Endocrine Lecture 5 Flashcards
Pancreas:
Exocrine vs Endocrine Pancreas
Exocrine pancreas: majority of cells, acinar cells secrete digestive enzymes “pancreatic juice” into pancreatic duct
Endocrine pancreas: consists of 3 major cell types clustered in groups called the islets of Langerhans
Explain the following endocrine pancreas cell types:
Explain which hormones they secrete and how abundant are they?
Beta Cells
Alpha Cells
Delta Cells
Epsilon Cells
Beta Cells (most abundant, 75%) secrete insulin
Alpha cells (20%) secrete glucagon
Delta cells (5%) secrete somatostatin (SS14)
Epsilon Cells (<1%) secrete ghrelin
What are the major and minor pancreatic hormones
Major Hormones: insulin (energy storage…anabolic hormone), glucagon (energy mobilization…catabolic hormone)
Minor: somatostatin, amylin, ghrelin
Explain the arrangement of alpha and beta cells in humans
Beta cells are clustered in the “____” while alpha cells are “______”
_____ effects between beta and alpha cells
Explain the flood flow pattern within the islet of langerhans
Arterioles that feed the islet come straight into the _____ (beta cells respond to _____)
Cells on outside are then___
Arterioles that feed into the islet come straight into the center (beta cells respond to blood glucose)
Cells on outside are then hit with hormones from beta cells (so insulin directly affects alpha and delta cells but the outside do not affect the inside cells)
Insulin rich blood flows from the center to the periphery islet
Insulin Synthesis:
Half life of insulin is _____
Insulin and ____ are released together
___ half life is _____: making it a good indicator of pancreatic function
Cleavage of _____ is critical for the insulin to be able to interact with its receptor
Insulin synthesis:
Half life of insulin is 3-8 minutes
Insulin and C peptide are released together
C peptide half life is 35 minutes: making it a good indicator of pancreatic function
Cleavage of C peptide is critical for the insulin to be able to interact with its receptor
(Note: endogenous insulin is what has C peptide, if you inject someone with EXogeneous insulin, it will NOT have c peptide)
You can measure C peptide in blood to see if someone is making endogenous insulin or not
Explain the seven steps of insulin release (look at the sheet)
- Glucose is high in the blood outside the beta cell and the beta cell senses it
- Glucose gets transported inside the beta cell by GLUT-2 (low affinity transporter, only active when glucose is high)…. glucose gets phosphorylated by GK, and the metabolism of G6P generates ATP
3/4. The ATP generated from the glucose 6 metabolism closes K+ channels
5/6: increased K inside the cell causes cell membrane to depolarize, opening voltage gated calcium channels
- Calcium influx causes exocytosis of insulin containing vesicles
Describe the basis of the biphasic response of insulin release following ingestion of a meal
Biphasic Insulin Response:
Insulin release is biphasic in response to glucose
5% of vesicles are available for immediate release - docked at membrane
95% are “stored” or reflext newly synthesized insulin
Insulin Receptors:
Receptor Tyrosine Kinases
Insulin binds receptor at ____ subunit
_____ is autophosphorylated
Autophosphorylation of receptor recruits IRS (insulin receptor substrates)
IRSs activate intracellular signaling cascades (explain the two intracellular cascades for insulint)
Insulin Receptors:
Receptor Tyrosine Kinases
Insulin binds receptor at alpha subunit
Beta subunit gets autophosphorylates
Autophosphorylation of receptor recruits IRS (insulin receptor substrates)
IRSs activate intracellular signaling cascades:
- AKt - metabolic actions
- MAPK: mitogenic actions
Insulin Receptors:
AKt pathway: muscle and adipose tissue
What is the glucose transporter for muscle and adipose tissue?
AKt pathway: all anabolic effects
GLUT 4 translocation in muscle and adipose tissue to get glucose into skeletal muscle and adipose tissue (GLUT 4 is insulin dependent)
AKT promotes anabolism so it promotes glycolysis, protein synthesis
Explain the following glucose transporters
GLUT 1
GLUT2
GLUT3
GLUT4
GLUT5
GLUT1: brain vasculature, insulin independent
GLUT2: pancreatic beta cells, liver, intestine, insulin indendent, but low affinity, only works when glucose is high
GLUT3: neurons, major transporter in brain
GLUT4: only one that is insulin dependent, in skeletal muscle and adipose tisse
GLUT5: sperm
Insulin: Physiological Effects on Adipose Tissue:
Primary action is energy ______
promotes _____ production
release of ___ from _____
inhibits lipolysis
glucose enters adipose tissue via which transporter
Insulin: Physiological Effects on Adipose Tissue
Primary action is energy storage
Promotes TG production
release of FFA from chylomicrons, glycolysis (for energy to make TG)
inhibits lipolysis
Glucose enters via GLUT 4
Insulin: Physiological Effects on Muscle
Primary action is ______
Muscle: promotes ____ and ____ production, and protein ______
Glucose enters through _____ (transporter)
Insulin: Physiological Effects on Muscle:
Primary action is energy storage
Muscle: promotes glycogen and TG production, protein synthesis
Glucose enters through GLUT 4
Insulin: physiological effects on liver:
Liver: promotes ___ and ____ production
____ glucose production output via:
- inhibits _____ (enzyme)
- stimulates ______ synthesis (enzyme)
Glucose enters liver via _______ (transporter)
Insulin: Physiological Effects:
Primary action: energy storage:
Liver - promotes glycogen and TG storage, reduces glucose production output:
- inhibits glucose 6 phosphatase
- stimulates glucokinase synthesis
Glucose enters liver via GLUT 2
note: the creation of TG in the presence of high glucose creates “fatty liver”
Glucagon Synthesis:
Products from the Pancreatic A cell include?
PRoducts from intenstinal L cell include?
- ______ (GLP-1 and GLP-2) are important in clinical use
- synthesizes from the same prohormone as glucagon
- tissue specific enzymatic activity
- Intestinal GLP is timulated by ______
Glucagon Synthesis:
Products from pancreatic a cells: active glucagon and inactive copeptides
Products from intestinal L cell: inactive glucagon-GRPP but active GLP-1 and GLP-2
Incretins (GLP-1 and GLP-2) are important clinical use
Synthesized from same prohormone as glucagon
Tissue specific enzymatic activity
Intenstinal GLP is stimulated via CARBS
Glucagon Release:
Major counterregulatory hormone to insulin - most things that stimulate insulin will ____ glucagon
Released in response to ___ glucose levels
What two things (other than low glucose) stimulate glucagon?
Glucagon Release:
Major counterregulatory hormone to insulin - most things that stimulate insulin will inhibit glucagon
Released in response to low glucose levels
AAs stimulate release (protein meals)
Catecholamines stimulate release (exercise)
Insulin Release: Other modulatory pathways:
GLP-1 (incretins):
- Produced in ___ by ___ cells
- Released in response to high ____
Potentiate insulin release by increasing intracellular calcium
Degraded by ____ enzyme
Drug target for T2DM
GLP-1: (incretins:
-Produced in intestine by L cells in response to high carb meal
Potentiate insulin release by increasing intracellular calcium
Degraded by DPP-4 enzyme
Drug target for T2DM
Protein/AA - metabolism generates ATP which can increase intracellular calcium _______ insulin released from protein alone
NE/EPI directly ___ insulin release from beta cell through activation of ______ receptors (decreases cAMP and prevents increase in intracellular Ca)
Action at ______ receptor is minor and contributes primarily to basal release
Protein/AA: very little insulin release from protein alone
NE/Epi (catecholamines) directly inhibit insulin release through activation of alpha-2 adrenergic receptors
Action at beta-2 is minor and contributes to basal release
Glucagon Actions:
Primary action: _______
Main targets are _____ and ____
There are NO glucagon receptors in ______
Glucagon is ____ of insulin
Glucagon Actions:
Primary actions: energy mobilization
Main targets: liver and adipose tissue
There are NO glucagon receptors in skeletal muscle
Opposite effects of insulin
Somatostatin (SS14)
- produced by ____ in pancreatic islet
- stimulated by ______ meals
- _____ by insulin
- how is it used to treat insulin producing tumors
Amylin:
- released with ______
- synergistic with insulin in regulation of blood glucose
- circulating amylin is ___ with obesity
Somatostatin (SS14)
- produced by delta cells in pancreatic islet
- stimulated by high fat, high carb meals
- inhibited by insulin (just how it works paracrine wise)
- SS14 is used to treat insulin producing tumors because it will supress insulin release
Amylin:
- released with insulin and C peptide in secretory vesicles
- synergistic with insulin in regulation of blood glucose
- circulating amylin increased with obesity, HTN
What is used to treat insulin producing tumors
Insulin producing tumors:
treated with SS14 (supress insulin release)
Ghrelin:
most circulating ghrelin is produced in the stomach
- Stimulates food intake at the hypothalanus
- _____ Gh release
______ relationship between ghrelin and obesity
Produced in ____ cells of islet
Paracrine action on beta cells:
____ insulin
Ghrelin: the stomach gremlin stimulating to your brain that you are hungry and food deprived
Stimulates food intake at the hypothalamus
STIMULATES GH release
inverse relationship between ghrelin and obesity
Produced in EPSILON cells of islet
Paracrine action on beta cells: ghrelin will inhibit insulin release (makes sense because you are already low in blood sugar, don’t need to be any lower)
When you haven’t eaten in a while:
what is released first
what is then released after 6 hours
When you haven’t eaten in a while and your blood glucose starts to go down
Glucagon - primary
Then cortisol and growth hormone are released 6 hours later (defense against prolonged hypoglycemia)
Catecholamines : ____ plasma glucose levels, increased during exercise and stress
Catecholamines: Epi:
- ______ insulin release
- ______ glucagon release
- ____ hepatic glucose output
- ______ glucose uptake in skeletal muscle
Catecholamines: raise plama glucose levels
Catecholamines; EPI:
- inhibit insulin release (a2 receptor)
- stimulate glucagon release
- increase hepatic glucose output
- decrease glucose uptake in skeletal muscle
