Lecture 15: Endocrine Pancreas Flashcards
What substances do endocrine pancreas cells secrete?
- insulin, glucagon, somatostatin
- from cells that make up the Islets of Langerhans
What innervates the cells of the Islet of Langerhans?
-adrenergic, cholinergic and petidergic neurons
What cells make up the Islet of Langerhans and what do they produce?
B cells - central, insulin and C peptide
a cells - peripheral, glucagon
delta cells - in between, somatostatin
F/PP cells - pancreatic polypeptide (satiety signal)
How do the cells of the Islet communicate with each other?
Gap junctions (between a-a, b-b, a-b) for rapid communication
Describe the blood flow to the islet
- 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
What is insulin?
How is it synthesized?
-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
What is C-peptide and how does it relate to insulin?
- 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)
Draw the pathway of insulin release
OK
What is the significance of the sulfonylurea receptor?
- increases depolarization > increased Ca2+ > increased vesicle fusion and release of insulin
What does it mean for insulin release to be biphasic?
Normal: big spike release (phase 1), then gradual release (phase 2)
Diabetics: big spike is absent
What happens to the insulin receptor?
-autophosphorylates when insulin binds and is internalized by cell
When insulin binds to target cell, what are its intracellular effects?
Metabolic: Glut 4 and 2 translocation on membrane to let glucose in
Growth: activation of mTORC1 & SREBP1c
Draw the pathway of insulin leading to expression of Glut 4
Ok
How can glucose uptake happen in the absence of insulin?
muscle contractions (exercise) > AMPK translocates GLUT4 to membrane > glucose uptake
What are the stimulators of insulin secretion?
What are the inhibitors of insulin secretion?
-K, GIP, Ach from CNX, sulfonylurea, obesity
fed and stressed processes
-NE, hypogly, diazoxide
hungry and active
What effects does ….have on Insulin secretion
Ach, CCK, GLP
Somatostatin
Glucagon
- activate release
- inhibit release
- inhibited by insulin, but activates insulin secretion
Effects of insulin on…
skeletal muscle
liver
adipocyte
- 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
What is glucagon?
How is it synthesized?
- straight chain polypeptide with 29 AAs, stored in granules of a-cells
- preproglucgon > proglucagon > glucagon
How is glucagon released?
Major stimulator is low glucose
same mechanism of insulin release, but just riggered by low ATP instead of high
What inhibits glucagon release?
-Insulin, somatostatin, FAs, ketoacids
What are the major effects of glucagon on …
liver
adipose
muscle
Liver: enhance processes that make/release glucose
Adipose: lipolysis, ketoacid production
Muscle: lipolysis
Be able to draw he overview of systemic DM effects
Ok
Type 1 DM:
Cause
Clinical
- rapid B cell destruction leading to lack of insulin production
- symptoms start appearing when 80% of B cells are destroyed, hyperglycemia, ketoacidosis
How does Type 1 DM lead to ….
hyperkalemia
osmotic diuresis/glucosuria
- 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)
What is the main treatment for Type 1 DM?
What is a possible emerging treatment for Type 1 DM:?
Insulin replacement, but takes time, painful, slow and poor glucose control
HEK-B, designed B cell that works like human B cell
How does obesity cause Type 2 DM?
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
Obesity induced insulin resistance is characterized by
decreased GLUT 4 uptake, decreased liver “sensing” of insulin, unsuppressed lipolysis
What is reactive hyperinsulinemia and how is it different in Type 2 DM?
Type 2 diabetics need to use more insulin to stabilize glucose compared to a normal person
What are incretin hormones?
- secreted in response to glucose and fat (e.g. GLP 1 or GIP)
- stimulates insulin spike in normal patients, reduced spike response in diabetics
