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| So just to remind you about the different parts of the cell, here's a basic eukaryotic cell. Here's the nucleus with its DNA and the gene expression nucleoli that make ribosomes. Here's the endoplasmic reticulum where proteins are synthesized and some organelles where waste products are managed and removed-- and in terms of today's videos, the mitochondria, which is an important part of energy metabolism. Sometimes people call the mitochondria the powerhouse of the cell because a lot of the ATP that's produced to support biochemical reactions is produced in the mitochondria by the process of oxidative phosphorylation. |
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So let's look at mitochondria a little bit more. Here's a pretty picture of a cell. The green is some kind of cytoskeleton protein, probably actin filaments, and the blue is the nucleus. And these little red granules, long and short, are the mitochondria. And we can see that the mitochondria forms a pretty vast network throughout the cell because it's going to be providing energy to all parts of the cell.
Mitochondria is a double-membrane organelle, unlike most other organelles. The only other double-membrane organelle would be the nucleus, but most organelles have a single membrane.
The mitochondria has an outer membrane and an inner membrane-- I'm sorry, an inner membrane, and a space in between, the intermembrane space. The intermembrane contains the electron transport chain. These are a series of large protein complexes that are embedded in the inner membrane that pass electrons back and forth and hydrogen ions back and forth and create a hydrogen-ion gradient between the matrix, which is here, the inside of the mitochondria, and the intermembrane space. That hydrogen-ion gradient will provide the energy to produce the ATP that the electron transport chain is ultimately tasked with providing to the cell.
In the matrix, some other things are happening. We see in this picture, just for your information, these blobs, these are DNA, actually. The mitochondria, you may know, has its own DNA. This is maternally inherited DNA, and it gives rise to 13 of the proteins of the electron transport chain. So it's an essential DNA, but it's completely separate from the nuclear genome. When we think about the human genome, we think of the nuclear genome, but the mitochondrial DNA is essential and provides important parts of the electron transport chain.
The other thing that happens in the matrix of the mitochondria is the Krebs cycle. This is very important because the Krebs cycle provides some of the electron donors that are required to drive the electron transport chain and provide ATP for the cell. |
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Electron transport involves a series of oxidation- reduction reactions that enable Complexes I–IV to pump H+ into the intermembrane space. Electron transport ends at Complex IV with the oxygen atom being the final electron acceptor and joining with hydrogens to form water.
The H+ gradient generates energy that drives the addition of high-energy PO4 groups to ADP to form ATP.
Some facts:
• O2 feeds Complex IV by interacting with Fe2+. It’s why we breath and why RBCs don’t have mitochondria.
• Electron transport can be “uncoupled” from ATP synthesis to produce heat in brown fat. This keeps babies warm.
• Carbon monoxide can poison the chain. Where do you think?
• mtDNA encodes 13 proteins that are part of Complexes I, III, IV, and ATP synthase. There are nearly 100 total proteins in these complexes.
• O2 can be reduced inappropriately by other complexes besides IV, resulting in superoxide
O2–. This highly reactive oxygen species (ROS) can damage lipids, proteins, and DNA. To eliminate it, mitochondria contain an enzyme called superoxide dismutase that converts O2– to H2O2, which diffuses out of the mitochondria and is inactivated by the enzyme catalase in peroxisomes.
• Glutathione regenerated by NADPH provided by the PPP also manages ROS. |
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So now we're going to step back a little bit and look at the interaction between oxidative phosphorylation and some of the other energy-production pathways. So here's our oxidative phosphorylation or electron transport. They're almost synonymous. And again, to get this started we need some electron donors, and the big electron donor is NADH and FADH2. And these are produced by the tricarboxylic acid, citric acid, or Krebs cycle. It has so many names and it can be confusing, but we'll try to always remember to call it the Krebs cycle.
And the Krebs cycle basically utilizes this compound called acetyl CoA. This is a two-carbon compound that gets fed into a system of enzymes. Carbons are added and then taken away through a series of reactions, and the side products of the reactions of the Krebs cycle are what's important. NADH is produced. FADH2 is produced. And we'll see in another slide several other important products are produced. But acetyl CoA is the feeder.
So where do we get acetyl CoA? We get it from two important places. One, we can get it from pyruvate. Pyruvate is the final output of the breakdown of glucose. So when we break down glucose in the cytoplasm of the cell via the process of glycolysis, we make pyruvate, which can be made into acetyl CoA.
In addition, amino acids can be broken down under starvation conditions, turned into pyruvate or directly into acetyl CoA, which can then be used to feed the Krebs cycle and provide those electron donors for oxidative phosphorylation. So glucose and amino acids can provide the substrates for Krebs, which then provide the substrates for electron transport and ATP production via ATP synthase.
The other way we can make acetyl CoA is by fatty-acid oxidation. Fatty acids are really neat because they are multicarbon chains-- sometimes very long, 20 or more carbon chains-- that can be broken down into individual two-carbon chains and made into acetyl CoA. So, this is kind of important. Glucose, when it's broken down, one glucose molecule can make two acetyl CoAs. But fatty acids, when they're broken down, depending on how long they are, they can make up to 9 or even 11 acetyl CoAs.
And what this means in layman's terms is that fat can provide way more energy than glucose. Another way of thinking about that, however, is that fat has more calories than carbohydrates or amino acids because it can provide more energy. And the reason for that is because it can be broken down into multiple acetyl CoAs which can feed the Krebs cycle and the oxidative phosphorylation. |
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And so if we look at this in a slightly different way, try to pull it together a little bit, we can see that our main source of energy, the one we like the best, is glucose. This comes from our carbohydrates in our diet. We break it down by glycolysis-- which we'll see in a moment. We'll look at that in a little more detail-- to pyruvate, which can be made into acetyl CoA to feed the Krebs cycle and then feed oxidative phosphorylation.
If we have too much glucose in our diet, we make it into fat, which we store. We can also make it into glycogen, which we can store. Glycogen is short-term storage. That's our long-term storage.
And glycogen, when we're fasting or when we don't have any glucose in our blood anymore, glycogen can be broken down by glycogenolysis to make new glucose, which can then go through glycolysis. When we don't have any glycogen left, we can break down triglycerides, which are the storage form of fats in our body. And we break those down and make them into acetyl CoAs that we can use to feed the Krebs cycle. And finally if we were running low on fats and we're really into starvation, we can also break down our proteins. And some proteins can be broken into amino acids that can feed either acetyl CoA or pyruvate, which eventually makes acetyl CoA. So these are the three ways that we can provide energy to the Krebs cycle and oxidative phosphorylation.
So let's go to glycolysis. This is the first step in breaking down glucose, and this is what we do when we actually have blood glucose to use. Or if we're pulling glucose from glycogen, we can use glycolysis. |
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Three phases:
1. Investment:twoATPsusedtoPO4-ateandconvert one glucose
• What is the role of PO4-ation?
2. Cleavage
• One 6-carbon glucose cleaved to two 3-carbon glyceraldehyde-3PO4
3. Energyharvest
• Two G3Ps are metabolized to pyruvates, yielding two NADHs and four ATPs
• NetATPyield=2
• NetNADHyield=2 |
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• Can be converted to acetyl CoA and continue into the Krebs cycle or be used to make fatty acids
• Can be converted into amino acid alanine
• Can be used to make new glucose through gluconeogenesis
• Can enter the pentose phosphate pathway
• Can be converted to lactate to recycle NADH when O2 is low
• Can make ethanol in yeast cells! |
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• Pyruvate derived from glycolysis or
conversion of amino acids or glycerol is a 3- carbon molecule that is broken down into a 2-carbon molecule by the pyruvate dehydrogenase complex. CO2 and NADH are generated.
• Acetyl CoA is the initiating substrate for the Krebs cycle.
• Acetyl CoA can be made by the
breakdown of fatty acids. |
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• Is a dysfunction of the endocrine pancreas.
• Affects metabolism of fat, protein, and carbohydrates.
• Is characterized by hyperglycemia, resulting from defects in insulin secretion, insulin action, or both.
• Categories:
- Type 1-No insulin produced-must be supplied
- Type 2-Insulin receptors reduced sensitivity-drugs to bypass receptors or to increase insulin release
- Other specific types-non immune type I-quite rare
- Gestational diabetes-associated with Type 2 risk factors |
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So let's consider some of the metabolic profiles of the major organs so that we can understand diabetes a little bit better. Of course, the pancreas-- it's a mixed exocrine and endocrine organ. Its endocrine function is to secrete glucagon and insulin. It secretes insulin in response to elevated blood sugar levels, and it secretes glucagon in response to reduced blood sugar levels.
The liver processes fats, carbohydrates, and proteins from the diet and, very importantly, manages the synthesis of lipids in forms that can be managed by the body. So it takes dietary lipids and converts them into the lipoproteins that we hear about so much, the LDLs, and the VDLs, and the HDLs. It also produces ketone bodies, which we'll talk about in a few minutes. It manages glucose levels by storing glucose in the form of glycogen, and it also manages energy storage by turning excess glucose into fats in the form of triglycerides that can be stored for later use. It also manages nitrogen levels, which is part of its amino acid metabolism process.
The portal system of the liver is important because nutrients that come into the body and are being digested in the gastrointestinal tract-- the blood from the gastrointestinal tract, before it goes back to the heart, before it goes back to the vena cava and into the right heart to be re-circulated, it actually goes through the liver through the portal hepatic system. And so the liver gets like a first pass at nutrients and other things that have been ingested into the GI tract. So the liver detoxifies things, many things before they get to the general circulation, and it gets ahold of nutrients before they actually can get into the general circulation. Small intestine can absorb the nutrients from the diet and move them around into blood and lymph.
In terms of its metabolic needs, the brain is a very active organ and requires a lot of energy in order to fire untold numbers of action potentials every nanosecond, so it needs a lot of energy. But it's kind of picky, and it really likes glucose. And it really doesn't like fat.
And in fact, it's useful for the brain not to have a fatty acid metabolism system, because the brain actually uses fat to make the myelin sheath. So you wouldn't want neurons that when they were starving could eat their own myelin sheath. So the brain is turned off fatty acid oxidation as a possible energy source. But it will work with ketones, and those have to be provided from the liver. So the liver can provide ketones to the brain in cases of starvation.
The lymph's role in metabolism is that it carries lipids around. Adipose tissue, this is the storage site for fat. This is where triglycerols or triacylglycerols same thing-- are stored. These are made from excess glucose or excess fats in the diet and stored in adipose tissue.
And skeletal muscle, finally-- skeletal muscle is the biggest energy user in the body. The blood glucose levels are largely managed by a skeletal muscle, because it's their mitochondria and electron transport chains and glycolysis and Krebs cycle that use up the most glucose that's in the blood. Because they require so much ATP to do their work. |
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The liver is the control of this metabolic network and plays a crucial role in regulating metabolite flux between tissues and organs. One of the primary roles of the liver is to export glucose and triacylglycerols to the peripheral tissues for use as metabolic fuel.
If we considered human metabolism from the perspective of the liver, we can wee that the liver can produce or provide two kinds of energy to the body. It can provide glucose. Now, of course, the glucose can come in through the diet, but in the absence of dietary glucose-- for example, during fasting and in between meals-- we have a storage of glucose in the liver called glycogen, which can quickly be converted back to glucose, which can then be released to give glucose anything that needs it, including, most importantly, skeletal muscle and the brain.
Once that's gone, the liver will produce ketones, which are not shown-- oh here they are-- shown here. So the ketones can be produced-- I'm not sure why they don't have an arrow going to the brain, but they should. Because ketones can go here too. So heart and brain can use those.
And then triglycerides or triacylglycerols are produced in the liver. They can feed the heart. They can feed fat, of course. They can go be stored in fat, and they can also feed skeletal muscle. |
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So diabetes is sometimes called a disease of starvation in the midst of plenty. So let's talk about starvation again for a moment. We eat, and our blood glucose goes up, and we're fed. And then, of course, we're not eating constantly, so our blood glucose goes back down. And we are hungry. We're nutrient-deprived. And so what do we do in those cases when we're nutrient-deprived?
Well, a couple of things can happen. As I mentioned before, the brain really only eats glucose or ketones. So we need to keep some glucose around, and this is why we have glycogen stored. Because we can make glucose quickly. So we can use glycogenolysis to provide-- there should be an arrow here-- to provide some glucose for our brain.
Once that's gone, the next things that happen are fat cells, adipocytes, start producing two things. One, triglycerides, can be broken down to glycerol and acetyl CoA, which can be used to drive the Krebs cycle, and they can also be used in ketogenesis to make ketone bodies, which are not going to be-- well, eventually, they can also be used to make acetyl CoA to drive the Krebs cycle. But ketones specifically are used up in the brain-- they're required for the brain.
When fat is broken down into triglycerides or triacylglycerols, that will not be used by the brain. Triacylglycerols will not be used by the brain, but ketones can be. And finally, muscle can be broken down. Under extreme starvation, we can start to break down the proteins in muscle and scavenge the amino acids, which can be sent to the liver for gluconeogenesis in order to provide, again glucose now, if we need it for the brain. |
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Cells perform different aspects of metabolism in different compartments
The enzymes required are constantly replenished. Sensitive to substrate availability.
Mitochondria are damaged by the ROS produced by the ETC-they must be turned over. Method is autophagy-specialized lysosomes
Peroxisome-proliferator activate receptors (PPAR) are proteins that increase the expression of fat metabolism genes in response to polyunsaturated fatty acids
AMP-Kinase promotes energy metabolism
Both PPAR and AMPK improve function of and in mitochondria
NOT ALL CELLS USE ALL METABOLIC PATHWAYS
At the cellular level, we'll sort of look at some things that we've already seen. We've got our own-- here we go. Here's our cell. Here's this nucleus.
And here in the cytoplasm, we have a couple of things. We've got our glycolysis. This is where we're going to break down glucose, first of all. We can perform gluconeogenesis from some amino acids or from some other components if we need to. We can make glycogen if we're in the liver cell, and we can break down glycogen if we need it for a liver cell.
We can utilize the pentose phosphate pathway, which can give a small amount of energy, but it's not the best energy pathway. It's a nice pathway for making nucleotides for cell growth. I'd feel from that. And we can perform fatty acid synthesis in certain cells, like in adipocytes or fat cells. These processes feed into the mitochondria to feed Krebs and electron transport. And fats can also be broken down in the mitochondria by the beta oxidation of fatty acids, or fatty acid oxidation, again, to provide fuel for the Krebs cycle.
A couple of players that sort of help to manage the enzymes that are required for these processes are the AMP kinase and the PPAR proteins. These are targets, actually, for some of the drugs that are used in diabetes, which is why I mentioned them. So the cells perform these different aspects of metabolism in different compartments, as we've just seen. The enzymes that are required for this are constantly turning over, so we're always having to make new metabolic enzymes. And they're very sensitive to substrate availability, meaning you can shift your metabolic profile if substrates change.
The mitochondria have to be turned over quite often, and mitochondrial damage by reactive oxygen species-- so sometimes, oxygen can be reduced before it's gone all the way through the electron transport chain and turned into water. And then when that happens, you end up with superoxide, and hydrogen peroxide, and things that cause damage to the mitochondria. These mitochondria need to be removed. And there's increasing evidence that defects in the removal of damaged mitochondria or the turnover of mitochondria can contribute to some metabolic disorders.
So as I said, AMP kinase and PPAR, Peroxisome Proliferator, these are two proteins that promote energy metabolism by managing the enzymes that are required for energy metabolism. PPAR, especially, is important in expressing enzymes for fat metabolism, and AMP kinase promotes energy metabolism by managing some of the autophagy that's required to remove damage mitochondria and by replenishing electron transport and Krebs cycle enzymes. Something that's important to note too-- we saw the metabolic profiles of different tissues.
We can also say that in different cells, not all metabolic pathways are really active. Some cells-- for example, fat cells synthesize fatty acids, but other cells don't necessarily synthesize fatty acids. Probably most cells do glycolysis, however. And most of us have mitochondria, but not all cells have mitochondria. And then, those are not using that pathway for producing energy. |
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Let's get back into diabetes, though. So we've gone over some-- reviewed some energy metabolism. And now, let's look at exactly what's going on with diabetes.
So the hormonal control of blood glucose-- when blood glucose is low, the pancreas releases glucagon from the alpha cells. And when blood glucose is high-- after eating, for example-- the pancreas releases insulin from the beta cells. Under these conditions, when glucagon is being released, the liver releases glucose into the blood from glycogen or from gluconeogenesis. So glucagon, again, is responding to low blood glucose. And one of its jobs is to get more glucose in the blood. It does that by acting on the liver trying to get some sources.
When blood glucose is high, insulin's job is to get rid of it. And the ways that it can do that is that it can get it taken out by cells that are metabolically active and can use it in glycolysis, Krebs, and electron transport. Or it can send some-- it's not showing it here, but it can send some to the lever to be stored as glycogen. Or it can get fat cells to take up the excess and turn it into fat. And either way, we try to get our blood glucose level to the normal level.
And we've seen already the response to starvation. We've gone over that before. So again, when blood glucose is very low, we want to get the liver to provide glucose or ketones for the brain. As we start using up our fats, we might start even breaking down muscle in order to provide some glucose for the brain. |
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Diabetes Mellitus
• Type I vs. Type II
• Type I is an autoimmune disorder in which the beta cells of the pancreas are destroyed and little or no insulin is produced or released. This is a juvenile-onset disease
• Type II is caused by loss of function of the insulin receptor. It is traditionally adult-onset; however, dietary changes and increasing childhood obesity rates are causing earlier onset
• Other specific types-non immune type I-quite rare
• Gestational diabetes-associated with Type 2 risk factors
- Treatments reflect the difference
• Type I-Insulin replacement
• Type II-Increased insulin, drugs that bypass the insulin receptor, and drugs that reduce blood sugar levels
• All involve lifestyle modification
- Glucagon in Diabetes: Complex
• Type I-some also lose or reduce glucagon-hypoglycemia
• Type II-Very complex- hyperinsulinemic
And diabetes-- let me go back to diabetes now again. So again, with our type 1 and type 2 diabetes-- type 1 diabetes, as we've said, is a loss of insulin. And the reason is that it's an autoimmune disorder in which the cells of the pancreas that make and release insulin are actually destroyed. It's usually a juvenile or early onset, so it comes on sometime in the teenage years, early adulthood. And there's no insulin being produced, or at least there is a reduction in the amount of insulin being produced.
What that means is that when blood glucose goes up after feeding, there is no way to get it into the cells, because insulin is not present to bind to its receptor. Again, in our healthy situation, blood glucose goes up. This pancreas releases insulin. Insulin binds to its receptor. And its first job is to insert the glucose transporter GLUT4 into the membrane. So glucose can diffuse into the cell.
In type 1 diabetes, there's no insulin, so GLUT4 does not get inserted into the membrane. And glucose in the blood stays high, and this is hyperglycemia. So this is why it's sort of one of the key symptoms of type 1 or of any diabetes is hyperglycemia.
Insulin replacement is the way of treating type 1 diabetes. Sometimes, the sulphonylurea drugs can work. They can help to get some insulin from remaining cells that may be able to secrete it, help to increase whatever insulin production is available. So what determines whether that's going to work in type 1 diabetes is the extent of damage to the pancreas.
And then our type 2 diabetes, which is caused by loss of function of the insulin receptor. this is later onset, usually adult onset. It can also occur in gestational-- during pregnancy in some women. So we have our increase in blood glucose after feeding. In this case, insulin is released. But it doesn't matter, because the receptor doesn't work properly. And so again GLUT4 is not inserted into the membrane, and glucose is high in the blood. We still have hyperglycemia, and the cells are not getting glucose.
So in both of these cases, the cells are starving. The cells are starving because they're not getting glucose, and they can't provide-- they can't make the energy that they need. So that's why sometimes people call this starvation in the midst of plenty. Because there's plenty of glucose, but cells can't use it in either case. But the reasons are different. In this case, it's because there's no insulin. In this case, it's because the insulin receptor's not working.
Different approaches to treating type 2 diabetes are-- so in some cases, you can do insulin replacement. So sometimes, the insulin receptor isn't working. It's almost as if the affinity has been reduced. So whereas when this person with type 2 diabetes was young, it only took a small amount of insulin to stimulate the receptor, as they got older, it takes more. So you can use insulin replacement or sulphonylureas to try to increase an insulin secretion from the pancreas, and sometimes that'll work.
But you can also use drugs that activate the downstream pathways, PPAR and AMPK, that are stimulated by glucose entering the cell, and that works quite well in type 2 diabetes. You don't need to do that in type 1, because if you just replace insulin, you basically GLUT4 to insert. But replacing insulin doesn't always do that in type 2 diabetes.
So again, the treatments reflect the differences in the underlying pathophysiology. But in all cases, you have to have lifestyle modifications where you reduce carbohydrate intake, and you manage food intake pretty closely. Now, what about glucagon and diabetes? Because what do you think might happen with glucagon?
Well, in type 1 diabetes, you could have high glucagon, because you have no insulin. So you might wind up with some high glucagon. Because insulin regulates glucagon levels. But it doesn't always happen that way, and glucagon regulation of diabetes is fairly complex.
So some people actually lose or reduce their glucagon in type 1 diabetes, but some people can have increased glucagon, which is why you'll see, sometimes, weight loss. Because they have a lot of glycolysis in type 1. Type 2 diabetes and glucagon is extremely complex.
Because there is insulin around, the glucagon levels can be kept actually kind of low. And then you wind up with hyperinsulinemia, and you can have weight gain, in fact, in type 2 diabetes sometimes. Sometimes, type 2, one of the risk factors for it is obesity. And it can contribute even more to obesity in that case. |
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So big problems with diabetes are hyperglycemia, and the really serious problem in type 1 diabetes is diabetic ketoacidosis, where the hyperglycemia is-- you're not able to get any of that glucose into the cells, so the cells are starving. So the liver, and fat cells, and muscle cells start to provide ketones and amino acids to the liver to try to provide some other glucose, which is no good, because there's still no insulin to get it into any cells. But the ketones keep the brain going, so that's important.
But this high levels of glucose in the blood result in glucose urea, sometimes osmotic diaresis, and often polydipsia polyuria. And the ketones are acids. And so the overproduction of ketones can lead to ketoacidosis, and this can lead to serious dehydration from the osmotic diuresis and confusion and problems with mental state from the acidosis. And it can be life-threatening.
In addition, insulin is required for plasma potassium concentration management. So potassium being taken up by cells is insulin-dependent. And so you can wind up hyperkalemic, which can, under the conditions of acidosis and dehydration, can have serious impacts on cardiovascular function. |
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And this just shows a little diagram of some of the things that can go on with diabetic ketoacidosis-- lack of insulin, gives you some GI upset, febrile illness. The breath will sometimes smell like Juicy Fruit gum. That's the ketones. They have kind of a fruity smell.
You'll have these Kussmaul respirations, which are these rapid deep respirations as you're trying to blow off carbon dioxide to get rid of the acid. So if you remember, the carbon dioxide, one of its roles in the blood is it creates the acid that's in blood. It is the major blood acid. And so when carbon dioxide levels get too high, you can go into acidosis, and one of the ways to try to get rid of that is with Kussmaul aspiration.
Extremely thirsty and dehydrated, tachycardia from the high-- the elevated potassium, low blood pressure, acidosis, blood sugar extremely high, polyuria, and this is a person who's sick and needs to be managed right away and pretty seriously. And what they need is water, insulin, and electrolytes. That's gets them back into good shape. And so that's DKA, one of the most serious diabetic complications that you will encounter in your medical practice. |
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• Diabetic patients using insulin can go into insulin shock in which they have a sudden, rapid decrease in blood sugar levels that can be life-threatening
• More common in Type I
• Associated with physical and emotional stress (sympathetic activation enhances the effect of the insulin). Sugar or glucagon can be given. |
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