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Glossary of ERM final UCSD SSPPS SOM

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Amenorrhea due to hypogonadotropic hypogonadism may result from all of the following EXCEPT:

A.Anorexia nervosa.
B.Hyperthecosis.
C.Large, non-functional pituitary tumor.
D.Long-distance running with very low body fat.
E.
BHypogonadotropic hypogonadism refers to amenorrhea due to lack of normal secretion of thegonadotropins, LH and FSH. Patients with hyperthecosis have amenorrhea, very high testosteronesecretion with hirsutism and sometimes virilization, very high insulin resistance and hyperinsulinemia, but normal LH and FSH levels. Very low body fat decreases the GnRH pulse generator, and bothanorexia nervosa and long-distance running with very low body fat can cause amenorrhea due tohypogonadotropic hypogonadism (answers A and D are true and therefore incorrect). Notice that LH and FSH can technically fall within low normal range, yet be unable to support ovulation due to abnormalsecretion patterns. Gonadotrophs appears to be particularly susceptible to compression, so large, non-functional pituitary tumors can cause hypogonadotropic hypogonadism as well (answer C is true and therefore incorrect). Transection of the pituitary stalk, e.g. by whiplash injury in a traffic accident,prevents GnRH from reaching the gonadotrophs as so can cause hypogonadotropic hypogonadism(answer E is true and therefore incorrect).
A patient has had chronic anovulation and mild hirsutism for several years. Blood tests indicate that herserum LH:FSH ratio is higher than normal, her androstenedione (AD) and testosterone levels are elevatedand her ACTH is within normal range. All of th
CThis patient has classic symptoms and lab findings of PCOS (polycystic ovarian syndrome), includingchronic anovulation, mild hirsutism and an elevated LH:FSH ratio. Congenital adrenal hyperplasia couldcause excess androgens, but as a result of high ACTH stimulating adrenal androgen synthesis, so DHEAS and androstenedione would be > testosterone. An androgen-secreting tumor would typically progress tosevere hirsutism and even virilization over a period of months or a year – not multiple years. Ultrasoundimaging of PCOS ovaries typically reveals increased size and presence of multiple follicles arrested in the mid-antral phase of development (answer A is true and therefore incorrect). The increased LH stimulatesthe thecal cells to secrete excessive amounts of androgens, which cause increased hair growth (hirsutism)and are aromatized to estrogens in fat, skin and muscle (“extraglandular”) (answer B is true and therefore incorrect). Because these patients do not ovulate, they do not develop a progesterone-secreting corpusluteum (answer C is not true and therefore the correct answer). As a result, the unopposed estrogen-stimulated proliferation of the endometrium increases the risk of endometrial cancer in these patients. The increased 17-OH P response to an injection of GnRH suggests an increased sensitivity of the P450C17enzyme to LH, which may be a result of serine phosphorylation of the enzyme (answer E is true andtherefore incorrect). Interestingly, serine phosphorylation of the insulin receptor causes insulin resistance, a common finding in PCOS (answer D is true and therefore incorrect).
A 22-year-old woman has a one-year history of amenorrhea. Her day 3 plasma FSH levels are 40 mIU/ml(normal follicular FSH = 3 – 17 mIU/ml). Which of the following is the most likely diagnosis?

A.Polycystic ovary syndrome
B.Premature ov
BOf the listed choices, the high FSH combined with amenorrhea is best explained by premature ovarianfailure, which is the equivalent of early menopause. When no ovarian follicles remain that can develop into Graafian follicles, no inhibin B is secreted and no estrogen peak occurs, so no LH peak occurs, so noovulation occurs, so no corpus luteum forms and no progesterone or inhibin A is secreted. Withoutinhibin or estrogen, FSH and LH levels rise to about 5 times menstrual levels. PCOS is associated with high LH but low normal or low levels of FSH (answer A is incorrect). Asherman’s syndrome can preventimplantation and pregnancy, and occlusion of the fallopian tubes can prevent fertilization and pregnancy,but neither affects any hormone levels (answers C and D are incorrect). An inhibin-producing tumor would cause very low levels of FSH (answer E is incorrect).
A 26-year old woman presents with 10 months of amenorrhea and increasing facial hair over that time. A physical exam reveals mild facial hirsutism but no virilization. Prior to this episode of amenorrhea,menstrual cycles had been normal since her menarch
EFacial hirsutism in women indicates excess androgens and excess androgens can also cause anovulationand so amenorrhea. Testosterone is typically an ovarian hormone, although some testosterone is formed by peripheral conversion of androstenedione (AD) or DHEA-S. DHEA-S is typically an adrenal hormone.In this woman, excess androgens developed over a period of months, suggesting an androgen-secretingtumor. Testosterone is significantly elevated, with a very mild elevation in DHEA-S, suggesting an ovarian tumor rather than an adrenal tumor. Her LH and FSH are at the low end of normal range but theyare unable to support normal ovulation due to excessive negative feedback by the androgens. Lipoidovarian tumors usually oversecrete all of the androgens, but secrete androstenedione (not reported) > testosterone > DHEA-S. They can also oversecrete cortisol and 17-OH progesterone – 17-OH P is aprecursor for both cortisol and androstenedione. So this woman’s condition is consistent with an ovarianlipoid tumor. The correct answer to this question is probably more easily reached by eliminating the remaining choices. Adrenal reticularis cell tumors secrete primarily DHEA-S, causing very elevatedDHEA-S with perhaps a mild elevation in testosterone due to peripheral conversion (choice A isincorrect). Congenital adrenal hyperplasia results from lack of cortisol (not excess) with a resulting excess of DHEA-S; testosterone might be mildly elevated (choice B is incorrect). Ovarian hilus cells are verysimilar to testicular Leydig cells, so hilus cell tumors secrete testosterone, but DHEA-S would be normal or minimally elevated, while cortisol would be normal (choice C is incorrect). Hyperthecosis, like PCOS,is usually present since puberty and develops slowly over years. Women with hyperthecosis do have anexcess of testosterone, sometimes to the point of virilization, but do not typically have elevated cortisol and their DHEA-S is normal or minimally elevated (choice D is incorrect).
A 28-year old female at 37 weeks in her first pregnancy reports decreased fetal movement over the last 3 days. Fetal monitoring in the hospital demonstrates fetal distress. Which of the following endocrine changesin maternal blood would best support a di
EEstriol (E3) synthesis requires placental, fetal adrenal and fetal liver function, and so can be used in laterpregnancy as an indicator of fetal well being. The fetal adrenal gland has minimal 3 βOH SHD and sosecretes primarily DHEA-S. The fetal liver hydroxylates this into 16-OH DHEA-S, which thesyncitiotrophoblasts aromatize into E3. Progesterone is synthesized from maternal LDL cholesterol and so only requires a functional placenta, not fetal well being (answer B is incorrect). Prolactin is secretedby the maternal pituitary and decidua, and so prolactin does not indicate placental or fetal function(answers C and E are incorrect). Oxytocin is secreted by the maternal posterior pituitary during labor and so does not indicate fetal well being (answer D is incorrect). Increased prolactin during pregnancy isexpected due to increased estrogen, but estradiol and estrone do not require fetal precursors and so do notindicate fetal well being (answer E is incorrect).
In managing a pregnant woman with chronic renal disease, the prognosis for continued maternal health and a successful pregnancy is improved with all of the following observations EXCEPT:

A.Her blood urea nitrogen (BUN) drops below normal non-p
B.During a normal pregnancy, renal blood flow and renal plasma flow should increase to about 135% ofnon-pregnant flow by the end of the first trimester (answer C is true and thus incorrect), which increasesGFR by about 40% – and both creatinine clearance and inulin clearance measure GFR. Renal plasma flow increases in part due to the expected increase in blood volume, that reaches 40% above non-pregnantmean by mid 3rd trimester. This increase in blood volume decreases her blood urea nitrogen (answer A istrue and thus incorrect), hematocrit and plasma oncotic pressure by dilution to below non-pregnant range by the end of the first trimester (answer D is true and thus incorrect). Renal regulation of osmolarity andsalt excretion is unchanged by pregnancy, so urine osmolarity can vary normally between about 50mOsm/L and 1200 mOsm/L (answer E is incorrect).
All of the following normally increase during pregnancy EXCEPT:

A.Femoral venous pressure
B.Fibrinogen
C.Hematocrit
D.Red blood cell mass
E.Total body water
C.During pregnancy, red blood cell mass does increase (answer D is true and thus not correct), but thenormal increase in blood volume (see answer 7) due to renal retention of salt and water (answer E is trueand thus not correct) which increases plasma volume is greater – this decreases hematocrit below the nonpregnant range. Hepatic synthesis of fibrinogen and other clotting factors increases enough to increaseplasma levels of these proteins. In fact, decreased fibrinogen is cause for concern in a pregnant woman,since it may indicate clotting is occurring somewhere, as can occur in preecclampsia (answer B is incorrect). Femoral venous pressure increases because the uterus compresses the iliac veins, and thecombination of increased venous pressure and decreased plasma oncotic pressure (see answer 7) typicallycauses ankle edema (answer A is true and thus not correct).
Which of the following cardiovascular values are expected to increase for the listed reason by the mid-secondtrimester in a normal pregnancy?

A.Diastolic blood pressure due to increased systemic vascular resistance.
B.Mean left atrial pr
C.Cardiac output increases to about 30-40% above non-pregnant mean by midpregnancy due to increases inboth heart rate and stroke volume. Increased stroke volume is due in part to the increased blood volume(see answer 7). At steady state, stroke volume = filling volume, so atrial volumes increase as well. Cardiac muscle compliance and pulmonary vascular compliance both increase during pregnancy. Theincrease in cardiac muscle compliance allows the atria and ventricles to fill to this greater volume with noincrease in atrial pressure (answer B is incorrect), while the increased pulmonary vascular compliance allows the increased pulmonary blood flow with no increase in pulmonary artery pressure (answer D isincorrect). Systemic vascular resistance decreases during the second trimester due in part to decreaseduterine, renal and breast vascular resistances; this decreases diastolic blood pressure (answer A is incorrect).
During a normal pregnancy, which of the following oxygen partial pressures are typically within 10 mmHg?

A.Uterine artery and umbilical artery.
B.Uterine artery and umbilical vein.
C.Uterine vein and umbilical artery.
D.Uterine
D.Maternal oxygen diffuses from uterine blood washing against the syncitiotrophoblasts lining the outsideof the chorionic (placental) villi into the chorionic (placental) capillaries within the villi, then travels through the umbilical vein to the inferior vena cava and circulates through the fetus. Maternal uterinearterial blood oxygen partial pressure (PO2) is ≈ same as any systemic arterial PO2 ≈ 100 mmHg. But theblood washing against the chorionic villi is a mix of arterial and venous blood and the placenta uses a portion of the O2 for its own metabolism. So the best estimate of fetal umbilical vein oxygen PO2 ismaternal uterine vein PO2, so increasing maternal uterine vein PO2 and O2 content is the target forincreasing fetal oxygenation. Typically uterine vein P O2 ≈ 45 mmHg, which is within 10 mmHg of the typical umbilical vein P O2 ≈ 35 mmHg (answers B and E are incorrect). The uterine vein PO2 is thehighest in the fetal-placental circulation for the same reason that pulmonary venous PO2 is the highest inthe maternal circulation. By the time fetal-placental blood has circulated through the fetus and is returning to the placenta through the umbilical arteries, oxygen consumption by fetal tissues has removed enoughO2 to decrease PO2 to its lowest level in the fetal-placental circulation. Umbilical artery PO2 is only ≈ 20mmHg (answers A and C are incorrect), although the higher O 2 affinity of fetal hemoglobin allows thisblood to be almost 50% saturated with O2, whereas maternal blood with the same PO2 of ≈ 20 mmHgwould be only ≈ 30% saturated. In summary, as a result of blood flow, O 2 diffusion and Hb O2 affinity:

PO2 O2 saturation
Uterine artery ≈ 100 mmHg≈ 98%
Uterine vein ≈ 45 mmHg ≈ 75%
Umbilical vein≈ 35 mmHg≈ 80% (increased O2 affinity of fetal hemoglobin)
Umbilical artery ≈ 20 mmHg≈ 50%
Which of the following fetal values is greater than the corresponding maternal value during the early third trimester?

A.Aortic blood pH.
B.Aortic oxygen concentration.
C.Hemoglobin P50-O2 (oxygen partial pressure (PO2) at which Hb
DBy midpregnancy, maternal cardiac output is increased ≈ 30-40% greater than the nonpregnant mean, butfetal cardiac output (C.O.) is even higher, which allows the fetus to deliver adequate O 2 to fetal tissues.O2 delivery = C.O.• CaO2 and PO2 and cO2 in fetal aortic blood will be similar to those values in umbilicalvenous blood and significantly below those in maternal arterial blood (see answer 10) (answer B is incorrect). Fetal C.O. is high enough to ensure that fetal tissues receive ≈ 2.5 times more blood/ml O2used than do adult tissues. However, only ≈ 1/8 of fetal left ventricular C.O. flows through the fetal lungsbecause of the severe hypoxic pulmonary vasoconstriction. The remaining 7/8 of the LV C.O. flows through either the foramen ovale (right atrium to left atrium) or ductus arteriosus (beginning ofpulmonary artery to aorta). So fetal pulmonary blood flow is less than adult pulmonary blood flow(answer E is incorrect). Fetal CO 2 production ( ̊VCO2) = fetal O2 consumption ( ̊VO2) and fetal CO2 mustdiffuse across the placenta into the maternal blood to be expired from maternal lungs. This diffusionrequires a small P CO2 gradient to drive it, so fetal PCO2 > maternal venous PCO2. Maternal PaCO2 is reducedslightly due to progesterone stimulating the mother’s respiratory centers, which causes a mild respiratoryalkalosis; the higher P CO2 of fetal blood ensures that fetal aortic blood pH < maternal aortic blood pH(answer A is incorrect). Fetal hemoglobin has a higher O2 affinity than adult hemoglobin, indicated by aleft shift in the O 2 dissociation curve and a reduced P50-O2. Although actual numbers are not necessary toeliminate this answer, from answer 10, fetal umbilical arterial blood ≈ 50% saturated with O2 at the verylow P of 20 mmHg, while normal adult P= 27 mmHg (answer C is incorrect).
Preecclamsia is a disorder unique to pregnancy and characterized by:

A.Increased risk of occurrence in 20 – 30 year old women in second or later pregnancies.
B.New onset of hypertension.
C.New onset of glucosuria.
D.Onset ty
BPreecclampsia is a disorder unique to pregnancy that includes the new onset of hypertension, proteinuriaand edema. Preecclampsia affects multiple organs but with the common denominator of vasospasm in various organ circulations. Preecclampsia occurs more commonly with first pregnancies (versus laterpregnancies), in older women (versus younger women, although the risk increases again below age 20)and in multi-fetal pregnancies (e.g., twins or triplets versus single births) (answer A is incorrect). Preecclampsia most often occurs in the last trimester of pregnancy and close to term – some patientsdevelop the disorder during labor or just postpartum (answer D is incorrect). Glucosuria is common inpregnant woman with no disease, since the normal increase in GFR increases the filtered load of glucose above the normal reabsorptive capacity of the proximal tubule (answer C is incorrect).
When compared to a normal pregnancy in the middle of the third trimester, which of the following wouldmost probably be higher in the same woman at the same gestational age, but with preecclampsia?

A.Blood platelet level (thrombocytopenia).
D.Preecclampsia is characterized by sustained hypertension, proteinuria and edema after the 20th week of gestation. Mild preeclampsia is characterized by BP ≥ 140/90 mmHg with minimal pathologic (beyondthat expected in pregnancy) edema and no evidence of end-organ pathology aside from minimal proteinuria (<2.0 g/d). Severe preeclampsia is indicated by SP > 160 mmHg or DP > 110 mmHg withsignificant proteinuria (>5.0 g/d) and evidence of end-organ damage due to vasospasm and/or hemorrhage. Soluble placental factors cause abnormalities in maternal vascular function and blood thatcan lead to vasospasm, abnormal clotting, and thrombocytopenia (low blood platelets) that can result in hemorrhage (answer A is true and thus is incorrect). Renal damage prevents adequate blood volumeexpansion, leading to non-pregnant or higher hematocrit and BUN and even oliguria (answer B is true and thus is incorrect). Inadequate blood volume expansion and renal damage prevent the normal increasein renal plasma flow and glomerular filtration rate seen in pregnancy (answer C is true and thus is incorrect). Uterine vasospasm and infarctions can decrease uterine blood flow, leading to poor fetaloxygenation and poor fetal growth (answer E is true and thus is incorrect).
caloric density of carbs?
avg 4.1kcal/g, but varies
caloric denisty of ethanol?
7.1kcal/g -so drinkers have high cal, low nutrient diet
caloric density of fat?
avg 9.3kcal/g, TGs-> Fas + glycerol. Fas have high caloric value, glycerol little (it's like carbs)
caloric density of protein?
avg 4.1kcal/g. Not completely combusted due to leftover urea. Each AA has different caloric value
3 major components of enegy expenditure?
BMR, physical activity, adaptive thermogenesis (change BMR in adipose and skeletal muscle
what's thermogenesis?
making heat at rest, resembles BMR at rest
what's BMR?
caloric consumption in resting, awake, post-absorptive state. It mean no muscular activity. It is the energy required to perform basic cell and organ functions
how does sleep affect BMR?
drop 10%
how does starvation affect BMR?
drop 40% (counterproductive in dieting)
how does age affect BMR?
decreases 10% from age 20-60
how does gender affect BMR?
slightly higher in males
how does thyroid hormone affect BMR?
(↑TH→ ↑BMR). Hypothyroidism -> obese. Hyperthyroid->thin
constancy/variability in TH?
relatively constant in most people, changes seasonally
how does surface area relate to BMR?
inverse due to greater heat loss in smaller animals (e.g. mouse BMR is 10x greater than horse)
relative role of physical activity in energy expenditure?
biggest determinant
how many times more energy does brisk walking require than BMR?
4-5 times
cycling, dancing?
6-7 times
characterisitics of insulin receptor?
tetrameric, part of RTK (receptor tyrosine kinase), 2 extracellular alpha subunits disulfide bonded to 2 membrane-spanning beta subunits
what happens to receptor upon insulin binding?
autophosphorylation of intracellular beta subunits, then activates other subunits via phosphorylation
activated insulin receptor activity in skeletal muscle and adipose?
translocate glut4 to surface (in these tissues only, not in liver).
what happens when insulin removed?
glut4 goes back into vesicles (implications in insulin resistance)
how does insulin affect mitosis?
mitogenic, like all RTKs, via SH2 and SH3 domains
how does insulin signaling stop?
insulin and receptors are internalized into vesicles.
what two things can happen after termination?
retroendocytosis (vesicles re-fuse with membrane, releasing insulin), or degradation of insulin.
three steps to insulin degradation?
1)vesicles acidified, cause insulin to fall off, 2)vesicles separate into receptor vesicles and insulin vesicles, 3)insulin degrades, and receptors with reused or degraded
how does glucagon signal?
via a specific glucagon GPCR.
how do GPCRs work?
ligand binds, GTP displaces GDP, alpha subunit activates adelylyl cyclase, converts ATP to cAMP, activates PKA
what do beta and gamma subunits do?
stay behind, recruit GRK-2 (G-receptor kinase), which phosphorylates GPCR, which recruits beta-arrestin, which associates with clatherin to internalize GPCR and activates MAP kinase
how do insulin and glucagon interact?
do exactly opposite things. Glucagon promotes catabolism, and inhibits anabolism. Insulin promotes anabolism and inhibits catabolism
what four specific processes do insulin and glucagon regulate?
ketogenesis from FA oxidation, glucogenesis from proteins, glycogenolysis, lipolysis
how is energy from food divied up?
40% lost to heat, then equally divided among cell maintenance, muscle work, internal work (also given off as heat)
how are carbs absorbed?
broken down to small saccharides by amylase. Disaccharidases on brush border cleave sugars to make monosaccharides. Lactase decreases with age.
what approach to diabetes treatment takes advantage of the above mechanism?
drugs can block amylase activity, so don't absorb carbs as much, and reduce glucose spike
how are proteins absorbed?
broken down into smaller peptides
how fats absorbed?
lipase in gut breaks TGs to glycerol, FAs, and monoglycerides. Bile helps FAs and monoglycerides get absorbed, but glycerol needs to help. TGs then resynthesized in epithelial cells, packaged in chylomicrons, and sent to periphery for absorption.
how does 100g of glucose get distributed among body tissues?
liver 60%, brain 15%, muscle 15%, fat 5%, other 5%, but it's not all metabolized by these tissues
what portion of glucose gets metabolized (used) by what tissues?
brain 70% (an obligate glucose consumer, and why hypoglycemia is so critical), muscle 20%, heart 10%, kidney 2%, and very little for rest of body
how is insulin taken up and used by muscle?
insulin stimulates glut4 transport, and breakdown by hexokinase.
how does insulin affect glycogen synthesis and breakdown?
promotes synthesis, inhibits breakdown.
what about glucokinase?
only in tissues that use glut2. Hexokinase only in tissues with glut4.
what regulates FA uptake by muscle?
amount in blood. It's insulin-independent
what regulates protein uptake by muscle?
insulin-dependent AA uptake
glucose uptake by fat?
insulin-dependent, and converted to FA and glycerol
FA uptake by fat?
70% of FA uptake is from lipoproteins using LPL
how is fat in adipocytes released?
hormone-sensitive lipase (HSL) is upregulated by glucagon and inhibited by insulin
2 ways to bring glucose to liver?
1) direct (40%), via glut2, followed by glucokinase (GK), and stored as glycogen. And 2) indirect (60%), derived from pyruvate and lactate (which are metabolites of glucose from other tissues), metabolized into glycogen. (only occurs for first 2 hours after meal ingested)
3 main effects of insulin on the liver?
1)protein, TG, glycogen synthesis, 2)AA uptake, 3)inhibits glucose-6-phosphatase to prevent glycogen breakdown
overall picture of what happens during fed state?
storage of protein, TG, glycogen. Oxidative phosphorylation by liver and muscle
what happens during 24 hr fast? To brain? Glycogen stores? Adipocytes? Muscle protein?
brain continues to consume glucose (obligate). glycogen in muscles and liver used first. adipocyte FA oxidation to provide energy for gluconeogenesis in liver. FAs in muscle breakdown to give energy to muscles. Muscle proteins breakdown, and taken up by liver for gluconeogenesis
importance of the corey cycle?
glycogen stores used up in 1 day, but brain still needs glucose.
how does it work?
lactate and pyruvate from glycolysis in blood cells, travels back to liver, where it is resynthesized into glucose for the brain to use. The energy to do this comes from FA oxidation
how much energy is stored in a person as glycogen?
900 calories (liver and muscle)
how much energy stored in protein?
24,000 calories
how much energy is stored in fat?
141,000 calories
how long can that last us?
about a month, if water and electrolytes are available
what changes occur after 24 hours of fasting?
gluconeogensis decreases due to lack of substrate (protein)
physiological changes to long fast?
brain starts using ketones (synthesized in liver from FFAs), prevents protein wasting and gluconeogenesis. Other major change is TH and symp tone drops, so less energy expenditure. Gluconeogenesis still continues a little as muscle breaks down less and less.
does brain work as well on ketones as on glucose?
not sure, but maybe subtle differences
why don't we become hypoglycemic when exercising (use up blood glucose)?
exercise upregulates glut4 in muscle INDEPENDENT of insulin, then liver replaces blood glucose by gluconeogenesis, which is stimulated to occur in two ways.
what two ways does gluconeogenesis increase during exercise?
1)lactate from muscles, and 2) increase in circulating NE and EPI (the MAIN WAY)
what effects on insulin and glucagon do circulating NE and EPI have?
stimulates glycogen breakdown, inhibits insulin production (to counter its inhibition on glucagon), and glucagon promotes gluconeogenesis
how many times more energy does brisk walking require than BMR? cycling, dancing? soccer, running, etc?
4-5 times, 6-7 times, 8-12 times
what's adaptive thermogenesis?
change in heat production in response to temp change or caloric intake
adaptive thermogeneis in response to cold? Change in O2 consumption?
shivering increases heat production. In small animals, this can increase oxygen consumption by 2-4 times (humans 5-10%)
how are BMR and adaptive thermogenesis related?
BMR is under normal conditions, but adaptive thermogenesis does modulate BMR, so they are inter-related
how does acute feeding affect BMR?
increase 25-40%
How does low protein diet affect energy storage?
decreases ability to store energy
how does cold temp affect energy balance? (acute)
increases sympathetic outflow, stimulates lipolysis, and UCP-1
chronic?
increased UCP-1 transcription, mitochondria synthesis, brown fat hyperplasia, recruitment of brown fat in white fat deposits
mechanism for adaptive thermogenesis?
use ATP to shiver, and ion leak to increase Na/K ATPase
what does UCP-1 do?
uncouples oxidative phosphorylation, so more protons move into mitochondria, where they make electron transport chain more efficient, so burn more calories (and make more NADH, FADH2)
within what range of environmental tempuratures, do humans have relatively constant body temp?
between 55 and 115F. But above and below this, core body temp changes a lot
how does ovulation affect body temp?
slightly increase after ovulation
what regions of body need tightest control of temp?
brain and viscera
relationship between core body temp and rectal and oral temps?
close to each other
what part of body produces most heat during BMR?
brain and heart
how does time of day affect body temp?
slightly lower in the morning
4 mechanisms of heat transduction?
evaporation, conduction, convection, radiation
what method(s) of heat transfer is/are used for cooling off?
only evaporation. Works even in absence of sweating. Doesn't work if humid.
physiology of sweat production?
sympathetic nerves make it happen. There is low activity at rest. Most of fluid in ducts gets reabsorbed. But, when hot, blood flow increases, increasing fluid at glands and limiting reabsorption. Can sweat between 1 and 3 L per hour, depending on how well adapted
how much can clothing reduce heat loss?
about 50%
how does sympathetic system reduce heat loss in cold environment?
constricting skin blood vessels. Below 75F, already maximally constricted
at what temp are skin blood vessels maximally dilated?
110F
location of 2 major temp sensors?
anterior hypothalamus, periphery
how are the sensors different?
ant. Hypo responds to hot and cold by inceasing firing, and measures temp of brain. But periphery sensors sense environmental temp, and mostly respond only to cold (a little sensitive to hot).
5 responses to cold?
vasoconstriction, shivering, behavioral changes, increase TH (over time), piloerection
3 responses to hot?
vasodiliation (withdraw symp tone), sweating, decrease heat generation
how does set point work?
determined by hypothalamus. Cooling mechanisms and heat generating mechanisms adjust according to body temp.
what raises the set point? How?
fever, via IL-1beta, which activates synthesis of PGs
how do NSAIDS reduce fever?
inhibit PG synthesis, so reduces set point
Pancreatic Islet are what percent of the pancreas?
2-3%
What are the three islet cell types of the pancreas and what do they secrete?
Alpha cells-secrete glucagons, Beta cells-secrete insulin, Delta cells-secrete somatostatin
Where are these cells located in the “mini portal” system?
Beta-middle, alpha, outer edge, D- mixed at border between alpha and beta
When the blood flows through the islets of langerhans, what order does it pass through the cells?
Capillaries, Beta cells, maybe delta (fewer), alpha, then enters vein
What is the consequence of this order of blood flow?
insulin immediately acts on alpha cells, but glucagon has to go through entire circulation before acting on beta cells
What are the 4 breakthroughs that insulin has been the prototype protein for?
First isolated protein, First sequenced gene, First cloned gene, First recombinant protein used therapeutically
Insulin gene has
3 exons and 2 introns
The insulin protein’s alpha and beta chains are connected by three _____.
Disulfide bonds
When Pro-insulin is cleaved to mature insulin, what is cleaved away?
C peptide
What are the proportions of Insulin and C peptide in the mature vesicle?
Equal
Insulin is highly conserved especially the ______, residues that make the _______ bonds.
Cysteine residues, disulfide
How many amino acids different are bovine and porcine insulin from human?
Bovine=3, porcine=1
What is the variable part of the pro-insulin protein?
C peptide
Cleavage of C peptide at highly specific sites is done by ______ only expressed in _____.
Proteases, beta cells
What is the first form in insulin before proinsulin?
Preproinsulin
What are the molecular weights of Insulin, proinsulin, and preproinsulin?
6000kda, 9000kda, and 11000kda
What are the steps in the classical ER pathway?
1. Ribosome begins making protein and a signal recognition protein (SRP) binds to protein and brings to ER
2. Signal sequence receptor (SSR) brings partially synthesized protein attached to ribosome into ER and ribosome continues to synthesize rest of preproinsulin protein from the outside of the ER
3. Signal peptidase cleaves signal peptide of protein and is released into ER
4. Proinsulin is properly folded in the ER
5. Secreted to Golgi in vesicles where proteases cleave C-peptide
How long does it take to make new insulin and get it ready to secrete?
2 hours
Where does insulin released during a meal come from?
storage
In Type II diabetes, insulin storage and release are ______ for the needs of the body.
Insufficient
Since insulin is difficult to measure directly, how do you measure it?
Measure C-peptide, which is not metabolized by liver and issecreted in the kidneys
What was the first company to make recombinant human insulin?
Ely-Lily.
What discovery made it possible to make properly folded recombinant human insulin?
You need to make proinsulin rather than mixing alpha and beta chains.
How do you remember how glucagons is synthesized?
Remember it is very similar to insulin
Describe the structure of the glucagons molecule.
Single chain, 29 a.a., 3500kda
What percent of circulating glucagons is active?
50%
What are the other forms of inactive glucagons?
Preproglucagon, proglucagon, little biological activity
What is the consequence of differential protease expression?
Different cells express different protease which causes selective cleavage. Once gene product can become many different protein products.
Preproglucagon is made if what two cell types?
Alpha cells of pancreas and L-cells of GI tract
What is the protein product produced by L-cells?
GLP I and GLP II
What does GLP I do?
Augments/ increases insulin secretion, acts on brain (sold as a drug to treat diabetics)
Where is GLP I degraded?
In the blood
Insulin secretion is subject to what 2 portal systems?
Intra-islet and hepatic
How much of the secreted insulin is removed by the liver?
50% first pass
What is the therapeutic dilemma with subQ administration of insulin?
1. Liver gets too little insulin and needs more
2. Systemic gets too much if give the portal vein [insulin]
How does the insulin get to its site of action (tissue) from vascular network?
Crosses the endothelial cells of vascular by transcytosis
What is the difference between the rate of change of insulin concentration in the vascular and interstitial spaces?
Interstium is much slower
What are the proportions of insulin decrease from pancreas to tissue?
50% lost in liver, of the remaining 50%, 40% of that is does not make it to interstitial space. So, only 30% of originally secreted insulin makes it to tissues.
What is the major regulator of insulin secretion and what is the feedback?
Glucose via negative feedback
What is the first phase of the biphasic insulin secretion?
High quick spike when stored insulin is released
What stimulates this first phase?
glucose, amino acids, sulfonylureas, glucagons, and GI hormones
What is the second phase?
slower rising, less dramatic amount of insulin, new insulin is made and released
What stimulates the second phase?
Only glucose
Of the total daily insulin secreted, what percent is basal?
30-40%
What percent of daily glucose exposure is basal?
60-70%
During meals _____ and _____ spike together.
Glucose, insulin
How does glucose get into the beta cell to stimulate insulin secretion?
Facilitated transport through Glut2
What enzyme is called the glucose sensor and what does it do?
Glucose kinase (GK), phosphorylates glucose on side of mitochondria
What is the consequence of excess glucose present in the beta cell?
ATP levels rise so ATP:ADP ratio rises
What happens when the ATP:ADP ratio rises?
causes depolarization of cell allowing calcium to enter cell
What is the effect of the calcium influx?
Exocytosis of secretory granules of insulin
What is the job of cAMP?
potentiates the process so anything that increases cAMP levels also increases insulin secretion (only if glucose present in first place)
When is the onset of GK-Mody disease?
During youth
What causes it?
GK mutation
Heterozygotes for GK _____.
Show decreased insulin secretion
What does this disease tell us about how the body senses glucose levels?
Glucose metabolism is how we sense glucose levels, not the actual present amount of glucose
What do different meal components do to insulin levels?
a.a., carbs, and fats all increase insulin levels, a.a. almost to the level associated with glucose feeding.
Why do glucose levels rise during protein feeding?
gluconeogenesis
During the cephalic phase of digestion, what causes insulin to be secreted? How do we know?
Anticipation, incretins (GLP I) and neurological stimulation. Insulin levels are greater when glucose is given orally more insulin is secreted than glucose is given IV
What are the effects of the PANS on insulin secretion?
Parasympathetic tone stimulates basal insulin secretion
Stimulation of SANS alpha receptors _____ insulin secretion while stimulation of beta receptors ______ secretion.
Blocks, stimulates
What does isoproterenol do to insulin secretion?
Increases
Why does an increase in SANS tone decrease insulin secretion?
b/c alpha receptors dominate
Why is glucagons called counter-regulatory?
almost everything that inhibits insulin secretion promotes glucagons secretion and vice versa
What are the two major regulators of glucagons secretion?
(1) Glucose-negative feedback -à High glucose = low glucagon
(2) Insulin-negative feedback à alpha cells immediately see insulin secretion b/c of the intra-hepatic blood flow so glucagon secretion is immediately inhibite
What is the one exception to everything of opposite for insulin and glucagon secretion?
Amino acids stimulate both insulin AND glucagons secretion
Why is this exception important?
glucagon promotes glucose synthesis while insulin promotes glucose breakdown so the overall glucose level is constant in a protein only diet, if only insulin was secreted then the person would become hypoglycemic b/c basal glucose levels would fall without glucagons to balance it.
Somatostatin is a single chain, ____ a.a. peptide with one ______ bond.
14, disulfide
____% of somatistatin is made in delta cells of pancreas while ____% is made in the gut
25%, 75%
What is the main job of somatistatin?
To inhibit the secretion of everything.
DM is leading cause of what three conditions?
adult blindness, renal failure, amputations. (also 2-4x more CVD)
% diabetics type I, II?
5% type I, 95% type II
two classifications of type I DM?
primary (autoimmune destruction). Secondary (physical destruction)
relative role of genetics is type I DM?
monozygotic twins 50% chance. So big environmental too
what HLAs are associated with type I DM?
DR3, DR4 haplotypes. DR2 appears protective. But none of these are absolutely required.
risk of type I to general pop?
0.20%
risk to parents of affected child?
6%
risk to offspring?
8% father, 3% mother. Don't know why difference
risk to sibling?
5%
risk to HLA identical sibling?
15%
risk to sibling with no HLA identity?
1%
evidences for virus-induced type I?
insulinitis (inflammation of pancreas), epidemiological clusters occur, viral titers in some type Is, animals can get type I if infected, in-vitro beta cells can be killed by certain viruses
what is only proven viral cause of type I?
congenital rubella gives 20% chance of infant getting type I
evidences for immunologic cause of type I?
insulinitis, associated with other autoimmune diseases, prevalence of anti-islet cell Abs (ICAb). High ICAb when diagnosed and falls after years pass.
possible chain of events for developing type I?
HLA linked genes, islet cell susceptibility, viral interaction with islet cells, immune response -> ICAb, beta cell failure, hyper alpha fxn
when do sxs manifest (in life of disease)
after 80-90% of beta cells gone, and often after traumatic event
is better to treat before sxs show up?
if therapy exists, and is very very safe, and if screening is very sensitive (especially with DM I being very rare)
% of DM pts that are obese?
90%
four classes of DM type II?
regular DM, gestational (always comes back later), MODY (mature onset DM of the young), impaired glucose tolerance.
what is MODY?
mature onset of diabetes in the young. 20-30yo, otherwise healthy. Due to mutation in glucogenesis pathway (such as glucokinase)
what is IGT?
impaired glucose tolerance. It's prediabetic. Pts usually become obese, then get IGT, then DM. Each year, 7% of IGT pts get DM
procedure for OGTT?
oral glucose tolerance test. Fast 14-18 hrs, measure glucose, then feed known amount of glucose, and measure over 3 hrs.
normal glucose levels (fasting, OGTT 30-90 minutes, and OGTT 120min)?
fasting <126. OGTT 30-90 minutes <200, OGTT 120 minutes <140. Must be all of these to be normal
what glucose is diagnostic of DM?
symptoms **AND*** (fasting >126, **OR** OGTT-2hr >200)
4 organs contributing to hyperglycemia in DM?
liver (increased glucogenesis, due to insulin resistance, hyperglucagonemia, corey cycle, more FA use), muscle (main culprit in DM, less uptake of glucose), pancreas (high insulin or burned out pancreas and little insulin), adipose (similar to muscle)
how does a real meal and OGTT differ in insulin and glucose response in DM?
in mild DM, other molecules stimulate insulin production, so glucose stays under control. In severe DM, insulin cannot be made
first step to developing DM?
insulin resistance due to aging, obesity, physical inactivity
how does body respond to initial insulin resistance?
produce more insulin. It occurs in IGT, metabolic syndrome or syndrome X
two ways to have beta cell failure?
apoptosis, or stop making insulin
after beta cell failure, what happens?
glucose diposal rates decrease dramatically (but can improve with adequate control), increased hepatic glucose output, and decreased insulin secretion
evidence that insulin resistance is first step in disease process?
non-diabetic children of diabetics with high insulin sensitivity (Si-insulin) much less likely to develop DM later in life
factors that contribute to having insulin resistance?
genetics, obesity, aging, some meds, rare disorders
4 conditions resulting from insulin resistance? (even in absence of DM)
HTN, dyslipidemia, atherosclerosis, PCOS (poly cystic ovarian syndrome)
diagnosis for syndrome X (metabolic syndrome)? Has 3 of what 5 risk factors?
1. Obesity (men>40in, women>35in) 2. TGs>150 3. Low HDL (men<40, women<50) 4. BP>130/85 5. Fasting glucose >110
three endocrine mediators adipose secretes?
adipokines, cytokines, chemokines
what's adiponectin?
an adipokine (only secreted by adipose), which promotes insulin sensitivity
what's resistin?
an adipokine that promotes insulin resistance
what other adipokine is there?
leptin
what cytokines do adiipocytes secrete?
TBFa, IL6, IL1beta, and inflammatory ones
role of chemokines secreted by adipocytes?
attract macrophages by chemical gradient, hay clusters of macrophages in fat
what happens physiologically and chemically to adipose tissue as fat accumulates?
adipocytes get bigger and more numerous. Adiponectin decreases, resistin increases. This is reversible in early DM via exercise and weight loss
how does inflammation iccur from insulin resistance?
free FAs (which increase during insulin resistance due to cells "starving" of glucose) activate inflammatory pathway. Pathway is advantageous during regular fasting, so conserve glucose.
how does inflammation occur due to obesity?
fat has high number of macrophages, which produce inflammatory cytokines (more fat->more inflammation)
what is basal glucose uptake?
Rd (rate of disposal). 70% of this is non-insulin mediated uptake (NIMGU), of which the brain is most responsible
what is IMGU?
insulin-mediated glucose uptake. This is 30% of Rd
how does hyperglycemia occur during fasting?
all from glucogenesis (overproduction)
how does hyperglycemia occur after a meal?
insulin resistance, glucose from food, IMGU doesn't upregulate enough, as it does in normal persons
how does NIMGU and IMGU change during feeding?
in normal persons, IMGU becomes much larger than NIMGU
what two things to control iin order to treat hyperglycemia?
overproduction and insulin resistance need to be treated.
postprandial or fasting hyperglycemia more dangerous?
postprandial
possible causes of insulin resistance?
(mutated insulin gene, incomplete conversion of proinsulin to insulin), (antagonists like hormones, Abs, FFAs), receptor or pathway defects
in type II DM, glucose transport defective in which part of the process?
translocation of glut4 to membrane decreased due to inflammation
4 different types of assaults on CV system due to hyperinsulinemia and insulin resistance?
hyperlipidemia, hyperglycemia, HTN, hypercoag/inflammation
step therapy for DM with FBG<140?
1) diet/exercise, 2)monotherapy with metformin or sulfonylurea, or others if criteria are met. 3)combo metformin + sulfonylurea 4) triple oral therapy, add insulin, refer to endocrinologist, 5)insulin-dependent
how does beta cell fxn and insulin resistance change over course of disease?
beta cell fxn declines over life of disease, but insulin resistance stops getting worse around the time of diagnosis
disadvantages of insulin therapy?
more insulin resistance, more CV risk, weight gain, hypoglycemia
what role does basal insulin play?
is 50% of all-day insulin, prevents glucose overproduction
characteristics of bolus insulin?
occurs after meal, peaks in 1 hr, 10-20% of daily insulin after each meal
onset, peak, duration of endogenous insulin?
30-60 min, 2-4 hrs, 6-10hrs
lispro, aspart?
15-30 min, 1-2hrs, 4-6 hrs
NPH/Lente?
1-2hr, 4-6hr, 10-20hr
glargine?
1-2hr, no peak, 24hrs
what is BIDS?
bedtime insulin + daytime sulfonylurea (to decrease nightime hepatic glucose production, decrease glucose toxicity on beta cells which increases beta cell response to sulfonylurea, and only 1 shot with limited side effects.

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