to keep up with the insulin needed to maintain glucose > this results in amylin secretion with insulin > amylin causes B cell hypotrophy and they die off

Question 27

Obesity induced insulin resistance is characterized by

Answer 27

decreased GLUT 4 uptake, decreased liver “sensing” of insulin, unsuppressed lipolysis

Question 28

What is reactive hyperinsulinemia and how is it different in Type 2 DM?

Answer 28

Type 2 diabetics need to use more insulin to stabilize glucose compared to a normal person

Question 29

What are incretin hormones?

Answer 29

• secreted in response to glucose and fat (e.g. GLP 1 or GIP)
• stimulates insulin spike in normal patients, reduced spike response in diabetics