Endocrinology - Pancreatic Hormones
Describe what happens beta cell (pathway) when the blood glucose is high
-->GLUT transporter influxes glucose into the beta cell -->there is an increase in glycolysis and the citric acid cycle -->this increases the amount of ATP in the cell -->Katp channels close (less K+ leaves the cell) -->the cell becomes depolarized -->Ca2+ channels open -->Ca2+ triggers exocytosis and insulin is secreted
Describe what happens in the beta cell (pathway) when the blood glucose is low
-->GLUT transporter is inactive -->metabolism slows -->there is a decrease in ATP -->the Katp channels open, allowing K+ to leak out (making the cell at resting potential) -->Voltage-gated Ca2+ channels are closed -->no insulin secretion
What is the genetic expression pathway from Pdx1 to beta, alpha, and other endocrine cells?
-->Pdx1+ cells -->Pdx1+/Ptf1a+/Cpa1+ cells -->Pdx1+/unknown+ cells -->Neurog3+ cells -->beta, alpha and other cells!
What is the genetic expression pathway from Pdx1 to acini?
-->Pdx1+ cells -->Pdx1+/Ptf1a+/Cpa1+ cells -->Ptf1a+/Cpa1+ cells -->acini!
Describe the Amplifying Pathway (phase 2) of the biphasic secretion of insulin
-->after the ready releasable pool is depleted, the beta cells enters into insulin synthesis (continues until the blood glucose is returned to a normal level)
How do sympathetic neurons affect insulin secretion? Pathway?
-->decrease insulin secretion -->sympathetic neuron fires catecholamine -->which attaches to an alpha-adrenergic receptor -->decreases insulin secretion
What happens to glucose in the liver when there is low blood glucose?
-->glucagon is secreted --->glycogen storage decreases -->gluconeogenesis increases -->glucogenolysis increases -->glucose production is initiated
What happens to glucose in the adipose tissue when there is low blood glucose?
-->glucagon is secreted -->glucagon causes triglycerides to break down to free fatty acids -->free fatty acids are sent to the liver for gluconeogenesis and ketone synthesis
What happens to glucose in the skeletal muscle when there is low blood glucose?
-->glucagon is secreted -->glucose uptake decreases -->glucogenolysis increases -->glycogen synthesis decreases -->protein breakdown to amino acids increases (aa's for gluconeogenesis in the liver)
Describe the Triggering phase (phase 1) of the biphasic secretion of insulin
-->glucose uptake -->metabolism and ATP production -->K+ channels close, and Ca2+ channels open -->Ca2+ rushes in and induces exocitosis of insulin
How do parasympathetic neurons affect insulin secretion? Pathway?
-->increase insulin secretion -->Parasympathetic neuron fires acetylcholine -->Ach attaches to the AchR -->increases insulin secretion
What is the pathway from insulin receptor to glucose metabolism and glycogen/lipid/protein synthesis?
-->insulin binds to the Insulin Receptor, which gets phosphorylated -->phosphorylates IRS (insulin receptor substrates) -->activates PI3K -->activates Akt -->activates GSK3 -->initiates glucose metabolism and glycogen/lipid/protein synthesis (as well as cell growth and differentiation)
What is the pathway from insulin receptor to the general gene expression for non-metabolic instances of insulin?
-->insulin binds to the Insulin Receptor, which gets phosphorylated -->phosphorylates IRS (insulin receptor substrates) -->activates Ras -->activates Mek -->activates Map Kinase -->initiates general gene expression (as well as cell growth and differentiation)
What happens to glucose in the skeletal muscle when there is high blood glucose?
-->insulin is secreted -->glucose uptake increases -->glucogenolysis decreases -->glycogen synthesis increases -->protein breakdown to amino acids decreases
What happens to glucose in the adipose tissue when there is high blood glucose?
-->insulin is secreted -->insulin causes glucose to break into free fatty acids and glycerol -->Free fatty acids convert into a triglyceride -->glucose is removed from the blood -->lipogenesis is increased
What happens to glucose in the liver when there is high blood glucose?
-->insulin is secreted -->glycogen storage increases -->gluconeogenesis decreases -->glucogenolysis decreases -->glucose uptake and storage
Describe the maturation of an insulin molecule
-->preproinsulin with a signal sequence is transcribed/translated -->signal sequence is cleaved and proinsulin is formed (but is still one connected chain) -->proinsulin is cleaved into an A chain, a B chain and a C peptide
What are two, non-hormone factors that also can influence the secretion of insulin?
-FFAs (increases insulin) -AAs like Arginine (increases Insulin)
What is the functional unit of the endocrine pancreas? Describe where it is located.
-Islet of Langerhans -scattered throughout the pancreas, surrounded by acini (varies in size too)
What are the two phases in biphasic insulin secretion?
-Triggering Pathway (1st phase) -Amplifying pathway (2nd phase)
What is the incretin effect?
-When insulin is given intravenously, the response to high glucose levels is not high -but when insulin is taken orally, the response is really high
What cells form the pancreatic acinus and what do they do?
-acinar cells -secrete enzymes into the intestines (characterized by the presence of zymogen granules)
What are the exocrine components of the pancreas?
-acini -pancreatic ducts
What is the function of glucagon?
-acts opposite of insulin -increase blood glucose
What are the three things that the liver can convert into glucose?
-amino acids (from the skeletal muscle) -lactate -glycerol (from the adipose tissue)
Describe what is seen in Insulin Receptor KO mice
-born at term with normal growth/development -have hyperglycemia and hyperketonanemia (die from ketoacidosis) conclusions:Insulin receptor mediates metabolic actions but not growth/development
What organs only USE glucose and cannot synthesize or store it?
-brain (a ton) -heart
What does the liver do in its role in glucose homeostasis?
-can synthesize and supply glucose -can convert glucose into glycogen and store it in the liver (itself)
What cells form the pancreatic duct?
-centroacinar cells
With what else is amylin secreted?
-co secreted with insulin after a meal
What does the skeletal muscle do in its role in glucose homeostasis?
-consumes glucose -stores glucose as glycogen CAN'T SYNTHESIZE IT
What is somatostatin secreted by?
-delta cells -gastrointestinal cells -immune cells -neuronal cells
What regulates the alpha cell in glucagon secretion?
-delta cells (somatostatin) inhibit glucagon secretion -Beta cells (insulin) inhibit glucagon secretion -the brain inhibits glucagon secretion -GLP-1 inhibits glucagon secretion
What are the two distinct structural components of the pancreas?
-exocrine component -endocrine component
At what stage of development (fetus to adult) do you find high expression of Ghrelin in the pancreas?
-fetal pancreas (PP cells to start?) (decreased greatly in adult pancreas--change to alpha cells later?)
What are the 3 main (organ) sources of blood glucose?
-food intake -liver (glucose synthesis) -kidneys (reabsorbing into the blood)
What can glucose convert fat released from adipose tissue to?
-free fatty acids -ketones
What is secreted by the epsilon cells and how does it regulate the Beta cells (and therefore insulin secretion)?
-ghrelin -it negatively regulates the beta cell and inhibits insulin secretion
What are the two enzyme targets for insulin and glucagon in the liver?
-glycogen synthase -glycogen phosphorylase
Describe what is seen in insulin receptor KO humans
-growth retardation -dysmorphic features -disturbed glucose metabolism Conclusions:in humans the Insulin receptor is not only needed for glucose metabolism but also growth/development
Describe the phenotypes of the IRS-1 KO mice
-growth retarded -mild resistance to insulin but don't get diabetes (have increased secretion of insulin--IRS-2 may compensate) Conclusions:IRS-1 is not associated with metabolism but with growth
What makes the liver a good target for insulin?
-has the hepatic portal vein (endocrine!) -insulin can diffuse into the liver tissue -insulin level in liver is very high
Describe what is seen in IRS-2 KO mice
-impaired insulin signaling -impaired beta cell function in pancreas -progressive deterioration of glucose metabolism due to insulin resistance (Liver/skeletal muscle) Conlcusions: IRS-2 KO get type 2 diabetes (defects in insulin action and insulin secretion) and the functions of IRS-1/-2 are different
What are the functions of ghrelin? and where is it secreted from?
-increased feeding -growth hormone secretion gastrointestinal tract (stomach)
Describe the functions of PP?
-increases after protein meal -inhibits exocrine secretion of the pancreas -inhibits gallbladder contraction -inhibits gut motility -influences food intakes -influences energy metabolism
What effect does GLP-1 have on Beta cells?
-increases glucose-stimulated insulin secretion -increases beta cell number
What are the functions of amylin?
-inhibit glucagon secretion -slow gastric emptying -lower effective levels of glucose intake
What is the function of Somatostatin?
-inhibits both insulin and glucagon secretion (but no direct effect on glucose metabolism)
How is the exocrine component of the pancreas stimulated to release enzymes? (describe pathway)
-initial secretion is stimulated by low grade stim of vagus nerve which causes the secretion of ACH -->Chyme enters the duodenum which stimulates the secretion of CCK and secretin -->CCK binds to the receptors on acinar cells, inducing them to secrete large amounts of enzymes; secretin stimulates the ducts to secrete water and bicarbonate to neutralize acid (usually after digestion is complete)
What are the different hormones released by the endocrine component of the pancreas?
-insulin -glucagon -somatostatin -Pancreatic Peptides (PP) -ghrelin
What is secreted by the beta cells and how does it regulate beta cells (itself) and insulin secretion?
-insulin -it negatively regulates the alpha cell secretion of glucagon -when insulin is not secreted and glucagon is made, it negatively feeds back to the beta cell to suppress insulin production
What are the 3 hormones that act in paracrine fashion to influence insulin secretion?
-insulin -somatostatin -ghrelin
What is starch? How can it be converted into glycogen in the liver?
-it is a poly glucose (many glucose linked together) -amalase cuts the bonds between the glucose and the glucose is then converted to glycogen
What are the organs that control glucose homeostasis?
-liver -skeletal muscle -fatty tissue -heart -brain -kidneys -pancreas
What is the function of insulin?
-lower blood glucose -stimulate glycogen synthesis (liver and muscle) -increase lipogenesis -inhibit gluconeogensis
How many and where are the disulfide bonds in mature insulin?
-one on the A chain -two between the A and B chains
What are the different stages of pancreas development?
-pancreatic bud invagination -endocrine cell differentiation -exocrine and endocrine (further) differentiation -Islets of Langerhans form
What do the kidneys do in their role in glucose homeostasis?
-reabsorbs the glucose and returns it to the blood/liver
What is the function of Pancreatic Polypeptide hormone?
-reduces appetite (released in response to ingestion of food)
What two hormones secreted from the duodenum are the principle regulators of the exocrine pancreas?
-secretin -cholecystokinin (CCK)
What is secreted by the delta cells and how does it regulate the Beta cells (and therefore insulin secretion)?
-somatostatin -it negatively regulates the beta cell and inhibits insulin secretion
What is the function of Ghrelin?
-stimulates growth hormone secretion -important in energy homeostasis (very rare in the pancreas of the adult, but abundant in the fetal pancreas)
Describe the structure of the insulin receptor
-two monomers put together to make a dimer -each monomer has an alpha and a beta subunit held together by an intrinsic disulfide bond -two monomers are held together by an extrinsic disulfide bond
How does amylin slowing gastric emptying help insulin function?
-when amylin slows down the delivery rate (and therefore the glucose absorption rate), insulin can do its job better to control blood glucose levels
What does fatty tissue do in its role in glucose homeostasis?
-when dissociated for energy, is released as a glycerol (a component of free fatty acids) into the blood. -The glycerol can be used to make glucose in the liver by gluconeogenesis
How many different receptor complexes can the monomers make for the insulin receptor?
5 -IRa -IRb -IRa/IGF1R -IRb/IGF1R -IGF1R
What is Pdx1?
A transcription factor that aids in the differentiation of the pancreatic cells. (Pcx1+ cells are considered pancreas "stem cells")
What cells secrete insulin?
Beta cells
What is the ready releasable pool?
Beta cells always have a sufficient amount of insulin in stock (so you get the immediate response)
T/F: Digestive enzymes in the zymogen granules are in the active form.
F: They are held in the INACTIVE form
T/F: Amylin is not a major component of amyloid in non-insulin-dependent Diabetes mellitus
F: it IS a major component
T/F: skeletal muscle can release glucose into blood circulation
F: it can't release it into circulation -can increase uptake of glucose and convert it to glycogen
What is the receptor type for acinar cells?
G-protein coupled receptors
What two incretins boost insulin secretion?
GLP-1: Glucagon-like peptide-1 GIP: Gastric inhibitory polypeptide
What does insulin induce the translocation of to increase the influx of glucose into the beta cell?
GLUT4 transporters
What are the other two factors that can initiate pathways in SOME insulin complexes?
IGF1 IGF2
Which gene is known as the "diabetic gene"?
IRS-2
Which receptor complexes can be initiated by insulin?
IRa IRb IRa/IGF1R
What is the endocrine component of the pancreas?
Islets of Langerhans
How does HNF3 affect the transcription of genes such as PEPCK? (no insulin and insulin)
No insulin: -->HNF3 binds to the IRE (Insulin response element) -->activates the transcription of the target gene (usually ending in gluconeogenesis) Insulin: -->Kicks HNF3 out -->no transcription and no expression of the target gene
What cells secrete pancreatic polypeptides?
PP cells
What are the target genes of insulin?
Repressed genes: -phosphoenolpyruvate carboxykinase (PEPCK) -Tyrosine amino acid transferase -IGF binding protein I
T/F: IAPP is associated with diabetes
T
T/F: Prostaglandin E inhibits insulin secretion
T
T/F:Growth hormone increases insulin secretion
T
T/F: Blood sugar is very stable and is tightly controlled
True
T/F: Secretin and CCK regulate the release of the enzymes from the pancreas
True
What are the different enzymes found in the zymogen granules? What does each digest?
Trypsinogen: proteins Pepsinogen: proteins Procarboxypeptidase:peptides amylase:carbohydrates lipase:lipids dexoyribonuclease/ribonuclease:nucleaic acids
What is HNF3 (hepatocyte nuclear factor 3)?
a transcription factor
What cells secrete glucagon?
alpha cells
"Somatotropin-release inhibiting factors" (SRIFs)
also known as Somatostatins
Which phase of the biphasic secretion of insulin is slow and low magnitude?
amplifying phase
What cells make amylin?
beta cells
What is the major second messenger in the function of glucagon?
cAMP
What are the secondary messengers within the acinar cells after activation of receptors?
cAMP and Calcium
What is the receptor for amylin?
calcitonin receptor (and a helper molecule RAMP)
What cells secrete somatostatin?
delta cells
What type of bond links the A and B chains?
disulfide bonds
What stimulates the release of these pancreatic regulatory hormones into the blood?
entry of acidic chyme into the duodenum
What cells secrete ghrelin in the pancreas (not the stomach)?
epsilon cells
What is the type of receptor for glucagon?
g-protein coupled receptor
What type of receptor does somatostatin have?
g-protein coupled receptor
Process of converting glucose to glycogen
glucogenesis
Process of converting Amino Acids, Lactate, and glycerol to glucose
gluconeogenesis
Process of converting glycogen to glucose
glycogenesis
Where is the insulin held during quiescent stages of the beta cells?
held in secretory vesicles
Describe the tissue dependent processing of glucagon synthesis?
in pancreas: creates active glucagon and inactive GLP-1/2 in intestine: creates an active GLP-2 (modified GLP-1) and inactive Glucagon
What is the end point/biological function of glucagon?
increase glucose
What cells secrete the Pancreatic Polypeptide (PP)?
islet PP cells
What does the pancreas do in its role in glucose homeostasis?
it responds to glucose (by releasing insulin, etc.)
What does the exocrine component of the pancreas do?
it synthesizes and secretes enzymes for digestion into the duodenum of the intestine
What doe the endocrine component of the pancreas do?
it synthesizes and secretes hormones that regulate glucose, lipid, and protein metabolism into the blood
What is the first target for insulin?
liver
What is the major metabolic regulatory organ for glucose homeostasis?
liver
What are the two subunits that make up the PI3-Kinase dimer? What does it associate with?
p85 and p110 associates with the IRS
What is another name for the cells that regulate the exocrine pancreas?
pancreozymin
What kind of hormone is amylin?
peptide hormone
What is the precursor molecule for insulin?
preproinsulin
What is the precursor molecule for glucagon?
proglucagon
What type of hormone is insulin?
protein hormone
What does PEPCK do?
stimulates gluconeogenesis
What is IAPP function an example of?
structural regulation (folding!)
Where is the endocrine component located in respect to the exocrine component?
the endocrine component is scattered throughout the exocrine component
Which phase of the biphasic secretion of insulin is fast and high magnitude?
triggering phase
What enzyme does glucagon up-regulate? down-regulate?
up-regulate: glycogen phosphorylase down-regulate: glycogen synthase
Which enzyme does insulin up-regulate? down-regulate?
up-regulate: glycogen synthase down-regulate: glycogen phosphorylase