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Glossary of ERM Midterm 1 UCSD SSPPS SOM

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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
soccer, running, etc?
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
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.
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
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?
Glucose-negative feedback -à High glucose = low glucagon
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
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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