8/28/17 Flashcards
Insulin, GLUT-4, and Glucose Uptake
Insulin binds to its receptor and causes signaling via IRS-1 and PI3K
GLUT4 fuses with PM and does facilitated transport
GLUT4 found in skeletal/cardiac muscle and adipose tissue, brain has glucose transporter that doesn’t rely on insulin
Post-translational modifications of insulin
- Start as preproinsulin, put in lumen of rough ER by signal peptide
- Signal peptidase removes the signal peptide as enter rough ER, makes proinsulin (inactive)
- Folding of the disulfide bond formation (between A and B chain) occurs in the rER, sent to Golgi and then sent to secretory vesicles
- Cleavage of C chain occurs in secretory vesicles by prohormone convertase, C peptide and insulin secreted together
Insulin Structure
1°: A chain shorter than B chain and also has an intrachain disulfide bond, has two interchain disulfide bonds
2°: Chain A has 2 alpha helices connected by disulfide bond, Chain B is an alpha helix
3°: A and B chains are perpendicular to each other
4°: six insulin molecules arranged around Zn ions surrounded by His
Storage form for secretory vesicles that dissociates into monomeric active forms after secretion
Insulin Secretion
Glucose enter beta cells via GLUT2
Glycolysis and ATP generation increase
ATP inhibits plasma membrane K+ channels, altered membrane potential opens voltage-gated Ca2+ channels
Incoming Ca2+ triggers export of storage granules by exocytosis
Biphasic Insulin Release
Rapid/transient insulin secretion at first by vesicles close to the PM and then a delayed but more sustained release of insulin
Second phase of release requires monomeric GTPases and vesicles movement by rearrangement of actin cytoskeleton
Glucagon structure
Simple alpha helix
Made as a preprohormone that has the signal peptide cleaved in the rER
Prohormone contains peptides for several hormones like GLP-1, cut by tissue-specific prohormone convertases
Glucagon Secretion
Not entirely clear
Low Glu triggers voltage-gated Ca2+ channels to let Ca2+ in the cell, expcytosis of glucagon vesicles
Biphasic release since two pools of glucagon
Effects of malnutrition during pregnancy
Glucose-insulin disorders Cardiovascular disease Renal dysfunction Airway disease Breast cancer Obesity
Kidney Hypertension from uterus
Insult to fetus like malnutrition, lack of protein, or glucocorticoid exposure slows tissue growth and leads to lower cell number
Nephrons have a higher glomerular filtration rate per cell to compensate and focal glomerulosclerosis occurs (leads to scarring and death)
Sodium builds up in blood and get high blood pressure
Adaptations as a fetus become maladaptive as an adult
Mid Brain
Develops first and fast
Emotional outbursts: fear, anxiety, impulsive, stressed, reactive
When get emotional they use all 5 senses and remember the experiences with long term memory
Front Brain
Develops slowly
Calculating
Plans ahead, thinks fast, multitasks, logical, organized
Prefrontal Cortex
Emotions: managing frustrations, modulating emotions
Activation, focus, effort, memory, action
Not fully developed until young adulthood
HPA Axis
Plays a role in response to stress
Stress: any real or perceived threat to homeostasis
Hypothalamus releases Corticotropin-releasing factor (CRF) to anterior pituitary, which releases adrenocorticotropic hormone to the adrenal cortex
Adrenal cortex releases cortisol, a glucocorticoid
How children can avoid toxic stress from Adverse Childhood Events
Social and Emotional Buffers
3 Executive Functions for Learning Something
Self-Control: ignore distractions, control emotions, stay focused
Working Memory: remember and connect, manipulate info, perform multiple steps
Flexible Thinking: switch perspectives, assess different strategies
Scaffolding
Adult support throughout everyday routines: highly responsive, encouraging, interactive, and playful
Intermediate Filament
Rope-like structures that can withstand mechanical stress
Toughest and most durable
Act as desmosomes and form nuclear lamina
Alpha helices that bundle in opposite directions, have no structural polarity
Classes of intermediate Filaments
- Keratin filaments: each type of epithelial cell has its own type of keratin filament
- Vimentin and vimentin-related filaments: connective tissue, muscle cells, and glial cells
- Neurofilaments: in nerve cells
- Nuclear lamins: in all animal cells, provide support and also involved in nuclear organization, cell cycle regulation, and gene expression
Defective Intermediate Filaments
- Epidermolysis Bullosa Simokex: skin blistering after little mechanical stress, mutation in the skin-specific keratin gene
- Progeria: the nuclear lamina on he inside of the nuclear membrane is defective
Can’t provide support so get misshapen nucleus that affects chromatin organization, cell division, and gene expression
Age prematurely so have hair loss, wrinkles, CV/kidney problems, die in teens
Microtubules
Hollow, rigid rods that are like RR tracks for vesicles, organelles, and other things
Made of alpha and beta tubulin stacked on top of each other, 13 parallel chains called protofilaments
Beta end is plus end, polymerize faster
Alpha end is minus end, polymerize slower
Grow out of centrosome that has 2 perpendicular centrioles, gamma tubule is a matrix protein that acts as a nucleation site
Found in cilia (lung epithelium) and the centrioles are called basal bodies, also do mitotic spindle
Microtubule Dynamic Instability
Like fisherman, will stop growing if not bind to specific proteins or cellular components
Alpha/beta tubule dimers added to plus end if have GTP bound
GTP becomes hydrolyzed to GDP, GDP-tubulin not bind to stuff as well so will depolymerize
GTP cap if add GTP tubulin faster than hydrolyze to GDP
Microtubule drugs
Prevent polymerization or stabilize so can’t shrink, used for tumor cells with rapid cell division
Taxol: stabilize microtubules
Colchicine, Vinblastine: prevent polymerization
Microtubule transport
Used in nerve cells with long axons, motor proteins direct cargo movement
Kinesins: walk toward plus end (cell periphery)
Dyneins: walk toward minus end (centrosome)
Different kind of each, tail binds specific cargo
Cilia and Flagella
Cilia in respiratory tract to move mucus, sperm have flagella
9 + 2 array with 9 doublets outside and 2 singles inside, use dyneins
Cilia in inner ear (used for sensory input) and in respiratory tract
Are stable, no dynamic instability
Actin Filaments
Create cell shape and movement, regulated by many different types of proteins
Polymerization of actin monomers into two stranded helix
Has cleft for ATP, can be hydrolyzed to ADP to create depolymerization
Faster growing plus end and slower minus end but can grow/shrink at both ends, do treadmilling, less rapid rate of change compared to microtubules
Stress bundles, contractile ring for dividing cells, transient cellular projections, microvilli
Microvilli
Made of actin filaments
Small intestines and kidney tubules
Non-motile, increase surface area of the cell membrane to improve absorption
Cell Migration via Actin
Lamellipodia: broad thin sheets that have dense actin network
Filopdia: long stiff finger-like projections with parallel actin filaments
Plus ends oriented towards PM that pushes the membrane outward
Myosin II
Muscle Cell: 2 myosin II can associate tail to tail to form myosin thick filament, create muscle contraction
Non-muscle Cell: double myosin II facing opposite direction walks the head along actin filament towards plus end to create cell contraction
Creates stress fibers- regulate cell shape, cell division, migration, and sensing of mechanical stress
Regulated by Rho GTPases (monomeric G protein from Ras family) that create downstream signaling to do stuff like filopedia
Congenital Myopathy
Skeletal muscle weakness that can be neonatal life threatening to mild muscle weakness in adults
No cure
Mutations in the actin cytoskeleton, can be a number of ways
Ultrasound propagation
Use pulse echo technique, utilizes a crystal
Duty factor: how much the ultrasound is actually on
Pulsed wave: 1% or 0.01
Continuous wave: 100% or 1.0
Velocity and Attenuation of Ultrasound by different media
Velocity: air slowest at 330, tissues are middle and 1500, bone fastest at 4080
Attenuation: water lowest at 0, tissues middle at 1, bone at 5, air highest at 12
Scanning planes and field edges for ultrasound
Sagittal: divides body into left and right
Coronal: divides body into front and back
Transverse: divides body into top and bottom
Near field: closest to probe
Far field: furthest from probe
Leading edge: closest to indicator mark
Receding edge: furthest side from indicator
Grayscale colors for ultrasound
Black (Anechoic): fluid like blood or bile
Gray (Hypoechoic): soft tissue and solid organs, includes muscle
White (Hyperechoic): air, bone, dense fascia, includes diaphragm
Ultrasound Modes
A Mode: amplitude, used rarely and in ophtho
B Mode: brightness, common
M Mode: motion, displays anatomy over time
Medical vs Surgical Asepsis
Asepsis: the state of being free from pathogenic microorganisms
Medical asepsis: clean technique to reduce /prevent spread of pathogens like hand washing, glove use, and cough etiquette
Surgical asepsis: sterile technique, practices to eliminate all microorganisms from an area, used for invasive procedures
Principles of Sterile Technique
Never turn back on sterile field Don't reach over sterile field Can become non-sterile if prolonged exposure to air Moisture contaminates sterile field Skin not sterile Check package sterility Consider not sterile when in doubt Items in sterile field must be sterile One inch border around sterile field is nonsterile Anything below waist is not sterile
SGLT2 Inhibitors
Sodium Glucose Co-Transporter 2
SGLT2 normally reabsorbs 90% of the glucose that is filtered by the kidney, located in the proximal convoluted tubule
SGLT2 Inhibitors prevent reabsorption, glycosuria, lose weight
Hypoglycemia
Glucose less than 70
Rule of 15: have 15g of carbs and check back in 15 mins, repeat if necessary
Causes: missed meal, too much exercise or insulin
Severe hypoglycemia associated with higher CV mortality and cognitive dysfunction
Macrovascular Diabetes Complications
Most common cause of diabetes death
Include coronary artery disease, cerebrovascular disease, and complications of peripheral vascular disease
Heart: myocardial infarction (heart attack), heart failure (heart pump failure)
Brain: stroke, cognitive impairment
Extremities: ulcers, amputations, aneurysms
Microvascular Complications of Diabetes
Eye: retinopathy, cataracts, glaucoma that can lead to blindness
Kidney: neuropathy like macro/microalbuminuria that can lead to kidney failure
Nerves: peripheral/autonomic neuropathy that can lead to amputation
All can lead to disability or death
3 key junctions in metabolism
Glucose-6 phosphate: can lead to glycogen, pyruvate, or ribose 5-phosphate
Pyruvate: can lead to oxaloacetate, alanine, or lactate
Acetyl CoA: FAs, CO2, and ketone bodies
Common Characteristics in Metabolic Regulation
Allosteric Interactions: PFK1 is stimulated by fructose 2,6 bisphosphate
Covalent Modification: phosphorylation of glycogen synthase inhibits the formation of glycogen
Adjustment of Enzyme Levels: glucagon induces expression of PEP carboxykinase, glucagon triggers gluconeogenesis of oxaloacetate into PEP
Compartmentation: transport of FAs into mitochondria for degradation
Metabolic specialization of organs
Glycogen Break Down
- Glucagon (in the liver only) or epinephrine (via a beta receptor) binds to a G protein receptor, activates adenylate cyclase to make cAMP
- cAMP activates PKA
- PKA activates phosphorylase kinase
- Phosphorylase kinase converts inactive glycogen phosphorylase b to active glycogen phosphorylase a
- PKA inactivates glycogen synthase by phosphorylation
- Glycogen is degraded to Glu 1-phosphate
Effect of catecholamines on different body areas
Epinephrine
Released by kidneys upon sympathetic NS signals, get acute response
- Muscle-
Greatly increased: glycolysis, glycogenolysis
Slight Increase: gluconeogenesis
Moderate decrease: glycogen synthesis
Liver-
Greatly increased: glycogenolysis
Slight increase: gluconeogenesis
Slight decrease: glycolysis, FA synthesis
Adipose tissue-
Greatly increased: Lipolysis
Slight decrease: triglyceride utilization
Fructose 2,6-bisphosphate
Fructose 2,6-bisphosphate activates PFK1 in liver and muscle to promote glycolysis
PFK2 makes it, different isoform for muscle and liver
Epinephrine causes PKA-cAMP to phosphorylate each isoform
Phosphorylation stimulates Fructose 2,6-bisphosphate in the muscle to turn on glycolysis, inactivates liver isoform to stop making Fructose 2,6-bisphosphate
Effect of glucocorticoids on different body areas
Cortisol
Chronic stress causes corticotropin-releasing factor in the hypothalamus to be released, leads to glucocorticoids in the adrenal cortex to be released
Regulates gene expression, takes hours or days
- Muscle: Protein degradation in peripheral tissues slightly increased
- Liver: gluconeogenesis and glycogen synthesis slightly increased
- Adipose tissue: lipolysis and expression of lipase slightly increased
Ethanol Metabolism
Alcohol Dehydrogenase System- occurs in cytoplasm of the liver
Ethanol to acetaldehyde to acetate, use NAD+
Microsomal Ethanol-Oxidizing System: used for large amounts of alcohol
Use O2 and NADPH to convert ethanol to acetaldehyde, which feeds back to cytoplasm for further detox
Effect of Alcohol on Liver Metabolism
Alcohol metabolism makes large quantities of acetyl-CoA, NADH, and ATP
TCA cycle inhibited by high ATP and NADH levels, glycolysis inhibited at PFK1 and PDH
FA oxidation impaired by NAD+ depletion
Gluconeogenesis inhibited cuz high NADH:NAD+ ratio drives lactate dehydrogenase towards lactate and malate dehydrogenase towards malate instead of pyruvate and oxaloacetate
Alcohol precipitates hypoglycemia
Health Requirements for Adults
25-45 kcal/kg for adult male, 25-35 for girls
Fewer kcal needed as we age, young people have the highest
Avoid chronic diseases, do prudent diet
Nutrition Requirements for Infants
Feed every 2-3 hours, double birth weight by 4 months, height by one year
Breast milk is better than bottle, low in protein and high in fats (good for babies though), higher conc. of immune components and growth factors, reduce illness
108 kcal/kg for first 6 months, want 7% calories from protein (half of adult amount), higher fats and avoid ketosis, less carbs than adult
Supplement with iron for first year and folate/B12 for first 6 months
Wean at one year
Nutrition for Lactating Moms
Normal healthy diet
Takes about 750 kcal to make milk each day
Take in polyunsaturated fats
Slight increase in protein
Nutrition for Toddlers
Picky eaters, developing healthy habits is crucial for later in life, less appetite since less growth so make eat
70-90 kcal/kg, want ideal growth specified by WHO not CDC, after 2 keep fat intake like adults, less protein and more carbs than adults, fluids since dehydrate faster than adults
Iron (anemia a big problem), zinc, and calcium are important
Iron deficiency and anemia symptoms (stages II and III)
Impaired body temp regulation so always cold, decreased immune function, sensitivity to light, pica, koilonychia (spoon nails), angular stomatitis (lesions around mouth), up susceptibility to lead poisoning
Nutrition for Childhood
Need nutrient dense foods, but needs vary greatly
Energy to ensure growth and spare protein degradation but not allow excess weight gain
Energy intake similar to an adult
Monitor calcium, iron, zinc, and vitamin D
Nutrition for Adolescence
47-65 kcal/kg with males needing more
Calcium important for acquiring bone mass, Vitamin D is crucial
Iron important for deposition of lean muscle mass and iron lost during menses
Folic Acid important for lean body mass and females of reproductive age
Nutrition for Old People
Lose lean mass, more sedentary
BMR declines so need slightly less calories
Vitamin C, B6, and B12 deficiency are common
Nutrients for repair/maintenance: A, D, Fe, Ca, and protein
Fiber and poly fats help fight disease
Exercise helps with cancer and CV probsq
Effects of Insulin
Anabolic hormone
Protein synthesis, glycogen synthesis, lipogenesis
Inhibits the catabolism of each of these
Role of FFA in Hyperglycemia
Adipose tissue insulin resistance leads to increased lipolysis and FFA mobilization as a result
FFA mobilization creates muscle insulin resistance by increasing FFA oxidation, causing lower glucose utilization
FFA mobilization creates liver insulin resistance by increasing FFA oxidation, increasing gluconeogenesis
Creates hyperglycemia
Mechanism of insulin resistance
Primary mechanism not known but probably a combo of genetics, obesity, cytokines, and FFAs
Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, most likely to hyperinsulinemia and not primary defect
Post receptor defects in insulin regulated phosphorylation and dephosphorylation play a predominant role
Insulin receptor and insulin signal transduction
Insulin binds to receptor tyrosine kinase
Interacts with IRS and Shc proteins for cell growth, protein synthesis, glycogen synthesis, and glucose transport
PI-3 kinase and the Cbl pathway promote translocation of intracellular vesicles with GLUT4 transporters to the PM
Clinical Features of Insulin Resistance
Central/android obesity
Acanthosis nigricans: hyperpigmentation and velvety plaques, high insulin levels bind to IGF receptors to stimulate growth of keratinocytes/dermal fibroblasts, can be painful and smelly, goes away with weight loss
Metabolic syndrome
Associated with Hypertension and dyslipidemia
Progression of Insulin Levels and beta cell mass before Diabetes
Insulin Secretion initially increases to maintain normal glucose levels, mild secretory defect initially
Eventually insulin secretory defect progresses to inadequate insulin secretion
Beta cell mass decreases by 50% when diagnosed, amyloid deposit in islet cells, elevation of FFAs (lipotoxicity) may worsen islet function
Incretin
Gut hormones released from intestine in response to ingestion of food like glucose, need sufficiently high conc. to stimulate release of insulin, release of insulin in response to physiological levels of the hormone occurs only when glucose levels are elevated (Glu-dependent)
Glucagon-like Peptide 1 (GLP-1) and Gastric Inhibitory Peptide (GIP), both rapidly metabolized by dipeptidyl peptidase-4 (DPP-4)
Both stimulate insulin response from beta cells in glucose-dependent manner
GLP-1 inhibits gastric emptying, reduces food intake, and inhibits glucagon Secretion from alpha cells in glucose-dependent manner unlike GIP
Reduced incretin effect in diabetics
Drug Induced Diabetes
Glucocorticoids
Steroids
Immunosuppressants
Niacin
HAART
Atypical antipsychotics
Diazoxide
Polycystic Ovary Syndrome
Insulin resistance
Obesity
Irregular menses
Reduced fertility
Hyperandrogenism (guy hair patterns)
Gestational Diabetes
Due to placental hormones (human placenta lactogen) which promotes insulin resistance through various mechanisms to increase nutrient supply to growing fetus
Higher risk for subsequent diabetes
Stress Hyperglycemia
Critically ill, ICU, burn victims
May or may not be reversible
Increased cortisol, catecholamines, glucagon, growth hormones, gluconeogenesis, and glycogenolysis
Underlying insulin resistance a contributing factor
Cushing’s Syndrome and Acromegaly
Cushing’s: excess cortisol
Associated with Central obesity, diabetes, Hypertension, muscle wasting
Acromegaly: excess growth hormone
Associated with Diabetes, Hypertension, sleep apnea
Type II Treatment
Entry A1C <7.5%: monotherapy, metformin
Entry A1C >7.5%: dual therapy, metformin plus another drug
Entry A1C >9%: dual or triple therapy if no symptoms, insulin and other agents if symptoms
DPP-4 Inhibitors (Gliptin Family)
Inhibit the enzyme DPP-4 that breaks down GLP-1 and GIP
Both incretins have an insulintropic effect leading to clearance of glucose from bloodstream
Incretins stay in system from 12 hours to several days
Lower A1C levels and do weight loss
How to Assess a Type II patient
Start with basics and don’t overwhelm
Assess their resources and support system
Make initial weight loss goal of 5-10%
Give education: starting new meds, nutrition counseling like what a carb is
Short term follow up with reachable short term goals
