80 - Pancreas Flashcards
Carbs, lipids, AA’s, and ketones can all be processed thru what catabolic pw?
TCA Cycle
What enzyme must be present for a cell to use ketone bodies for energy?
Thiophorase
Brain can only use ________ or ________ for energy source.
Glucose or ketone bodies
What’s a consequence of large accumulations of fat in organs, such as w/obesity?
Cell death
Is the majority of the pancreas endocrine or exocrine?
Exocrine
How is the endocrine pancreas arranged?
Consists of 3 major cell types clustered in groups “islets of Langerhans”
What are the 2 main cells of the endocrine pancreas, in order from largest to smallest amount? What about the other 3?
What does each cell secrete?
- Beta cells: 73-75%. Synthesize and secrete insulin.
- Alpha cells: 18-20%. Synthesize and secrete glucagon.
- Delta cells: 4-6%. Synthesize and secrete somatostatin (SS14).
- PP cells: (less than 1%): secrete pancreatic polypeptide.
- Epsilon cells (less than 1%): synthesize ghrelin
What is the function of PP? (endo/para/autocrine?)
Inhibit acinar cells via paracrine action.
What’s the other type of SS besides SS14 (released by delta cells of pancreas), and where is it released from?
SS28
- Released from stomach
What are the major, general functions of insulin and glucagon?
- Insulin: energy storage (anabolic hormone)
- Glucagon: energy mobilization (catabolic hormone)
Besides being produced by epsilon cells of the pancreas, ghrelin is produced in the stomach. What’s its fcn in the stomach?
Stimulates appetite
Describe the blood flow pw of the islets of Langerhans?
What’s the hormonal significance of this?
- Blood comes in thru arterioles, first contacts beta cells in “core”. Then, insulin rich blood reaches alpha cells in “mantle” (periphery) and leaves thru venules
- Significance of “inside-out” flow: insulin affects glucagon, but not vice versa
What is the approx. half-life of insulin?
3-8 min
Is insulin released alone or with another peptide?
W/ “C peptide”
What is the half-life of C peptide?
What is the significance of this?
- 35 min
- Good, measurable indicator of pancreatic fcn (tells if insulin is being released from pancreas)
Why is C peptide synthesized w/proinsulin?
Essential for proper folding w/alpha and beta subunits of insulin (A and B), as well as di-S bond formation
- They are all packaged in storage vesicles together than then C peptide is removed.
Name the 5 steps of insulin release.
- Glucose xported into beta cell via GLUT-2
- Glucose P’lated by glucokinase; ATP generated
- ^[ATP] closes ATP-sensitive K+ channel
- Depolarization, Ca2+ channel opens
- Ca2+ influx causes exocytosis of insulin-containing vesicles
Does GLUT-2 have low or high glucose affinity?
Low, so this occurs when glucose conc is high
How do sulfonylurea drugs specifically act on the process of insulin release?
What is the net effect?
The ATP-sensitive K+ channel has a SUR subunit
- Like ATP, sulfanylurea also close this channel, stimulating the release of insulin (DM tx)
What is known as the pancreatic “glucose sensor”?
Glucokinase
How can FFAs/AAs influence the steps of insulin release from the beta cell?
They increase intracellular ATP, thus shutting off the K+ channel, depolarizing the cell, causing Ca2+ influx and exocytosis of insulin
How do incretins (GLP-1) influence insulin release from the beta cell?
They potentiate insulin release, but still need glucose!
How do catecholamines influence insulin release from the beta cell?
Inhibition (act on alpha-adrenergic receptors of pancreas)
Once a beta cell is stimulated via glucose infusion, describe the pattern of insulin secretion.
Biphasic
- Phase 1 is a spike (5% via docked and ready insulin-containing vesicles
- Phase 2 is a slower rise (95% via new synthesis and vesicle trafficking)
Which of the 2 phases of insulin release is affected by DM?
1st phase
What type of receptor is the insulin receptor?
- Name and describe its subunits
Receptor tyrosine kinase
- Extracellular alpha subunit (w/hormone-binding domain)
- Intracellular beta subunit w/ATP-binding and tyrosine kinase domain)
*Describe the process of insulin binding its receptor.
After, what is recruited and what do they do?
What’s the end result of all of this on a cell (e.g. skeletal myocyte)?
- Insulin binds alpha subunit of receptor, causing autophosphorylation of intracellular beta subunit
- Autophosphorylation of receptor recruits IRSs (insulin receptor substrates).
- IRSs activate intracellular signaling cascades
- End result: GLUT-4 inserted on membrane, glucose can enter cell
What are the 2 key pathways that are stimulated upon insulin binding its receptor?
- PKB/PI3K pathway
2. MAPK pathway
In insulin receptor stimulation, what is the PKB/PI3K pw a mediator of?
What other important protein is involved?
Main mediator of insulin’s metabolic effects.
- TC-10
In insulin receptor stimulation, what is the MAPK pw a mediator of?
Main mediator of insulin’s growth and mitogenic effects
Where is GLUT-1 found?
Brain vasculature, RBCs
- Also SkM, fat, heart (minor)
- Uptake under basal conditions
Where is GLUT-2 found?
Pancreatic beta cells, liver, intestines, kidney
Where is GLUT-3 found?
Neurons
Which is the major transporter of glucose to the brain, GLUT-1 or GLUT-3?
GLUT-3
Where is GLUT-4 found?
SkM, fat, stored inside cell under basal conditions
Where is GLUT-5 found?
Spermatozoa, small intestine
What does GLUT-5 uniquely do?
Xports fructose
Which of the GLUTs are insulin-dependent?
GLUT-4 only!
Which of the GLUTs are, importantly, saturated w/DM?
GLUT-2 (normally have low affinity for glucose)
What are the physiological effects of insulin on the liver?
- Increases glucose uptake
- Promotes glycogen and TG production
- Reduces glucose production/output (inhibits glucose-6 phosphatase and stimulates glucokinase synthesis- for liver)
What are the physiological effects of insulin on the muscle?
- Increases glucose uptake
- Promotes glycogen and TG production, protein synthesis
What are the physiological effects of insulin on fat?
- Increases glucose uptake
- Promotes TG production, release of FFAs from chylomicrons, glycolysis
- Inhibits lipolysis
Besides glucagon, what else does preproglcagon have attached to it?
- Signal sequence
- GRPP
- GLP-1, GLP-2
Describe the products of preproglucagon released from the pancreas (not the stomach).
- Inactive GRPP (co-peptide)
- Active glucagon
- Inactive GLP-1 bound to inactive GLP-2
Describe the product of preproglucagon released from the intestinal L cells.
- Inactive glicentin (glucagon + GRPP co-peptide)
- Active GLP-1 and GLP-2
What does GLP stand for?
What is another name for GLP?
- Glucagon-like peptide
- Incretin
What are the effects of incretins?
Potentiate insulin release from pancreatic beta cells
What, in the intestines, stimulates the release of GLP1/2?
Carbohydrates
If you have a meal of pure carbohydrates, what will be secreted from the pancreas?
Insulin only
What is the major counter-regulatory hormone to insulin?
Glucagon
- Most things that stimulate insulin will inhibit glucagon
What 3 condition stimulates glucagon release from alpha cells?
- Low blood glucose
- Proteinacious meal
- Catecholamines (exercise)
What are the 2 (not 3) main targets of glucagon?
Adipose and liver (not SkM- no receptors)
(From big pic she uses lots of slides)
Overall, what are the effects of insulin?
- ^ glucose uptake + utilization (m. + adipose)
- v hepatic glucose production
- ^ hepatic conversion of glucose to glycogen, lipids
- Inhibit GNG
- Inhibit HSTL, v release of FFA from adipose
(From big pic she uses lots of slides)
Overall, what are the effects of glucagon?
- ^ hepatic GNG and glycogenolysis
- v hepatic conversion of glucose to glycogen/lipids
- v uptake by adipose and muscle
- ^ hepatic ketogenesis
- ^ release of GNG substrates from m., adipose
- ^ HSTL and release of FFA from adipose
What do glucagon and insulin share, w/r/t how they act on enzymes?
Many act on the exact same enzymes
recall: glucagon/epi leads to P’lation, insulin is opposite
What is specifically produced by delta cells in the pancreas?
Somatostatin 14 (SS14)
What types of meal stimulate SS14 production?
What does SS14 do?
- High fat, high carb
- Slows down digestive process
How does insulin affect the production of SS14?
Inhibits it
How does SS14 act on insulin release?
Suppresses it (not physiologically)
What hormone is released w/insulin in beta cells?
Amylin
What does amylin do?
Acts synergistically w/insulin
Circulating amylin has been found to be increased in what 2 disease states?
Obesity, hypertension
How might amylin be related to DM?
Possibly contributes to beta cell destruction by forming amyloid plaques
How many AA’s is ghrelin?
28 AAs
Most circulating ghrelin produced in the ________.
Stomach
What does ghrelin do? (2 things)
- Stimulates food intake at level of hypothalamus (hunger)
- Stimulates GH release (anticipates consumption of food)
How are ghrelin levels related to obesity?
Inverse correlation between circulating ghrelin and obesity
What newly described cells of the pancreas release ghrelin?
Epsilon cells
How does pancreatic ghrelin act on pancreatic beta cells?
- Inhibits insulin release via Gαi activation (opens) of K+ channels
- Decreases intracellular Ca++; decreases insulin release
Besides glucagon, what other hormones have a counter-regulator effect on insulin?
- GH, cortisol
- Catecholamines
How do cortisol and GH serve as counter-regulatory hormones to insulin?
How is IGF-I involved?
- Permissive effects on GNG and lipolysis
- Delayed response (6 hours): defense against prolonged hypoglycemia (starvation).
- In absence of insulin, GH is elevated but cannot stimulate IGF-1. Result: direct glucose mobilization effects of GH, but no cellular proliferation effects of IGF-1. Also, no negative feedback to GH (cuz no IGF-I)
How do catecholamines serve as counter-regulatory hormones to insulin?
- 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
If a normal, mixed meal of fats, carbs, and lipids, what is the balance b/w glucagon and insulin?
What about in an all protein meal?
- More insulin than glucagon
- Glucagon only
When insulin is present (read)…
- AA from protein stimulate GH which stimulates IGF-I (liver).
- IGF-I stimulates glucose uptake in muscle (like insulin), proliferation of visceral organ tissues; inhibits proteolysis.
- GH opposes insulin lipogenesis.
What hormone would be clinically useful in managing insulin-producing tumors?
Somatostatin-14
