What Is Gluconeogenesis? How Does Does It Control Blood Sugars?
What is gluconeogenesis? How does does it control blood sugars? by breaknutrition | Sep 12, 2017 | Ketogenic Diets | 8 comments Step into the low-carb world and soon enough youll hear the term GlucoNeoGenesis. GNG for short, is your bodys ability to construct glucose, a kind of sugar, out of molecules that arent glucose. It does this to ensure that, if you dont eat any carbs, the cells in your body that need glucose will still get enough of it. Its one reason why humans are so good at fasting or delaying death from starvation for weeks or months. We can meet our own need for glucose by producing it ourselves. What do I mean by cells in your body that need glucose? I mean a reliance on glucose to accomplish its basic physiological tasks over a long time maybe a lifetime. You then might ask, but is there a difference when meeting your glucose needs with GNG versus by eating carbs? Fair question. You could also ask although no one seems to is it better to meet your glucose needs through GNG than by eating carbs? Also a fair question I think but one people will most likely scoff at. These questions deserve more space than Im according them here, so theyll have to be wrestled with in a follow-up post. Background: why do we make our own glucose? As mentioned in the introduction, it helps us handle a lack of calories or carbohydrates but that can only be because at least some of our cells depend on glucose (or other monosaccharides ) to some significant degree. Most cells in your body do just fine using varying amounts of fatty acids, glucose, amino acids, lactate, ketones etc However, a few cell types well call obligate glucose users cant use any other fuel but glucose. Then there are what well call quasi obligate glucose users whose metabolisms are adapted to specialized fu Continue reading >>
Each Organ Has A Unique Metabolic Profile
The metabolic patterns of the brain, muscle, adipose tissue, kidney, and liver are strikingly different. Let us consider how these organs differ in their use of fuels to meet their energy needs: 1. Brain. Glucose is virtually the sole fuel for the human brain, except during prolonged starvation. The brain lacks fuel stores and hence requires a continuous supply of glucose. It consumes about 120 g daily, which corresponds to an energy input of about 420 kcal (1760 kJ), accounting for some 60% of the utilization of glucose by the whole body in the resting state. Much of the energy, estimates suggest from 60% to 70%, is used to power transport mechanisms that maintain the Na+-K+ membrane potential required for the transmission of the nerve impulses. The brain must also synthesize neurotransmitters and their receptors to propagate nerve impulses. Overall, glucose metabolism remains unchanged during mental activity, although local increases are detected when a subject performs certain tasks. Glucose is transported into brain cells by the glucose transporter GLUT3. This transporter has a low value of KM for glucose (1.6 mM), which means that it is saturated under most conditions. Thus, the brain is usually provided with a constant supply of glucose. Noninvasive 13C nuclear magnetic resonance measurements have shown that the concentration of glucose in the brain is about 1 mM when the plasma level is 4.7 mM (84.7 mg/dl), a normal value. Glycolysis slows down when the glucose level approaches the KM value of hexokinase (~50 μM), the enzyme that traps glucose in the cell (Section 16.1.1). This danger point is reached when the plasma-glucose level drops below about 2.2 mM (39.6 mg/dl) and thus approaches the KM value of GLUT3. Fatty acids do not serve as fuel for the brain, beca Continue reading >>
Chapter 20. Gluconeogenesis & The Control Of Blood Glucose
Chapter 20. Gluconeogenesis & the Control of Blood Glucose David A. Bender, PhD; Peter A. Mayes, PhD, DSc Bender DA, Mayes PA. Bender D.A., Mayes P.A. Bender, David A., and Peter A. Mayes.Chapter 20. Gluconeogenesis & the Control of Blood Glucose. In: Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil P. Murray R.K., Bender D.A., Botham K.M., Kennelly P.J., Rodwell V.W., Weil P Eds. Robert K. Murray, et al.eds. Harper's Illustrated Biochemistry, 29e New York, NY: McGraw-Hill; 2012. Accessed April 05, 2018. Bender DA, Mayes PA. Bender D.A., Mayes P.A. Bender, David A., and Peter A. Mayes.. "Chapter 20. Gluconeogenesis & the Control of Blood Glucose." Harper's Illustrated Biochemistry, 29e Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW, Weil P. Murray R.K., Bender D.A., Botham K.M., Kennelly P.J., Rodwell V.W., Weil P Eds. Robert K. Murray, et al. New York, NY: McGraw-Hill, 2012, After studying this chapter, you should be able to: Explain the importance of gluconeogenesis in glucose homeostasis. Describe the pathway of gluconeogenesis, how irreversible enzymes of glycolysis are bypassed, and how glycolysis and gluconeogenesis are regulated reciprocally. Explain how plasma glucose concentration is maintained within narrow limits in the fed and fasting states. Gluconeogenesis is the process of synthesizing glucose or glycogen from noncarbohydrate precursors. The major substrates are the glucogenic amino acids ( Chapter 29 ), lactate, glycerol, and propionate. Liver and kidney are the major gluconeogenic tissues; the kidney may contribute up to 40% of total glucose synthesis in the fasting state and more in starvation. The key gluconeogenic enzymes are expressed in the small intestine, but it is unclear whether or not there is significant glucose produ Continue reading >>
Why Can't Animals Turn Fatty Acids Into Glucose?
Animals can’t turn fatty acids into glucose because fatty acids are metabolized 2 carbons at a time into the acetyl units of acetyl-CoA, and we have no enzymes to convert acetyl-CoA into pyruvate or any other metabolite in the gluconeogenesis pathway. Essentially, as I tell my students, the pyruvate dehydrogenase reaction is crossing the Rubicon: once it’s done, you can’t go back. The oxidative decarboxylation of pyruvate is irreversible, and there is no reverse bypass in animal cells. Acetyl-CoA of course enters the Krebs cycle, which ends with oxaloacetate, which is on the gluconeogenic pathway, but the Krebs cycle starts by reacting acetyl-CoA with OAA, and thus OAA production is balanced by OAA consumption: there is no net conversion of acetyl-CoA into OAA. Plants, fungi, and some microbes do have a way to do this: a bypass in the Krebs cycle called the glyoxylate cycle. Isocitrate, instead of being oxidized to alpha-ketoglutarate, is split into succinate and glyoxylate (HC(O)-COO), by an enzyme called isocitrate lyase. The glyoxylate reacts with another acetyl-CoA to form malate, in a reaction catalyzed by malate synthase. The succinate and malate both undergo their usual reactions in the Krebs cycle, resulting in the formation of two oxaloacetates. Thus the cell achieves a net conversion of two acetyl-CoA into OAA, and the OAA can be used for gluconeogenesis. This allows, among other things, plant seeds to store energy and carbon in the form of fats, but use them to create glucose and thus cellulose for cell walls when the seed germinates into a sprout. If we had isocitrate lyase and malate synthase, we could do this trick to, and diabetics wouldn’t have to worry about ketoacidosis. But, we don’t. Edit: for the sake of accuracy, I should mention that fat Continue reading >>
Lecture 22: Specialised Metabolism Of Differentiated Tissues.
Lecture 22: Specialised metabolism of differentiated tissues. Click here to download the printed handout sheets for lectures 21 & 22. Differentiated tissues have specialised biochemical functions. Individual enzyme activities may be markedly raised or lowered in particular organs, or coded by tissue-specific genes with unique regulatory properties. Although the absolute enzyme activities may differ by two or three orders of magnitude in different tissues, groups of related enzymes often maintain constant proportions to one another. This suggests that they are controlled as a unit, and their genes may share regulatory motifs. Differentiated tissues cooperate with one another, but this may involve doing opposite things at the same time: e.g. Cori cycle between liver and skeletal muscles, ketone metabolism, amino acid metabolism in starvation. Lactate is normally produced only by red blood cells and type 2B muscle fibres, which have very few mitochondria. It is almost all recycled into glucose by the liver, and the overall process is known as the Cori cycle. Type 2B muscle fibres are only recruited during very strenuous exercise, when blood lactate concentrations may rise sharply. Under these conditions some of the surplus lactate may be oxidised by highly aerobic tissues, such as heart muscle. Ketone bodies (acetoacetate, hydroxybutyrate & acetone) are produced in the liver during periods of rapid fat oxidation, when the rate of fat breakdown exceeds the capacity of the Krebs cycle to process the resulting acetyl CoA. Acetone is produced by the non-enzymic decarboxylation of acetoacetate and may sometimes be smelt on the breath in acute diabetes. Hydroxybutyrate is an "honorary" ketone, because it is chemically related to acetoacetate, but it is in fact a secondary alcoh Continue reading >>
Energy Metabolism In The Liver
Go to: Introduction The liver is a key metabolic organ which governs body energy metabolism. It acts as a hub to metabolically connect to various tissues, including skeletal muscle and adipose tissue. Food is digested in the gastrointestinal (GI) tract, and glucose, fatty acids, and amino acids are absorbed into the bloodstream and transported to the liver through the portal vein circulation system. In the postprandial state, glucose is condensed into glycogen and/or converted into fatty acids or amino acids in the liver. In hepatocytes, free fatty acids are esterified with glycerol-3-phosphate to generate triacylglycerol (TAG). TAG is stored in lipid droplets in hepatocytes or secreted into the circulation as very low-density lipoprotein (VLDL) particles. Amino acids are metabolized to provide energy or used to synthesize proteins, glucose, and/or other bioactive molecules. In the fasted state or during exercise, fuel substrates (e.g. glucose and TAG) are released from the liver into the circulation and metabolized by muscle, adipose tissue, and other extrahepatic tissues. Adipose tissue produces and releases nonesterified fatty acids (NEFAs) and glycerol via lipolysis. Muscle breaks down glycogen and proteins and releases lactate and alanine. Alanine, lactate, and glycerol are delivered to the liver and used as precursors to synthesize glucose (gluconeogenesis). NEFAs are oxidized in hepatic mitochondria through fatty acid β oxidation and generate ketone bodies (ketogenesis). Liver-generated glucose and ketone bodies provide essential metabolic fuels for extrahepatic tissues during starvation and exercise. Liver energy metabolism is tightly controlled. Multiple nutrient, hormonal, and neuronal signals have been identified to regulate glucose, lipid, and amino acid me Continue reading >>
Not to be confused with Glycogenesis or Glyceroneogenesis. Simplified Gluconeogenesis Pathway Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. From breakdown of proteins, these substrates include glucogenic amino acids (although not ketogenic amino acids); from breakdown of lipids (such as triglycerides), they include glycerol (although not fatty acids); and from other steps in metabolism they include pyruvate and lactate. Gluconeogenesis is one of several main mechanisms used by humans and many other animals to maintain blood glucose levels, avoiding low levels (hypoglycemia). Other means include the degradation of glycogen (glycogenolysis) and fatty acid catabolism. Gluconeogenesis is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis takes place mainly in the liver and, to a lesser extent, in the cortex of the kidneys. In ruminants, this tends to be a continuous process. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise. The process is highly endergonic until it is coupled to the hydrolysis of ATP or GTP, effectively making the process exergonic. For example, the pathway leading from pyruvate to glucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. Gluconeogenesis is often associated with ketosis. Gluconeogenesis is also a target of therapy for type 2 diabetes, such as the antidiabetic drug, metformin, which inhibits glucose formation and stimulates glucose uptake by cells. In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs Continue reading >>
How Does The Body Adapt To Starvation?
- [Instructor] In this video, I want to explore the question of how does our body adapt to periods of prolonged starvation. So in order to answer this question, I actually think it's helpful to remind ourselves first of a golden rule of homeostasis inside of our body. So in order to survive, remember that our body must be able to maintain proper blood glucose levels. I'm gonna go ahead and write we must be able to maintain glucose levels in our blood, and this is important even in periods of prolonged starvation, because it turns out that we need to maintain glucose levels above a certain concentration in order to survive, even if that concentration is lower than normal. And this of course brings up the question, well, how does our body maintain blood glucose levels? So let's go ahead and answer this question by starting off small. Let's say we have a mini case of starvation, let's say three or four hours after a meal. Your blood glucose levels begin to drop, and so what does your body do to resolve that? Well, at this point, it has a quick and easy solution. It turns to its glycogen stores in the liver. Remember that our body stores up these strings of glucose inside of our body so that we can easily pump it back into the blood when we're not eating. But unfortunately humans only have enough glycogen stores to last us about a day, so after a day of starvation, our body's pretty much reliant exclusively on the metabolic pathways involved in gluconeogenesis, which if you remember is the pathway by which we produce new or neo glucose. And we produce this glucose from non-carbohydrate precursor molecules. So let's think about what else we have in our body. Remember that our other two major storage fuels are fats, and we usually think about fatty acids containing most of th Continue reading >>
Principles Of Biochemistry/gluconeogenesis And Glycogenesis
Gluconeogenesis (abbreviated GNG) is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids. It is one of the two main mechanisms humans and many other animals use to keep blood glucose levels from dropping too low (hypoglycemia). The other means of maintaining blood glucose levels is through the degradation of glycogen (glycogenolysis). Gluconeogenesis is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In animals, gluconeogenesis takes place mainly in the liver and, to a lesser extent, in the cortex of kidneys. This process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise and is highly endergonic. For example, the pathway leading from phosphoenolpyruvate to glucose-6-phosphate requires 6 molecules of ATP. Gluconeogenesis is often associated with ketosis. Gluconeogenesis is also a target of therapy for type II diabetes, such as metformin, which inhibits glucose formation and stimulates glucose uptake by cells. Lactate is transported back to the liver where it is converted into pyruvate by the Cori cycle using the enzyme lactate dehydrogenase. Pyruvate, the first designated substrate of the gluconeogenic pathway, can then be used to generate glucose. All citric acid cycle intermediates, through conversion to oxaloacetate, amino acids other than lysine or leucine, and glycerol can also function as substrates for gluconeogenesis.Transamination or deamination of amino acids facilitates entering of their carbon skeleton into the cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle. Whether fatty acids can be converted into glucose in animals has been a longst Continue reading >>
There are three groups of molecules that form the core building blocks and fuel substrates in the body: carbohydrates (glucose and other sugars); proteins and their constituent amino acids; and lipids and their constituent fatty acids. The biochemical processes that allow these molecules to be synthesized and stored (anabolism) or broken down to generate energy (catabolism) are referred to as metabolic pathways. Glucose metabolism involves the anabolic pathways of gluconeogenesis and glycogenesis, and the catabolic pathways of glycogenolysis and glycolysis. Lipid metabolism involves the anabolic pathways of fatty acid synthesis and lipogenesis and the catabolic pathways of lipolysis and fatty acid oxidation. Protein metabolism involves the anabolic pathways of amino acid synthesis and protein synthesis and the catabolic pathways of proteolysis and amino acid oxidation. Under conditions when glucose levels inside the cell are low (such as fasting, sustained exercise, starvation or diabetes), lipid and protein catabolism includes the synthesis (ketogenesis) and utilization (ketolysis) of ketone bodies. The end products of glycolysis, fatty acid oxidation, amino acid oxidation and ketone body degradation can be oxidised to carbon dioxide and water via the sequential actions of the tricarboxylic acid cycle and oxidative phosphorylation, generating many molecules of the high energy substrate adenosine triphosphate (ATP). Interplay between metabolic pathways The interplay between glucose metabolism, lipid metabolism, ketone body metabolism and protein and amino acid metabolism is summarized in Figure 1. Amino acids can be a source of glucose synthesis as well as energy production and excess glucose that is not required for energy production can be stored as glycogen or metabo Continue reading >>
Do Fat And Protein Turn Into Glucose?
Sandi Busch received a Bachelor of Arts in psychology, then pursued training in nursing and nutrition. She taught families to plan and prepare special diets, worked as a therapeutic support specialist, and now writes about her favorite topics nutrition, food, families and parenting for hospitals and trade magazines. Glucose keeps you energized.Photo Credit: Ridofranz/iStock/Getty Images When blood glucose gets low, your energy plummets and you may find it hard to concentrate. Your body can temporarily fill the gap by drawing on glucose stored in your liver, but those supplies are limited. When they run out, your body can produce glucose from fats and proteins. Fats are good for backup energy, but your body doesnt like to divert protein into energy due to its other vital functions. The best way to keep your body fueled is to consume the right amount of fats, proteins and carbs. Carbohydrates consist of molecules of sugar, which your body digests into glucose and uses for energy. When youre short on carbs, glucose can be created from fat and protein in a process called gluconeogenesis. Gluconeogenesis takes place mostly in your liver, which also has the job of maintaining a steady amount of glucose in your blood. If blood sugar drops too low due to problems in the liver, your kidneys can boost blood sugar by converting the amino acid glutamine into glucose. The saturated and unsaturated fats in your diet consist of two substances bound together: glycerol and fatty acids. During digestion, they're separated, and each one follows a different path. Glycerol is easily metabolized and used to make glucose. Fatty acids are carried to tissues throughout your body, where they help build cell walls, produce hormones and digest fat-soluble nutrients. Fatty acids can be converted i Continue reading >>
Nutr 251 Exam 2 Review (minus Lipids)
Briefly outline the process of digestion and absorption of beef protein. 2) Stomach-HCL denature proteins, pepsin is activated to further break down proteins to smaller polypeptides 3) Small intestine-90% of digestion of proteins occurs here, pancreatic/enzymes break polypeptides down further to amino acids 4) Absorbed by active transport, travels to the portal vein and then to the liver 4 functions of essential amino acids other than protein synthesis 1) Act as precursors (ex- tryptophan can be converted to serotonin) 2) Used for fuel, but to lesser degree than fatty acids and glucose 3) Converted to fatty acids and put into fat cell storage when energy in is greater than energy out (there is too much protein being converted to fat) 4) Carbon portion can be converted to glucose in a process called gluconeogenesis which happens in starvation Chemical structure of protein vs. complex carbohydrates -A protein is made of long chains of amino acids linked together by peptide bonds -Complex carbohydrates are made of glucose units in straight or branched chains How is the chemical structure of a monosaccharide different from that of an amino acid? 1) Collagen- the framework for bone/teeth structures 2) Regulate fluid balance- R groups are charged and can attract water 6) Hormones (insulin and gastrin are protein hormones) What happens to the ammonia and urea as an end product of this process? Deamination- amino acids are stripped of their nitrogen containing amino groups, first step when amino acids are broken down [Products of deamination are ammonia and a keto acid (the carbon part of the amino acids)] Ammonia combines with CO2 and is excreted as urea How many essential amino acids are in the diet? Describe the sources of amino acids for the "amino acid pool." Why must thi Continue reading >>
We Really Can Make Glucose From Fatty Acids After All! O Textbook, How Thy Biochemistry Hast Deceived Me!
Biochemistry textbooks generally tell us that we can’t turn fatty acids into glucose. For example, on page 634 of the 2006 and 2008 editions of Biochemistry by Berg, Tymoczko, and Stryer, we find the following: Animals Cannot Convert Fatty Acids to Glucose It is important to note that animals are unable to effect the net synthesis of glucose from fatty acids. Specficially, acetyl CoA cannot be converted into pyruvate or oxaloacetate in animals. In fact this is so important that it should be written in italics and have its own bold heading! But it’s not quite right. Making glucose from fatty acids is low-paying work. It’s not the type of alchemy that would allow us to build imperial palaces out of sugar cubes or offer hourly sweet sacrifices upon the altar of the glorious god of glucose (God forbid!). But it can be done, and it’ll help pay the bills when times are tight. All Aboard the Acetyl CoA! When we’re running primarily on fatty acids, our livers break the bulk of these fatty acids down into two-carbon units called acetate. When acetate hangs out all by its lonesome like it does in a bottle of vinegar, it’s called acetic acid and it gives vinegar its characteristic smell. Our livers aren’t bottles of vinegar, however, and they do things a bit differently. They have a little shuttle called coenzyme A, or “CoA” for short, that carries acetate wherever it needs to go. When the acetate passenger is loaded onto the CoA shuttle, we refer to the whole shebang as acetyl CoA. As acetyl CoA moves its caboose along the biochemical railway, it eventually reaches a crossroads where it has to decide whether to enter the Land of Ketogenesis or traverse the TCA cycle. The Land of Ketogenesis is a quite magical place to which we’ll return in a few moments, but n Continue reading >>
Ketone Bodies Formed In The Liver Are Exported To Other Organs
Ketone Bodies In human beings and most other mammals, acetyl-CoA formed in the liver during oxidation of fatty acids may enter the citric acid cycle (stage 2 of Fig. 16-7) or it may be converted to the "ketone bodies" acetoacetate, D-β-hydroxybutyrate, and acetone for export to other tissues. (The term "bodies" is a historical artifact; these compounds are soluble in blood and urine.) Acetone, produced in smaller quantities than the other ketone bodies, is exhaled. Acetoacetate and D-β-hydroxybutyrate are transported by the blood to the extrahepatic tissues, where they are oxidized via the citric acid cycle to provide much of the energy required by tissues such as skeletal and heart muscle and the renal cortex. The brain, which normally prefers glucose as a fuel, can adapt to the use of acetoacetate or D-β-hydroxybutyrate under starvation conditions, when glucose is unavailable. A major determinant of the pathway taken by acetyl-CoA in liver mitochondria is the availability of oxaloacetate to initiate entry of acetyl-CoA into the citric acid cycle. Under some circumstances (such as starvation) oxaloacetate is drawn out of the citric acid cycle for use in synthesizing glucose. When the oxaloacetate concentration is very low, little acetyl-CoA enters the cycle, and ketone body formation is favored. The production and export of ketone bodies from the liver to extrahepatic tissues allows continued oxidation of fatty acids in the liver when acetyl-CoA is not being oxidized via the citric acid cycle. Overproduction of ketone bodies can occur in conditions of severe starvation and in uncontrolled diabetes. The first step in formation of acetoacetate in the liver (Fig. 16-16) is the enzymatic condensation of two molecules of acetyl-CoA, catalyzed by thiolase; this is simply Continue reading >>
Biochemistry 12: Diabetes
These are notes from lecture 12 of Harvard Extension’s biochemistry class. starvation The first priority is to provide enough glucose to tissues that are solely dependent on glucose – the brain and red blood cells. It was long thought that fatty acids cannot be converted to glucose, though there is now some evidence that this conversion may occur under some circumstances. Amino acids are a poor fuel source because they’re not stored (no equivalent of glycogen or triacylglycerol), so you’d just be catabolizing proteins you need to live. Starvation occurs in stages. Exogenous glucose can be used for the first 4 hours after a meal. Then glycogen reserves kick in from hour 4 to hour ~28. As the glycogen mobilization peaks around hour 8, gluconeogenesis begins, and can continue full steam for about 2 days, after which it dampens slightly but can continue for up to 40 days at a lower level. During days 2-24, the kidney begins gluconeogenesis and the brain begins using ketone bodies. In Stage V (days 24-40), the liver and kidney continue to do gluconeogenesis and the brain relies solely on ketone bodies. Muscle protein degradation is about 75 g/day at day 3 of starvation, 20 g/day at day 40 of starvation. The initial sources of proteins are rapid turnover proteins from the intestinal epithelium and secreted pancreatic proteins. After three days, the liver forms ketone bodies (from fatty acid catabolism) which become the predominant energy source, preventing additional protein degradation. After an average of 40 days (more if you have more adipose tissue), TAG stores are depleted, and protein degradation increases again, impacting heart, liver and kidney function and leading ultimately to death. See [Berg 2002] for an overview of all this, esp. muscle protein degradatio Continue reading >>