14) Pancreas, Gastrointestinal Hormones and Leptin Flashcards
What is central to many metabolic pathways?
Glucose
Which tissues are dependent on glucose as an energy source?
- Neurons
- RBCs
The brain uses 60% of _________ glucose in the post-absorptive stage.
hepatic
How does gluconeogenesis vary in a day?
High late at night or early in the day
How does glycogenolysis vary in a day?
Increase in glycogenolysis between meals to deliver glucose
Hormones that affect glucose levels are affected by what three factors?
- Appetite
- Cell metabolism
- Physiology of the GI tract
What are the major hormones of glucose control?
- Insulin
- Glucagon
What are other hormones involved in glucose control?
- Epinephrine
- Cortisol
- Growth hormone
- Thyroid hormone
- Secretin
- Cholecystokinin
Which hormones act to lower blood glucose?
Insulin is the ONLY hormone that lowers blood glucose
What allows for the regulation of enzymatic activity?
Phosphorylation and dephosphorylation, allowing for the switching between an active and inactive state
What enzymes catalyze phosphorylation and dephosphorylation?
- Phosphorylation: phosphokinases
- Dephosphorylation: phosphatases
Which type of receptor do glucagon and epinephrine utilize?
GPCR
Which type of receptor does insulin utilize?
Receptor with intrinsic tyrosine kinase activity
How many peptide hormones regulate the gastrointestinal tract?
- More than 20 active peptides
- Forms one of the largest endocrine organs in the body
Which areas of the gastrointestinal tract are hormonally regulated?
- Stomach
- Intestine
- Pancreas
Which gastrointestinal tract hormones are contained within the central or peripheral nervous system?
- Somatostatin
- Gastrin
- Cholecystokinin
- Insulin
- Calcitonin
What is the function of gastrointestinal tract hormones are contained within the central or peripheral nervous system?
- The function is unknown
- They are produced in the cell body of neurons
- May modulate signal transmissions (used as neurotransmitters)
What did Minkowski discover?
- Observed diabetes in dogs after a pancreactomy
- Discovery of the abnormalities of the islets of Langerhans
What did Banting and Best discover?
Isolated insulin and demonstrated that it lowers blood glucose
What did Sanger discover?
Determined the amino acid sequence of insulin
What was the first recombinant hormone that was commercially marketed? When? How?
- Insulin
- 1982
- Genetic engineering
Which hormones were discovered after insulin was uncovered?
- Glucagon
- Somatostatin
- Pancreatic peptide
How many islets of Langerhans are there? What is their total weight?
- 1 million
- 1 to 2 grams
What are the two types of cells contained in the exocrine portion of the pancreas?
- Acinar cells
- Duct cells
What are acinar cells of the pancreas responsible for?
Secretion of digestive enzymes (protease, amylase, lipase)
What are duct cells of the pancreas responsible for?
Secretion of sodium bicarbonate
Differentiate the exocrine and endocrine portions of the pancreas.
- Exocrine: empties into the duodenum
- Endocrine: releases hormones into the bloodstream
What do alpha-cells of the islets of Langerhans secrete?
Glucagon
What do B-cells of the islets of Langerhans secrete?
Insulin
What do D-cells of the islets of Langerhans secrete?
Somatostatin
What do F-cells of the islets of Langerhans secrete?
Pancreatic polypeptide
Which hormones are also produced by cells of the gastrointestinal mucosa? (3)
- Glucagon
- Somatostatin
- Pancreatic polypeptide
Is the exocrine or endocrine portion of the pancreas highly vascularized?
Endocrine portion (islets of Langerhans) is highly vascularized
How does blood flow through an islet of Langerhans?
1) Blood is supplied to B-cells to detect glucose levels
2) Travels to peripheral alpha and delta cells
What is the function of the particular flow of blood through the islets of Langerhans?
Allows for the reaction of insulin prior to glucagon or somatostatin release
How does glucagon affect insulin and somatostatin?
- Stimulates insulin
- Stimulates somatostatin
How does insulin affect glucagon?
Inhibits glucagon
How does somatostatin affect insulin, glucagon, and pancreatic polypeptide?
Inhibits insulin, glucagon, and pancreatic polypeptide
How is glucagon produced?
Preproglucagon is processed to proglucagon and glucagon
How does the size of glucagon compare to insulin?
Glucagon is smaller than insulin
How does an increase in blood glucose affect alpha and beta cells of the pancreas? What are the subsequent effects?
- Inhibits alpha cells (decreases glucagon)
- Stimulates beta cells (increases insulin)
- Decreases blood glucose to normal
Which nutrients increase the release of insulin from B-cells?
- Glucose
- Amino acids
- Keto acids
- Fatty acids
Which gastrointestinal hormones increase the release of insulin from B-cells?
- Gastrin
- CCK
- Secretin
How does growth hormone affect the release of insulin?
Stimulates
How does adrenaline affect the release of insulin?
Inhibits
How does cortisol affect the release of insulin?
Inhibits
How does glucagon affect the release of insulin?
Stimulates through a paracrine signal
How does somatostatin affect the release of insulin?
Inhibits through a paracrine signal
How do B-adrenergic and cholinergic autonomic nerves affect the release of insulin from B-cells?
Stimulates
Which nutrients increase the release of glucagon from alpha-cells?
- Hypoglycemia
- Amino acids
Which nutrient decreases the release of glucagon from alpha-cells?
Free fatty acids
Which gastrointestinal hormones increase the release of glucagon from alpha-cells?
- Gastrin
- CCK
- Gastric inhibitory peptide
Which gastrointestinal hormone decreases the release of glucagon from alpha-cells?
Secretin
How does growth hormone affect the release of glucagon?
Stimulates
How does adrenaline affect the release of glucagon?
Stimulates
How does insulin affect the release of glucagon?
Inhibits through a paracrine signal
How does somatostatin affect the release of glucagon?
Inhibits through a paracrine signal
How do adrenergic and cholinergic autonomic nerves affect the release of glucagon from alpha-cells?
Stimulates
Does environment, stress and starvation increase the release of insulin or glucagon?
Glucagon
What is the longest nerve in the human body?
Vagus nerve
Is the vagus nerve a sensory or motor neuron?
The vagus nerve acts as a sensory and motor neuron
How is the vagus nerve related to the gastrointestinal system?
It is the main neuronal coordinator of appetite control, digestion and metabolism
How is the vagus nerve associated with insulin?
Stimulates the release of acetylcholine in the pancreas, which stimulates insulin release
How do parasympathetic and sympathetic stimulation affect the secretion of insulin?
- Parasympathetic stimulation stimulates insulin secretion
- Sympathetic stimulation inhibits insulin secretion
Which glucose transporter is used to mediate the uptake of glucose into the B-cells of the pancreas?
GLUT2
What is the effect of the entry of glucose into the B-cells of the pancreas on the ATP to ADP ratio?
Aerobic glycolysis increases glycolysis, which increases the ATP to ADP ratio
What is the effect of the alteration of the ATP to ADP ratio in B-cells of the pancreas?
Inhibition of ATP-sensitive potassium channels, which reduces potassium efflux, causing membrane depolarization
What is the consequence of membrane depolarization following glucose entry into B-cells of the pancreas?
- Opening of voltage-gated calcium channels
- Increased intracellular calcium triggers exocytosis of insulin-containing granules
What occurs following the exocytosis of insulin-containing granules?
Opening of calcium-activated potassium channels leads to the repolarization of the membrane
What factors generated during glucose metabolism facilitate exocytosis and/or proinsulin synthesis?
Metabolic coupling factors
What are examples of metabolic coupling factors?
- Plasma free-fatty acids
- Succinate
How does GLP-1 potentiate the amplification pathway and exocytosis of insulin?
Binds to GLP-1 receptors and triggers cAMP production
Which hormones are responsible for the hormonal regulation of the fasting state?
- Glucagon
- Adrenaline
- Glucocorticoids
What is serum glucose in the fasting state?
3 to 5 mM
How does serum glucose vary after a meal? At what concentration does glycosuria occur?
- 7 mM
- 10 mM (glycosuria)
What are the anabolic effects of insulin?
- Synthesis of protein, lipids and glycogen
- Inhibition of their degradation (usage of glucose)
What are the three target tissues of insulin?
Liver, muscle, adipose tissue
Glucagon increases many catabolic processes, particularly in the ________.
liver
Why is the release of glucose from the liver tightly regulated between meals or at fast?
Because most tissues rely predominantly on glucose as an energy source
How do free fatty acids vary in a glucose tolerance test?
- Insulin increases, which stimulates lipogenesis
- Free fatty acids decrease
How does growth hormone vary in a glucose tolerance test?
Glucose increases, which suppresses growth hormone
How does glucagon vary in a glucose tolerance test?
- Initially increases due to neural anticipatory stimulation
- Subsequently decreases with insulin suppression
How does growth hormone affect glucose uptake and lipolysis?
- Reduces glucose uptake
- Increases lipolysis
How does glucose metabolism vary in a sleep-deprived and fully rested brain?
Greater glucose metabolism in a fully rested brain
Where are GLUT2 receptors expressed?
- B-cells of the pancreas
- Liver
- Small intestine
- Kidney
Where are GLUT3 receptors expressed?
- Skeletal and cardiac muscle
- Adipose tissue
Which GLUT receptor is insulin-stimulated?
GLUT4
Where are GLUT4 receptors expressed?
- Skeletal and cardiac muscle
- Adipose tissue
How does insulin promote glucose uptake in muscle and adipose tissue?
By increasing GLUT4 transporters on the cell surface
How does insulin promote glucose uptake in the liver?
- Stimulating glucokinase
- Promoting phosphorylation of glucose to form glucose-6-phosphate
- Maintenance of the concentration gradient
Which glucose transporter is present in the liver?
GLUT2
What are the two pathways that are activated by the binding of insulin to its cognate receptor?
- MAPK
- PI3K
Which receptors may insulin cross-react with?
IGF-I
Which receptors may IGF-I and IGF-II bind to?
- Insulin
- IGF-I
- IGF-II
GLUT_ is the insulin-responsive glucose transporter.
4
The activation of ____ by insulin speeds the translocation of the GLUT4-containing endosomes into the cell membrane.
PI3K
How many membrane-spanning domains does GLUT4 possess?
12
What are the two GPCR pathways utilized by glucagon?
- Gq
- Gas
What are the two pathways that are affected by the activation of Gas by glucagon? (2)
- Increase in PKA (increase in gluconeogenesis)
- Increase in phosphorylase kinase (increase in glycogenolysis)
What pathway is affected by the activation of Gq by glucagon?
- Increase in calcium
- Decrease in glycolysis and glycogenesis
How does insulin affect fat stores?
Increase in triacylglycerol synthesis
How does glucagon affect fat stores?
Increase in fatty acid mobilization
(Glycogen synthase a/glycogen phosphorylase a) is favored in an insulin-dominant pathway.
Glycogen synthase a
(Glycogen synthase a/glycogen phosphorylase a) is favored in an glucagon-dominant pathway.
Glycogen phosphorylase a
Is glycogen synthase a or b phosphorylated? Which one is active? What is its function?
- Glycogen synthase b is phosphorylated
- Glycogen synthase a is active
- Glycogen synthesis is favoured with glycogen synthase a
Is glycogen phosphorylase a or b phosphorylated? Which one is active? What is its function?
- Glycogen phosphorylase a is phosphorylated
- Glycogen phosphorylase a is active
- Glycogen breakdown is favoured with glycogen phosphorylase a
Does insulin activate glycogen phosphorylase or glycogen synthase? Which one?
Glycogen synthase a
Does glucagon activate glycogen phosphorylase or synthase? Which one?
Glycogen phosphorylase a
Which enzyme catalyzes the conversion of glycogen synthase b to glycogen synthase a?
Phosphoprotein phosphatase
Which enzyme catalyzes the conversion of glycogen phosphorylase a to glycogen phosphorylase b?
Phosphorylase a phosphatase
Which enzyme catalyzes the conversion of glycogen synthase a to glycogen synthase b?
Protein kinase
Which enzyme catalyzes the conversion of glycogen phosphorylase b to glycogen phosphorylase a?
Phosphorylase b kinase
What are the effects of glucagon on islet cells of the pancreas?
Stimulates insulin secretion
What are the effects of glucagon on the liver?
- Stimulates glycogenolysis, gluconeogenesis, fatty acid oxidation and ketogenesis
- Inhibits glycogen synthesis and fatty acid synthesis
What are the effects of GLP-1 on islet cells of the pancreas in terms of insulin, somatostatin and glucagon?
- Increases insulin secretion
- Increases somatostatin secretion
- Inhibits glucagon secretion
How does GLP-1 affect B-cell mass?
- Increases B-cell mass
- By inhibiting B-cell death and inducing B-cell proliferation
How does GLP-1 affect the stomach?
- Inhibits gastric acid secretion
- Inhibits gastric emptying
How does GLP-1 affect appetite?
Inhibits appetite
How does GLP-2 affect the intestine?
- Stimulates mucosal growth and nutrient absorption
- Inhibits motility
How does insulin affect plasma potassium?
- Increases potassium intake into cell
- Plasma potassium decreases (hypokalemia)
Glucose and insulin relieve (hypokalemia/hyperkalemia), and is effective to treat renal failure.
hyperkalemia
How does insulin affect calcium flux?
Increase of calcium into the mitochondria
How does an increase in calcium flux into the mitochondria increase fatty acid synthesis, ketone-body formation and entry into the TCA cycle?
- May activate pyruvate dehydrogenase
- Increase the conversion of pyruvate to acetyl-CoA
What is the pathology of T1DM?
Viral or autoimmune B-cell destruction
What are different types of pathologies that may lead to T2DM? Give an example for each.
- Pre-receptor resistance (e.g. antibodies against insulin)
- Receptor resistance (e.g. decrease in insulin receptor number)
- Post-receptor resistance (e.g. underexpression of B-cell glucose transporters)
What is insulinoma?
- Excess insulin secretion from B-cell pancreatic tumour
- Severe hypoglycemia
What is the difference between slow- and fast-acting insulin?
- Slow (long half-life)
- Fast (short half-life)
How may insulin be administered?
- Needles
- Pens
- Pumps
What condition predisposes individuals to T2DM?
Obesity
What factors may influence the incidence of T2DM?
- Genetic vulnerability
- Behavioural and lifestyle factors
- Psychological factors
- Demographic characteristics
How does an increased quantity of fatty acids in the blood due to an increase in visceral adipose tissue affect T2DM?
- Liver releases increased glucose and triacylglycerols, which leads to insulin resistance in peripheral tissues
- Hyperglycemia leads to B-cell damage, which decreases production of insulin
Why has there an increase in gastric bypass surgery in recent years?
- Because the prevalence of obesity has increased
- Bariatric surgery allows for a significant decrease in weight
What is the wait time for gastric surgery in Canada if an individual’s BMI is over 40?
- 5 years in Canada
- 5 to 15 years in Quebec
What are benefits of weight loss surgery? How does it affect diabetes specifically?
Resolves a number of issues related to metabolic syndrome, including T2DM
How does somatostatin affect the pituitary?
Negative regulator of GH release
How does somatostatin affect the pancreas? How does it act?
- Inhibitor of insulin and glucagon secretion
- Acts in a paracrine fashion
How does somatostatin affect the GI tract?
- Inhibitor of the release of many GI hormones
- Additional direct inhibitory effects of GI functions
How many amino acids are contained in somatostatin? How many different types of receptors are there? How many types of isoforms?
- 14 amino acids
- 5 receptors
- 2 isoforms
What are the main sources of circulating somatostatin?
- GI tract
- Pancreatic D cells
What are the main sources of pancreatic polypeptide?
- Pancreatic F cells
- Between acinar cells of the pancreas
How does pancreatic polypeptide affect appetite?
Reduces appetite
How does pancreatic polypeptide affect the secretion of digestive enzymes of the pancreas?
Powerful inhibitor
How does pancreatic polypeptide affect the gallbladder?
- Blocks contraction of the gallbladder
- Inhibitor of bile secretion
How does a meal affect the secretion of pancreatic polypeptide?
- Increases after a meal and remains high for several hours
- Conservation of digestive enzymes and bile
How may the increase of pancreatic polypeptide be mediated?
Vagus nerve and cholecystokinin in response to a meal
How does an oversecretion of pancreatic polypeptide due to a tumour affect metabolic disturbances?
They are not associated with metabolic disturbances
What produces gastrointestinal hormones in response to food intake?
Cells interspersed in the GI tract
What is the action of gastrointestinal hormones on the central nervous system?
- Appetite control
- GI motility
What is the action of gastrointestinal hormones on the pancreas?
Stimulation of insulin and/or glucagon secretion
What are incretins?
Group of metabolic hormones that stimulate a decrease in blood glucose levels
Which gastrointestinal hormone was the latest to be discovered?
Ghrelin (2000)
What are the functions of cholecystokinin?
- Gallbladder contraction
- Gastrointestinal motility
- Pancreatic exocrine secretion
What is the function of secretin?
Pancreatic exocrine secretion
What is the major function of GIP?
Incretin activity
How does ghrelin affect growth hormone release?
Increases growth hormone release
Ghrelin is isolated from the ______, and consists of __-amino acids.
stomach
28
What increases ghrelin secretion?
Fasting
What decreases ghrelin secretion? (3)
- Glucose
- Growth hormone
- Obesity
How does ghrelin release vary in a day?
- Increase with every meal
- Increase in the middle of the night
How does dose-dependent ghrelin affect food intake in rodents?
Greater ghrelin results in a greater food intake
How do ghrelin antagonists affect food intake in rodents?
Reduce food intake and body weight
What is Prader-Willi syndrome? What are characteristic symptoms?
- Excessive ghrelin secretion
- Individual is constantly hungry, which leads to obesity and T2DM
What does proteolytic processing of proglucagon form in pancreatic alpha cells?
Glucagon
What does proteolytic processing of proglucagon form in intestinal L cells?
GLP-1 and GLP-2
Where is GLP-1 synthesized?
L-cells in the ileum and colon
What is the half-life of GLP-1?
90 seconds
How does GLP-1 affect the brain and nervous system in terms of appetite?
- Decrease appetite
- Increase satiety
How does GLP-1 affect glucose uptake and glycogen synthesis/breakdown?
- Increase glucose uptake
- Increase glycogen synthesis
How does GLP-1 affect the stomach?
- Gastric emptying is decelerated
- Decrease acid secretion
How does GLP-1 affect the secretions of the pancreas?
- Increase insulin
- Decrease glucagon
- Increase somatostatin
GLP-1 is an ______ since it enhances glucose-dependent insulin secretion.
incretin
What mechanisms allow GLP-1 to amplify the release of insulin from stored granules?
- cAMP
- Ca2+
- MAPK
- PI3K
