Exam 2: Pancreas Flashcards
What are the 5 peptide hormones the pancreas secretes and cell types that secrete them?
- Insulin (beta cells)
- Glucagon (alpha cells)
- Somatostatin (delta cells)
- Pancreatic polypeptide (F cells)
- Ghrelin (major production site = stomach)
What do insulin and glucagon do?
function in a coordinated way to regulate glucose, FAs, and AA metabolism
What endocrine organ does Ghrelin signal? What is it promoting?
signals hypothalamus to promote food intake (hunger signal)
What are the endocrine cells of the pancreas that are arranged in clusters and make up 1-2% of the pancreatic mass called?
Islets of Langerhans
How Islets of Langerhans are in the pancreas and about how many cells does each contain?
1 million in pancreas, each containing about 2500 cells
2.5 billion cells in total
What are the four types of cells in the Islets of Langerhans? What do they secrete?
- alpha- 20%–> glucagon (outer rim)
- beta- 65%–> insulin (central core)
- delta -10% –> somatostatin (interspersed)
- PP (F) - 5%–> pancreatic polypeptide
What are the three way of paracrine communication for the islets cells?
- Gap junctions
- Blood supply
- Neural innervation (SNS, Parasym.)
What do the gap junctions ass. with Islet cells connect?
alpha – alpha
beta – beta
alpha – beta
Describe the blood supply aids in communication for the Islet cells.
arranged so that venous blood of one cell type bathes the other cell types
What is the neural innervation of the islet cells of the pancreas?
richly innervated with Parasymathetic, Sympathetic, and peptidergic fibers that terminate on or near secretory cells
Where are the parasympathetic preganglionic fibers that are synapsing with postganglionic cholinergic and peptidergic neurons in the pancreatic ganglia from?
from dorsal motor nucleus of vagus
Where are the parasympathetic preganglionic fibers from the dorsal motor nucleus of the vagus synapsing with in the pancreas?
synapse with postganglionic cholinergic and peptidergic neurons in the pancreatic ganglia
What goes Vagal stimulation of the islets cells stimulate and via what substances?*
vagal simulation via Ach and VIP stimulates release of insulin
Where do the sympathetic preganglionic cell bodies originate that synapse with postganglionic fibers in the paravertebral ganglia and celiac ganglia of the pancreas?
in the cord intermediolateral horn cells
What do the sympathetic preganglionic cell bodies orginating in the cord intermediolateral horn cells synapse with when they get to the pancreas?
with postganglionic fibers in the paravertebral ganglia and celiac ganglia
What does activation of pancreatic sympathetic nerve fibers cause the pancreas to do?*
causes stimulation of glucagon and inhibition of insulin release from the pancreas (in both human and animal studies)
What is another name for insulin? What cells of the pancreas secrete it?
1st hormone
beta cells
What type of hormone is insulin?
peptide hormone consisting of two straight chains (A and B) linked by two disulfide bridges, and a third disulfide bridge w/in A chain
Where is insulin metabolized? What happens?
in liver and kidneys by enzymes that break disulfide bonds
separate A and B chins (inactive) and excreted in the urine
What is the inactive precursor of insulin that has a signal peptide cleaved early in biosynthetic process to become proinsluin?
Preproinsulin (four peptides)
- A chain
- B chain
- Connecting peptide = C peptide
What is preproinsluin minus the signal peptide?
Proinsulin
Where is proinsulin shuttled? What occurs here?
to the ER where disulfide bridges form and create folded form
C peptide is removed by proteases and both C peptide and insulin are packaged into secretory granules by golgi apparatus and released together in EQUAL amounts
What is secrete with the biologically active form of insulin in equal amounts?
C peptide (can help measure B cell fxn in ind with Type I diabetes)
What is used as the basis for a test of beta-cell fxn in ppl with Type i diabetes mellitus who are receiving injections of exogenous insulin? Why?
C-peptide
b/c secreted in equimolar amounts with insulin and excreted unchanged in urine
What will stimulate insulin secretion?
- increase glucose, AA, FA, ketones
- cortisol
- GIP
- GLP-1
- K+
- Ach (vagal stimulation)
- obesity
- GH/Prolactin
- Glucagon (weirddd)
- beta-adrenergic agonists
- Sulfonylurea drugs
What will inhibit insulin secretion?
- decrease glucose conc.
- fasting
- exercise
- somatostatin (inhibits GH)
- IGF-1
- Leptin
- SNS mediated by alpha-adrenergic receptors on beta cells
- diazoxide
Why can’t we use insulin to monitor endogenous beta-cell function of Type 1 diabetics?
since insulin levels include both endogenous production and exogenous administration
(therefore use C-peptide)
How is insulin secreted/regulated at the cellular level?
glucose transported into beta-cell via GLUT 2 –> phosphorylated by glucokinase –> G-6-P –> G-6-P oxidized yielding ATP (key regulatory factor) –> ATP closes K+ channels –> depolarization –> opens Ca++ channels –> increase intracellular Ca++ –> increase insulin secretion
What has a greater affect as a stimulant of insulin, Oral glucose or intravenous glucose?* Why?
oral glucose–> stimulates secretion of GIP (type of incretin, in the gut)
(intravenous glucose bypasses GIP)
T/F. Intravenous glucose causes the release of GIP and therefore has a greater affect than oral glucose.
FALSE– intravenous glucose does not cause the release of GIP and therefore ONLY acts directly*
What does GIP (Glucose dependent insulinotropic polypeptide) do in humans?
gut hormone–> has independent stimulation effect on insulin secretion adding to the direct stimulation effect of glucose on the beta-cell
What is the group of GI tract hormones that cause increase insulin release after eating?
Incretins
What are the two major incretins?
- GIP (glucose-dependent insulinotropic polypeptide/ gastric inhibitory peptide)
- GLP (glucagon like peptides, aka enteroglucagon)
What effect to incretins have on the gut?
slows rate of intestinal absorption by slowing rate of emptying of stomach and may also decrease food intake
What rapidly inactivates incretins?
dipeptidyl peptidase 4 (DPP-4)
What affect to DPP-4 inhibitors have on the gut?
block DPP-4 and therefore decrease blood glucose by preventing breakdown of GIP and GLP in gut (types of incretins)
What drugs are used to treat type II (non-insulin-dependent) diabetes mellitus? How does it work?
Sulfonylurea drugs
stimulates insulin release by closing K+ channels
Describe the receptor that insulin binds to.
binds to alpha subunits of the receptor
Receptor = Tetramer
- 2 alpha (extracellular)
- 2 beta (span cell membrane and tyrosine kinase activity)
When insulin binds to the receptor what does it activate and in what part of the receptor?
activates tyrosine kinase in the beta subunit and phosphorylates itself in presence of ATP
What happens after tyrosine kinase is activated in the insulin receptor?
phosphorylates several other proteins/enzymes –> physiologic effects
phosphorylation either activates or inhibits these proteins to produce various metabolic actions of insulin
What is insulins affect on its own receptor? What could this partly be responsible for?
it down regulates its own receptor by rate of synthesis and increases rate of degradation
for decrease insulin sensitivity or target tissues in obesity (metabolic syndrome) and type II diabetes mellitus
What happens tot he insulin-receptor complex?
internalized by endocytosis and is degraded by intracellular proteases OR stored OR recycled to the cell membrane to be used again
What affect does insulin have on gene transcription? What other substance does this have similar actions of?
stimulates gene transcription (similar to somatodmedins IGF-1 and IGF-2) by nuclear binding
What is considered “the hormone of abundance”?
insulin
What does insulin do when the availability of nutrients is greater than body demands?
ensures that excess nutrients are stored in:
- Glycogen in liver
- Fat in adipose tissue
- Proteins in muscle
We know insulin ensures storage of excess nutrients, why/when would this be important?
stored nutrients are then available when body demand is greater than intake of nutrients (i.e. fasting) to maintain glucose delivery to CNS
What are the actions of insulin on?
- blood glucose conc
- blood FA and ketoacid conc
- blood AA conc
- K+ and glucose
- satiety center
- decrease blood glucose conc.
- decrease blood FA and ketoacid conc.
- decrease AA conc
- promote K+ uptake into cells and glucose
- direct effec ton hypothalamic satiety center
What nucleus does insulin have a direct effect on in the hypothalamic satiety center?
ventromedial nucleus
How does insulin decrease blood glucose?
- increase glucose transport into cells (muscle and adipose) via GLUT 4
- promotes formation of glycogen in liver/muscle and inhibits glycogenolysis
- Inhibits gluconeogenesis
How does insulin inhibit gluconeogenesis?
increases production of 2,3-bisphosphate –> which increases fructokinase activity –> therefore substrates are directed away from the formation of glucose
T/F. Liver requires insulin for glucose uptake.
False— liver does NOT require insulin for glucose uptake
– GLUT 2 is insulin independent
How does insulin decrease blood FA and ketoacids concs? (in adipose and liver specifically)
- inhibit mobilization and oxidation of FA and increase storage
In adipose–> stimulates fat deposition and inhibits lipolysis
In liver–> inhibits ketoacid formation by decrease FA degradation and therefore decrease acetyl coenzyme A available for formation of ketoacids
How does insulin decrease blood AA conc.?
- has anabolic effect on tissues
- increases AA and protein uptake by tissues
- increases protein synthesis and decrease protein degradation
What are the tissues that do not need insulin for glucose uptake?
"BRICKLE" B- brain R- RBSs I - intestine C - cornea K - kidney L - liver E - exercising skeletal muscle
Which GLUT transporter is insulin independent?
GLUT 2
How is glucose transport into pancreatic beta-cells done?
via GLUT 2
Impaired insulin homeostasis can cause what?
hyperinsulinemia or hypoinsulinemia
What is a symptoms of insulin resistance and may contribute directly or indirectly to a vast array of metabolic diseases associated with insulin resistance?
hyperinsulinemia
What are some chronic metabolic diseases that are linked to hyperinsulinemia?
- all inflam conditions
- all vascular disease
- gestational diabetes
- Type II diabetes
- non-alc fatty liver disease
- obesity
- certain cancers
- certain dementias
What are some possible mechanisms of hyperinsulinemia in chronic disease?
- increased production of IGF-1
- ROS (free radical damage)
- TG and FA abnorms
- effects on leptin, adiponectin, estrogen
What does Mellitus = ? What does insipidus = ?
= sweet
= tasteless
What type of diabetes mellitus is insulin dependent? What occurs?
Type I
- inadequate insulin secretion (destruction of beta-cells–often autoimmune)
- increase blood glucose, FA, ketoacid, AA concs (lose of lean body mass and adipose)
- increase ketoacid–> metabolic acidosis
- glucosuria (glucose in urine)
- Hyperkalemia (increase K+)–(b/c insulin helps more K+ into cells too)
What would the hyperkalemia associated with Type I Diabetes Mellitus cause?
muscle flaccidity and weakness
insulin helps move K+ into cells
What Type of diabetes is non-insulin dependent? What occurs?
Type II
- insulin resistance of target tissues
- ass. with inflam. ass. w/ obesity–>metaboic syndrome
- caused by down regulation of insulin receptors and insulin resistance
- elevated blood glucose
-
What is the Tx for Type I diabetes mellitus? What about Type II?
Type I –> insulin replacement therapy
Type II –> caloric restriction, weight reduction, drugs that stim. insulin secretion, and up regulate insulin receptors, and exercise
What test assess the ability to dispose of a glucose load?
Oral Glucose Tolerance Test
What is the Oral Glucose Tolerance Test used for?
evaluate existing or impending diabetic conditions
- take glucose orally and ass. blood glucose levels over next 4 hrs
What is the normal and abnormal results for an Oral Glucose Tolerance Test?
Normal–> peak blood glucose levels not exceeding 180mg/dl and back to baseline w/in 2 hrs
Abnormal–> blood glucose peak much higher and take a longer time to return to normal
What is the concentration of glucose in b/w meals in normal inds? What can that of diabetics be?
normal = 90 mg/dl
diabetics can be 300-400 mg/dl
What is a common blood test used to Dx type I and type 2 diabetes and then to gauge how well patient is managing their diabetes? What do the results reflect?
A1C test
- results reflect average blood glucose level for past 2-3 months
What does the A1C test measure specifically?
what percentage of hemoglobin is glycated (coated w/ glucose)
higher A1C level = poorer blood glucose control, and increase risk of diabetes complications
What is a normal A1C level? What is pre diabetes? What is diabetes?
Normal = 4-5.6 mg/dl
Pre diabetes = 5.7-6,4 mg/dl
Diabetes = >6.5 mg/dl
What type of cells is glucagon synthesized and secreted by?
islet alpha-cells of panreas
What is considered the hormone of starvation?
glucagon
What does glucagon promote?
mobilization and utilization of CHO, fats, AAs (metabolic fuels)
What other fuel-mobilizing hormones does glucagon act in concert with to counterbalance the fuel-storing effects of insulin?
cortisol
Epinephrine
GH
T/F. States of glucagon excess or deficiency commonly lead to overt diseases.
FALSE— the commonly do NOT lead to overt disease due to other hormonal compensation
Describe glucagon structure. What is it synthesized as?
single straight-chain polypeptide
synthesized as preproglucagon
What others are in the family of peptides that glucagon belongs to?
one that includes GI hormones, such as secretin and GIP
What are stimulatory factors for glucagon secretion?
- fasting
- decrease glucose conc
- increase AA conc
- CCK
- SNS stimulation
- alpha-adrenergic agonists (Epi, NE)
- Ach
- GIP
What are inhibitory factors for glucagon secretion?
- glucose
- insulin
- somatostatin
- increase FA and ketoacid
- GLP-1
What maintains blood glucose in the fasting state?
glucagon
Where is glucagon’s main site of action? what does it stimulate it to do?*
liver–stimulates it to produce and secrete glucose* and ketone bodies
How does the liver release glucose from glucagon stimulation?
Increase glycogenolysis, gluconeogenesis, lipolysis –> which increases blood levels of glucose, FA, ketoacids
What are the physiological actions of glucagon?
- stimulates hepatocyte to produce glucose
- glycogeneolysis and inhibits formation of glycogen from glucose
- gluconeogenesis
- lipogenesis and ketogenesis
- ureogenesis
What affect does insulin have on glucagon?
inhibits secretion of glucagon
If plasma glucose is greater than 200 mg/dl, how is glucagon secretion effected?
inhibited maximally
What effect do free fatty acids have on glucagon secretion?
inhibits it
Is glucagon secretion stimulated by a protein rich meal? Why or why not?
yes;
- alpha cells stimulated directly by arginine (which also stimulates insulin)
- digestion of protein rich foods stimulates release of CCK and GIP –> stimulating pancreatic islet cells –> therefore stimulating release of BOTH insulin and glucagon)
What is the point of release glucagon in response to a protein rich meal?
- prepares liver to dispose of excess AAs by gluconeogenesis
- Signals liver to release glucose and counteract potential hypoglycemic effects of insulin (whose secretion is simultaneous increased by AAs)
What is somatostatin secreted by, organ and cells?
delta cells of pancreas
What stimulates the release of somatostatin?
ingestion of all forms of nutrients, glucagon, beta-adrenergic agonists
What inhibits the release of somatostatin?
insulin
What affect does somatostatin have on insulin? What about glucagon?
inhibits secretion of BOTH
What is the function of somatostatin?
modulate or limit responses of insulin and glucagon to ingestion of food
What secretes Pancreatic Polypeptide?
PP (F) cells of pancreas (they also secrete other peptides)
What is the function of PP (pancreatic polypeptide?
self regulate the pancreas secretory activities (both endocrine and exocrine)
- also has effects on hepatic glycogen levels and GI secretions
When is Pancreatic Polypeptide (PP) secreted in humans? When is its secretion decreased?
after a protein meal, fasting, exercise, and acute hyoglycemia
is decreased by somatostatin and intravenous glucose
Where is Ghrelin mainly secreted from and when? What other organs can secrete it?
stomach mucosa in b/w eating
pancreas*, brain, ovary, adrenal cortex
What is the only GI tract hormone that promotes food intake?
Ghrelin
What can stimulation of ghrelin receptors on afferent neurons initiate?
vago-vagal reflexes and local enteric reflexes
What are the affects of Ghrelin?
- released into the blood and can cross the BBB affecting the hypothalamus where it stimulates appetite
- increase feelings of hunger
- increase gastric acid secretion, gastric motility and gastric emptying