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Hillyard, a bunch of jargon about metabolism
Terms in this set (45)
Energy Content of Carbohydrates, Fats, and Proteins
Fats, the highest= 9kCal/g-> because these are more reduced, more elctrons to strip so 1g will yield more kCal
They all produce about 5 kCal per liter of Oxygen, fats more reduced so they need more O2 to reduce them
The hormone of abundance. When the influx of nutrients exceeds the amount used for energy and the rates of anabolism, insulin induces effiecient storage of the excess nutrients while suppressing mobilization of endogenous substrates. It stores this insulin so it can then be avaiable when blood glucose levels drops, and will be there to unleash
The specific ways insulin stores nutrients
It promotes storage of glucose and amino acids in muscle, it promotes storage of glucose and free fatty acids in adipose tissue, it promotes glucose-6-P conversion to glycogen for storage in the liver
Proinsulin to Insulin, describe process
Proinsulin is translated across the rough ER membrane just like other secreted proteins (the ribosomes on the membrane transcribe the protein into the lumen. This long protein is called the C peptide. The C peptide is cleaved in the Golgi Apparatus resulting in insulin and then secretory granules release insulin and C peptide into the blood when there is elevated bloos glucose.
A family of transport proteins that allow cells to TAKE UP GLUCOSE from the blood
Right After a big meal, describe the process that occurs in the B cell of the pancreas
Glucose and other nutrients in high concentration after a meal, Glut 2 (the transport protein that facilitates uptake of glucose specifically for the kidney) brings in glucose that stimulates energy metabolism and ATP production
ATP then blocks the K+ channel which depolarizes the membrane and activates Ca2+ channels
Ca2+ stimulates exocytosis of insulin, so the insulin can facilitate uptake of glucose in the various tissues
Glut 2, Glut 4
Glut 2 = Liver and pancreatic cells
Glut 4=muscle and fat cells
Km of Glut proteins
Glut 2 has a much larger Km (15-20 mM) than all the other including Glut 4 for muscle and adipose(5 mM).
Plasma Glucose vs Insulin
As plasma cell glucose increases, insulin increases. Type 1 diabetes is the loss of B cell function due to an autoimmune destruction of the cells. This can be treated by exogenous insulin
How Insulin affects Target Cells of Muscle and adipose tissue
Insulin binds to the insulin receptor on the cells of muscle and adipose tissue. This receptor is of the RTK category. Insulin binding causes the receptor to autophosphorylate tyrosine residues of the receptor. This activates tyrosine kinase that will activate the insulin receptor substrates.
The insulin receptor substrates cause the insertion of Glut4 containing vesicles into the target cell membrane. This allows glucose uptake to occur in the cell.
Serine and threonine kinases are also activated to stimulate rapid activation and inactivation of key enzymes that are present in the cell
The long term affect Insulin has on target cells of muscle and adipose
RTK, autophosphorylates tyrosine which activates tyrosine kinase which phosphorylates Insulin receptor substrates.
Insulin receptor substrates activates transcription factors that cause long term synthesis of key enzymes. Insulin is important for maintenance as well.
Enzymes and molecules STIMULATED by Insulin
1. Glucokinase/Hexokinase- we want glucose being taken in and converted to glucose-6-P because from here we can convert to storage items
4. Glycogen synthase- we want to be converting Glucose-1-phosphate and adding it the storage molecule, glycogen
5. Phosphofructokinase- we want this to be converting Fructose-1,6-bisphosphate to eventually get to pyruvate and then acetyl CoA, because then we can take acetyl CoA and store it either as cholesterol or triglycerides.
7. Pyruvate kinase- we want this activated because we want phosphoenolpyruvate to be converted to pyruvate and then converted to acetyl CoA, because we need to convert this to cholesterol or to triglycerides
Basically, all these enzymes are activated for the goal for storing glucose to glycogen, cholesterol, and triglycerides
Insulin vs Glucagon
Insulin and Glucagon are often secreted and act in reciprocal fashion; The ratio of their concentrations is MORE IMPORTANT than their actual concentrations
The pancreatic islet is responsible for cleaving glucagon's prohormone into its functional subunit
Glucagon is CATABOLIC-> it stimulates the mobilization of energy substrates and the breakdown of the big stored compounds to GET glucose along with free fatty acis, glycerol, etc
It facilitates glycogenolysis->glycogen to glucose-6-P so it can be converted to glucose and shipped out of the liver. It also facilitates pyruvate to glucose-6-P to do the same thing (we dont want pyruvate building things like cholesterol, triglycerides, etc). We also have Amino Acids being converted to pyruvates and those being converted to glucose.
It facilitates triglycerides stored in adipose tissue to be broken down and released as free fatty acids and glycerol.
We are unleashing all of the stored nutrients in our tissues and releasing them into the blood.
Glucagon and Gluconeogenesis
Glucagon stimulates gluconeogenesis: so it stimulates Oxaloacetate to phophoenolpyruvate(this has to do with pyruvate being carboxylated and then decarboxylated) This enzyme that is stimulated by glucagon is Phosphoenolpyruvate carboxykinase. Also, Fructose-1,6-bisphosphate is converted to Fructose-6-P by Fructose 1,6- bisphosphatase. And then the last step of gluconeogenesis, glucose-6-P converted to glucose by Glucose-6-phosphatase
Inhibits Insulin and glucagon secretion
Insulin regulation on glucagon
The directional blood flow in the islets promotes the bathing of mantle alpha cells with high concentrations of inhibitory insulin from the core Beta cells. So insulin INHIBITS glucagon
Glucagon's regulation on Insulin
Glucagon stimulates the formation of glucose by glycogenolysis and also gluconeogenesis and this glucose is released for tissue metabolism.
Glucose also STIMULATES insulin release so the glucose in the hypoglycemic individual can enter cells and provide metabolic energy.
AMP (the fuel gauge of the cell)
When AMP is present it will activate an AMP kinase that will stimulate glucose CATABOLISM and inhibit glucose ANABOLISM. We want the glucose we have to be broken down through glycolysis and krebs and oxidative phosphorylation to produce ATP in the body.
Excercise will cause the breakdown of ATP to AMP and is a trigger to this reaction
Another product of the glucagon "gene"
Another piece that can be cleaved from the preproglucagon is GLP-1 which is what is cleaved when it is in the intestine.
GLP-1 actually ENHANCES insulin activity
APUDS and GLP-1
In the ilium/colon you have APUD cells on the lining. Glucose and nutrients reach the ilium and colon and are absorbed into the APUD cell. This causes the APUD cell to release GLP-1 into the bloodstream and this will enhance insulin, because insulin is needed to take up glucose into tissue as the blood is overconcentrated with nutrients after a meal.
The different roles of GLP-1
It works entirely to enhance insulin funtioning. It does this is a number of ways:
It increases Insulin biosynthesis
It increases B cell proliferation
It decreases B cell apoptosis
It increases Insulin secretion
It decreases Glucagon secretion
Increase parasympathetic NS stimulation of insulin secretion
a drug that inhibits DPP-4 to enhance the beneficial effects of GLP-1 including an increase in insulin synthesis-> could be beneficial in type 2 diabetes
Effects of Epinephrine in the skeletal muscle or glucagon in the liver rlsed During exercise or fasting
These hormones activate a cascade of sequences that ultimately activate Glycogen Phosphorylase (a to b), while simultaneously deactivating Glycogen synthase (b to a). These are reciprocally regulated. Its either one or the other, and it this circumstance you need it this way, because we need to be breaking down glycogen to get glucose release.
After ATP produced and exported out of the motochondria and used up
ATP hydrolysis provides energy for biological work, ADP and P MUST be transported back into the mitochondrial matrix, we have A LOT of ATP that is being made constantly and this recycling is what enables us to do so.
Three carrier proteins in the inner mitochondrial matrix
ATP-ADP translocase- ATP out, ADP in
Pyruvate carrier- Pyruvate in to go to the Krebs cycle, and OH- out (we have -'s going out because there is such a negative charge inside the inner mitochondria because we have all the protons being pumped across the membrane
Phosphate carrier- Phosphate in, OH- out
NADH and FADH2 to elctron transport chain
NADH and FADH2 are transferred into the mitochondria to the electron transport chain where e- are transported along a chain of cytochromes (CoQ and cytochrome C) and the energy derived from the e- transport is used to generate a H+ gradient
Proton motive force
The electrical and chemical gradients for H+ transport through the ATP synthase complex are collectively termed proton motive force that is coupled to the synthesis and release of ATP from the F-1 subunit of the complex
Anionic charge retained in the matrix
As H+ are being pumped outside the matrix into the intermembrane space you have a very anionic charge in the matrix. This negative matrix potential relative the intermembrane space drives the co-transporters described earlier, and the pH gradient being 8 inside the matrix and 7 outside of it, that also contributes to the proton motive force.
The differing concentration gradients can be converted to a voltage
Uncoupling proteins in brown adipose tissue
Uncoupling proteins are in the inner mitochondrial membrane and they DISSIPATE the proton motive force. They are protein channels that let H+ back into the matrix and destroy that built up Proton gradient. So they inhibit ATP synthesis because there is no more gradient to churn ATP synthase.
The point is, Glycolysis and heat production continues because it not being inhibited by ATP, which is the feedback inhibitor to this pathway.
This process is very evident in newborns and small mammals. When newborns are born it is SO COLD and there is environmental stress. The newborn needs this process to stay warm.
The hypothalamus will tell you that you are cold signaling the thyroid to make more hormones to stimulate metabolism, because you are cold
Anaerobic Conditions after Glycolysis
The NADH will donate the H to pyruvate to make lactate. This permits ATP production but results in a lactate accumulation. This usually happens in the skeletal muscle where you are working out and have a shortage of O2
The NAD+ left over is sent back which is important because it is necessary for continued glycolysis
Lactate from anaerobic metabolism
Muscle converts Pyruvate to Lactate in anaerobic conditions and then sends lactate by the bloodstream to the liver where it is converted to pyruvate and then, via gluconeogenesis, to glocuse that is available for energy metabolism. There is a high energy cost for gluconeogenesis. You send 6 ATP. In skeletal muscle glycolysis only produced us 2 ATP, so we lose energy in this situation and we lose weight
This is the Cori cycle- it allows us to get a regeneration of that NAD+ for continued glycolysis and ATP production in muscle at low O2 conditions
During an overnight fast
75% of resting metabolic demands are met by GLYCOGENOLYSIS- so the breaking down of glycogen in the liver so provide glucose for resting metabolism.
The other 25% is provided through GLUCONEOGENESIS, most of which is from lactate to pyruvate. (Lactate sent to the liver, and the liver converts lactate to pyruvate, then feeds pyruvate into gluconeogenesis)
Lactate accounts for 60% of the "precursors" gluconeogenesis needs to facilitate glucose production
%'s of precursors used in gluconeogenesis during an overnight fast for:
Lactate and amino acids
Amino Acids: 25%
Glucagon is produced, which stimulates gluconeogenesis. The specific enzymes that would be triggered are
Pyruvate carboxylase which will convert pyruvate to oxaloacetate
Phosphoenolpyruvate carboxykinase which will convert oxaloacetate to phosphoenolpyruvate
and Fructose-1,6-bisphosphatase which will convert Fructose- 1,6- bisphosphate to fructose 6-phosphate
Once we have fructose-6-P it can interconvert to glucose-6-P and we can convert this to glucose in the ER by glucose-6-phosphatase which is on the ER membrane
Carb, Protein, Fat storage in our bodies
We store our calories, for the most part, in the form of Fats (76%). There is only 1% stored as carbohydrates.
Thus, fat storage and mobilization is critical for survival
Fatty Acid mobilization
We must mobilize fatty acids from Triglycerides by glucagon. (Remember glucagon doesnt just facilitate breakdown of glycogen to glucose- glycogenolysis, and conversion of pyruvate to glucose-gluconeogenisis; but it also induces Triglyceride breakdown to fatty acids)
So, glucagon stimulates triglycerides in Adipocytes to be cleaved by lipase into free fatty acids and glycerol and shipped out.
Glycerol from Breakdown of triglyceride
It can enter the glycolytic pathway via DHAP or Dihydroxyacetone phosphate
FFA from Breakdown of triglyceride
FFA are converted to acetyl CoA, but they CANNOT produce glucose. There is no reaction from acetyl CoA back up to pyruvate.
FFA can instead be converted to ketoacids by the liver (this is how you can get ketoacidosis in diabetes type 1, you are only using fat for fuel and you get all these free FFA that cant be turned into glucose, and the only thing to do is convert them into ketoacids and these build up and cause problems)
Carboxyl groups donate H+ and produce metabolic acidosis.
These are produced as byproducts of FFA being broken down for energy in the liver's mitochondria. 2 of them- Acetoacetate and D-3-Hydroxybutyrate are used as a source of energy for the heart, brain, and kidney. While the third, acetone, is a waste product. These do however raise the pH of blood and could cause acidosis.
Ketone bodies and the brain
Keto bodies are very good in starvation. The brain uses pretty much solely glucose, but during starvation keto bodies can be there in a pinch. Ketone bodies, i.e. acetoacetate is cleaved to uield 2 acetyl CoA's and they can run on the Krebs and generate electrons for oxid phos.
Ketone bodies are like transportable water soluable equivalents of fatty acids. So in glucose shortage to the brain, this will be fast traveling and traverse the blood brain barrier to provide energy. Free fatty acids, because they are bound to albumin in plasma, do not
**** Summary of important points about FASTING
Glucagon in fasting:
You need to get pyruvate for gluconeogenesis when blood glucose it low due to fasting. We get 60% from lactate in muscles, and 25% from amino acids. Once we have this pyruvate we run gluconeogenesis and make glucose.
In fasting you also have break down of triglycerides-> glyceral to liver, converted to glucose, but the free fatty acids CAN NOT make glucose. Instead they are broken down acetyl CoA for energy, and form by products called Ketoacids. The ketoacids can be used to provide energy to brain (it is portable, water soluble, crosses the blood brain barrier), heart, and kidney
Muscle and Glycogen
Muscle stores 3/4 of the body's glycogen. It uses the glycogen as an immediate energy source; glycogen is readily converted to G-6-P for use in muscle cells
Muscle also lacks G-6-Pase which dephosphorylates glucose(in gluconeogenesis) and so it does NOT export glucose
In resting muscle, fatth acids are the major fuel
Glucose, fatty acids, ketones
Heart muscle prefers acetoacetate to glucose
Protein degradation is a source of energy in prolonged fast
Protein degradation in prolonged fast
Protein is degraded to alanine which is brought to the liver where it is converted into pyruvate, which can go to glucose in gluconeogenesis
Increases muscle proteolysis and stimulates hepatic conversion of the liberated amino acids into glucose precursors then glucose, which is then released into the circulation or stores in the liver as glycogen. Cortisol also inhibits insulin-stimulated glucose uptake by muscle (MORE FOR YOUR BRAIN) Cortisol stimulates colaric intake
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