Metabolism - Exam#4, Part One Flashcards Preview

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Flashcards in Metabolism - Exam#4, Part One Deck (187):

What are the 5 stages of glucose homeostasis?

I – Absorptive → FED
II – Post-absorptive → IN-BETWEEN MEALS
III – Early Fast
IV – Intermediate Starvation
V – Long-term Starvation
**We usually spend all of our time in Phase 1 (fed) and Phase 2 (in-between meals) as long as we eat breakfast


When is metabolic fuel provided to cells?

ALL the metabolic states → Fed (absorptive), in between meals (post absorptive) and the other three.


What fuel is used for energy in Stages 1 and 2?

GLUCOSE is always required by the central nervous system for 100% of the energy;
Other tissues include: erythrocytes (red blood cells), gastrointestinal tract (smooth muscle cells?), renal medulla, retina, and skin.


What is metaboliccaly different about mature RBCs?

Mature red blood cells DO NOT have mitochondria and thus produce lactate → No TCA or ETC cycle to produce other energy metabolites


What happens during Phase 2, or between meals?

-Metabolic changes that occur in b/w meals are the consequences of the need to PRESERVE GLUCOSE and the limited reserves of glycogen in liver for use by tissues that burn ONLY GLUCOSE;
-Ensure the provision of alternative fuels for other tissues.
**Remember that skeletal muscle DOES NOT have the glucose 6-phosphatase enzyme so glycogen in muscle cannot leave as glucose, but as lactate.


What happens during Phase 4, or ~2 days without food?

-As body reaches state IV, intermediate starvation, the central nervous system uses KETONE BODIES, which are derived from fatty acids and ketogenic amino acids;
-Ketone bodies can meet about 20% of central nervous system’s energy needs, but the other source states 50%


What metabolic changes regarding glucose take place during PREGNANCY?

1. Fetus requires a significant amount of glucose (possibly exclusively)
-=Mother’s hormone secretions during pregnancy promote LOWER INSULIN SENSITIVITY to spare glucose for the fetus; also spares protein (amino acids) and fat for structural and functional development in the fetus. → Mother gives up her affinity for storage to provide for the fetus FIRST
2. Lower insulin sensitivity allows greater glucose for mammary glands for synthesis of lactose for breast milk


What is the difference between Fed (1) and Fasted (2) states?

FED = metabolic fuel reserves are laid down;
FASTED (in-between meal) = metabolic fuel reserves are mobilized.


How are fats catabolized?

-Lipolysis of TAGs in a fat droplet ;
-Beta-oxidation of fatty aicds = fatty acyl → acetyl-CoA


What are the roles of the two types of adipocytes?

1. White adipocyte store TAGs.
2. Brown adipocyte undergo thermogenesis – production of heat in organisms, particularly warm-blooded animals → Loaded with mitochondria and maintains body temperature → Goes through beta-oxidation but it NOT coupled with TCA, so it just produces heat.


Where are fatty acids synthesized and stored?

-Much of the fatty acid synthesis goes on in HEPATOCYTES (liver cells);
-In contrast, Adipocytes then store TAGs arriving from the GI tract (DIETART fat) as part of chylomicrons and from the liver as part of VLDL = Fatty acids and glycerol put back together, but very little synthesis of fatty acids. → Just preformed, not totally synthesized as within the liver.


How do tissues use fatty acids BETWEEN meals?

-In BETWEEN MEALS, when many tissues need for oxidation of fatty acids is high, LIPASES in adipocytes hydrolyze stored TAGs to release free fatty acids into the bloodstream;
-Beta-oxidation of stored fats is catalyzed by lipoprotein lipase to release the fatty acids to be oxidized to generate energy when glucose is not present.


How is Glycerol-3-PO4 made for TAG synthesis?

1. Glycerol is released from adipose tissue as a result of lipolysis, and only tissues such as liver and kidney that possess glycerol kinase, can convert to glycerol 3-phosphate;
2. Glycerol 3-phosphate may be oxidized to dihydroxyacetone phosphate by NAD+ catalyzed by glycerol-3-phosphate dehydrogenase.”
→ Glycerol-3-phosphate in adipose tissue produced via glycolysis


What are the steps in Glycerol Utilization?

-Glycerol Kinase is found in the LIVER and KIDNEY → Can use glycerol to create TAGs = Catalyzes Glycerol to L-Glycerol 3-Phosphate so it can be used for TAG synthesis;
If reactions continue, in the adipose tissue, D-glyceraldehyde can be generated and used for Glycolysis


What hormones regulate the body's response to food consumption or lack of?

1. Insulin (lower blood glucose)
2. Glucagon (raise blood glucose)!


What cells make insulin?

-Insulin is secreted by the β-islet cells of the pancreas in the fed state in response to nutrients (primarily glucose) absorbed into the portal blood.


What are the Islets of Langerhans?

-Endocrine cells of the pancreas;
-Contains alpha, beta, and delta (A, B and D cells) that secrete peptide hormones


How is glucose regulated by actions of the Pancreas?

1. Pancreas is a lot like liver in that it has GLUT 2 and cytoplasm has same glucose concentration as blood;
-Glucose is trapped in cell by phosphorylation by Glucokinase then catabolized;
2. Increased ATP causes CLOSING of K+ channels. Reduced efflux of K+ causes…
3. DEPOLARIZTION of the membrane which causes opening of voltage gated Ca2+ channels.
4. The resulting increase in cytosolic [Ca2+] triggers
5. insulin release by EXOCYTOSIS;.
**Note that K+ efflux through a channel HYPERPOLARIZES a membrane.
**From portal blood glucose: Direct effect on membrane by Nervous System


How does Insulin affect Glucose UPTAKE in Phase 1?

-Into muscle and adipose tissue.;
-Insulin causes the migration of glucose transporter vesicles to the cell surface, exposing active glucose transporters, GLUT 4.;
-Muscle and adipose will only take up glucose from the blood stream to any significant extent in the PRESENCE OF INSULIN. (Recall though muscle and exercise)


What happens when Insulin levels falls?

-Insulin drops as blood glucose drops, the GLUT 4 transporters are internalized again, reducing further glucose uptake by muscle and adipose;


What are the different circumstances that drive glucose uptake?

-Remember is that there is glucose uptake driven by insulin and glucose uptake driven by a high glucose level in the blood stream.;
-And also remember the effect of exercise INDEPENDENT of insulin


How do MOST tissues uptake glucose?

-Glucose uptake by most other tissues is INDEPENDENT of INSULIN;
-So in the case of Diabetes, when blood glucose stays high longer than in healthy condition, more glucose gets into tissues in higher amounts than is healthy.
**One of the keys to a healthy life is to remain INSULIN SENSITIVE.


How does the concentration of glucose in the LIVER compare to the blood?

Hepatocyte (liver) glucose concentration (cytoplasm) is essentially the same as blood serum;
-One of the isoforms of HEXOKINASE (the first enzyme in glycolysis pathway) is GLUCOKINASE (hexokinase IV);


How does Glucokinase regulate glucose in the liver?

-Glucokinase acts at levels BEYOND the LIVER’s energy requirement to convert glucose to glucose 6-phosphate. → Will only allow storage in the liver AFTER the rest of the body is well supplied. Would be pointless to stored in the liver and have to waste energy to pump out and supply the other tissues


What opposing reactions are stimulated by Insulin?

-Both liver and muscle;
-STIMULATE glycogen synthase → synthesis of glycogen);
-INHIBIT glycogen phosphorylase → glycogen breakdown;
-Much of control of enzymes is driven by OPPOSING phophorylations and dephosphorylations = Pairs of enzymes have opposite activities depending on their phosphorylation states:
**This control is driven by PREDOMIANT hormone, e.g. insulin to glucagon ratio.


How else can the Liver use glucose?

-Lipogenesis – production of glycerol and fatty acids → and synthesis of triacylglycerol (triglycerides);
-If glucose is available and stimulating the release of insulin, glucose will be used FIRST to supply energy; ONLY when there is excess glucose after all cells have been supplied through glycolysis and glycogen stores are resupplied in the liver, then EXCESS glucose can be converted to fatty acids in the liver once insulin is not longer secreted.


What oppositions does Insulin stimulate in ADIPOSE?

-In ADIPOSE tissue, insulin STIMULATES conversion of glucose to glycerol 3-phosphate (liver as well) and maybe conversion of glucose to fatty acids;
-In ADIPOSE, insulin INHIBITS intracellular lipolysis and release of free fatty acids


How does Insulin affect the products of LIPID digestion?

-On the surface of CAPILLARIES near adipose tissue and skeletal muscle, LIPOPROTEIN LIPASE IS activated in response to INSULIN;
-Lipoprotein Lipase – enzyme REMOVES fatty acids from glycerol in chylomicrons (lipoprotein of FED state), and the fatty acids enter the adipose cells and to some extent muscle cells;
-Glycerol remains in the and is taken up by the liver and used for glycogen synthesis or lipogenesis;
**Muscle and adipose CANNOT phosphorylate glycerol to use;
-Liver takes up chylomicron remnants, repackages and ships out as VLDL.


What are the different effects on WHERE fat is stored?

-Trained athletes have some fat stores in muscle tissue. It appears to be IN THE CELLS because electron micrographs show small fat droplets surrounded by mitochondria in athletes;
-However, some people develop too much fat in NON-ADIPOSE tissue that is large fat droplets and this makes them prone to develop T2DM


How does Insulin affect proteins in Phase 1?

-INCREASE in protein synthesis in the ABSORPTIVE phase in response to insulin;
-Increased 20-25%;
-Balanced by a net protein catabolism in the post-absorptive phase so that under normal feeding patterns the rate of tissue protein catabolism, no net gain or loss of body protein.


When would protein balance not be equal?

-Athletes would be different. → More synthesis and net gain;
-A starvation diet would be different. → More breakdown and catabolism


What is the overall condition of the Fed State, or Phase 1?

In the FED state (absorptive phase), under the control of insulin, metabolic fuels are laid down and EXOGENOUS (dietary) glucose is the major fuel.


How does insulin affect signaling in brain when FED?

Insulin goes to the BRAIN;
-Sends signal to the liver to STOP glucose production via gluconeogenesis;
-Also a satiety effect


What ratio defines Phase 2?

LOW insulin to glucagon ratio:
-FED stated ENDS, POST-absorptive = in-between meal = fasted state or phase
-Conc. of glucose in the portal BLOOD drops and so INSULIN drops. (No glucose, No insulin needed);
-With the drop in insulin, muscle and adipose DON’T take up much glucose and glycogen synthase in liver and muscle is no longer stimulated;
-Muscle and adipose use GLUT4 and are DEPENDENT upon insulin glucose uptake!!


What is now secreted by the Pancreas when glucose is LOW?

-Pancreas responds to the lack of exogenous glucose and fall in blood glucose by secretion of GLUCAGON by APLPHA cells;
-Glycogen Synthase is INHIBITED;
-Glycogen PHOSPHORYLASE is ACTIVATED by Glucagon.
**Remember that the RATIO is the real key: insulin/glucagon.


Where do the glucose regulators come from in the pancreas?

-Pancreas secretes INSULIN from the beta cells → Uptake glucose;
-Pancreas secretes GLUCAGON from the alpha cells → Release glycogen


How does GLUCAGON stimulate the release of stored glycogen?

-Glucose 6-phosphate from GLYCOGEN in the LIVER is converted to FREE glucose by glucose 6-phosphatase.;
-Glucose can then leave the cells and circulate in the blood for use;
-Muscle glycogen does NOT contribute directly to blood glucose because muscle LACKS glucose 6-phosphatase = keeps for its own energy;
-POST-absorptive, muscle and adipose are using glucose for energy, but at a much REDUCED rate.


What happens in ADIPOSE in response to GLUCAGON?

In adipose tissue, the effect of decreased insulin and increased glucagon results in:
1. inhibition of lipogenesis;
2. inactivation of lipoprotein lipase;
3. activation of hormone-sensitive lipase


How are stored TAGs mobilized for energy use in adipose in response to Glucagon?

1. Glucagon stimulates adenylyl cyclase to produce cAMP;
2. Activated PKA phosphorylates hormone-sensistive lipase and perilipins on the lipid droplet;
-Adding PO4 allows perilipins to be acted on by the Lipase;
3. Lipase hydrolyzes TAGs to fatty acids;
4. Fatty acids leave the adipocyte and bind albumin in the blood and released as needed;
5. Will enter a myocyte (muscle cell) by a specific transporter; oxidized to CO2 and energy is saved in ATP, which can then fueld muscle contraction and other metabolism in the myocute


What are Perilipins?

A family of proteins that restrict access to lipid droplets, preventing untimely lipid mobilization.


How does Epinephrine be involved in low blood glucose?

Epinephrine would also be involved with low blood glucose and during stress situations. → Epinephrine induces the release of glycerol stores in the MUSCLE to provide quick energy in needed stressful situations


Why is Phosphorylation so important in FA mobilization per the Lipase?

-Phosphorylation of hormone sensitive lipase increases its activity 2-3 fold. → Adding PO4 to hormone sensitive lipase INCREAESES activity to metabolize the TAG stores;


Why is Phosphorylation so important in FA mobilization per the Perilipins?

-The BIGGEST effect for increased lipid mobilization occurs with the phosphorylation of the PERILIPINS = 50 fold increase in lipid mobilization;
-Cells with defective perilipin genes have almost no response to the hormonal stimuli because their hormone sensitive lipase does not associate with the lipid droplets.


What are the controls of adipose tissue lipolysis?

*Insulin is the main regulator!;
-Lipolytic stimulus is turned OFF by:
1. Removal of stimulating hormone;
2. Lipase phosphatase;
3. Inhibition of adenylyl cyclase by lots of FFA and adenosine;
4. Inhibition of cAMP by Phosphodiesterase


What results from increase LIPASE activity during Phase 2?

-INCREASED amounts of blood levels of GLYCEROL (a substrate for gluconeogenesis in the liver) and free fatty acids;
-Glycerol can be used to make GLUCOSE (from a non-carb source);
-Fatty acids – beta oxidation for energy production


How are the free fatty acids used for energy during Phase 2?

-FFA are used by skeletal muscle, liver and adipose as their preferred metabolic fuel, so glucose is spared → Beta oxidation;
-In MUSCLE (liver and adipose), the acetyl Co-A formed by beta oxidation INHIBITS pyruvate dehydrogenase to prevent absorptive phase levels of glucose being converted to acetyl-CoA. → Have plenty of acetyl-CoA so DON’T NEED MORE!!;
-Glucose is spared;
-Pyruvate from glucose can be converted to OAA to maintain the activity of the Kreb’s cycle to handle the acetyl-CoA from fatty acid oxidation.


How do Glycolysis and Gluconeogenesis compare?

-Glycolysis = breakdown of glucose;
-Gluconeogenesis = make glucose from a non-CHO source;
-Three steps are catalyzed by different enzymes = Gluconeogenesis "bypass reactions";
-Seven steps are catalyzed by the same enzymes


How is Beta-Oxidation in the liver different than muscle?

-The liver has a greater capacity for beta-oxidation than muscle;
-Produces KETONE bodies for use by skeletal muscle, heart muscle and eventually if food is not consumed, the brain


How does the plasma concentration of Glucose change with the phases?

-Fed = 5.5
-40 hrs starvation (Int) = 3.6
-7 days starvation = 3.5


How does the plasma concentration of FFAs change with the phases?

-Fed =0.3
-40 hrs starvation (Int) = 1.15
-7 days starvation = 1.39


How does the plasma concentration of Ketone bodies change with the phases?

-Fed = Negligible
-40 hrs starvation (Int) = 2.9
-7 days starvation = 4.5


What is Pyruvate Kinase?

-Pyruvate kinase catalyzes phosphoenolpyruvate (PEP) to pyruvate;
-Needed for gluconeogenesis to synthesize glucose when needed to raise blood levels → Glucose created from a NON-CHO source!!


What is AMP-activated protein kinase (AMPK)?

-Controls cellular ENERGY homeostasis;
-Found in the liver, brain, and skeletal muscles → NO UNNECESSARY synthesis;
-Net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells


What is the role of AMP-activated protein kinase (AMPK) in regulating ATP metabolism?

-ADP produced in SYNTHEIC reactions is converted to AMP by adenylate kinase;
-AMP activates AMPK, which regulates anabolic and catabolic pathways by PHOSPHORYLATION of key enzymes


What is Adiponectin?

Produced when fat stores SHRINK;
-Telling you that you need MORE fat;
-Stimulates AMPK


What is Leptin?

-Also stimulates AMP-activated protein kinase (AMPK) in liver and muscle;
-INHIBITS fatty acid synthesis and stimulates fatty acid oxidation. → Leptin tells the body to stop consuming fats;
-My guess is that this may be a long term effect of high leptin and not short term with meal. Insulin may be stronger signal for fatty acid synthesis in short term
** Only leptin and insulin are known to act as adiposity signals that signify the amount of body fat → Have leptin circulating in proportion with body fat


What are the possible metabolic pathways for Glucose-6-PO4?

1. Glycolysis for glucose to convert to pyruvate and yield Acetyl-CoA;
2. If not needed for glucose, stored as glycogen;
3. Or can enter into pentose phosphate pathway generating NADPH . This pathway also produces D-ribose 5-phosphate, a precursor for nucleotide biosynthesis


What can happen to the Acetyl-CoA generated from G6P?

-Acetyl-CoA can be oxidized by citric acid cycle (with electron transfer and oxidative phosphorylation)
-Or Acetyl-CoA can serve as precursor of fatty acids, incorporated into TAGs and phospholipids, or converted into cholesterol


What is the NADPH used for when generated from G6P?

-REDUCING power for bio- synthesis of fatty acids and cholesterol;
-Also detoxification and elimination of many drugs and other xenobiotics metabolized by the liver


What metabolic routes can AMINO ACIDS that enter the hepatocytes after digestion or protein degradation?

1. protein synthesis → Biosynthesis of most plasma proteins and liver constantly renewing its own proteins;
2. pass into blood to other organs for protein synthesis
3. precursors for bio-synthesis of nucleotides, hormones and other nitrogenous compounds in liver and other tissues;
if NOT NEEDED then,
4a. transaminated or deaminated to yield PYRUVATE and citric acid cycle intermediates;
4b. ammonia released is converted to urea;
5. pyruvate and citric acid cycle intermediates converted to GLUCOSE (gluconeogenesis) and glycogen;
6. converted to acetyl-CoA


What can happen to the Acetyl-CoA created from amino acids in the liver?

1. oxidized via citric acid cycle and electrons to ETC coupled to oxidative phosphorylation;
2. converted to fatty acids or cholesterol for transport to other tissues via VLDL


What are the possible metabolic routes of FATTY ACIDS in the liver?

1. Some converted to liver lipids;
2. Under most circumstances (except absorptive phase), fatty acids are primary oxidative fuel in liver. → Fatty acids converted to acetyl-CoA and reducing compound, NADH; And Acetyl- CoA is further oxidized via citric acid cycle.
3. Some converted to phospholipids and TAGs for VLDL;
4. Some become bound to serum ALBUMIN to go to other tissues – heart, skeletal muscle


What happens to EXCESS Acetyl-CoA in the liver from Beta-Oxidation of FFAs?

-Excess acetyl-CoA from β-oxidation and not required by the liver is converted by the liver to KETONE bodies;
-These circulate in the blood to other tissues to be used as fuel for the TCA;
-Ketone bodies may be regarded as a transport form of acetyl groups. → They can supply a significant fraction of energy in some extrahepatic tissues:
•up to 1/3 in HEART and as much as 60 to 70% in BRAIN during prolonged fasting


How are Insulin and Leptin related?

-Insulin and leptin both INHIBIT food intake;
-Make sense because when insulin becomes elevated it means nutrients in blood;
-Something has to cause us to STOP eating – insulin and leptin;
-But insulin also promotes FAT STORAGE;
-Insulin sensitivity is the key!


What is the Lipostatic Theory?

-Leptin vs. adiponectin → Too much leptin for most overweight and obese;
-Homeostatic theory of hunger according to which the brain monitors the level in the blood of free fatty acids that result from the metabolism of fat. A low level indicates that fat has not recently been metabolized, and this leads to a lessening of hunger, whereas a high level indicates recent fat metabolism and increases hunger


How does a person gain weight?

-A person must be in POSITIVE energy balance to become overweight, obese or gain healthy weight → Consuming MORE than is BURNED;
-It is NOT positive energy balance if you normally consume 2000 kcal and expend 2000 kcal, then start consuming 2100 kcal and adapt and expend 2100 kcal


What work was done by Jules Hirsch?

-At Rockefeller University, 1995;
-Published a paper in which they UNDERFED people by 10% of the energy they needed to maintain their weight → they SLOWED their metabolism and maintained their weight;
-Also OVERFED people by 10% of the energy they needed to maintain their weight → they INCEAESED their metabolism and maintained their weight
**Brought back the Set Point Hypothesis


What is the Set Point Hypothesis?

A deterministic theory that explains the interplay of appetite and other factors (fats and carbohydrates in weight control) → the brain is constantly adjusting the metabolic rate and manipulating behavior to maintain a target weight;
-Had fallen out of favor because scientists had fed people fairly large increases in energy and they gained weight; so it appears that the set point hypothesis has LIMITS → obesigenic environment


How does a "Western" high fat diet compare to the Mediterranean diet?

-Normally think of is a diet high in fat (usually high saturated), high sugar, high refined complex carb, high energy density;
-Mediterranean diets are high fat diets, but LOW in energy b/c they contain whole grains, fruits and vegetables; fiber and water dilute the energy density; and the fat is from PLANT sources → PUFA fats that are much healthier and beneficial than saturated animal fats!


What are the 3 energy brakes?

1. Protein,
2. Fiber,
3. Water
-FIber and water DILUTE the energy density and may also promote satiety;
-PROTEIN is the most SATIATING of the three energy nutrients because there are NO STORES like with carbohydrate and fat


What did Walter Willet say about carbs and fat?

-Came to LSU in 2000;
-It is NOT the amount of CHO that is important, but the TYPE → he said the same for FAT;
Key for Willett was carbohydrates with low glycemic load and the key for fat was plant oils – high in unsaturated fatty acids
-(came to LSU after Bill Lands) stated that it didn’t matter as long as consumed unsaturated fatty acids (EB 2013 may have resolved)


What did Gary Taubes say about carbs and fat?

-“never met a carb he liked” (author of “what if it’s all a big fat lie”);
-He pointed out like Hirsch did in 1995 that:
oE retained = E intake - E expended
oE intake and E expended are NOT INDEPENDENT
*The behavior of eating less or expending more energy are not operating in a vacuum, but are LINKED → so if eat less, will expend less; and if expend more will eat more


What different groups did Taube present at Pennington?

-Presented people that:
1. Ate lower energy, but expended less;
2. People that expended a lot of energy at high energy-expending jobs, but were still obese because they ate a lot more energy
3. He presented people with lipodystrophy in upper body or lower body, but obese in the other half


What is Lipodystrophy?

-Medical condition characterized by abnormal or degenerative conditions of the body's adipose tissue; loss of fat from one area → Characterized by a lack of circulating Leptin


What was Taube's argument based of Lipodystrophy?

-Defect in fat tissue that “hogged” energy in non-lipodystrophy half, and the other half could not store fat → rather than a matter of one half ate too much energy relative to expenditure and other half vice-versa;
-His argument was that OBESE people have a physiological defect of fat storage → obese people store too much fat (fat tissue hogs the energy) and then they are hungry;
-He argued the defect was IN THE FAT TISSUE (but probably the BRAIN )


How would obesity researchers define the argument?

-The defect can be in the fat (ob/ob mice, no leptin); OR;
-In the brain and other tissues (db/db mice, defective leptin receptors)


What is the Set Point Model?

-When the mass of adipose tissue INCREASES, released Leptin INHIBITS feeding and fat synthesis and stimulates oxidation of fatty acids;
-When the mass of adipose tissue DECREASES, a lowered leptin production favors a greater food intake and less fatty acid oxidation.


Where in the brain do the hormones Leptin and Insulin send signals?

-In the arcuate nucleus (hypothalamus), two sets of neurosecretory cells receive hormonal input and relay neuronal signals to the cells of muscle, adipose tissue, and liver;
1. anorexigenic neurosecretory
2. orexigenic neurosecretory


How do Leptin and Insulin act on Anorexigenic Neurosecretory Cells?

-The two hormones act on anorexigenic neurosecretory cells to trigger release of α-MSH (melanocortin) → this produces neuronal signals to EAT LESS and METABOLIZE more fuel.


How do hormones act on Orexigenic Neurosecretory Cells?

-Leptin & Insuling orexigenic neurosecretory cells to INHIBIT the release of NPY, reducing the "eat" signal sent to the tissues.;
-Gastric hormone Ghrelin STIMULATES appetite by activating the NPY-expressing cells;
-PYY3-36, released from the colon, INHIBITS these neurons and thereby decreases appetite.


How do the Neurosecretory cells relate to one another?

-Each of the two types of neurosecretory cells INHIBITS hormone production by the other;
-Any stimulus that activates orexigenic cells inactivates anorexigenic cells, and vice versa;
**This STRENGTHENS the effect of stimulatory inputs.


When was adipose/brain communication first suspected?

Some communication between adipose and brain was suspected when COLEMAN in the 1970s linked the blood supplies of ob/ob mice and db/db mice =
-Ob/ob mice became thin → hypothesized db /db mice made a compound that they did not respond to and ob/ob mice did not make it, but responded to it; (and we all know how that worked out)


When was Leptin discovered?

-Published in 1955;
**Leptin triggers a signaling cascade that regulates gene expression, similar to insulin;
-Everyone thought this was the discovery that would solve the obesity “epidemic”;
-People with the MONOGENIC absence of leptin respond beautifully to leptin treatment just like ob/ob mice;
-BUT, most overweight and obese people have POLYGENIC obesity and lots of leptin → they have become RESISTANT or non-responders to leptin


What is the JAK-STAT mechanism of leptin signal transduction in the hypothalamus?

1. Leptin binding induces dimerization of the leptin receptor;
2. Then phosphorylation of specific Tyr residues, catalyzed by Janus kinase (JAK);
3. STATs bound to the phosphorylated leptin receptor through their SH2 domains are now phosphorylated on Tyr residues by a separate activity of JAK;
4. The STATs dimerize, binding each other's P–Tyr residues, and enter the nucleus.


What then happens when the STATs dimerized and bind the P-TyR residues and enter the nucleus?

-Here, they bind specific regulatory regions in the DNA and alter the expression of certain genes;
-The products of these genes ultimately influence the organism's feeding behavior and energy expenditure.


What are the roles of Minerals in the body?

-Help with osmotic properties of body fluids, impart hardness to bones and teeth, and function as obligatory cofactors in metalloenzymes;
-Historically there was a point when carbohydrates, fat , protein and minerals were regarded as necessary in the diet → BEFORE vitamins were known;
-Known component of fluids and tissues


How are Marcro- and Micro-minerals distinguished?

-% in the body (at least 0.01% of body weight) or
-Required in the diet in amounts >100 mg/day;
-Macromineral amounts range from ~35 to 1,400 g;
-Micromineral amounts range from <1 mg to up to ~4 g


What are the Electrolytes?



Calcium and the Body

-Calcium is the most abundant MINERAL in the body as well as the most abundant DIVALENT CATION in the body;
-Represents 1.5 to 2% of the human body or between ~1,000 and 1,400 g in a 70 kg man;
-99% of the calcium is in the BONES and TEETH, while 1% is found in intra- and extracellular fluids (includes blood)


Phosphorous and the Body

-Phosphorus is second to calcium among inorganic elements in the body;
-Represent a range of 0.8 to 1.2% of body weight or between ~560 to 850 g in a 70 kg human ;
-85% of phosphorus is in BONES and TEEHTH, 1% is in blood and body fluids, and 14% is in soft tissue such as muscle;
-Phosphorus is usually found in COMBINATION with other inorganic elements or with organic compounds


What are the BEST sources of Calcium?

-Milk and other dairy products such as cheese and yogurt,;
-Some seafoods (salmon and sardines, both with bones), clams and oysters;
-Veggies and dried fruits can be
-Soy milk and orange juice are FORTIFIED with calcium


What forms of Calcium are available?

-Many forms of calcium are available including calcium carbonate, calcium acetate, calcium lactate, calcium gluconate, calcium citrate, calcium citrate malate, and calcium monophosphate


What foods are POOR sources of calcium?

-Meats, grains and nuts are POOR sources of calcium;
-Spinach, rhubarb, and swiss chard are high in OXALATES that bind calcium in the plant product and prevent its absorption→ They bind DIVALENT metals, such as Ca2+ and FE2+ to for insolubale precipitants that prevent them form being digested and absorbed when found in foods with these metal ions


What are the food sources of Phosphorous?

WIDELY distributed in foods:
-Meat, eggs, poultry, fish, milk, and milk products are VERY GOOD SOURCES;
-Nuts, legumes, cereals, and grains are also sources;
-Cola soft drinks contain phosphoric acid;
form in foods is the reason for the difference in absorption between animal and plant foods


How do the different forms of Phosphorous in foods affect absorption?

-Animals source are superior to plant sources for absorption of phosphorus;
-Phosphorus in PLANTS = form of phytate (also called phytic acid or myoinositol hexaphosphate)


What are the Phosphorous Supps?

SUPPS are available and they also contain POTASSIUM:
-K-Phos and Neutra-Phos K → these are used to replenish phosphorus in people that have had malnutrition


How is Phosphorous normally found?

Usually NOT FOUND FREE, but in inorganic or organic forms;
-Inorganic forms are PHYTATES = Plants
-Meats contain phosphorus bound to ORGANIC compound= phosphorylated proteins → HYDROLYSIS is required to free this form of phosphorus


What is the mechanisms of Calcium absorption into the INTESTINE and then to blood?

1. Ca2+ enters through TRPV6;
2. Ca2+ binds to Calbindin D9K (carriers acros the cell);
3. Ca2+-ATPase pump across basolateral membrane to blood;
4. Some Ca2+ absorbed b/w cells (paracellular) with high con by Claudin proteins


What is the TPV6?

Calcium channel Transporter TRPV6 (AKA CaT1) = membrane calcium channel which is particularly involved in the first step in calcium absorption in the intestine.


What is Calcindin D9K?

Transports over 90% of calcium that enters cells THROUGH the cell


What is Calcitriol?

-Also ENHANCES gene expression of CLAUDINS 2 and 12 that are essential for paracellular calcium absorption in the intestine;
-Paracellular = transfer of substances across an epithelium by passing through the intercellular space between the cells;
-KO mice for calbindin D9k and TRPV6 seem to be fine as far as calcium absorption with paracellular being stepped up


What is the TRANSCELLULAR process of Calcium absorption?

-THROUGH the cell, passing through the apical and basolateral membrane;
-Stimulated by 1,25OH2D =
1. Uptake from intestinal lumen to microvillus border;
2. Translocation across the cell to basolateral membrane
3. Active extrusion of calcium into circulation


What happens during 1. Uptake of calcium from the intestinal lumen to the microvillus border?

-Involves a calcium channel which is an integral membrane transporter (CaT1; AKA TRPV6);
-Then there is controlled movement of calcium down a steep electrochemical gradient;
-Calcium-binding protein CALMODULIN binds several target protein such as myosin –I, a membrane ATPase that can link F-actin filaments to the microvillar membrane that may affect the permeability of the membrane


What happens during 2. Translocation of calcium across the cell to the basolateral membrane?

-Involves CALBINDIN protein;
-Calbindin functions as a calcium transporter and a buffer for cytosolic calcium


What happens during 3. Active extrusion of calcium into the circulation?

Done by calcium ATPases residing in the basolateral membrane and is done AGAINST a substantial thermodynamic gradient


In what form is Calcium found in food and supps?

-Part of INSOLUBLE SALTS → stomach acid promotes release , but even its solubilization does not guarantee absorption as calcium can bind to other dietary components to prevent absorption


What are the 2 main transports of Calcium along the GI tract?

2. Paracellular process is diffusion BETWEEN cells and is TOTALLY PASSIVE with no carriers (? Claudins) or energy required


What effects SATURABLE transport work with TRPV6 for Calcium?

-With AGE this process is NOT as effective as less calcitriol is produced in the kidney;
-Increased plasma phosphorus also diminished calcitriol production;
-Estrogen deficiency at menopause also decreases this calcium absorption process


What effects the PARACELLULAR transport of Calcium?

-Occurs when HIGH levels of calcium in the GI tract;
-Occurs throughout the GI tract, but dominates in the JEJUNUM and ILEUM;
-Normally the cells have TIGHT junctions;
-Increases in INTRACELLULAR calcium appear to promote OPENING of the tight junctions;
-Fructans have been shown to increase paracellular calcium absorption


What Calcium absorption takes place in the LARGE intestine?

-Shown as diffusion across the COLONOCYTE;
-May be of calcium released when fermentable fibers are fermented and release the calcium bound to them;
-As much as 8 mg per day or more in people who don’t absorb as much calcium in small intestine


What substances ENHANCE calcium absorption?

-PTH and vitamin D (1,25OH2D);
-Ingestion of food or lactose with calcium is believed to increase solubility of calcium;
-Effects of lactose more pronounced in INFANTS especially in ILEUM;
-Other sugars, sugar alcohols and protein also enhance absorption


What substances INHIBIT calcium absorption?

-Phytate binds calcium and prevents its absorption especially when the ratio of phytate:calcium is>0.2;
-Oxalates CHELATE calcium and this has very low solubility;
-Divalent cations as well as other minerals can COMPETE with calcium for intestinal absorption;
-Low levels of calcium in the diet with supps of ZINC REDUCE calcium absorption;
-UNABSORBED fatty acids can form INSOLUBLE calcium soaps that are excreted in the feces;
-Some fibers may also bind calcium and prevent its absorption coordinate bonds


How do PHYTATES inhibit absorption?

-Phytates cause calcium to bind to the intestine and prevent its absorption into the bloodstream.;


How do OXALATES inhibit absorption?

-Act to Chelate calcium;
-Chelate = noting a heterocyclic compound having a central metallic ion attached by covalent bonds to two or more nonmetallic atoms in the same molecule;
-Bind the Ca2+ metal ion and prevent it absorption because it is insolubly bound


How does the absorption of Calcium compare with supplements?

-39% as calcium carbonate;
-32% calcium acetate;
-30% calcium citrate;
-27% calcium gluconate;
-Calcium CARBONATE has the highest percentage of calcium by weight: 40%;
-•Calcium carbonate from fossilized oyster shell or dolomite should be avoided because of contamination;;
-Bone meal preparations should also be avoided


What is the avg. Calcium absorption?

-In adults, calcium absorption averages at 30%, this value is used for recommendations;
-Range = 20 to 50%


HOW is calcium transported?

Calcium is transported in the BLOOD in THREE forms:
1. ~ 40% is bound to PROTEINS, mainly ALBUMIN and PREALBUMIN (tranthyretin, TTR);
2. ~ 10% is complexed with SULFATE, PHOSPHATE or CITRAT;
3. ~ 50% is found FREE (ionized) → Ca2+


What form of Phosphorous is absorbed into the intestine?

-Most in an INORGANIC form → PHYTATES;
-ORGANICALLY bound phosphorus is hydrolyzed enzymatically for release of inorganic phosphate;
-Range of 50 to 70% → variations in phosphorus intake DO NOT affect absorption;
-Throughout the small intestine, but most occurs in the duodenum and jejunum


How is Phosphorous HYDROLYZED?

1. Phospholipase C, a ZINC-dependent enzyme, hydolyzes the glycerophosphate bond in phospholipids → breaks bond holding PO4- to the glycerol backbone
2. Alkaline phosphatase, also a ZINC-dependent enzyme and it is stimulated by CALCITRIOL (1,25OH2D; active Vit. D), functions at the brush border and FREES phosphorus from most bound forms, but NOT FROM PHYTATES


What are the processes of Phosphorous absorption?

1. A saturable, carrier-mediated active transport system dependent on sodium and enhanced by CALCITRIOL and
2. A concentration-dependent facilitative diffusion process
**Most phosphorus, based on levels in diet, are absorbed by the SECOND process → when phosphorus is LOW in the diet then the FIRST process is dominant


What affects Phosphorous absorption?

-1,25OH2D stimulates absorption in BOTH the duodenum and jejunum;
-Phytate, the major form of phosphate in grains and legumes, is VERY POORLY ABSORBED form of phosphorus because mammals lack phytase;
-Magnesium, calcium and aluminum IMPAIR absorption of phosphate


What is Phytase?

Phosphate esterase that liberates phosphate → Yeasts in breads possess phytase so some of phosphates from the grains liberated for absorption
o Bacteria can also break down phytate as long as the attached phosphate groups are not complexed to cations such as calcium, zinc or iron


How do other inhibit Phosphorous?

Magnesium, calcium and aluminum IMPAIR absorption of phosphate;
-Aluminum and magnesium as hydroxides
-Calcium as carbonate or acetate are in antacids
-These antacids have been used in pharmacological doses to lower high blood phosphorus concentrations (hyperphosphatemia) in patients with kidney disease


What is Hyperphosphatemia?

Electrolyte disturbance in which there is an abnormally elevated level of phosphate in the blood;
-Often, calcium levels are lowered (hypocalcemia) due to precipitation of phosphate with the calcium in tissues


How is Phosphorous transported in the BLOOD?

-In the BLOOD in both organic and inorganic forms
-~ 70% is as organic phosphate such as in phospholipids in lipoproteins;;
-~ 85% of the remaining 30% is inorganic as HPO42- or H2PO4- , with small amounts as PO43-
-Some inorganic phosphate is BOUND to other minerals such as calcium, magnesium, and sodium;
-Inorganic phosphorus in blood is sometimes called ultra-filterable phosphate and ranges in adults from 2.5 to 4.5 mg/dl (0.81 to 1.45 mmol/L);
-Ultra-filterable Phosphate – Inorganic phosphate concentrated in the BLOOD


How are Calcium concentrations regulated?

-Both INTRAcellular and EXTRAcelular
-Very tightly!;
-Extra = by PTH, calcitriol, and calcitonin


How is Extracellular (Serum) calcium regulated?

1. Low blood Ca causes release of PTH from parathyroid gland;
2. PTH binds bone cell receptors for resorption and Ca release to blood;
3. PTH activates kidneys to make active Vitamin D, Calcitriol (1,25OH2D);
4. PTH and Calcitriol promote kidney retention and send to blood;
5. Calcitriol leaves kidney for intestine to promote synthesis of Calbindin = increased intestinal absorption;
6. Calcium enter the blood from bone resoprtion, release from kidneys, and intestinal absorption


What is the role of PTH in Extracellular calcium regulation?

PTH secreted by chief cells in parathyroid glands;
-Respond to LOW SERUM ionized calcium;
-Low phosphorous in the blood, stimulates the secretion of PTH → Increased PTH = Increased Calcitriol;
-At the bone surface PTH promotes release of amorphous calcium salts on the surface of the bones → PTH stimulates oxyoclasts to realases enzymes that break down bone!


What are Calcium-Sensing Receptors (CaR)?

-Calcium-sensing receptors (CaR) in parathyroid glands and kidneys change conformation when INCREASED concentrations of calcium and magnesium in the blood;
-Through a second messenger in the parathyroid glands and results in REDUCING the PTH release → High serum Calcium STOPS PTH from being released


What is the role of CALCITRIOL in Extracellular calcium regulation?

-Promotes INCREASED amounts of calbindin D28k for renal tubular reabsorption of calcium in the kidney;
-And in the intestine the increased protein for absorption of calcium is calbindin D9k


What is the role of CALCITONIN in Extracellular calcium regulation?

-Calcitonin is synthesized in the parafollicular cells of the thyroid gland;
-Calcitonin INHIBITS bone resorption and reduces retention in the kidneys


How is Intracellular (within) calcium regulated?

-Intracellular FREE calcium concentrations in the CYTOPLASM are maintained very LOW compared to extracellular values;
-Because calcium is such an important and powerful signal as a second messenger;
-Increased cytoplasmic calcium can increase very quickly , but then has to be decreased just as rapidly when the need for it is done;
-Within organelles, calcium binds to and forms complexes protein =
1. Binds with protein, CALSEQUESTRIN in the sarcoplasmic reticulum in muscle cells;
2. Complexed with phosphate in the mitochondria


What is Calsequestrin that binds calcium in organelles?

Calcium-binding protein helps hold calcium in the cisterna of the sarcoplasmic reticulum AFTER a muscle contraction, even though the concentration of calcium in the sarcoplasmic reticulum is much higher than in the cytosol (intracellular fluid).


How can Calcium be REMOVED from the cell cytoplasm?

Two ways:
1. ATP-dependent pumps w/ Mg2+ and Na+ to export calcium out of cell;
2. ATPase and other pumps sequester in organelles such as ER and mitochondrion


What tissues of the body contain Phosphorous?

-Phosphorus is found in ALL CELLS of the body;
-Organic phosphates are formed in intermediary metabolism;
-Bone and muscle contain most of the phosphorus, BONE THE MOST


What are the main components of BONE?

-Bone is made up primarily of calcium, phosphorus, and magnesium;
-Other minerals in smaller amounts (fluoride, potassium, sodium, strontium, [maybe zinc], and hydroxyl groups);
-Bones have an outer CORTICAL bone layer that surrounds inner TRABECULAR bone


What is Trabecular bone?

-Trabecular bone is like scaffolding that SUPPORTS the outer cortical bone;
-Contains cells and blood vessels;
-LESS dense than cortical b/c less bone per volume, but where there is bone it is EQUALLY DENSE;
-Both types of bone contain layers of mineralized protein mainly as COLLAGEN;
-Trabecular bone is MORE metabolically active and MORE susceptible to low dietary calcium intakes


What is the main mineral structure in bones?

-Hydroxyapatite = which is a crystal lattice-like substance found bound to protein;
-Hydroxyapatite crystals have the formula: Ca10(PO4)6(OH)2;
-Carbonate is also found in bone associated with calcium, potassium, or sodium


What PROTEINS are found in bone?

1. Collagen (85 to 90% of protein),
2. Osteonectin → binds both calcium and collagen;
3. Osteopontin → binds to both hydroxyapatite and bone cells
4. Bone sialoprotein,
5. Osteocalcin (also called bone Gla protein, BGP)
5. matrix Gla protein (MGP);
→ Osteocalcin and MGP are DEPENDENT on vitamin K and function in calcium binding and matrix modification;
6.Also ground substance made up of glycoproteins and proteoglycans (similar but proeteoglycans are larger with longer CHO chains)


What are the 3 major types of bone cells?

1. Osteoblasts;
2. Osteocytes;
3. Osteoclasts


What are Osteoblasts?

-Osteoblasts secrete collagen and other proteins and ground substance – this is the extracellular matrix or bone matrix osteoid (non-mineralized bone);
-Osteoblasts get embedded in the bone and become osteocytes, which maintain bone


What are Canaliculi?

-Processes in canals or channels that connect Osteocytes, osteoblasts, and osteoclasts keeping them all in contact with one another;
-Like a big nervous system communicating in the bone


What are Flat Cells?

-Lining cells on the surface of the bone (might be derived form osteoblasts) that form a membrane the PERIOSTEUM that lines the bone;
-The periosteum membrane contains calcium pumps


What is the Bone Periosteum?

-Membrane that covers the outer surface of all bones, except at the joints of long bones


What are Osteons?

-AKA Haversian system in honor of Clopton Havers;
-Predominant structures found in some lamellar or compact bone;
-Roughly cylindrical structures that are typically several millimeters long and around 0.2mm in diameter


What is Compact bone?

AKA Cortical Bone – Cortical bone facilitates bone's main functions: to support the whole body, protect organs, provide levers for movement, and store and release chemical elements, mainly calcium.


What is Lamellar?

concentric layers of the compact bone tissue


What are Osetoclasts?

-Function to BREAK DOWN BONE to release calcium and to model and remodel bone → Osteoclasts are large MULTINUCLEATED cells (range of two to ten nuclei);
-MODEL during bone growth;
-REMODEL for maintaining bone or responding to bone use (jumping and stronger bones in the legs)


What are Osteoblasts?

Osteoblasts secrete factors that start the RESORPTION =
1. Macrophage colony stimulating factor (M-CSF) and receptor activator of nuclear factor кB (RANKL);
2. These proteins bind to RANK receptors on precursor cells to stimulate their development to osteoclasts;
-Osteoblasts also produce osteoprotegerin that binds to RANKL;
**So osteoblasts stimulate bone REMODELING


What is Osteoprotegerin?

-Decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL);
-By binding RANKL, OPG inhibits nuclear kappa B (NF-κB);
-PREVENTS the production of osteoclasts by inhibiting differentiation of osteoclast precursors


What is NONOSSEOUS calcium required for?

-blood clotting
-nerve conduction
-muscle contraction
-enzyme regulation
-membrane permeability


What is the active REGULATORY form of Calcium?

-The IONIZED calcium is the active REGULATORY form, so a very, very small amount is critical for regulation → Ca2+


How does Calcium regulate nerve conduction?

Calcium enters the end of motor neurons at the muscle and it releases ACETYLCHOLINE that causes DEPOLARIZATION of the muscle which increases sodium and potassium conductance


How does calcium enter the Cytoplasm of cells?

-Calcium enters the cytoplasm of cells either externally or from internal stores → Dietary sources or removed from bone and stores;
-INCREASED FREE ionized calcium (Ca2+) in the cytoplasm of cells can result in a variety of functions;
-May be direct or with calcium binding proteins


What is Troponin C that binds calcium for nerve conduction and muscle contraction?

-Part of a 3-part protein reg. complex found in skeletal MUSCLE binds calcium in a similar mechanism with conformational changes like CALMODULIN;
-With motor neuron signaling, there is INCREASED cytoplasmic calcium and binding by troponin C;
-Actin and myosin can interact and muscle contraction occurs


What happens after the contraction takes place?

-Once nerve signaling is done then calcium is re-sequestered into sarcoplasmic reticulum and troponin C gives up the calcium bound to it;
-Ca2+ is re-bound to Calsequestrin (binding protein) in the sarcoplasmic reticulum which helps hold it there


What are the the steps in nerve signal transduction?

1. Neurotransmittes and hormones bind cell receptors and trigger Ca2+ release;
2. Hydrolysis of cell membrane phospholipids;
3. IP3 acts as second messenger to release calcium from ER;
4. Calcium free or bound to calmodulin activates/deactivates enzymes with phosphorylation;
5.PKC associates with DAG and free calcium to phosphorylate proteins/enzymes in cell


What is the role of the Calmodulin-Ca2+ complex?

Active form and able to stimulate and interact with other compounds/enzymes to cause signal transduction


What are the functions of Phosphorous?

-bone mineralization
-energy transfer and storage
-nucleic acid formation
-cell membrane structure
-acid-base balance


What is the function of phosphorous in BONE?

-Phosphorus is part of AMORPHOUS CALCIUM PHOSPHATE forms and in crystalline hydroxyapatite;
-Amorphous = w/o defined shape;
-In AMORPHOUS bone and extracellular fluids, the ratio of calcium to phosphorus is 1.3:1;
-In HYDROXYAPATITE the ratio is 1.5 to 2.0:1


What is the role Phosphorous WITHIN cells?

-Major ANION → P3-;
-Important STRUCTURAL role in nucleic acids as phosphate groups (PO4-) alternate with pentose sugars for the backbone of RNA and DNA;
-Needed for ATP, ADP, AMP, and creatine phosphate, also for UTP and GTP and TTP and derivatives → all these are critical in ENERGY production and use;
-Phosphorus is also part of a couple of second messengers in cells = cAMP;
-Major component of membrane phospholipids;
-In RBC synthesis of 2,3-diphosphoglycerate affects oxygen release from hemoglobin


What is cAMP?

-cAMP produced from ATP and stimulates → certain protein kinases and inositol triphosphate (IP3) which plays a role in INTRACELLULAR CALCIUM RELEASE;
-used for intracellular signal transduction, such as transferring into cells the effects of hormones like glucagon and adrenaline, which cannot pass through the plasma membrane;
-Involved in the activation of protein kinases and regulates the effects of adrenaline and glucagon. cAMP also binds to and regulates the function of ion channels


How is Phosphate a BUFFER?

-WITHIN cells, phosphate is the main intracellular buffer
-PO43- + H+ → HPO42- + H+ → H2PO4- + H+ → H3PO4


What are Phosphoproteins?

-Phosphoproteins are critical in REGULATION of INTERMEDIARY metabolism;
-Protein which is posttranslationally modified by the attachment of either a single phosphate group, or of a complex molecule = PHOSPHORYLATION → Control enzymatic reactions ;
**Phosphorylation and dephosphorylation of proteins and enzymes turns ON and OF various reactions in the cells of the body


What is the role of Phosphorous in CELL MEMBRANES?

-Phosphorus is necessary for structural lipids of CELL MEMBRANES the phospholipids in the bilayer structure; phospholipids include:
1. phosphatidyl choline (PC),
2. phosphatidylinositol (PI)
3. phosphatidyl serine (PS),
4. phosphatidylethanolamine (PE)


How does Calcium interact with Phosphorous?

**Diets high in phosphorous relative to calcium =
-Believed that these ratios were not healthy as these diets may lead to mild secondary hyperparathyroidism that would be unhealthy for bones with calcium loss from bone → but, increased bone resorption has NOT been seen;
-Ratio may be important for infants and children, but more research is needed for adults


What results from HIGH serum phosphorous compared to calcium?

-Higher serum PHOSPHOROUS results in LESS bone resorption at ANY PTH concentration;
-Recall that LOW ionized Ca2+ increases plasma PTH which increases urinary phosphorus and thus lowers plasma phosphorus;
-When PTH is increased, Phosphorus is reduced in the plasma so that resorption can occur, but retained in the kidneys so body levels wont’ be depleted! → Just changes locations to concentrate in the body ;
-High BLOOD Phosphorous = NO Resorption to provide Ca2+, so much lower → Activated by PTH


How does Calcium interact with Protein?

-High dietary PROTEIN increases urinary calcium, but also increases dietary calcium absorption which may be the reason for the increased urinary calcium;
-Protein containing foods have a good amount of phosphorus;
-Prevents losses of calcium in urine as PTH not increasing calcitriol as much with higher phosphorus in blood


How do Calcium and Sodium interact?

-Sodium and calcium excretion are LINKED → excreted together in the proximal renal tubule;
-Sodium consumption of 500 mg INCREAES calcium excretion by 10 mg;
-Because sodium intakes are much higher than are sodium needs, the excess needs to be excreted and takes calcium with it;
-Urinary sodium excretion has been NEGATIVELY correlated with changes in bone density, (bone loss);
-High potassium may prevent calcium losses in urine (counter sodium)


How does Calcium interact with Caffeine?

-Caffeine can increase urinary and fecal losses of calcium;
-Caffeine and alcohol have been POSITIVELY correlated with risk of fracture in middle-aged women


How does Calcium interact with Iron?

Calcium DECREASES non-heme iron absorption when the two are consumed together, but calcium supplementation DOES NOT appear to negatively affect iron status


How does Calcium interact with Lead?

Low calcium increases lead accumulation in blood and organs


What benefit can be seen with high dose Calcium sups?

High dose supplements may improve lipoprotein profiles and reduce amounts of bile acids released and improve colon health


What other nutrients does Phosphorous interact with?

-EXCESSIVE use of phosphorus binding ANTACIDS contain high magnesium or aluminum that bind dietary phosphorus and thus DECREASE serum phosphorus;
-To INCREASE serum phosphorus, bone is resorbed and the excess calcium in serum is excreted in the urine


How are Calcium and Phosphorous EXCRETED?

-Calcium is excreted in urine and feces, but also excreted from skin in fat;
-Majority of Phosphorus is excreted in inorganic form in the urine with the remainder excreted in the feces


What the adult RDA for Calcium?

*RDA for all but infants based on different measures based on age and gender=
-Adults 19-50 = 1000 mg/day
-Men 51 to 70 = 1000.g/day is based on the amount to maintain calcium balance by the body;
-Women 51 and older = 1200 mg/day → based on bone mineral density
-Adults older than 70 based on minimizing fracture risk


What are the Calcium requirements for children?

-Boys and girls 9-18 = 1300 mg/day → based on bone calcium accretion;
-Infants just need to consume breast milk;
**AI for infants is based on the amount of calcium in breast milk → pregnancy and lactation reflect the ages of the women and match their respective requirements (breast milk will automatically provide the needed calcium naturally)


What is the RDA for Phosphorous?

-Adults 19 to 50 years = 700 mg/day;
-Based on ability to maintain serum inorganic phosphate (Pi) at the normal end of the adult Pi of 0.87 mmol/L (2.7 mg/dl)


What problems results from DEFICIENCY of Calcium?

-Low calcium in BONE in children = Rickets;
-Low ionized calcium in the BLOOD (hypocalcemia) = Tetany;
-Osteomalacia and osteoporosis occur when there are problems with calcium in adults


What is Tetany?

Tetany is characterized by intermittent muscle contractions that fail to relax, especially in muscles of the arms and legs; also included in tetany can be muscle pain, muscle spasms, and parasthesia (numbing or tingling in the hands and feet);


What problems results from DEFICIENCY of Phosphorous?

-Deficiency is RARE and usually occurs in people with renal disease given large amounts of ANTAIDS that BIND phosphorus in the GI tract → Prevent absorption;
-People refed with enteral or parenteral nutrition without extra phosphorus develop deficiency called “re-feeding syndrome.”


When serum phosphorus drops to <1.5 mg/dl, what symptoms can occur?

-Leukocyte dysfunction
-Reduced cardiac output
-Decreased diaphragmatic contractility
-Skeletal muscle and cardiac myopathy
-Neurological problems (ataxia and parasthesia)
-Finally death


What GENETIC disorders prevents re-absorption in the kidney?

-Phosphorus X-linked hypophosphatemia;
-Hypophosphatemic rickets (Dent’s syndrome)


What is the TOXICITY of calcium?

-High calcium intakes and kidney stone development and reduced kidney function in the elderly;
-UL Adults 51 and older = 2,000 mg/day;
-UL Adults younger than 51 = 2,500 mg/day,
-UL Adolescents 14 to 18 years old = 3,000 mg/day → Adolescents with their growth spurt should be able to handle higher levels of calcium
**The UL would only be from SUPPS


What is the TOXICITY of Phosphorous?

-Toxicity is RARE;
-Reported only in INFATNTS when significantly higher phosphorus:calcium ratio → hypocalcemia and tetany
**UL = 4 mg/day ;
-Derived by dividing 10.2 g/day (value at which there is metastatic mineralization by an uncertainty factor of 2.5)


How is Calcium assessed?

-SERUM levels are commonly measured and normal range for adults is 8.5 to 10.5 mg/dl;
-Dual energy x-ray absorptiometry (DXA) is the gold standard for calcium status of bone


How is Phosphorous assessed?

-SERUM phosphate concentrations and urinary excretion are often assessed, but these are NOT very SENSITIVE;
-Serum phosphate concentrations can be maintained at the EXPENSE of tissue phosphorus