Flashcards in Week 4 Problem Concepts Deck (149):
Intermediate filaments: fxn and classes
Fxn: resist mechanical stress (most durbale of all filaments)
Classes: nuclear lamins, keratin filaments, vimentin filaments, neurofilaments
Role of nuclear lamins (3)
found in nucleus of ALL cells. Play a role in gene expression, differentiation, cell cycle
Progeria: cause, symptoms
mutation in nuclear lamins (Lamin A). wrinkling of skin, kidney issues, MSK degeneration (Benjamin button)
Microtubule Fxn: 2
movement within cell, cilia/flagella
MT have a + end and - end. whats the difference?
(+): beta tubulin, more likely to grow
(-): alpha tubulin, more likely to shrink
Motor proteins associated with MT? which is used in flagella and cilia movements?
Dynein (move towards - end, towards centrosome/nucleus), seen in flagella and cilia
Kinesin (move toward + end, cell periphery)
what is the role of basa bodies?
serve as MT organizing center for cilia
dynamic instability is associated with..role
MT. they can grow or shrink at + end (GTP=grow, GDP=shrink), helps "search" for proteint to bind to
Taxol: effects? use?
cancer treatment; stabilizes MTs
B/c MT play a major role in cell division (separates chromosomes) they are often targets of....
Colchicine: effects? use?
prevents MT polymerization; cancer treatment
Vinblastine: effects? use?
prevents MT polymerization
Actin is composed of...ATP bound?
actin monomers combined to form 2-stranded helix. free actin is ATP bound. Actin monomers in filaments are ADP bound
Actin filaments play a role in making what 5 structures?
Stress fibers, microvilli, contractile ring, lamellipodia, filopodia
Congential Myopathy: cause? symptoms?
skeletal muscle weakness caused by mutation in muscle-specific actin
Insulin triggers glucose uptake in what three cell types?
adipose, liver, muscle
describe insulin signaling
Insulin=>RTK=>IRS-1=>PI-3K=>GLUT4 containing vesicle exocytosed
describe the process of insulin production
1. pre-proinsulin: [signal peptide-BCA]--> produced in rER
2. proinsulin: loss of signal peptide and formation of sulfide bonds (2 between B and A, one within A) produced in rER
3. mature insulin: Cleavage of C-peptide within vesicle
describe the storage form of insulin. where is this seen? when is it undone?
3 AB/AB dimers of insulin surrounding a Zn ion. seen in storage vesicles. undone once contents of vesicle are released
compare half-life of insulin vs. C-peptide
insulin has a short half life, but C-peptide is very stable and can be used as a measure of insulin production
pro-enzyme convertase and insulin: role, location
used to convert pro-insulin to insulin. located within vesicle
what is the difference between GLUT2 and GLUT4
GLUT4 is the only insulin sensitive glucose transporter (seen in muscle cells, liver cells, adipocytes). GLUT2 is located in Beta cells (insulin producing) of pancreas and play an important role in insulin release
describe the signal cascade associated with insulin release from beta cell
1. Alpha and beta cells of pancreas are highly vascularized
2. increase in blood glucose increases the amount of glucose entering beta cells through GLUT2
3. increased glucose increased ATP
4. ATP inactivates K channels
5. B cell depolarizes
6. Voltage gated calcium channels open
7. Ca binds insulin vesicle and insulin released
describe insulin release over time?
biphasic. insulin is released in two phases: phase 1=short burst, phase 2=prolonged
(glucagon release is also biphasic)
In ultrasound: high f gives? low f gives?
high f=better resolution
low f= better depth/penetration
what are the four ultrasound probes? uses?
-phased array: adbomen, cardiac
-endoluminal: vaginal, oral, rectal
what is attenuation? what is the attenuation of water? air?
how much an object decreases a sound wave (higher attenuation = less signal)
what are the modes of US?
-A mode: out dated
-B mode: babies!
-M mode: beach
-Pulsed Wave Doppler
-Color doppler: red=towards, blue=going away
-Power doppler: tells if you have flow
what is the piezoelectric effect
this is how ultrasound works. the crystal in the US converts electrical signal to sound waves and a sound waves back to electrical signal
does Type I or II diabetes have a stronger familial correlation? genetic?
What is the function of human leukocyte antigen (HLA) gene complex?
set of genes, some of which code for antigens that are presented by cells
which locus within the HLA complex is associated with T1DM?
which alleles within the DR locus of HLA increase risk of T1DM? how?
DR3: B-cells present antigens that are targeted by antibodies
DR4: antigen present that triggers production of antibodies against insulin
which allele within the DR locus of HLA protects against T1DM?
what is MODY, cause? prevelance?
Maturity onset diabetes of the young. a type of DM (NOT T1DM or T2DM) caused by genetic defects in B cels. 1-2% of diabetes cases
MODY 2 cause
mutation in glucokinase of B-cells (increased B-cell glucose threshold)
MODY 1,3,4,5,6 cause
all caused by mutations of genes in the same pathway; delayed response to glucose uptake
How do you treat MODY? how does it work? is it effective?
treat with sulfonylureas. high effective monotherapy. Increase intracellular calcium and increases proinsulin secretion
what was the goal of the genome-wide association study?
determine if genetic differences predispose people to certain diseases
what did the GWA study conclude with diabetes? 2
>50 SNPs identified to increase risk for diabetes (slight increase)
new genes have been associated with diabetes
what are 3 weaknesses of the GWA study
association does not mean causation
data collected in 1980s
name two genes that were ORIGINALLY identified in GWA study to increase risk of diabetes
what is the role of TCF7L2 gene? increased risk for diabetes?
TF in Wnt signaling; proglucagon synthesis
Homozygous carriers 2x increased risk for T2DM
what is the role of TFO? is it an inependent risk factor for diabetes?
originally thought to be an independent risk factor for diabetes. was found to be associated with obesity (a secondary risk factor for diabetes). Fxn: methylates RNA and causes preferential production of fat (epigenetic)
how is lifestyle associated with epigenticc; give 2 diabetes related examples
increase carbs: influence histone modification
stress can change methylation patterns
diabetes is a complex disease; what does that mean
diabetes is influenced by biolgical, behavioral and environmental factors
what causes T1DM? how common?
immune system destroys beta cells; less than 10% of popn with diabetes
what causes T2DM? how common?
insulin resistance and decreased insulin production. more than 90% of popn with diabetes
what causes gestational diabetes? how common?
placental hormones increase amount of glucose in blood. 3-5% of pregnant women
what is polydipsia?
what is polyuria?
what Fasting blood glucose is normal? diabetic?
125 mg/dL= diabetes
what HbA1C value is normal? diabetic?
what is the difference between IGT and IFG
IGT: impaired glucose tolerance
IFT: imparired fasting glucose
both refer to a pre-diabetic state, but represent different mechanisms of insulin resistance
inhibits gluconeogenesis in liver. very effective monotherapy
SGLT2 inhibitors: MOA
prevent glucose reabsorption in kidneys
decrease insulin resistance of skeletal muscle/fat
what are the two types of insulin?
Note: insulin should be used always in T1DM and only in special circumstances in T2DM:
Basal insulin: long acting
bolus insulin: fast acting, after meal
hypoglycemia is when blood glucose is below
Below 70 mg/dL
what are the diabetes ABCs
A: elevated A1C
B: high BP
C: Increased LDL cholesterol
all risk factors for CVDs that are associated with diabetes
what are the vascular complications that arise in diabetes?
Macrovascular: heart (MI, heart failure), brain (stroke), extremities (amputations)
Microvascular: retinopathy, neuropathy, nephropathy
Catecholamines: what are they? where are they produced?
produced by adrenal gland
what are the effects of catecholamines in skeletal muscle
increase: glycolysis, TG utilization
decrease: glycogen production
what are the effects of catecholamines in liver
Increase: gluconeogenesis, glycogenolysis
decrease: glycogen synthesis, glycolysis, FA synthesis
what are the effects of catecholamines in adipose
decrease: TG storage
E/NE binds what type of receptor? activates what enzyme?
adrenergic receptor. activates cAMP-PKA
what explains how E can have opposing effects in liver and muscle cells?
In liver: PKA phosphorylates and inactivates PFK-2/F-2,6-BPase (no F-2,6-BP produced, glycolysis not active)
In muscle PKA phosphorylates and activates PFK-2. F-2,6-BP produced and glycolysis active.
glucocorticoids: role? example? produced?
long-term response to stress (gene expression). Cortisol. Adrenal gland
what are the effects of glucocorticoids in skeletal muscle?
increase protein degradation in peripheral muscle (increase proteasome expressions)
what are the effects of glucocorticoids in liver cells?
increase gluconeogenesis and glycogen production
what are the effects of glucocorticoids in adipose?
why is ethanol bad? 4
ehtanol metbaolism produces an abundance of NADH, Acetyl-Coa and ATP. This high NADH/NAD+ and high ATP causes:
-decreases glucose production (hypoglycemia)
-increased lactate production (lactic acidosis)
-Decreases FA oxiation (hyperlipidemia)
T2DM is characterized by hyperglycemia caused by...5
1. peripheral insulin resistance
2. progressive B-cell dysfunction
3. hype-secretion of glucagon
4. accelerated gastric emptying
5. impaired incretin effect
Incretin: produced, role,
hormone produced by cells of the gut. increase insulin production following a meal.
more insulin is produced following a meal than following an IV injeciton with the same amount of glucose
what are the insulin and glucagon levels after a meal in a person with T2DM?
insulin: delayed and depressed levels
GLP-1 produced, fxn 7
incretin produced by L-cells of distal ileum and colon.
Fxn: increase insulin, increase size of Beta cells, suppress glucagon, enhance insulin sensitivity, slows gastric emptying, cardioprotection and neuroprotection
GIP produced? fxN 2
produced by gut K-cells of duodenum and jejunum
fxn: increase insulin release, increase size of B-cells
is GLP-1, GIP, or both a therapeutic target for T2DM?
only GLP-1, GIP levels are not typically altered in T2DM
incretins are degraded by?
Exenatide (Byetta) fxn, how do you admin?
GLP-1 receptor agonist, 2x daily injections
Liraglutide fxn, how do you admin?
modified synthetic GLP-1, 1x daily injected
Vildagliptin/sitagliptin fxn, how do you admin
DPP4 inhibitors (1x daily ingestion)
when blood glucose decreases, what is the normal progression of events in CRH?
what are the four CRH? overall role?
Glucagon, Catecholamines, Glucocorticoids, Growth Hormones. Increase blood glucose levels
in T1DM>5 years what is lost completely?
what is hypoglycemia induced autonomic failure
E/NE response decreased after recurring hypoglycemia; after glucagon response is lost E/NE becomes new line of defense
what causes Diabetic Ketoacidosis
Hyperglycemia and ketonemia (increased ketones in blood). Body cant use glucose even though it is present. FA oxidation occurs and ketone bodies accumulate. Excess ketones and glucose causes increase in urine volume. Further concentration of ketones in body,
what are the physical findings of DKA
tachycardia, dehydration, respiratory distress, coma, abdominal tenderness
DKA is a characteristic of what type of DM?
T1DM; although it can be triggered in T2DM
what is acanthosis nigricans? what is it an indication of? cause
darkening of skin fold as a result of INSULIN RESISTANCE (insulin binds IGF receptor and stimulates keratinocyte growth). High risk for developing T2DM
rank the order of these:
impaired glucose tolerance
increased plasma glucose
Normal--> increased plasma glucose-->insulin resistance-->impaired glucose tolerance-->T2DM
A patient was just diagnosed with polycystic ovary syndrome; what are they at an increased risk of?
increased risk of insulin resistance and therefore T2DM
how is cushing's syndrome associated with an increased risk for diabetes
excess cortisol; glucose levels raised too high-->insulin resistance-->T2DM
how is acromegaly associated with an increased risk for diabetes?
excess GH; blood glucose chronically elevated
Diabetes Prevention Program: setup, findings
3 pre-diabetes groups; placebo, metformin, lifestyle change
Lifestyle change>metformin>placebo in preventing T2DM
(1kg weight loss correlated with 16% reduction in incidence of T2DM)
The DPP found that metformin was only useful in individuals with...
Look AHEAD study: setup, findings
will intensive lifestyle intervention (lose 7-10% of weight by diet, exercise, pillls) reduce the incidence of cerebrovascular/cardiovascular event.
ILI group had better ABCs
FInnish Diabetes Prevention study findings
individualized advice is more effective than generalized diet instructions for preventing T2DM
what is the legacy effect?
early glucose control (diet, exercise, lifestyle changes) will have a lasting postive impact
what are the physical activity recommendations for adults?
30 min PA/day ~5 days/wk
role of nodal cilia
motile cilia that plays role in L+R asymmetry during embryo development
Primary Ciliary Dyskensia: cause, results in (3)
auto rece disorder caused by Loss of dynein (essential in motile cilia). Loss of mucociliary escalator, immotile sperm, and situs inversus (NOT caused by loss of primary cilia)
Autosomal Dominant Polycystic kidney Disease (ADPKD); cause, results in
loss of polycystin proteins essential for primary cilia (non-motile;used for mechanoreceptors)
large cystic kidneys
Cell Adhesion Molecules invovled in cell-cell connecitons
Cadherin and Integrin
Cadherin; role, intracellular domain, extracellular domain
cell-cell interaction; intracellular=associate with cetenins; extracellular domain=calcium dependent
General structure/fxn of cell-cell CAMs
transmembrane proteins that link interior of cell to ECM or other cells
cell-cell and cell-ECM binding, mechanoreceptors
cell jxns of lateral domain (in order from apical to basal)
Zonula Occludens (tight jxn), Zonula Adherin (intermediate jxn), Macula Adherin (Desmosome), Gap Jxn
Role of Zonula Occludens; important proteins
separate apical and basal domains.
Role of Zonula Adherens; important proteins
anchor adjacent cells; cadherins, catenins, actin
role of Macula Adherens; important proteins
resist shearing force (spot welds);
desmoglein, desmocolin (Cadherin), desmoplakin, plakoglobin, keratin
Role of gap jxn; important protieins
connexin and connexons
types of basal domain jxns
focal adhesions, hemidesmisomes
focal adhesion; role, proteins
link cytoplasmic actin and the ECM, relay signals from ECM to cell
integrins, fibronectin, collagen, laminin
hemidesmisomes; role, proteins
anchors basal PM to basal lamina
BP230, Type XVII collagen, Type VII collagen, integrins
Pemphigus Vulgaris: cause, blister type, nikolsky sign
-skin disorder; body creates antibody against desmogleins (desmosome); loss of lateral domain but basal domain still attached to BM
-flaccid (easily popped) blisters
-Nikolsky sign +
Bullous Pemphigoid: cause, blister type, nikolsky sign
-skin disorder; body creates antibodies against BP230 or collagen XVII (hemidesmosomes); basal domain lost (epidermis and dermis separated)
-tense blister (not easily popped)
Dystrophic Epidermolysis Bullosa: cause, symptoms
-Group of inherited diseases resulting from mutated basal domain (inherited defect in collagen VII); epidermis and dermis separated,
-Skin literally falls off, esophageal symptoms as well
what is alpha-phase of drug distribution, beta-phase?
alpha: sharp decline in plasma drug concentration due to plasma protein/tissues binding drug
beta phase: gradual loss of drug from metabolism and excretion
phase of drug metabolism
phase I: Cytochrome P450 (ER membrane of liver cells); oxidation, hydrolysis, reducction
phase II: addition of larger group that make the drug more polar and easily excreted
Vd=amount of drug given/[plasma drug]
what eqn relates t(1/2), Vd, and CL
what eqn relates k, CL and Vd
what four processes (performed on a drug) occurs when we take in a drug?
Absorption, Distribution, Metabolism, Excretion
what is Css in regard to drug accumulation
the steady state concentration of a drug accomplished when rate of intake=rate of elimination
for an IV: relate Css and rate of admin, Clearance
Css directly proportional to rate of admin, inversely proportional to CL
what factors will alter the time to reach a Css
factors that alter t(1/2) such as altering clearance or metabolism of a drug. rate of infusion will NOT change the TIME to reach Css
for oral admin drugs relate Css and frequency of dose, dose interval, dose of drug, CL, fraction of drug absorbed
directly proportional: frequency of drug, dose of drug, fraction of drug absorbed
Inversely proportional: CL, dose interval
what are the three functions of sER
lipid synthesis (steroid hormones in adrenal cortex), calcium storage (muscle cells), detoxification (Cyt P450 in sER membrane of liver cells)
the sER of liver aids in detox of what two substances (high yield)
Role of CYP2C9 detoxes what? 3
hydroxylates drugs such as warfarin, phenytoin (anticonvulsant), tolbutamide (insulin release stimulator)
Warfarin; complication, genes involved, is screening required
3% of people have bleeding during first month. VKORC1 gene (drug target of warfarin) and CYP2C9 gene (Cyto P450 that metabolizes warfarin). FDA does not require screening
CYP2D6 metabolizes what 4
Anti-psychotic, antidepressants, metoprolol (decrease BP), tamoxifen (anti-cancer pro-drug)
CYP2D6 inhibited by (4)
coke, prozac, paxil, protease inhibitors
metabolizer groups of CYP2D6
poor metabolizer (LOF), intermediate metabolizer, efficient metabolizer, utrarapid metabolizer (*2xn=increase copy number)
what is the active from of the pro-drug tamoxifen
three people; one is UM, one is PM, one is IM. each take same dose of tamoxifen, who has the most benefit
UM because there is more active from of the drug
for non pro-drugs how should you augment dose for individuals who are UM, PM
UM: increase dose
PM: decrease dose
does FDA require genetic screening prior to Tamoxifen use?
G6PD def has a higher risk for ADRs when taking? genetic screen?
rasburicase, uricemia, primaquin, dapsone
genetic screen is recommended
HLA-B*1502 has a higher risk for ADRs (steven-johnson syndrome) when taking? genetic screen?
carbamazepine; screen recommended
HLA-B*5701 has increase risk for ADRs when taking? genetic scree?
abacavir. screen recommended
TPMT-deficient have increased risk of ADRs when taking? screen?
role of TPMT
phase II inactivation of thiopurines (immuno-suppresant). if thiopurines accumulate leukopenia occurs (drop in plasma WBCs)
Imatinib has increased efficacy in... screen?
C-KIT-positive GI tumors. Screen required
Maravicor has increased efficacy in....screen?
treating CCR5-tropic HIV-1
Trastuzumab has increased efficacy in....screen?
treating HER-2 positive breast cancer. screen required