4.1 Food intake and pancreas Flashcards
historical view of regulation of food intake
- what are the 2 hypothesis?
- lipostatic hypothesis (Kennedy, 1953), adipose tissue produces a “lipostatic” factor (chemical) –> regulates food intake –> how much fat should body accumulate –> based on animal hibernation
- glucostatic hypothesis (insulin was already discovered) (Mayer& Thomas 1967): fluctuations in glycaemia lead to stimulation/inhibition of food intake
- every food intake regulation is to serve the homeostatic glucose concentration
physiological regulation of food intake is a complex _________ process that is regulated by many _______ and _______ factors
- other influencing factors include (7)
- complex homeostatic process
- many endocrine and metabolic factors
- visual, olfactory, taste sensation, emotions, memory, life conditions (stress), culture/customs
which gastrointestinal hormone was first discovered? then which one?
- these hormones impact ______ ______ –> which impact metabolism, which impacts everything in life
- secretin! (1902), then gastrin
- impact food intake
name hormones (+ functions ish) produced in:
- stomach (2)
- duodenum (4)
STOMACH:
- ghrelin (hunger + growth hormone release)
- gastrin (acid secretion)
DUODENUM:
- cholecystokinin (gall bladder contraction, GI motility, pancreatic exocrine secretion)
- secretin (pancreatic exocrine secretion)
- gastrointestinal peptide (GIP) (incretin activity)
- motilin (GI motility
name hormones (+ functions ish) produced in:
- pancreas (3)
- small intestine/colon (4)
PANCREAS:
- insulin and glucagon (glucose homeostasis)
- pancreatic polypeptide (gastric motility and satiation)
- amylin (glucose homeostasis + gastric motility)
COLON:
- GLP-1 (incretin activity + satiation)
- GLP-2 (GI motility and growth)
- oxyntomodulin (satiation + acid secretion)
- PYY (satiation)
define pancreatic exocrine secretion + incretin activity
(both are functions of GI hormones)
PANCREATIC EXOCRINE SECRETION:
- helps digestion and absorption
INCRETIN ACTIVITY:
- any chemical signal that modulates glucose homeostasis by regulating insulin and glucagon
what (2) are crucial in central regulation of feeding/food intake? their functions ish
- in one of those regions, there is integration of (4)
- which 2 nuclei connects the 2?
- hypothalamus (regulatory center) + brain stem (fundamental central nervous system –> controls fundamental living processes of body)
- hypothalamus –> integration of brain neurotransmitters, peripheral neurohumoral afferents, adipocyte-derived signals, GIT peptides
- nucleus tractus solitarius and PVN –> connects brain stem with hypothalamus (serotoninergic neurons)
what are the 5 “things”/centers that have a role in feeding regulation? (apart from hypothalamus, brainstem and nucleus tractus solitarius)
- ventromedial hypothalamus (VMH) –> satiety center = tells you when you’re full
- lesion leads to hyperphagia (ie animals that don’t have VMH don’t have control of how much they eat, so they overeat) - lateral hypothalamus nucleus –> hunger center = tells you to find food
- lesion leads to anorexia - suprachiamic nucleus (SCN) –> light entrainment regulates circadian rhythm –> timing –> lesions in humans lead to hight hyperphagia and obesity
- PVN and ARC –> integrate signals from hypothalamus-pituitary-thyroid (HPT) axis and HP-adrenal axis
- vagus nerve (direct neuronal regulation) –> satiety signals to brain stem after ingestion of a meal
all neuronal and hormonal regulation feed through which 2 neurons?
- these 2 neurons receive & integrate ___(2)______ input from what?
- describe both neurons
- what nucleus are they from?
a-MSH and NPY neurons! –> receive and integrate hormonal & metabolic input from peripheral organs
- a-MSH –> regulate neurons that stimulate anorexia (stop eating) and catabolism (spend energy/metabolize more)
- NPY neurons –> regulate neurons that stimulate orexia (food intake) and anabolism (store energy/metabolize less)
- arcuate nucleus!
which hormones from adiposity signal, satiety signal and hunger signal are anorexigenic vs orexigenic hormones?
ADIPOSITY SIGNALS
- leptin (more adipose tissue = more leptin) –> main anorexigenic hormone: stimulates a-MSH (supports lipostatic homeostasis) and inhibits NPY
- insulin (from pancreas): anorexigenic –> inhibits NPY
SATIETY SIGNALS:
- PYY and GLP-1 (from gut): anorexigenic –> both inhibit NPY
HUNGER SIGNALS:
- ghrelin (stomach): orexigenic –> stimulates NPY neurons
- what is the active ingredient in marijuana? mainly signals through what receptor?
- what are the 2 endocannabinoid hormones? –> both have what as a precursor?
- what are the 2 receptors for endocannabinoids? through which signalling pathway?
- receptors are mainly expressed where?
- how to regulate [hormone] at tissue level?
- THC –> CB1 receptor
- anadamide (AEA) and 2-arachidonoylglycerol (2-AG) –> both come from arachidonic acid
- receptors: CB1 and CB2 –> GPCR with Gai (inhibits cAMP)
- CB1 –> highly expressed in CNS
- CB2 –> highly expressed in PNS
*but both are expressed in both - local/tissue metabolizing enzymes for endocannabinoids –> metabolize AEA & 2-AG are local level
endocannabinoid system:
- overall effect depends on what?
- net effect of system? on metabolism
- depends on type and amount of CB1 vs CB2
- net effect of anabolism! store energy and decrease catabolism
what happens when CB1 is inhibited?
- hypothalamus (1)
- adipose tissue (2)
- muscle (2)
- liver (1)
- GI tract (1)
THUS, OVERALL EFFECT OF ENDOCANNABINOID SYSTEM?
HYPOTHALAMUS:
- decrease food intake
- weight loss + reduced waist circumference
ADIPOSE TISSUE:
- increase adiponectin (opposite of leptin) + decrease lipogenesis
- reduces visceral fat + improved lipidemia + insulin sensitivity
MUSCLE:
- increase glucose uptake and increase o2 consumption (= glycolysis)
- enhances insulin sensitivity
LIVER:
- decrease lipogenesis
- improved lipidemia and insulin sensitivity
GI TRACT:
- increase satiety
- weight loss (increase catabolism)
OVERALL EFFECT:
- inhibit CB1 = weight loss = increase catabolism
- endocannabinoid system –> anabolic effects!
what are the 2 cell types in exocrine pancreas?
- secreted into what?
- acinar cells –> secretion of digestive enzymes (proteases, amylases, lipases)
- duct cells –> secretion of NaHCO3
- secreted into duodenum
endocrine pancreas consists of what?
- 5 types of cells that secrete what hormone?
- hormones are secreted into what?
- islets of Langerhans (3 million islets, 1-2gm)
1. a-cells –> glucagon
2. b-cells –> insulin –> most abundant cells and most studied
3. d-cells –> somatostatin
4. e-cells –> ghrelin (comes from stomach as well)
5. f-cells (PP cells) –> pancreatic polypeptide - hormones secreted into blood! –> endocrine pancreases has rich blood supply!
explain blood supply to pancreas
- artery vs vein
- hepatic artery (branching from aortic artery (main artery in body)) brings blood in
- splenic and mesenteric veins bring blood out to portal vein
*portal vein connects and collects all blood from GI tract –> leads to liver for metabolic processes
- is endocrine or exocrine portion of pancreas more vascularized?
- blood first supplies what?, then travels to what (2)
- endocrine is 5 to 10 times more vascularized/ more blood flow) than to exocrine pancreas
- blood first goes to middle and supplies centrally located b cells (detect glucose levels). then blood travels to peripheral a (glucagon) and d cells (SST)
- islets of langerhans are homogenous or heterogenous?
- within islets, groups of b cells function ________ –> how?
- do b cells always proliferate?
- avg lifespan of b cells?
- b-cells differentiate from what?
- what is another way b-cells are formed?
- heterogenous! –> multiple cell types and sizes
- within islets, groups of b-cells function together as a unit –> through gap junctions
- proliferation of b cells is minimal after 5 years of age in humans (but doesn’t mean no new cells are formed)
- avg lifespan = 25 years
- neogenic niche (stem cells) at periphery of islets –> differentiate into b cells when needed
- transdifferentiation of a and d cells under extreme b-cell loss
explain complex interplay of insulin, glucagon and somatostatin within islets of langerhans
- insulin inhibits glucagon
- glucagon directly stimulates insulin BUT indirectly inhibits insulin by stimulating SST
- SST inhibits insulin and inhibits glucagon and inhibits pancreatic polypeptide
what is the main regulator for insulin secretion?
what are 3 other regulators?
glucose!
- neural, endocrine and paracrine factors
insulin vs glucagon
- type of hormone?
- structure?
INSULIN
- peptide hormone –> 51 aa
- post-translational modifications: 1 gene –> produces a, b and c –> C-peptide is cleaved off –> a and b peptide chains are connected by 2 disulphide bridges
GLUCAGON:
- smaller peptide hormones: 29 aa
- produced as preproglucagon –> processed to proglucagon and glucagon
- single chain
where is insulin metabolized? vs where is C-peptide metabolized?
- C peptide is a measure of what?
- insulin is metabolized in liver
- C-peptide is metabolized in kidney
- C-peptide is a better measure of b-cell function/insulin secretion from islets than insulin itself
- beta cells contain ______-_______ granules of __________
- half life of granules?
- younger granules (2) vs older granules (1)
- granules contain insulin ______ stabilized by (2)
- 5000-8000 granules of insulin
- half-life = 5 days
- YOUNGER: deeper in cytoplasm, but more mobile than older ones
- OLDER: degraded intracellularly –> intracellular degradation of insulin
- insulin hexamer stabilized by calcium and zinc
- what is the main stimulatory of insulin synthesis and release? ____a_____
- enters through what
- which enzyme serves as ___a____ sensors
- glucose!
- through GLUT2
- hexokinase/glucokinase = glucose sensors (primary mechanism by which rate of insulin secretion adapts to changes in blood glucose)
what are the 6 steps in release of insulin from b-cells?
- uptake of glucose by type 2 facilitated glucose transporter (GLUT2)
- aerobic glycolysis (glucokinase, Krebs Cycle…) and increase of ATP/ADP ratio
- increase ATP/ADP ratio = inhibition of ATP sensitive K+ channels –> reduction of K+ efflux = membrane depolarization
- opening of voltage gated Ca2+ channels (VDCC)
- increased intracellular Ca2+ triggers exocytosis of insulin containing granules
- opening of Ca2+ activated potassium channels (K-Ca) leads to repolarization of membrane (resetting)
what 2 things helps/facilitate insulin exocytosis (among other things)?
- metabolic coupling factors generated during glucose metabolism facilitate exocytosis and/or proinsulin synthesis (ie FFA from circulation and intracellularly formed succinate)
- glucagon-like peptide (GLP-1 form intestine) or related peptides bind to GLP-1 receptors and trigger cAMP production. It potentiates amplification pathway, ion channels and exocytosis
- which nerve is the longest nerve in the body + serves as neural regulator for insulin secretion?
- this nerve acts as ______ and _______ neuron
- main neuronal coordinator of (3)
- release of ___________ in the _________ stimulates insulin release
- vagus nerve!
- sensory and motor neuron (providing and receiving signals from peripheral organs)
- appetite control + digestion + metabolism
- acetylcholine (cholinergic) in the pancreas
what are the major factors controlling release of insulin from b-cells?
- nutrients (4)
- GI hormones (5)
- Hormones (2 positive, 4 negative)
- autonomic nerves (2 pos, 1 neg)
NUTRIENTS:
+ glucose
+ amino acids
(+) keto acids
(+) TG/FA
GI HORMONES:
+ gastrin, CCK, GIP, GLP-1, Secretin
HORMONES:
+ Growth hormone
+ glucagon (?)
- Adrenaline
- cortisol
- somatostatin
- other peptides
AUTONOMIC NERVES:
+ cholinergic
+ b adrenergic
- a adrenergic
what are the major factors controlling release of GLUCAGON from a-cells?
- nutrients (2 pos, 1 neg)
- GI hormones (3 pos, 2 neg)
- Hormones (2 positive, 2 negative)
- autonomic nerves (2)
NUTRIENTS:
+ hypoglycemia
+ amino acids (arginine, alanine
- FFA
GI HORMONES:
+ gastrin, CCK, GIP
- GLP-1, Secretin
HORMONES:
+ Growth hormone
+ Adrenaline
- insulin
- somatostatin
AUTONOMIC NERVES:
+ cholinergic
+ adrenergic
metabolic functions (pathways ish + enzyme) of insulin:
- liver (6)
- adipose (4)
- muscle (4)
LIVER:
- increase glucose uptake (glucokinase)
- increase glycolysis (increase PFK1, pyruvate dehydrogenase complex)
- increase glycogenesis (glycogen synthase)
- increase lipid accumulation (Acetyl-coa carboxylase)
- decrease gluconeogenesis
- decrease glycogen breakdown (decrease glycogen phosphorylase)
ADIPOSE:
- increase glucose uptake (GLUT4)
- increase lipogenesis (Acetyl-coa carboxylase (for FA) + lipoprotein lipase (for TG))
- increase glycolysis (increase PFK1, pyruvate dehydrogenase complex)
- decrease lypolysis
MUSCLE:
- increase glucose uptake (GLUT4)
- increase glycogenesis (glycogen synthase)
- increase glycolysis (increase PFK1, pyruvate dehydrogenase complex)
- decrease glycogen breakdown (decrease glycogen phosphorylase)
function and where?
- GLUT2
- GLUT3
- GLUT4
GLUT2:
- b-cell glucose sensor + transport out of intestinal and renal epithelial cells
- b cells of islets + epithelial cells of small intestine and kidneys
GLUT3:
- basal glucose uptake
- brain, placenta, kidneys, many other organs
GLUT4:
- insulin-stimulated glucose uptake
- skeletal and cardiac muscle, adipose tissue, other tissues
- insulin promotes glucose uptake in (2) by increasing _____ transporters on cell surface
- insulin promotes glucose uptake in (1) by stimulating which enzyme and thus promoting what? –> therefore, what is maintained?
- muscle and adipose tissue by increasing GLUT4 transporters
- in liver –> stimulating glucokinase: promote phosphorylation of glucose to form glucose-6-phosphate –> concentration gradient of non-phosphorylated glucose needed for facilitated uptake via GLUT2 is therefore maintained
glucose levels are regulated by _______ that affect ____a__ and ___b___
- a and b also affect blood glucose levels
- hormones! that affect appetite control/ physiology of GI tract + cell metabolism
- double way arrow btw blood glucose levels & appetite, and blood glucose & cell metabolism
explain pathway for hormonal regulation of glycogenesis (insulin receptor) 4 ish steps
- insulin binds to insulin receptor
- phosphorylation –> IRS –> PI3K
- PI3K converts PIP2 to PIP3 –> activates PDK-1 and PKB
- PKB phosphorylates active GSK3 –> phosphorylated GSK3 = inactive
4.1 if GSK3 is inactive –> CANNOT phosphorylate (on Ser residues) glycogen synthase a (active) to glycogen synthase b (inactive), thus glycogen synthase a remains active!
- which enzyme converts glycogen synthase b to glycogen synthase a? and vice versa?
- what inhibits (2) and activates (2) the enzyme that converts inactive glycogen synthase to active?
- GS a (active) –> GS b (inactive), by GSK3
- GS b (inactive) –> GS a (active), by PP1
- PP1 is inhibited by glucagon and epinephrine
- PP1 is activated by insulin and glucose/glucose6-phosphate –> therefore stimulating glycogen synthase a for more glycogen synthesis
- which 2 molecules stimulate glycogenolysis? in which tissue?
= explain pathway of glycogenolysis (6 steps)
- epinephrine in myocytes
- glucagon in hepatocytes
1. epinephrine and glucagon –> activate Gsa
2. Gsa activates adenyl cyclase: ATP to cAMP
3. cAMP activates PKA
4. PKA and Ca2+ activate phosphorylase b kinase
5. phosphorylase b kinase activates glycogen phosphorylase b into glycogen phosphorylase a
6. glycogen phosphorylase a + AMP convert glycogen to glucose 1-phosphate
glucagon has 2 signaling pathways in liver
- explain
- glucagon –> GPCR –> Gq –> phospholipase C –> PIP2 to inositol 1,4,5 triphosphate –> Ca2+ –> inhibits glycolysis & glycogenesis + activates gluconeogenesis
- glucagon –> GPCR –> Gas –> adenylate cyclase –> cAMP –> PKA –> increase phosphorylase kinase –> activates glycogen phosphorylase a = increase glycogenolysis
*PKA also stimulates gluconeogenesis
- OVERALL: decrease glycolysis + decrease glycogenesis + increase gluconeogenesis + increase glycogenolysis = increase glucose!
endocrine control of blood glucose
- 2 major hormones
- 6 other important hormones
- all those hormones act at the same time?
- which hormone is the only one that lowers blood glucose?
- insulin + glucagon = major hormones
- epinephrine + cortisol + growth hormone + thyroid hormone + secretin + CCK
- all act at same time and form an integrated control system
- INSULIN is the only hormone that lowers blood glucose
- which receptors does insulin has? vs glucagon and epinephrine?
- insulin, glucagon and epinephrine –> regulation of enzyme activities by (2) –> switching btw _______ and _______ states –> activation cascade
- insulin: RTK
- glucagon and E: GPCR
- regulation of enzyme activities by phosphorylation (kinases) and dephosphorylation (phosphatases)
- switching btw active and inactive state
SCHÉMA:A
regulation of blood glucose:
- post meal hormonal control by _________ –> what happens (in general terms) in gut, muscle, liver, adipose and nerve/other tissues?
- fasting state hormonal control by (3) –> what happens (in general terms) in gut, muscle, liver and adipose?
POST MEAL
- insulin!
1. carbs from meal –> from gut to blood glucose
2. from blood, glucose goes to:
- muscle –> forms glycogen!
- liver –> forms glycogen and TG
- adipose: forms TG
- nerve and other tissues for function
FASTING STATE:
- glucagon, adrenaline or glucocorticoids
1. muscle: protein –> aa –> to liver
2. adipose: TG –> FA –> to liver
3. liver:
- aa (from muscle) converted to glucose
- glycogen converted to glu
- FA –> ketone bodies!
- glucose goes to blood
regulation of blood glucose:
- serum glucose in fasting stage: __-__ mM (generally < ____ mM or ______ mg/dL)
- rise to ___ mM after meal (glycosuria if exceeding ____ mM or _____ mg/dL)
- anabolic effects of insulin: 2 ish
- key target tissues of insulin (3)
- insulin promotes what?: essential for normal (2)
- 3-5 mM (<6.1 mM or < 140 mg/dL)
- rise to 7 mM after meal (glycosuria if >11.1 mM or 200 mg/dL)
- synthesis of protein, lipid and glycogen + inhibition of their degradation (usage of glucose)
- liver, muscle, adipose tissue
- promotes cell growth! essential for normal growth and development
regulation of blood glucose (continued):
- glucagon increases many anabolic/catabolic processes? particularly where?
- btw meals/fasting, the release of _______ from ______ is tightly regulated (most tissues rely predominantly on _______ as an energy source)
- other energy sources are (2)
- is insulin continuously secreted? or only after meal?
- catabolic processes! particularly in liver! (production of glucose)
- release of glucose is tightly regulated –> rely on glucose as energy source
- fatty acids and ketones (muscle)
- insulin is continuously secreted to enable peripheral tissues to uptake glucose
muscle vs liver glucose metabolism (glucagon vs epinephrine ish)
- 5 differences
- 1 similarity
(SCHÉMA)
DIFFERENCES:
- muscle doesn’t have glucagon receptor! only responds to epinephrine VS liver responds to epinephrine AND glucagon
- muscle isoform pyruvate kinase is not phosphorylated by PKA
- muscle doesn’t produce F26BP
- increase glycolysis in muscle (glu-6-P converted to pyruvate) VS decrease glycolysis in liver (bc glu-6-P is exported to blood) (pyruvate is converted to glucose 6 P)
- increase gluconeogenesis in liver
SIMILARITIES:
- increase glycogenolysis in both: glycogen to glucose 6 phosphate
fuel metabolism in prolonged fasting: 9 steps
- protein degradation yields glucogenic aa –> some parts of aa enter TCA cycle + release of NH3
- NH3 –> urea –> urea exported to kidney and excreted in urine
- TCA intermediate (oxaloacetate) is diverted to gluconeogenesis in liver
- glucose (produced from gluconeogensis) is exported via bloodstream to brain
- FA from adipose tissue are oxidized for fuel, producing acetyl-CoA
- lack of oxaloacetate prevent acetyl-coA entry into TCA cycle –> acetyl-CoA accumulates
- Acetyl-CoA accumulation favors ketone body synthesis
- ketone bodies are exported via bloodstream to brain, which uses them as fuel
- excess ketone bodies end-up in urine
