LGS Week 5, 6, 7 Flashcards
What are the counterregulatory hormones of insulin?
Glucagon, Epinephrine, Cortisol
Glucagon maintains blood glucose levels during the [a] state by activating [b]
a. Fasting
b. gluconeogenesis and glycogenolysis in liver, FA and glycerol release from adipose
Epinephrine mobilizes fuel during [a] by stimulating [b]
a. acute stress or exercise
b. glycogenolysis from muscle and liver, FA and glycerol release from adipose
Cortisol provides fuel during [a] by stimulating [b]
a. Stress, illness, trauma
b. AA mobilization and glucose uptake in muscle, gluconeogenesis in liver, FA and glycerol release from adipose, and inhibits insulin secretion from B cells, increases glucagon secretion by a-cells
Highly vascularized clusters of pancreatic endocrine cells
Islets of Langerhans
a-cells produce
Glucagon
B-cells produce
Insulin
The cluster of cells in the center is called [a] and the surrounding cells are [b]
a. Islet of Langerhans
b. Pancreatic acini
Preproglucagon is expressed as a long peptide which is eventually processed down into what smaller peptides
Glucagon
GRPP
IP1
Major Proglucagon fragment (GLP-1/2)
Glucagon secretion from a-cells is stimulated by
- Hypoglycemia
- Epinephrine/Cortisol
- Acetylcholine
- High AA
Glucagon secretion is inhibited by
- Hyperglycemia
- GLP1
- Insulin
Explain Glucagon’s MOA on glycogenolysis
Glucagon is stimulated by low blood sugar –> binds to GPCR (Gas) –> activation of Adenylate cyclase –> activation of cAMP –> stimulation of PKA –> activates Glycogen Phosphrylase –> stimulates conversion of glycogen to glucose through glycogenolysis
What effects does Glucagon have on hepatic metabolism?
Decreases: Glycolysis, Glycogenesis, and FA Biosynthesis – stops glucose from becoming anything other than glucose
Increases: Gluconeogenesis, Glycogenolysis, FA Oxidation – builds glucose from other molecules and builds FA to fuel the liver
What effects does Glucagon have on Adipocyte metabolism?
Decrease: Lipogenesis – stops glucose from becoming TG
Increase: Lipolysis - increased FA/glycerol release –> increased B-oxidation, ketogenesis, and gluconeogenesis in liver
What effects does Glucagon have on Skeletal muscle metabolism?
No effect
What is secreted with insulin that can be used as an index of secretory capacity of the endocrine pancreas?
C-peptide
Explain the MOA of insulin release
Hyperglycemia and increase of AA –> glucose and AA enter cell (glucose through GLUT4) –> go through TCA cycle to create ATP –> increase of ATP closes K+ channels –> K+ increases the RMP of cell –> stimulates opening of Ca2+ channels –> Ca2+ acts as second messenger –> binds Insulin granule to membrane for exocytosis –> Insult and C peptide released from cell
What is the biphasic insulin release?
Spike of insulin secretion from readily releasable pool for several minutes after eating
Then smaller, more prolonged spike of secretion from reserve pool sustained release over 1 hr
Outline the MOA of insulin and it’s overall effect
Insulin binds to TKR –> phosphorylated TK activates intracellular signaling proteins –> activates PI3K pathway which stimulates GLUT4 intra and extramembranous receptors, as well as PIP2 –> which stimulates PIP3 –> AKT pathway –>
Increased: glucose uptake, glycolysis, glycogen synthesis, lipogenesis, protein synthesis, cell survival and growth - do whatever it takes to get excess glucose out of the blood
Decreased: gluconeogenesis, lipolysis, proteolysis - stop anything from becoming more glucose
What effects does Insulin have on hepatic metabolism?
Increased: Glycolysis, Glycogenesis, FA synthesis, PPP - break down/convert glucose
Decreased: Gluconeogenesis, Glycogenolysis - avoid making more glucose
What effects does Insulin have on adipose metabolism?
Increased: Glycolysis, PPP, Pyruvate Oxidation, Lipogenesis
Decreased: Lipolysis
What effects does Insulin have on Skeletal muscle metabolism?
Increased: Glycolysis, Glycogenesis, protein synthesis
Decreased: Glycogenolysis
This illustrates the role of [a] in integration of metabolism
Glucagon
This illustrates the role of [a] in integration of metabolism
Insulin
The presence of food in the intestines induces the release of [a] from the intestines, which is a(n) [b].
a. GLP-1
b. Incretin - targets endocrine pancreas to produce and secrete insulin
During the fed state, liver becomes a (creator/consumer) of glucose
Consumer
List the metabolic changes in the liver during the fed state
Increase chylomicron and glucose uptake
Increase glycogenesis, PPP, glycolysis (Acetyl-CoA for FA synthesis and energy, DHAP for lipogensis)
Increase VLDL release
Increase AA release, AA catabolism, protein synthesis
Increase urea cycle
List the metabolic changes in adipose during the fed state
Increase LPL activity, FA uptake
Increase glucose uptake, glycolysis
Produces and secretes leptin
What is leptin and what is its function?
A hormone that acts on the hypothalamus to induce satiety
List the metabolic changes in skeletal muscle during the fed state
Increase glucose uptake, glycolysis, glycogenesis
Increase AA uptake and protein synthesis
Decrease LPL activity
What tissue solely takes up glucose independently of insulin?
the brain
What are the different fates of Glucose in the fed state?
What are the different fates of AA in the fed state?
What are the different fates of lipids in the fed state?
Label the glucose sources used during fasting
Label which illustration is during which state of fasting
When does the brain switch to ketone bodies as a fuel source? What does it use until then in the fasting state?
2nd week of fasting
Protein degradation
What is the body’s last attempt to create glucose?
Gluconeogenesis in the kidneys after 5-6 weeks of fasting
Differentiate Type I and Type II DM
Type 1: results from inability to produce insulin
Type 2: results from insulin resistance, inadequate insulin secretion and/or excessive glucagon secretion
A pt with acetone breath and low blood pH is indicative of
DKA - Diabetic Ketoacidosis
What antibody plays a key role in the pathogenesis of Type 1 Diabetes?
Anti-glutamic acid decarboxylase antibody
Which HLA serotype is most strongly associated with Type 1 Diabetes?
HLA-DR3
Outline the mechanism of Passive Chloride Channels found in the intestines
Located in the small and large intestines - Chloride ions are pushed in from the lumen into the cell, and from the cell through the basolateral side
Outline the mechanisms of Chloride/Bicarb Exchangers found in intestines
Located in small and large intestines
Exchanges Chloride for Bicarb by secreting Bicarb into the Lumen and bringing Chloride into the cell
Electroneutral because it exchanges a negative ion for another negative ion
Outline the mechanism of Chloride secretion in the small and large intestine
NKCC channel created negative gradient within the cell which drives chloride out of the cell into the lumen through the CFTR channel
Electrogenic bc only chloride is crossing the membrane –> pulls water and Na+ into lumen between cells
What regulates the CFTR channel?
What else can go through CFTR channels?
cAMP, cGMP, Ca2+
HCO3
Outline the mechanism of Sodium-Nutrient Cotransporter in small intestine
Glucose/Galactose follows Na+ into cell through SGLT1
AAs follow H+ into cell through PEPT1
Glucose leaves through diffusion on BL side once gradient builds
AA leaves through BL side once broken down into monomers
Na/K ATPase pushed Na out of cell on BL side, brings K in
Chloride and water move between cells by electrogenic force balancing Na+ being excreted to BL side
Outline mechanism of Sodium-Hydrogen Exchanger in the small and large intestine
Na is pulled into the cell while H+ is pushed out of the cell into the lumen
Found close by Cl/Bicarb exchanger
Helps regulate absorption in the fasted state
Outline the mechanism of Epithelial Sodium Channel in the large intestine
Na+ is pulled into the cell
Regulated by hormones - Gs stimulates, Gq inhibits
Gradient creates elecrtogenic cell –> pulls water and Cl- to BL side through cells
Malabsorptive diarrhea is caused by [a]
Secretory diarrhea is caused by [b]
a. nutrients not being absorbed keeping water in the lumen
b. upregulation of CFTR causing water to follow Cl into lumen
Which anti-diarrheals decrease motility
Loperamide
Alosetron
Dicyclomine
Which anti-diarrheals decrease secretions?
Octreotide
Colestripol
Alosetron
Loperamide
Clonidine
Polycarbophile
Bismuth subsalicylate
Explain the MOA of Enterotoxigenic coli-induced diarrhea
Two pathways:
Heat-stable toxin - binds to receptor guanalyl cyclase –> generates cGMP –> activates PKG II –> phosphorylation of CFTR –> increased Cl- secretions
Heat-labile toxin - binds to GPCR (Gs) –> activates adenylyl cyclase –> stimulates cAMP –> activates PKA –> phosphorylation of CFTR –> increased Cl- secretions
Explain how secretory diarrhea can lead to metabolic acidosis and low potassium
Upregulation of CFTR –> increased secretions of Cl- and HCO3 –> body becomes more acidic as it loses basic molecules –> metabolic acidosis –> hydrogen ions move into cells from blood in exchange for K+ ions –> reduce acidity but lower serum potassium
Explain how and why a Xylose test is used
Given to see if pt can breakdown monosaccharides and uptake them by SGLT1
Urine measured after 24 hrs, fecal measured after 72 hrs
If lower in urine and high in stool –> not being absorbed in small intestine
Can show if something is wrong with transporters or damage to intestinal lining
What is the source of foul smelling food?
Undigested food in the small intestine
List which macros and micros each part of the intestine takes up
Duodenum - Carbs, fats, proteins, iron, calcium
Jejunum - Carbs, fats, proteins
Ileum - Fats and proteins; bile salts and Vit B12 in distal ileum
Explain how lower serum FGF19 and higher stool bile salt concentration can cause fatty stool and diarrhea
FGF19 is the transcription factor that regulates Bile Salt synthesis
When Bile Salts are taken up in the cell, FGF19 is activated –> inhibition of CYP7A1, the transcription factor for Bile Salt Synthesis.
FGF19 inhibits the synthesis of more Bile Salts bc its saying the body is reusing and they don’t need to make more.
If FGF19 is low, that means Bile Salts aren’t being taken up by the cells and recycled, and are being excreted. This leads to downregulation from FGF19 –> no longer inhibiting CYP7A1 –> activating transcription factors to synthesize Bile Salts –> increased Bile Concentration in stool but still not enough to breakdown all the fats without the bile salts that should have been recycled –> fatty stool
Too many Bile acids in the lumen –> upregulation of Cl- channels –> increase water secretion –> diarrhea
What are some sources of malabsorptive diarrhea?
Lactose Intolerance
Pancreatic Insufficiency
Celiac disease
Bile Acid Malabsorption
What are some sources of secretory diarrhea?
V. Cholerae
C. Difficile
E. Coli
Bile Acid Malabsorption
Compare and Contrast the Visceral afferent innervation of the ascending colon vs the distal half of the sigmoid colon for reflex and pain sensations
Ascending Colon:
Pain - retrograde sympathetics - (DRG T10-T11)
Reflex - retrograde parasympathetics - (DRG S2-S4 through Pelvic Splanchnic n)
Sigmoid Colon:
Pain - retrograde parasympathetics - (DRG S2-S4 through Pelvic Splanchnic n)
Reflex - retrograde parasympathetics - (DRG S2-S4 through Pelvic Splanchnic n)
Circular muscle and longitudinal muscle are responsible for what type of contraction?
Circular - segmentation
Longitudinal - Peristalsis
What is the function of Interstitial Cells of Cajal?
Generate basoelectrical rhythm to keep the threshold of cells high for easy depolarization
Explain the physiology of the small intestines during the fed state
Segmentation churns the food with back and forth motions to increase contact time for absorption
Duration depends on caloric contents
Regulated by ACh and NO/VIP
Explain the physiology of large intestines during the fed state
Segmental propulsion creates Haustra (pouches) in large intestine, pushing stool from one to the next with forward and backward movement
High amplitude propulsions precede defecation (mass movement)
What is the gastrocolic reflex?
The urge to defecate after eating stimulated by distention of the stomach
Explain large intestine physiology during the fasted state
No caloric content in the small intestine stimulates MMC (migrating motility complex)
Excretes anything left in the colon
Keeps any contents from staying stagnant or traveling backwards - prevents bacterial overgrowth in small intestine
Describe the Migrating Motility Complex
Phase 1 - quiescent
Phase 2 - intermittent action potentials
Phase 3 - max action potentials stimulated by Motilin
What medication classes increase motility? (anti-constipation)
Dopamine antagonists
Macrolide antibiotics
AChE inhibitors
Opioid Receptor Antagonists
5-HT4 Receptor Agonists
What medication classes decrease motility? (anti-diarrheal)
5-HT3 Receptor Antagonists
Opioid Receptor Agonists
Anticholinergics
How does injury to the internal anal sphincter innervation lead to fecal incontinence?
Pressure of feces isn’t being regulated by the internal sphincter –> pt doesn’t know to contract external sphincter
What medications increase H2O in the lumen?
Lubiprostone
Linilactide
Lactulose
What medications increase H2O in the stool?
Psyllium
Docusate
What medications increase smooth muscle contractions?
Methylnaltrexone
Prucalopride
Bisacodyl
General sensation and taste of the posterior 1/3 of the tongue is supplied by
Lingual branch of glossopharyngeal n
General sensation and taste of anterior 2/3 of the tongue is supplied by
Sensation: lingual n
Taste: facial n
Vallate Papillae: glossopharyngeal n
The Lingual nerve contains which nerve fibers upon reaching the submandibular ganglion?
Pre-ganglionic Parasympathetic fibers (splitting off into SMG)
Taste sensation (chorda tympani)
General sensation (lingual)
How would you differentiate Campylobacter jejuni and Shigella dysenteriae on diagnosis?
Campy - curved, motile, oxidase +
Shigella - rod, non-motile, oxidase -
How would you differentiate E. Coli from other gram negative bacteria with similar clinical presentation?
Ferments lactose
Pink on MacConkey Agar
Green sheen on Eosin-methylane blue
Indole positive
How would you differentiate Yersinia enterocolitica from Salmonella typhi?
Yersinia - Non H2S producing
Salmonella - Produces H2S
How would you differentiate Yersinia enterocolitica from other gram negative bacteria?
Non H2S producing
Stains bipolar
Nonfermenting
Motile at 25, not motile at 37
How do you differentiate Staph aureus, Bacillus cereus and Clostridium perfringens?
S. aureus - doesn’t produce spores
Bacillus - produces spores, motile
C. perf - produces spores, nonmotile
What diarrheal causing bacteria can you treat with Macrolides?
Campylobacter jejuni, Shigella dysenteriae
What diarrheal causing bacteria can you treat with Fluoroquinolones?
Shigella dysenteriae, Yersinia enterocolitica, Salmonella typhi
What diarrheal causing bacteria can you treat with TMP-SMX?
Shigella dysenteriae, Yersinia enterocolitica
What diarrheal causing bacteria can you treat with Ceftriaxone?
Shigella dysenteriae, Salmonella typhi
What diarrheal causing bacteria do you treat with supportive care?
Staphylococcus aureus, Bacillus cereus, Clostridrium perfringens
What are xenobiotics?
Foreign substances metabolized by the body for excretion
What is the purpose of Phase I and Phase II metabolism?
Make xenobiotics more hydrophilic for excretion
What four things are needed for Phase I metabolism to occur?
CP450
NADPH
O2
P450 Reductase
Briefly explain the steps of Phase I metabolism
Step 1 - Fe3+/P450 binds with the Xenobiotic (RH)
Step 2 - NADPH donates an electron to Flavoprotein via P450 reductase which donates to Fe3+/P450-RH –> Fe2+/P450-RH
Step 3 - Fe2+/P450-RH binds to O2 and NADPH donates another electron to allow O2 to bind –> Fe2+/P450-O2-RH
Step 4 - O2 splits into H2O and Fe2+/P450-ROH –> ROH leaves and Fe2+/P450 turns back into Fe3+/P450
What are some examples of inducers of CP450?
Cabamazepine
Phenobarbital
Phenytoin
Rifampin
Smoking
St. John’s Wort
What are some examples of Inhibitors of CP450?
Azole antifungals
Cimetidine
Grapefruit Juice
Macrolides
Protease inhibitors
SSRIs
How does the Ultrarapid Metabolizer polymorphism effect drug metabolism?
How is it different from prodrug metabolism?
URM in regular drugs:
Faster metabolism –> more drug broken down –> lower plasma concentration –> less drug response
URM in prodrugs:
Faster metabolism –> more drug created –> higher plasma concentration –> higher drug response
How does the Poor Metabolizer polymorphism effect drug metabolism?
How is it different from prodrug metabolism?
PM in regular drugs:
Slower metabolism –> less drug broken down –> higher plasma concentration –> greater drug response
PM in prodrugs:
Slower metabolism –> less drug created –> lower plasma concentration –> less drug response
What polymorphism can effect the metabolism of Warfarin? What issues can that cause?
2C9
Can cause bleeding or clotting complications
Explain how an inducer can effect drug metabolism
A CP450 inducer increases the synthesis or decrease degradation of CP450
Increased speed of metabolism –> increased breakdown –> decreased drug response
Explain how an inhibitor can effect drug metabolism
A CP450 inhibitor decreases the synthesis or decrease degradation of CP450
Decreased speed of metabolism –> decreased breakdown –> increased drug response
What CP450 enzyme is responsible of the converstion of codeine –> morphine?
CP4502D6
What CP450 enzyme is responsible for the breakdown of statins?
CP4503A4/5
What are the major contributing enzymes of Phase I metabolism?
CP4503A4/5
CP4502D6
CP4502C9
What are the major contributing enzymes of Phase II metabolism?
UGT
What does the Hepatic Extraction Ratio tell us?
Ratio of what you give divided by what the liver takes out in first pass
What does it mean to have a high hepatic extraction ratio?
Low extraction ratio?
High hepatic ratio = decreased bioavailability
Low hepatic ratio = increased bioavailability
Where does Phase I and Phase II metabolism take place?
Phase I - SER
Phase II - cytoplasm
What does a low insulin:glucagon ratio tell us?
Glucose is being made instead of used
A diabetic patient with acetone breath and a low pH is likely having an episode of
Diabetic ketoacidosis
Describe diabetic ketoacidosis and how it’s treated
Glucose is being made rather than used because glucose can’t be taken up –> fats broken down and made into ketone bodies –> acetone byproduct causes acetone breath, ketones low pKa lower blood pH
Treated with insulin to take up glucose from the blood
Outline MOA and AE of Metformin
MOA: inhibits mitochondrial electron complex 1 –> less ATP, more AMP –> AMP stimulates AMPK –> stimulates phosphorylation of transcription factors –> decrease gluconeogenesis, shunts Pyruvate to Lactate pathway
Also increases glucose uptake in cells, glucose absorption to help with insulin sensitivity
AE: GI distress, Lactic acidosis (rare)
Outline MOA and AE of Sulonylureas
Binds to pancreatic beta cell SUR1 receptor –> closes K+ channel –> influx of Ca2+ –> depolarization –> insulin release
AE: Hypoglycemia, weight gain, icnreased risk of MI (receptors on cardiomyocytes), B-cell exhaustion (stops working after a few years)
Outline MOA and AE of TZDs
Binds to PPAR-y –> activates transcription involved in glucose and fat metabolism –> increased production of GLUT4
AE: Edema - can precipitate heart failure, increased risk of fractures (decreased production of osteoblasts)
CI in Stage 3+ HF, and bladder cancer
Outline MOA and AE of GLP1 Receptor Agonists
MOA: works like endogenous GLP-1 –> stimulates insulin biosynthesis
AE: Increased risk of pancreatitis, weight loss, expensive
First line for pts with CVD
CI: thyroid cancer
Describe the different types of insulin combinations
Prandial (before meal) always paired with basal (thoughout day)
Long acting (q24hrs) paired with rapid (injected 10-15 mins before eating)
Regular (1hr before eating) paired with NPH (intermediate - q12hrs)
What are the biggest risks of using insulin
Hypoglycemia (most likely with prandial) if they don’t eat in time
Weight gain
Hypersensitivity reaction
Identify the vitamin and mineral recommendations for children, pregnant women, and older adults
Children: Vit A & D; zinc
Pregnant women: Folate, Vit D; iron
Older adults: Vit D, Vit B12; calcium
Identify the vitamin and mineral recommendations for age-related eye diseases, obesity and T2DM
Eye diseases: Vit A / Carotenoids
Obesity: Vit B6, C, D, E
T2DM: Vit A, C, E, thiamine, biotin, folate, B12
What vitamins are fat-soluble?
Retinoids Vit A
Calciferol Vit D
a-Tocopherol Vit E
Vit K
What vitamins are water-soluble?
Thiamin B1
Riboflavin B2
Niacin B3
Pantothenic Acid B5
Vit B6
Biotin B7
Folic Acid B9
Cobalamin B12
Choline
Ascorbic Acid Vit C
Fill in the chart
What diseases can B1 deficiency cause?
Beriberi - malnutrition
Wernicke-Korsakoff Syndrome - alcohol use disorder
Outline Beriberi disease
Thiamin deficiency
Dry beriberi - peripheral neuropathy, muscle weakness/wasting, weight loss
Wet beriberi - heart enlargement/failure, peripheral vasodilation, edema
Outline Wenick-Korsakoff syndrome
Thiamine deficiency from alcohol use disorder
Wernicke encephalopathy (acute) - delerium, ataxia, eye muscle paralysis
Korsakoff psychosis (chronic) - anterograde amnesia
Outline Riboflavin deficiency disease
Ariboflavinosis - nutritional deficiency of Vit B2
Sore throat, cheilosis (cracking, crusting of mouth corners), glossitis (painful magenta tongue), seborrheic dermatitis, anemia
Why is Vit B3 crucial to our diet, and how much do we need?
Vit B3 = Niacin –> part of NAD+ & NADP+
Need 14-16mg per day
Outline the Vit B3 related diseases
Pellagra - 4 Ds - Diarrhea, Dermatitis (C3-4), Dementia, Death
Hartnup syndrome - decreased Trp –> decreased Niacin synthesis
Carcinoid syndrome - excess Trp utilization = decreased Niacin synthesis
Toxicity Diseases:
Niacin flush
N/V, liver damage, impaired glucose tolerance, gout
Outline Vit B5 related diseases
Nutritional deficiencies rare
Pantothenate kinase-associated neurodegeneration (PKAN)
PANK2 mutation –> abnormal Fe accumulation –> parkinsonism, dystonia, dementia
Outline Vit B6 related diseases
Nutritional deficiency from malnutrition, alcohol use disorder, etc –> dermatitis, sideroblastic anemia, depression, confusion, peripheral neuropathy
Toxicity diseases - depression, fatigue, irritability, headaches
Outline Vit B7 related diseases
Biotinidase deficiency - BTD mutations –> encodes biotinidase (enzyme that releases biotin from proteins)
Infants: hypotonia, seizures, optic atrophy
Included in NBS
How does the overconsumption of egg whites cause a Biotin deficiency
Egg whites contain avidin –> avidin binds to biotin that prevents absorption
What are the functions of the different forms of Folic Acid B9
formyl-THF –> THF - purine biosynthesis
methylene-THF –> DHF –> THF - dTMP biosynthesis
THF <–> methylene-THF - Ser & Gly degradation and biosynthesis
methyl-THF –> THF - Vit B12-mediated Met recycling
What symptoms would you see in Folic Acid Deficiency Diseases
Nutritional deficiency:
Megaloblastic anemia
Glossitis, fatigue, depression
Neural tube defects (ancephalopathy, spina bifida) if mother has Folate def.
Methylene-THF reductase deficiency - MTHFR mutation
Defect in enzyme involved in folic acid metabolism
High conc of homocysteine in blood, developmental delay, eye disorders, thrombosis
What is the function of Cobalamin B12
Involved in coupled conversion of methyl-THF to THF
Involved in conversion of homocystine to Met
Propionyl-CoA metabolism
Outline the absorption of Cobalamin
Cobalamin (B12) binds to R-binders in saliva and stomach –> protein-bound cobalamin must be released by protease digestion in stomach or small intestine –> binding to Intrinsic factor –> IF-B12 complex undergoes receptor-mediated endocytosis in terminal ileum –> In enterocytes, IF-B12 dissociates and B12 binds to transcobalamin II –> B12-TCII complex is released into blood
Explain Cobalamin B12 deficiencies and findings
Nutritional deficiency:
Megaloblastic anemia
Fatigue, subacute degeneration of spinal cord, paralysis, anorexia
Methylmalonic acidemia & homocystinuria - MMACHC mutations
Encodes CblC - protein involved in cobalamin metabolism
Neurological symptoms, intrauterine growth retardation, microcephaly
What can come from Choline deficiency?
What about Choline toxicity?
Deficiency - liver damage
Toxicity - Sweating, salivation, hypotension, liver damage
