In the next step, DHAP is converted to DGLYAL3P in a reaction catalyzed by the enzyme triosephosphate isomerase. At this point, the six carbon glucose molecule has been broken down to two units of three carbons each - D-GLYAL3P. From this point forward each reaction of glycolysis contains two of each molecule.

Reaction 5 is fairly readily reversible in cells. The apparent reason for the enzyme evolving in this way is that the mechanism of the reaction produces an unstable, toxic intermediate Figure 6. With the reaction proceeding as rapidly as it does, there is less chance of the intermediate escaping and causing damage in the cell.

In this reaction, D-GLYAL3P is oxidized in the only oxidation step of glycolysis catalyzed by the enzyme glyceraldehyde phosphate dehydrogenase, an oxidoreductase.

The aldehyde in this reaction is oxidized, then linked to a phosphate to make an ester - D-1,3-bisphospho-glycerate D- 1,3BPG. Note here that ATP energy was not required to put the phosphate onto the oxidized D-GLYAL3P.

The reason for this is because the energy provided by the oxidation reaction is sufficient for adding the phosphate. The two phosphates in the tiny 1,3BPG molecule repel each other and give the molecule high potential energy.

This energy is utilized by the enzyme phosphoglycerate kinase another transferase to phosphorylate ADP and make ATP, as well as the product, 3-phosphoglycerate 3-PG.

This is an example of a substrate-level phosphorylation. Such mechanisms for making ATP require an intermediate with a high enough energy to phosphorylate ADP to make ATP.

Though there are a few substrate level phosphorylations in cells including another one at the end of glycolysis , the vast major of ATP is made by oxidative phosphorylation in the mitochondria in animals.

In addition to oxidative phosphorylation, plants also make ATP by photophosphorylation in their chloroplasts. Since there are two 1,3 BPGs produced for every glucose, the two ATPs produced in this reaction replenish the two ATPs used to start the cycle and the net ATP count at this point of the pathway is zero.

Conversion of the 3-PG intermediate to 2-PG 2- phosphoglycerate occurs by an important mechanism. An intermediate in this readily reversible reaction catalyzed by phosphoglycerate mutase - a mutase enzyme is 2,3-BPG.

This intermediate, which is stable, is released with low frequency by the enzyme instead of being con- Figure 6. The molecule can also be made from 1,3-BPG as a product of a reaction catalyzed by bisphophglycerate mutase Figure 6.

Cells which are metabolizing glucose rapidly release more 2,3-BPG and, as a result, get more oxygen, supporting their needs. Notably, cells which are metabolizing rapidly are using oxygen more rapidly and are more likely to be deficient in it.

The reaction is readily reversible, but with PEP, the cell has one of its highest energy molecules and that is important for the next reaction. Conversion of PEP to pyruvate by pyruvate kinase is the second substrate level phosphorylation of glycolysis, creating ATP.

Consequently, this energy is lost as heat. If you wonder why you get hot when you exercise, the heat produced in the breakdown of glucose is a prime contributor and the pyruvate kinase reaction is a major source. Pyruvate kinase is the third and last enzyme of glycolysis that is regulated see below.

The primary reason this is the case is to be able to prevent this reaction from occurring when cells are making PEP while going through gluconeogenesis see more HERE. Though glycolysis is a pathway focused on the metabolism of glucose and fructose, the fact that other sugars can be readily metabolized into glucose means that glycolysis can be used for extracting energy from them as well.

Galactose is a good example. It is commonly produced in the produced in the body as a result of hydrolysis of lactose, catalyzed by the enzyme known as lactase Figure 6.

Deficiency of lactase is the cause of lactose intolerance. Galactose begins preparation for entry into glycolysis by being converted to galactose phosphate catalyzed by galactokinase - Figure 6.

Galactosephosphate swaps with glucosephosphate from UDP-glucose to make UDP-galactose Figure 6. An epimerase converts UDPgalactose back to UDP-glucose and the cycle is complete. Each turn of the cycle thus takes in one galactosephosphate and releases one glucosephosphate.

Deficiency of galactose conversion enzymes results in accumulation of galactose from breakdown of lactose.

Excess galactose is converted to galactitol, a sugar alcohol. Galactitol in the human eye lens causes it to absorb water and this may be a factor in formation of cataracts. First, it can be phosphorylated to fructosephosphate by hexokinase. A more interesting alternate entry point is that shown in Figure 6.

Phosphorylation of fructose by fructokinase produces fructosephosphate and cleavage of that by fructose phosphate aldolase yields DHAP and glyceraldehyde. Phosphorylation of glyceraldehyde by triose kinase yields GLYAL3P. This alternative entry means for fructose may have important implications because DHAP and GLYAL3P are introduced into the glycolysis pathway while bypassing PFK-1 regulation.

Some have proposed this may be important when considering metabolism of high fructose corn syrup, since it forces production of pyruvate, a precursor of acetyl-CoA, which is itself a precursor of fatty acids when ATP levels are high. Mannose can also be metabolized in glycolysis.

In this case, it enters via fructose by the following two-step process - 1 phosphoryla- Figure 6. Glycerol is an important molecule for the synthesis of fats, glycerophospholipids, and other membrane lipids.

Most commonly it is made into glycerol phosphate Figure 6. The relevant intermediate in these pathways both for producing and for using glycerolphosphate is DHAP.

The enzyme glycerolphosphate dehydrogenase reversibly converts glycerol phosphate into DHAP Figure 6. In the reverse reaction, production of glycerol phosphate from DHAP, of course, requires electrons from NADH for the reduction.

Both glycolysis and gluconeogenesis are sources DHAP, meaning when the cell needs glycerol- 3-phosphate that it can use sugars glucose, fructose, mannose, or galactose as sources in glycolysis. For gluconeogenesis, sources include pyruvate, alanine and Figure 6.

All of the intermediates of the citric acid cycle and glyoxylate cycle can be converted ultimately to oxaloacetate, which is a gluconeogenesis intermediate, as well.

It is worth noting that animals are unable to use fatty acids as materials for gluconeogenesis in net amounts, but they can, in fact, use glycerol in both glycolysis and gluconeogenesis. It is the only part of the fat molecule that can be so used. As noted, pyruvate produced in glycolysis can be oxidized to acetyl-CoA, which is itself oxidized in the citric acid cycle to carbon dioxide.

That is not the only metabolic fate of pyruvate, though Figure 6. Pyruvate in animals can also be reduced to lactate by adding electrons from NADH Figure 6. In the absence of oxygen, however, NADH cannot be converted to Figure 6. Thus, fermentation of pyruvate is essential to keep glycolysis operating when oxygen is limiting.

It is also for these reasons that brewing of beer using yeast involves depletion of oxygen and muscles low in oxygen produce lactic acid animals. Pyruvate is a precursor of alanine which can be easily synthesized by transfer of a nitrogen from an amine donor, such as glutamic acid. Pyruvate can also be converted into oxaloacetate by carboxylation in the process of gluconeogenesis see below.

The enzymes involved in pyruvate metabolism include pyruvate dehydrogenase makes acetyl-CoA , lactate dehydrogenase makes lactate , transaminases make alanine , pyruvate carboxylase makes ox- Figure 6. When oxygen is absent, pyruvate is converted to lactate animals or ethanol bacteria and yeast.

When oxygen is present, pyruvate is converted to acetyl-CoA. Not shown - Pyruvate transamination to alanine or carboxylation to form oxaloacetate. aloacetate , and pyruvate decarboxylase a part of pyruvate dehydrogenase that makes acetaldehyde in bacteria and yeast.

Catalytic action and regulation of the pyruvate dehydrogenase complex is discussed in the section on the citric acid cycle HERE. The anabolic counterpart to glycolysis is gluconeogenesis Figure 6. In seven of the eleven reactions of gluconeogenesis starting from pyruvate , the same enzymes are used as in glycolysis, but the reaction directions are reversed.

Two of the enzymes pyruvate carboxylase and PEP carboxykinase - PEPCK catalyze reactions that bypass pyruvate kinase. F1,6BPase bypasses PFK-1 and G6Pase bypasses hexokinase. Notably, pyruvate carboxylase and G6Pase are found in the mitochondria and endoplasmic reticulum, respectively, whereas the other two are found in the cytoplasm along with all of the enzymes of glycolysis.

Biotin An important coenzyme used by pyruvate carboxylase is biotin Figure 6. Biotin is commonly used by carboxylases to carry CO2 to incorporate into the substrate. Also known as vitamin H, biotin is a water soluble B vitamin B7 needed for many metabolic processes, including fatty acid synthesis, gluconeogenesis, and amino acid metabolism.

Deficiency of the vitamin is rare, since it is readily produced by gut Gluconeogenesis and glycolysis. Only the enzymes differing in gluconeogenesis are shown Image by Aleia Kim teria. There are many claims of advantages of taking biotin supplements, but there is no strong indication of benefits in most cases.

Deficiencies are associated with inborn genetic errors, alcoholism, burn patients, and people who have had a gastrectomy. Some pregnant and lactating women may have reduced levels due to increased biotin catabolism.

All of the enzymes of glycolysis and nine of the eleven enzymes of gluconeogenesis are all in the cytoplasm, necessitating a coordinated means of controlling them. Cells generally need to minimize the extent to which paired anabolic and catabolic pathways are occurring simultaneously, lest they produce a futile cycle, resulting in wasted energy with no tangible product except heat.

The mechanisms of controlling these pathways have opposite effects on catabolic and anabolic processes. This method of control is called reciprocal regulation see above.

Reciprocal regulation is a coordinated means of simultaneously controlling metabolic pathways that do opposite things. Reciprocal allosteric effects For example, in glycolysis, the enzyme known as phosphofructokinase PFK-1 is allosterically activated by AMP and a molecule known as F2,6BP Figure 6.

The corresponding enzyme from gluconeogenesis catalyzing a reversal of the glycolysis reaction is known as F1,6BPase. F1,6BPase is inhibited by both AMP and F2,6BP. In glycogen metabolism, the enzymes phosphorylase kinase and glycogen phosphorylase catalyze reactions important for the breakdown of glycogen.

The enzyme glycogen synthase catalyzes the synthesis of glyco- Directional velocity Inverts with reciprocity If glycolysis is flowing Glucose synthesis awaits But when the latter is a-going Sugar breakdown then abates Figure 6.

Each of these enzymes is, at least partly, regulated by attachment and removal of phosphate. Phosphorylation of phosphorylase kinase and glycogen phosphorylase has the effect of making them more active, whereas phosphorylation of glycogen synthase makes it less active.

Conversely, dephosphorylation has the reverse effects on these enzymes - phosphorylase kinase and glycogen phosphorylase become less active and glycogen synthase becomes more active.

The advantage of reciprocal regulation schemes is that they are very efficient. Further, its simplicity ensures that when one pathway is turned on, the other is turned off.

A simple futile cycle is shown on Figure 6. If unregulated, the cyclic pathway in the figure shown in black will make ATP in creating pyruvate from PEP and will use ATP to make oxaloacetate from pyruvate. It will also use GTP to make PEP from oxaloacetate.

Thus, each turn of the cycle will make one ATP, use one ATP and use one GTP for a net loss of energy. The process will start with pyruvate and end with pyruvate, so there is no net production of molecules.

see HERE for one physiological use of a futile cycle. Besides reciprocal regulation, other mechanisms help control gluconeogenesis. First, PEPCK is controlled largely at the level of synthesis.

Overexpression of PEPCK stimulated by glucagon, glucocorticoid hormones, and cAMP and inhibited by insulin produces symptoms of diabetes. Pyruvate carboxylase is sequestered in the mitochondrion one means of regulation Figure 6.

Acetyl-CoA concentrations increase as the citric acid cycle activity decreases. Glucose phosphatase is present in low concentrations in many tissues, but is found most abundantly and importantly in the major gluconeogenic organs — the liver and kidney cortex. Control of glycolysis and gluconeogenesis is unusual for metabolic pathways, in that regulation occurs at multiple points.

For glycolysis, this involves three enzymes:. Regulation of hexokinase is the simplest of these. The enzyme is unusual in being inhibited by its product, glucosephosphate. This ensures when glycolysis is slowing down hexokinase is also slowing down to reduce feeding the pathway.

It might also seem odd that pyruvate kinase, the last enzyme in the pathway, is regulated Figure 6. Pyruvate kinase catalyzes the most energetically rich reaction of glycolysis. In other words, it takes two enzymes, two reactions, and two triphosphates ATP and GTP to go from one pyruvate back to one PEP in gluconeogenesis.

When cells are needing to make glu- igure 6. Consequently, pyruvate kinase must be inhibited during gluconeogenesis or a futile cycle will occur and no glucose will be made.

Another interesting control mechanism called feedforward activation involves pyruvate kinase. Pyruvate kinase is activated allosterically by the glycolysis intermediate, F1,6BP. This molecule is a product of the PFK-1 reaction and a substrate for the aldolase reaction.

When this happens, some of the excess F1,6BP binds to pyruvate kinase, which activates and jump- Figure 6. As a consequence, the concentrations of GLYAL3P and DHAP fall, helping to pull the aldolase reaction forward.

PFK-1 has a complex regulation scheme. First, it is reciprocally regulated relative to F1,6BPase by three molecules. F2,6BP activates PFK-1 and inhibits F1,6BPase. PFK-1 is also allosterically activated by AMP, whereas F1,6BPase is inhibited. On the other hand, citrate inhibits PFK-1, but activates F1,6BPase.

PFK-1 is also inhibited by ATP and is exquisitely sensitive to proton concentration, easily losing activity when the pH drops only slightly. The root of this conundrum is that PFK-1 has two ATP binding sites - one at an allosteric site that binds ATP relatively inefficiently and one that the active site that binds ATP with high affinity.

Thus, only when ATP concentration is high is binding at the allosteric site favored and only then can ATP turn off the enzyme. Regulation of PFK-1 by F2,6BP is simple at the PFK-1 level, but more complicated at the level of synthesis of F2,6BP. Instead, it is made from fructosephosphate and ATP by the enzyme known as phosphofructokinase-2 PFK- 2 - Figure 6.

With respect to energy, the liver and muscles act complementarily. The liver is the major or- Figure 6.

Muscles are major users of glucose to make ATP. Actively exercising muscles use oxygen faster than the blood can deliver it. As a consequence, the muscles go anaerobic and produce lactate. This lactate is of no use to muscle cells, so they dump it into the blood. Lactate travels in the blood to the liver, which takes it up and reoxidizes it back to pyruvate, catalyzed by the enzyme lactate dehydrogenase Figure 6.

Pyruvate in the liver is then converted to glucose by gluconeogenesis. The glucose thus made by the liver is dumped into the bloodstream where it is taken up by muscles and used for energy, completing the important intercellular pathway known as the Cori cycle.

The glucose alanine cycle also known as the Cahill Cycle , has been described as the amine equivalent of the Cori cycle Figure 6. The Cori cycle, of course, exports lac- Figure 6.

The liver, in turn, converts lactate to glucose, which it ships back to the muscles via the bloodstream. The Cori Cycle is an essential source of glucose energy for muscles during periods of exercise when oxygen is used faster than it can be delivered.

In the glucose-alanine cycle, cells are generating toxic amines and must export them. This is accomplished by transaminating pyruvate the product of glycolysis to produce the amino acid alanine. The glucose-alanine process requires the enzyme alanine aminotransferase, which is found in muscles, liver, and intestines.

Alanine is exported in the process to the blood and picked up by the liver, which deaminates it to release the amine for synthesis of urea and excretion.

The pyruvate left over after the transamination is a substrate for gluconeogenesis. Glucose produced in the liver is then exported to the blood for use by cells, thus completing the cycle.

Sugars are metabolized rapidly in the body and that is one of the primary reasons they are used. Managing levels of glucose in the body is very important - too much leads to complications related to diabetes and too little gives rise to hypoglycemia low blood sugar.

Sugars in the body are maintained by three processes - 1 diet; 2 synthesis gluconeogenesis ; and 3 storage. The storage forms of sugars are, of course, the polysaccharides and their metabolism is our next topic of discussion. The energy needs of a plant are much less dynamic than those of animals.

Muscular contraction, nervous systems, and information processing in the brain require large amounts of quick energy. Because of this, the polysaccharides stored in plants are somewhat less complicated than those of animals.

Plants store glucose for energy in the form of amylose Figure 6. These structures differ in that cellulose contains glucose units solely joined by β-1,4 bonds, whereas amylose has only α-1,4 bonds and amylopectin has α-1,4 and α-1,6 bonds. Animals store glucose primarily in liver and muscle in the form of a compound related to amylopectin known as glycogen.

The structural differences between glycogen and amylopectin are solely due to the frequency of the α-1,6 branches of glucoses. In glycogen they occur about every 10 residues instead of every , as in amylopectin Figure 6.

Glycogen provides an additional source of glucose besides that produced via gluconeogenesis. Because glycogen contains so many glucoses, it acts like a battery backup for the body, providing a quick source of glucose when needed and providing a place to store excess glucose when glucose concentrations in the blood rise.

The branching of glycogen is an important feature of the molecule metabolically as well. Since glycogen is broken down from the "ends" of the molecule, more branches translate to more ends, and more glucose that can be released at once.

Just as in gluconeogenesis, the cell has a separate mechanism for glycogen synthesis that is distinct from glycogen breakdown. As noted previously, this allows the cell to separately control the reactions, avoiding futile cycles, and enabling a process to occur efficiently synthesis of glycogen that would not occur if Figure 6.

Breakdown of glycogen involves 1 release of glucosephosphate G1P , 2 rearranging the remaining glycogen as necessary to permit continued breakdown, and 3 conversion of G1P to G6P for further metabolism. G6P can be 1 used in glycolysis, 2 converted to glucose by gluconeogenesis, or 3 oxidized in the pentose phosphate pathway.

Glycogen phosphorylase sometimes simply called phosphorylase catalyzes breakdown of glycogen into glucose Phosphate G1P - Figure 6. The reaction that produces G1P from glycogen is a phosphorolysis, not a hydrolysis reaction.

The distinction is that hydrolysis reactions use water to cleave bigger molecules into smaller ones, but phosphorolysis reactions use phosphate instead for the same purpose. Note that the phosphate is just that - it does NOT come from ATP.

Since ATP is not used to put phosphate on G1P, the reaction saves the cell energy. Glycogen phosphorylase will only act on nonreducing ends of a glycogen chain that are at least 5 glucoses away from a branch point.

A second enzyme, Glycogen Debranching Enzyme GDE also called debranching enzyme , is therefore needed to convert α branches to α branches. GDE acts on glycogen branches that have reached their limit of phosphorylysis with glycogen phosphorylase.

GDE acts to transfer a trisaccharide from an α-1,6 branch onto an adjacent α-1,4 branch, leaving a single glucose at the 1,6 branch. Note that the enzyme also catalyzes the hydrolysis of the remaining glucose at the 1,6 branch point Figure 6. Thus, the breakdown products from glycogen are G1P and glucose mostly G1P.

Glucose can, of course, be converted to GlucosePhosphate G6P as the first step in glycolysis by either hexokinase or glucokinase. G1P can be converted to G6P by action of an enzyme called phosphoglucomutase.

This reaction is readily reversible, allowing G6P and G1P to be interconverted as the concentration of one or the other increases. This is important, because phosphoglucomutase is needed to form G1P for glycogen synthesis. Regulation of glycogen metabolism is complex, occurring both allosterically and via hormone-receptor controlled events that result in protein phosphorylation or dephosphorylation.

In order to avoid a futile cycle of glycogen synthesis and breakdown simultaneously, cells have evolved an elaborate set of controls that ensure only one pathway is primarily active at a time.

Regulation of glycogen metabolism is managed by the enzymes glycogen phosphorylase and glycogen synthase.

Its regulation is consistent with the energy needs of the cell. High energy molecules ATP, G6P, glucose al- Figure 6. Glycogen phosphorylase exists in two different covalent forms — one form with phosphate called GPa here and one form lacking phosphate GPb here.

GPb is converted to GPa by phosphorylation by an enzyme known as phosphorylase kinase. GPa and GPb can each exist in an 'R' state and a 'T' state Figure 6. For both GPa and GPb, the R state is the more active form of the enzyme. GPa's negative allosteric effector glucose is usually not abundant in cells, so GPa does not flip into the T state often.

There is no positive allosteric effector of GPa. When glucose is absent, GPa automatically flips into the R more active state Figure 6. It is for this reason that people tend to think of GPa as being the more active covalent form of the enzyme.

GPb can convert from the GPb T state to the GPb R state by binding AMP. Unless a cell is low in energy, AMP concentration is low.

Thus GPb is not converted Figure 6. This is why people think of the GPb form as less active than GPa. The relative amounts of GPa and GPb largely govern the overall process of glycogen breakdown, since GPa tends to be active more often than GPb.

It is i. Phosphorylase kinase itself has two covalent forms — phosphorylated active and dephosphorylated inactive. It is phosphorylated by the enzyme Protein Kinase A PKA -. Another way to activate the enzyme is allosterically with calcium Figure 6.

Phosphory- Figure 6. PKA is activated by cAMP, which is, in turn, produced by adenylate cyclase after activation by a G-protein See HERE for overview.

G-proteins are activated ultimately by binding of ligands to specific membrane receptors called 7-TM receptors, also known as Gprotein coupled receptors. These are discussed in greater detail HERE. Common ligands for 7-TM receptors include epinephrine binds β- adrenergic receptor and glucagon binds glucagon receptor.

Epinephrine exerts its greatest effects on muscle and glucagon works preferentially on the liver. Thus, epinephrine and glucagon can activate glycogen breakdown by stimulating synthesis of cAMP followed by the cascade of events described above.

Turning off signals is as important, if not more so, than turning them on. Glycogen is a precious resource. If its breakdown is not controlled, a lot of energy used in its synthesis is wasted.

The steps in the glycogen breakdown regulatory pathway can be reversed at every level. First, the ligand epinephrine or glucagon can leave the receptor, turning off the stimulus. Second, the G-proteins have an inherent GTPase activity.

GTP, of course, is what activates Gproteins, so a GTPase activity converts the GTP it is carrying to GDP and the G-protein becomes inactive.

Thus, G-proteins turn off Figure 6. Interfering with their ability to convert GTP to GDP can have dire consequences, including cancer in some cases.

Third, cells have phosphodiesterase enzymes inhibited by caffeine for breaking down cAMP. cAMP is needed to activate PKA, so breaking it down stops PKA from activating phosphorylase kinase.

Fourth, the enzyme known as phosphoprotein phosphatase also called PP1 plays a major role. It can remove phosphates from phosphorylase kinase inactivating it and form GPa, converting it to the less likely to be active GPb. Regulation of phosphoprotein phosphatase activity occurs at several levels.

Two of these are shown in Figures 6. In Figure 6. The inhibitor PI-1 can block activity of phosphpoprotein phosphatase only if it PI-1 is phosphorylated. When PI-1 gets dephosphorylated, it no longer functions as an inhibitor, so phosphoprotein phosphatase be- Figure 6.

Now, here is the clincher - PI-1 gets phosphorylated by PKA thus, when epinephrine or glucagon binds to a cell and gets dephosphorylated when insulin binds to a cell.

Another way to regulate phosphoprotein phosphatase in the liver involves GPa directly Figure 6. In liver cells, phosphoprotein phosphatase is bound to a protein called GL. GL can also bind to GPa.

As shown in the figure, if the three proteins are complexed together top of figure , then PP1 phosphoprotein phosphatase is inactive. When glucose is present such as when the liver has made too much glucose , then the free glucose binds to the GPa and causes GPa to be released from the GL.

This has the effect of activating phosphoprotein phosphatase, which begins dephosphorylating enzymes. As shown in the figure, two such enzymes are GPa making GPb and glycogen synthase b, making glycogen synthase a.

These dephosphorylations have opposite effects on the two enzymes, making GPb, which is less active and glycogen synthase a, which is much more active.

The anabolic pathway opposing glycogen breakdown is that of glycogen synthesis. Just Figure 6. Synthesis of glycogen starts with G1P, which is converted to an 'activated' intermediate, UDPglucose.

This activated intermediate is what 'adds' the glucose to the growing glycogen chain in a reaction catalyzed by the enzyme known as glycogen synthase Figure 6.

Once the glucose is added to glycogen, the glycogen molecule may need to have branches inserted in it by the enzyme known as branching enzyme Figure 6.

Let us first consider the steps in glycogen synthesis. G1P is reacted with UTP to form UDP-glucose in a reaction catalyzed by UDP-glucose pyrophosphorylase.

Glycogen synthase catalyzes synthesis of glycogen by joining carbon 1 of the UDP-derived glucose onto the carbon 4 of the non-reducing end of a glycogen chain, to form the familiar α 1,4 glycogen links. Another product of the reaction is UDP.

It is also worth noting, in passing, that glycogen synthase will only add glucose units from UDP-Glucose onto a preexisting glycogen chain that has at least four glucose residues. Linkage of the first few glucose units to form the minimal "primer" needed for glycogen synthase recognition is catalyzed by a protein called glycogenin, which attaches to the first glucose and catalyzes linkage of the first eight glucoses by α 1,4 bonds.

Branching enzyme breaks α 1,4 chains and carries the broken chain to the carbon 6 and forms an α 1,6 linkage Figure 6. The regulation of glycogen biosynthesis is reciprocal to that of glycogen breakdown.

It also has a cascading covalent modification system similar to the glycogen breakdown system described above. Our mediation analysis also revealed that the individual factor of external cued eating is linked to changes in blood glucose levels Fig.

In contrast to internally directed eaters, externally cued eaters are heavily influenced by factors such as visual and olfactory cues Consequently, especially those who were diagnosed with diabetes at least 12 months ago may be more aware of nutritional facts and, thus, form strong food perception from reading nutrition labels.

These findings provide an interesting new direction for future research in diabetes management. If external cued eating is an individual factor that mediates the relationship between perceived sugar intake and blood glucose levels, it would be worthwhile to examine a possibility that the high glycemic variability in type 2 diabetes is directly linked to the idiosyncratic strength in their association between feelings about nutrition facts and expectations about blood glucose response.

Our study has limitations that must be addressed. First, participants were required to consume a beverage containing sugar. Consequently, we must be cautious in generalizing our findings to the full scope of the type 2 diabetic population.

Currently, no data are available to accurately compare our sample to the overall population. In addition, our study took place in a psychology laboratory on a school campus rather than in a hospital or medical school. Some participants indicated that the study location made them doubt whether our procedure was legitimately aligned with our advertised purpose.

We asked all study participants to indicate what other purposes might be behind our study at the end of the final session, however, and they were unable to identify our purpose or manipulations.

However, as described earlier Fig. If so, the results could actually be even stronger. Nonetheless, we used altered nutrition facts mainly to induce two contrasting beliefs about the identical beverage, and the manipulations successfully produced the contrasting beliefs, despite the non-zero mean rating of perceived sugar levels on the sugar-free beverage.

Finally, future studies can be benefit by including a non-treatment group, or use a design that manipulates actual sugar contents to compare psychological and physiological effects.

Our study indicates that blood glucose level in people with type 2 diabetes is influenced by the perception of sugar consumption. Blood glucose levels increased in accordance with how much sugar participants believed they consumed rather than how much they actually consumed.

These findings clearly show the inadequacy of the classical pathways to explain the metabolic and physiological reactions to food intake in diabetics suggested by the biomedical framework. Similarly, recent studies of chronic diseases, as well as on aging 28 , 29 , are consistently revealing the undeniable influence that psychological processes exert on various chronic physiological and biochemical conditions including diabetes 19 , cardiovascular disease 30 , and chronic obstructive pulmonary disease In the face of rapidly surging epidemiological patterns of noninfectious fatal chronic diseases, we hope that our efforts to return the mind back to the equation of the dominant biomedical formulae will help stimulate more research endeavors in the biopsychosocial field.

The goal is to find more effective treatments for millions who have resigned to feeling helpless in the battle against uncontrollable biological processes causing illness and disease, perhaps by recognizing that the mind has meaningful control in regulating health.

Pagnini, F. The potential role of illness expectations in the progression of medical diseases. BMC Psychol. Article Google Scholar. Langer, E. Believing is seeing using mindlessness mindfully to improve visual acuity. Illness expectations predict the development of influenza-like symptoms over the winter season.

Crum, A. Mind-set matters exercise and the placebo effect. Mind over milkshakes: mindsets, not just nutrients, determine ghrelin response. Health Psychol. Panayotov, V. Studying a possible placebo effect of an imaginary low-calorie diet.

Psychiatry 10 , Baltazar-Martins, G. Carbohydrate mouth rinse decreases time to complete a simulated cycling time trial. Bavaresco, B. et al. Carbohydrate mouth rinse improves cycling performance carried out until the volitional exhaustion. Sports Med. Fitness 59 , 1—5 Google Scholar.

Brietzke, C. Effects of carbohydrate mouth rinse on cycling time trial performance: a systematic review and meta-analysis. Benedetti, F. Neuropsychopharmacology 36 , — Watve, M. Doves, diplomats, and diabetes: a Darwinian interpretation of type 2 diabetes and related disorders.

Springer, Berlin, World Health Organization. Global report on diabetes American Diabetes Association. Standards of medical care in diabetes— Diabetes Care 37 , S14—S80 Goetsch, V. Stress and blood glucose in type II diabetes mellitus.

Article CAS Google Scholar. Wing, R. Psychologic stress and blood glucose levels in nondiabetic subjects. Yasunari, K. Oxidative stress in leukocytes is a possible link between blood pressure, blood glucose, and C-reacting protein.

Hypertension 39 , — van Dooren, F. Depression and risk of mortality in people with diabetes mellitus: a systematic review and meta-analysis. PloS one 8 , e Egede, L. Serious psychological distress and diabetes: a review of the literature.

Psychiatry Rep. Park, C. Blood sugar level follows perceived time rather than actual time in people with type 2 diabetes. Schur, E. Association of cognitive restraint with ghrelin, leptin, and insulin levels in subjects who are not weight-reduced.

Daly, J. An assessment of attitudes, behaviors, and outcomes of patients with type 2 diabetes. Board Family Med. Dietzen, D. Analytic characteristics of three Bayer Contour blood glucose monitoring systems in neonates.

Diabetes Sci. Cohen, S. Perceived stress scale. Measuring stress: A guide for health and social scientists 10 Van Strien, T. The Dutch Eating Behavior Questionnaire DEBQ for assessment of restrained, emotional, and external eating behavior.

Watson, D. Development and validation of brief measures of positive and negative affect: the PANAS scales. Cardello, A. Development and testing of a labeled magnitude scale of perceived satiety. Appetite 44 , 1—13 Diwekar-Joshi, M.

Does insulin signalling decide glucose levels in the fasting steady state?. BioRxiv 1 , Counter Clockwise: Mindful health and the power of possibility. Ballantine Books, Ageing as a mindset: a study protocol to rejuvenate older adults with a counterclockwise psychological intervention.

BMJ Open 9 , e Lagraauw, H. Acute and chronic psychological stress as risk factors for cardiovascular disease: insights gained from epidemiological, clinical and experimental studies. Brain Behav. Panagioti, M. Overview of the prevalence, impact, and management of depression and anxiety in chronic obstructive pulmonary disease.

Chronic Obstr. Download references. The data analysis of the current study was reviewed by Dr. Simo Goshev sgoshev iq.

edu from Harvard Institute for Qualitative Social Science. We are deeply grateful to Dr. Jim Sidanius for his constructive recommendations on this project and to Holmes J.

for support in collecting the data. Department of Psychology, Harvard University, 33 Kirkland St, Cambridge, MA, , USA. Department of Psychology, Università Cattolica del Sacro Cuore, Milan, Italy. You can also search for this author in PubMed Google Scholar.

and E. designed research; C. performed research; C. analyzed data; and C. wrote the paper. Correspondence to Chanmo Park. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.

The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Reprints and permissions. Glucose metabolism responds to perceived sugar intake more than actual sugar intake. Sci Rep 10 , Download citation. Received : 02 May Accepted : 18 August Published : 24 September Anyone you share the following link with will be able to read this content:.

Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature.

nature scientific reports articles article. Download PDF. Subjects Human behaviour Metabolic disorders. Abstract The authors examine study participants who have Type 2 diabetes to determine whether cognition affects glucose levels in contrast to widely held suppositions.

Introduction There is a growing acknowledgement that both mind and body exert a role in the course of many physical diseases. Psychological influence in diabetic metabolism The World Health Organization WHO reports that diabetes rates have almost quadrupled globally over the past three decades, making diabetes one of the most important international public health challenges causing an estimated 1.

Methods Participants We used flyers and local advertisements to recruit volunteers who have insulin-independent type 2 diabetes mellitus and were being treated with diet and metformin, a biguanide antidiabetic medication.

Design and procedure In a within-subject design, participants were instructed to come to the laboratory twice, with a three-day interval between visits. Figure 1. Two labels used in the study left and actual nutrition contained in the beverage right.

Full size image. Figure 2. The effect of the label manipulation on perceived sugar intake. Figure 3. Average blood glucose levels over time. Figure 4. Average blood glucose levels over time as a function of beverage type.

Figure 5.

We use HDPE and PET recyclable plastic to reduce packaging waste. Please recycle your bottles. Adults, take 1 tablet with water twice daily, after food, or as directed by your health professional.

CAUTION: Use as recommended: Pregnant or nursing mothers, children under 18, and individuals with a known medical condition should consult a physician before using this product. Vitamin and mineral supplements should not replace a balanced diet. Keep out of reach of children.

Storage instructions: Store below 77°F in a cool, dry place away from direct heat and sunlight. Avoid excessive heat about °F. Do not sure if tamper evident seals are broken or missing. This is an international product. Slight variations to label text may occasionally occur.

Zinc maintains and supports healthy body metabolism and metabolic rate, while Magnesium maintains and supports energy levels. Vitamin B6 supports nervous system health. Our team of health experts source the ingredients in our products with great care.

We ensure quality and specific doses of actives are placed in each of our targeted formulas to achieve its indications. The indications behind our ingredients:. This product is not intended to diagnose, treat, cure or prevent any disease. JSHealth believes in truly nurturing the body and nourishing it with the right nutrients, minerals and herbs to reach its full potential.

SHOP Best-Sellers Supplements Signatures Everyday Health Twin Packs Dynamic Duos Trusted Trios. ABOUT Our Founder, Jessica Sepel The JSHealth Standard FAQs Blog JSHealth App Nourish Hub Take Our Quiz Giving Back Loyalty.

Shop Everyday Health. Shop Our Best-Selling Formula. Created with Lunacy Continue Shopping. Your shopping bag is empty. Remove from cart?

Are you sure you want to remove this item? Glucose serves as the major precursor for the synthesis of different carbohydrates like glycogen, ribose, deoxyribose, galactose, glycolipids, glycoproteins, and proteoglycans. On the contrary, in plants, glucose is synthesized from carbon dioxide and water photosynthesis and stored as starch.

At the cellular level, glucose is usually the final substrate that enters the tissue cells and converts to ATP adenosine triphosphate. ATP is the energy currency of the body and is consumed in multiple ways, including the active transport of molecules across cell membranes, contraction of muscles and performance of mechanical work, synthetic reactions that help to create hormones, cell membranes, and other essential molecules, nerve impulse conduction, cell division and growth, and other physiologic functions.

During starvation, the liver provides glucose to the body through gluconeogenesis, synthesizing glucose from lactate and amino acids. After a meal, there is a rise in blood glucose levels, which raises insulin secretion from the pancreas simultaneously.

Insulin causes glucose to be deposited in the liver as glycogen; then, during the next few hours, when blood glucose concentration falls, the liver releases glucose back into the blood, decreasing fluctuations.

Clinical significance: During severe liver disease, it is impossible to maintain blood glucose concentration. High blood glucose causes insulin secretion, which concomitantly lowers blood glucose levels as glucose is driven from extracellular to intracellular.

Conversely, a fall in blood glucose stimulates glucagon secretion, which in turn raises blood glucose levels. Low blood glucose level is sensed by the hypothalamus, leading to activation of the sympathetic nervous system to maintain glucose levels and avoid severe hypoglycemia.

Prolonged hypoglycemia for hours and days leads to the secretion of growth hormone and cortisol that maintain blood glucose levels by increasing fat utilization and decreasing the rate of glucose utilization by cells. For glucose to be utilizable in most tissue cells, it needs to be transported across the cell membrane into the cytoplasm.

Glucose cannot readily diffuse through because of its high molecular weight. Transport is made possible through protein carrier molecules; this is known as facilitated diffusion, and it takes place down the gradient from high concentration to low concentration.

There is an exception for the gastrointestinal tract and renal tubules. Here, glucose is transported actively by sodium-glucose co-transport against the concentration gradient.

Normally, the amount of glucose that can diffuse in the cells is limited except for liver and brain cells. This diffusion is significantly increased by insulin to 10 times or more.

As soon as glucose enters the cell, it becomes phosphorylated to glucosephosphate. This reaction is mediated by glucokinase in the liver and hexokinase in most other cells. This phosphorylating step serves to capture glucose inside the cell. It is irreversible mostly except in liver cells, intestinal epithelial cells, and renal tubular epithelial cells where glucose phosphatase is present in these locations, which is reversible.

This glucose can then either be utilized immediately for the release of energy through glycolysis, a multi-step procedure to release energy in the form of ATP, or it can be stored as glycogen polysaccharide. Liver and muscle cells store large amounts of glycogen for later utilization to release glucose by glycogenolysis, ie, the breakdown of glucose.

In a developing fetus, regulated glucose exposure is imperative to normal growth because glucose is the primary energy form used by the placenta. In late gestation, fetal glucose metabolism is essential to the development of skeletal muscles, fetal liver, fetal heart, and adipose tissue.

Three components that are crucial to fetal glucose metabolism are maternal serum glucose concentration, maternal glucose transport to the placenta, which is impacted by the amount of glucose the fetus uses, and finally, fetal pancreas insulin production.

Fetal insulin secretion gradually increases during the gestational period. Pulsatile peaks in glucose levels are beneficial to insulin secretion; however, constant hyperglycemia down-regulates insulin sensitivity and glucose tolerance. Glucose metabolism involves multiple processes, including glycolysis, gluconeogenesis, glycogenolysis, and glycogenesis.

Glycolysis in the liver is a process that involves various enzymes that encourage glucose catabolism in cells. One enzyme, in particular, glucokinase, allows the liver to sense serum glucose levels and to utilize glucose when serum glucose levels rise, for example, after eating.

During periods of fasting, when there is no glucose consumption, for example, overnight while asleep, gluconeogenesis takes place. Gluconeogenesis happens when there is glucose synthesis from non-carbohydrate components in the mitochondria of liver cells. Additionally, during fasting periods, the pancreas secretes glucagon, which begins glycogenolysis.

In glycogenolysis, glycogen, the stored form of glucose, is released as glucose. The process of synthesizing glycogen is termed glycogenesis and occurs when excess carbohydrates exist in the liver. Glucose tolerance is regulated with the circadian cycle.

In the morning, humans typically have their peak glucose tolerance for metabolism. Afternoon and evenings are a trough for oral glucose tolerance. This trough likely occurs because pancreatic beta-cells are also most responsive in the morning—similarly, glycogen storage components peak in the evening.

Adipose tissue is most sensitive to insulin in the afternoon. The varied timings of fuel utilization throughout the day compose the cycle of glucose metabolism. Glycolysis is the most crucial process in releasing energy from glucose, the end product of which is two molecules of pyruvic acid.

It occurs in 10 successive chemical reactions, leading to a net gain of two ATP molecules from one molecule of glucose. The overall efficiency for ATP formation is only approximately forty-three percent, with the remaining 57 percent lost in the form of heat.

The next step is the conversion of pyruvic acid to acetyl coenzyme A. This reaction utilizes coenzyme A, releasing two carbon dioxide molecules and four hydrogen atoms. No ATP forms at this stage, but the four released hydrogen atoms participate in oxidative phosphorylation, later releasing six molecules of ATP.

The next step is the breakdown of acetyl coenzyme A and the release of energy in the form of ATP in the Kreb cycle or the tricarboxylic acid cycle, taking place in the cytoplasm of the mitochondrion. Although not completely understood, Type 1 and Type 2 diabetes differ in their pathophysiology.

Both are considered polygenic diseases, meaning multiple genes are involved, likely with multifactorial environmental influences, including gut microbiome composition and environmental pollutants, among others. Without the insulin hormone, the body is unable to regulate blood glucose control.

Type 1 diabetes more commonly presents in childhood and persists through adulthood, equally affects males and females, and has the highest prevalence of diagnosis in European White race individuals.

Life expectancy for an individual with Type 1 diabetes is reduced by an estimated 13 years. Type 2 diabetes results when pancreatic beta cells cannot produce enough insulin to meet metabolic needs. Therefore, individuals with more adipose deposition, typically with higher body fat content and an obese BMI, more commonly have type 2 diabetes.

Type 2 diabetes is more common among adult and older adult populations; however, youth are demonstrating rising rates of type 2 diabetes. Type 2 diabetes is slightly more common in males 6.

It is also more common in individuals of Native American, African American, Hispanic, Asian, and Pacific Islander race or ethnicity. Poor glucose metabolism leads to diabetes mellitus.

According to the American Diabetes Association, the prevalence of diabetes in the year was 9. Every year, 1. As the seventh-highest cause of mortality in the United States, diabetes mellitus poses a concerning healthcare challenge with large amounts of yearly expenditures, morbidity, and death.

Type 2 DM- due to insulin resistance with a defect in compensatory insulin secretion. Key features of this type are-. Uncontrolled diabetes poses a significantly increased risk of developing macrovascular disease, especially coronary, cerebrovascular, and peripheral vascular disease.

It also increases the chances of microvascular disease, including retinopathy, nephropathy, and neuropathy. Diagram of the relationship between the processes of carbohydrate metabolism, including glycolysis, gluconeogenesis, glycogenesis, glycogenolysis, fructose metabolism, and galactose metabolism Contributed by Wikimedia User: Eschopp, CC BY-SA 4.

Disclosure: Mihir Nakrani declares no relevant financial relationships with ineligible companies. Disclosure: Robert Wineland declares no relevant financial relationships with ineligible companies. Please, no personal attacks, obscenity or profanity, selling of commercial products, or endorsements of political candidates or positions.

We reserve the right to remove any inappropriate comments. We also cannot address individual medical concerns or provide medical advice in this forum.

CSD research informs Senate proposal. Expanded child tax credit would ultimately save money, reduce poverty. Replacing Chevron would have far-reaching implications. The importance of higher purpose, culture in banking. Brumation and torpor: How animals survive cold snaps by playing dead-ish.

Proteins may predict who will get dementia 10 years later, study finds. NEWS ROOM. Sections Find an Expert Media Resources Newsroom Stories Perspectives WashU Experts WashU in the News.

Sugar metabolism is surprisingly conventional in cancer Study has implications for targeting metabolism in cancer treatment. Research from Washington University in St.

Louis shows that cancer cells only waste glucose sugar because transport into mitochondria is too slow. The study has implications for targeting sugar metabolism in cancer treatment. Image: Shutterstock.