You may have already guessed that these cells and tissues then must produce ATP by metabolizing glucose only. In these situations, glucose is degraded to pyruvate, which is then promptly converted to lactate Figure 2.

This process is called lactic acid fermentation. Although not highly metabolically active, red blood cells are abundant, resulting in the continual uptake of glucose molecules from the bloodstream.

Additionally, there are cells that, despite having mitochondria, rely almost exclusively on lactic acid fermentation for ATP production.

This is the case for renal medulla cells, whose oxygenated blood supply is not adequate to accomplish oxidative phosphorylation. Finally, what if the availability of fatty acids to cells changes?

The blood-brain barrier provides a good example. In most physiological situations, the blood-brain barrier prevents the access of lipids to the cells of the central nervous system CNS.

Therefore, CNS cells also rely solely on glucose as fuel molecules Figure 2. In prolonged fasting, however, ketone bodies released in the blood by liver cells as part of the continual metabolization of fatty acids are used as fuels for ATP production by CNS cells.

In both situations and unlike red blood cells, however, CNS cells are extremely metabolically active and do have mitochondria. Thus, they are able to fully oxidize glucose, generating greater amounts of ATP.

Indeed, the daily consumption of nerve cells is about g of glucose equivalent, which corresponds to an input of about kilocalories 1, kilojoules. However, most remaining cell types in the human body have mitochondria, adequate oxygen supply, and access to all three fuel molecules.

Which fuel, then, is preferentially used by each of these cells? Virtually all cells are able to take up and utilize glucose. What regulates the rate of glucose uptake is primarily the concentration of glucose in the blood. Glucose enters cells via specific transporters GLUTs located in the cell membrane.

There are several types of GLUTs, varying in their location tissue specificity and in their affinity for glucose. Adipose and skeletal muscle tissues have GLUT4, a type of GLUT which is present in the plasma membrane only when blood glucose concentration is high e. The presence of this type of transporter in the membrane increases the rate of glucose uptake by twenty- to thirtyfold in both tissues, increasing the amount of glucose available for oxidation.

Therefore, after meals glucose is the primary source of energy for adipose tissue and skeletal muscle. The breakdown of glucose, in addition to contributing to ATP synthesis, generates compounds that can be used for biosynthetic purposes. So the choice of glucose as the primary oxidized substrate is very important for cells that can grow and divide fast.

Examples of these cell types include white blood cells, stem cells , and some epithelial cells. A similar phenomenon occurs in cancer cells, where increased glucose utilization is required as a source of energy and to support the increased rate of cell proliferation.

Interestingly, across a tumor mass, interior cells may experience fluctuations in oxygen tension that in turn limit nutrient oxidation and become an important aspect for tumor survival. In addition, the increased glucose utilization generates high amounts of lactate, which creates an acidic environment and facilitates tumor invasion.

Another factor that dramatically affects the metabolism is the nutritional status of the individual — for instance, during fasting or fed states. After a carbohydrate-rich meal, blood glucose concentration rises sharply and a massive amount of glucose is taken up by hepatocytes by means of GLUT2.

This type of transporter has very low affinity for glucose and is effective only when glucose concentration is high. Thus, during the fed state the liver responds directly to blood glucose levels by increasing its rate of glucose uptake.

In addition to being the main source of energy, glucose is utilized in other pathways, such as glycogen and lipid synthesis by hepatocytes. The whole picture becomes far more complex when we consider how hormones influence our energy metabolism.

Fluctuations in blood levels of glucose trigger secretion of the hormones insulin and glucagon. How do such hormones influence the use of fuel molecules by the various tissues? Demands by one cell type can be met by the consumption of its own reserves and by the uptake of fuel molecules released in the bloodstream by other cells.

Energy use is tightly regulated so that the energy demands of all cells are met simultaneously. Elevated levels of glucose stimulate pancreatic β-cells to release insulin into the bloodstream.

Virtually all cells respond to insulin; thus, during the fed state cell metabolism is coordinated by insulin signaling. Figure 3: Blood glucose concentration after carbohydrate-rich and carbohydrate-poor meals.

An extraordinary example is how insulin signaling rapidly stimulates glucose uptake in skeletal muscle and adipose tissue and is accomplished by the activity of GLUT4.

In the absence of insulin, these transporters are located inside vesicles and thus do not contribute to glucose uptake in skeletal muscle and adipose tissue. Insulin, however, induces the movement of these transporters to the plasma membrane, increasing glucose uptake and consumption.

As different tissues continue to use glucose, the blood glucose concentration tends to reach the pre-meal concentration Figure 3.

This, in turn, decreases the stimulus for insulin synthesis and increases the stimulus for the release of glucagon, another hormone secreted by the α-pancreatic cells. Therefore, during fasting, cell metabolism is coordinated by glucagon signaling and the lack of insulin signaling.

As a consequence, GLUT4 stays inside vesicles, and glucose uptake by both skeletal muscle cells and adipocytes is reduced. Now, with the low availability of glucose and the signals from glucagon, those cells increase their use of fatty acids as fuel molecules.

Therefore, the use of fatty acids during fasting clearly contributes to the maintenance of adequate blood glucose concentration to meet the demands of cells that exclusively or primarily rely on glucose as a fuel. But, mentioned above, glucose is used at an apparently high rate by the brain and constantly by red blood cells.

And, under physiological conditions, blood glucose is maintained at a constant level, even during fasting. How, then, is that delicate balance achieved? The liver is a very active organ that performs different vital functions.

In Greek mythology, Prometheus steals fire from Zeus and gives it to mortals. As a punishment, Zeus has part of Prometheus's liver fed to an eagle every day. Since the liver grows back, it is eaten repeatedly. This story illustrates the high proliferative rate of liver cells and the vital role of this organ for human life.

One of its most important functions is the maintenance of blood glucose. The liver releases glucose by degrading its glycogen stores. This reserve is not large, and during overnight fasting glycogen reserves fall severely.

However, only the liver supplies the blood with glucose since it has an enzyme that make it possible for glucose molecules to be transported across cell membranes. Since glycogen stores are limited and are reduced within hours of fasting, and blood glucose concentration is kept within narrow limits under most physiological conditions, another mechanism must exist to supply blood glucose.

Indeed, glucose can be synthesized from amino acid molecules. This process is called de novo synthesis of glucose, or gluconeogenesis. Amino acids, while being degraded, generate several intermediates that are used by the liver to synthesize glucose Figure 2.

Alanine and glutamine are the two amino acids whose main function is to contribute to glucose synthesis by the liver. The kidneys also possess the enzymes necessary for gluconeogenesis and, during prolonged fasting, contribute to some extent to the supply of blood glucose.

Furthermore, since de novo glucose synthesis comes from amino acid degradation and the depletion of protein stores can be life-threatening, this process must be regulated.

Insulin, glucagon, and another hormone, glucocorticoid, play important roles in controlling the rate of protein degradation and, therefore, the rate of glucose production by the liver.

Alterations in factors that control food intake and regulate energy metabolism are related to well-known pathological conditions such as obesity, type 2 diabetes and the metabolic syndrome , and some types of cancer.

In addition, many effects and regulatory actions of well-known hormones such as insulin are still poorly understood. The consideration of adipose tissue as a dynamic and active tissue, for instance, raises several important issues regarding body weight and the control of food intake.

These factors point to the importance of further studies to expand our understanding of energy metabolism, thereby improving our quality of life and achieving a comprehensive view of how the human body functions. Cahill, G. 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.

Disclosure: Fatima Anjum declares no relevant financial relationships with ineligible companies. This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

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Search term. Physiology, Glucose Metabolism Mihir N. Author Information and Affiliations Authors Mihir N. Affiliations 1 Nova Southeastern University. Introduction Glucose is central to energy consumption. We can summarize blood glucose regulation and its clinical significance in the following ways: The liver serves as a buffer for blood glucose concentration.

Cellular Level Following are the critical steps in the utilization of glucose at the cellular level- Transport of glucose through the cell membrane.

Development In a developing fetus, regulated glucose exposure is imperative to normal growth because glucose is the primary energy form used by the placenta.

Organ Systems Involved Nervous system: The pancreas performs autonomic function through the sympathetic and parasympathetic innervation of the pancreas. The brain itself also houses insulin receptors in multiple regions, including the hypothalamus, cerebellum, hippocampus, among other areas.

Pancreas: The pancreas is behind the stomach in the right upper quadrant of the abdomen. The endocrine functionality of the pancreas regulates glucose homeostasis. Liver: Glycogenesis and gluconeogenesis are the storing and releasing of glucose, respectively. These processes occur using insulin, glucagon, and hepatocyte derived factors.

Gut: Hormones in the gut are released in response to the ingestion of nutrients. These hormones are involved in appetite, glucose production, gastric emptying, and glucose removal. Adipocytes: Adipose tissue secretes adipokines, which regulate insulin release through their involvement in glucose metabolism, control of food intake, and insulin gene expression.

Function Glucose metabolism involves multiple processes, including glycolysis, gluconeogenesis, glycogenolysis, and glycogenesis. Mechanism Glycolysis is the most crucial process in releasing energy from glucose, the end product of which is two molecules of pyruvic acid. Related Testing HbA1c. Since the HbA1C value summarizes long-term glycemic control, it is frequently used to evaluate patients with long-standing hyperglycemia, as seen in patients with diabetes, and to forecast the risk of diabetic complications.

Fasting Plasma Glucose. Plasma blood glucose level is measured after a period of fasting, typically at least 8 hours. Random Plasma Glucose. The following discussions of glycolysis include the enzymes responsible for the reactions.

When glucose enters a cell, the enzyme hexokinase or glucokinase, in the liver rapidly adds a phosphate to convert it into glucosephosphate. A kinase is a type of enzyme that adds a phosphate molecule to a substrate in this case, glucose, but it can be true of other molecules also.

This conversion step requires one ATP and essentially traps the glucose in the cell, preventing it from passing back through the plasma membrane, thus allowing glycolysis to proceed. It also functions to maintain a concentration gradient with higher glucose levels in the blood than in the tissues.

By establishing this concentration gradient, the glucose in the blood will be able to flow from an area of high concentration the blood into an area of low concentration the tissues to be either used or stored.

Hexokinase is found in nearly every tissue in the body. Glucokinase , on the other hand, is expressed in tissues that are active when blood glucose levels are high, such as the liver. Hexokinase has a higher affinity for glucose than glucokinase and therefore is able to convert glucose at a faster rate than glucokinase.

This is important when levels of glucose are very low in the body, as it allows glucose to travel preferentially to those tissues that require it more. In the next step of the first phase of glycolysis, the enzyme glucosephosphate isomerase converts glucosephosphate into fructosephosphate.

Like glucose, fructose is also a six carbon-containing sugar. The enzyme phosphofructokinase-1 then adds one more phosphate to convert fructosephosphate into fructosebisphosphate, another six-carbon sugar, using another ATP molecule. Aldolase then breaks down this fructosebisphosphate into two three-carbon molecules, glyceraldehydephosphate and dihydroxyacetone phosphate.

The triosephosphate isomerase enzyme then converts dihydroxyacetone phosphate into a second glyceraldehydephosphate molecule. Therefore, by the end of this chemical- priming or energy-consuming phase, one glucose molecule is broken down into two glyceraldehydephosphate molecules.

The second phase of glycolysis, the energy-yielding phase , creates the energy that is the product of glycolysis. Glyceraldehydephosphate dehydrogenase converts each three-carbon glyceraldehydephosphate produced during the. energy-consuming phase into 1,3-bisphosphoglycerate.

NADH is a high-energy molecule, like ATP, but unlike ATP, it is not used as energy currency by the cell. Because there are two glyceraldehydephosphate molecules, two NADH molecules are synthesized during this step.

Each 1,3-bisphosphoglycerate is subsequently dephosphorylated i. Each phosphate released in this reaction can convert one molecule of ADP into one high- energy ATP molecule, resulting in a gain of two ATP molecules.

The enzyme phosphoglycerate mutase then converts the 3-phosphoglycerate molecules into 2-phosphoglycerate. The enolase enzyme then acts upon the 2-phosphoglycerate molecules to convert them into phosphoenolpyruvate molecules.

The last step of glycolysis involves the dephosphorylation of the two phosphoenolpyruvate molecules by pyruvate kinase to create two pyruvate molecules and two ATP molecules. In summary, one glucose molecule breaks down into two pyruvate molecules, and creates two net ATP molecules and two NADH molecules by glycolysis.

Therefore, glycolysis generates energy for the cell and creates pyruvate molecules that can be processed further through the aerobic Krebs cycle also called the citric acid cycle or tricarboxylic acid cycle ; converted into lactic acid or alcohol in yeast by fermentation; or used later for the synthesis of glucose through gluconeogenesis.

When oxygen is limited or absent, pyruvate enters an anaerobic pathway. In these reactions, pyruvate can be converted into lactic acid. In this reaction, lactic acid replaces oxygen as the final electron acceptor.

Anaerobic respiration occurs in most cells of the body when oxygen is limited or mitochondria are absent or nonfunctional.

For example, because erythrocytes red blood cells lack mitochondria, they must produce their ATP from anaerobic respiration. This is an effective pathway of ATP production for short periods of time, ranging from seconds to a few minutes.

The lactic acid produced diffuses into the plasma and is carried to the liver, where it is converted back into pyruvate or glucose via the Cori cycle. Similarly, when a person exercises, muscles use ATP faster than oxygen can be delivered to them.

They depend on glycolysis and lactic acid production for rapid ATP production. The NADH and FADH2 pass electrons on to the electron transport chain, which uses the transferred energy to produce ATP.

As the terminal step in the electron transport chain, oxygen is the terminal electron acceptor and creates water inside the mitochondria. Figure 3. Click to view a larger image. The process of anaerobic respiration converts glucose into two lactate molecules in the absence of oxygen or within erythrocytes that lack mitochondria.

During aerobic respiration, glucose is oxidized into two pyruvate molecules. The pyruvate molecules generated during glycolysis are transported across the mitochondrial membrane into the inner mitochondrial matrix, where they are metabolized by enzymes in a pathway called the Krebs cycle Figure 4.

The Krebs cycle is also commonly called the citric acid cycle or the tricarboxylic acid TCA cycle. During the Krebs cycle, high-energy molecules, including ATP, NADH, and FADH2, are created.

NADH and FADH2 then pass electrons through the electron transport chain in the mitochondria to generate more ATP molecules. Figure 4. During the Krebs cycle, each pyruvate that is generated by glycolysis is converted into a two-carbon acetyl CoA molecule.

The acetyl CoA is systematically processed through the cycle and produces high- energy NADH, FADH2, and ATP molecules. The three-carbon pyruvate molecule generated during glycolysis moves from the cytoplasm into the mitochondrial matrix, where it is converted by the enzyme pyruvate dehydrogenase into a two-carbon acetyl coenzyme A acetyl CoA molecule.

This reaction is an oxidative decarboxylation reaction. Acetyl CoA enters the Krebs cycle by combining with a four-carbon molecule, oxaloacetate, to form the six-carbon molecule citrate, or citric acid, at the same time releasing the coenzyme A molecule.

The six-carbon citrate molecule is systematically converted to a five-carbon molecule and then a four-carbon molecule, ending with oxaloacetate, the beginning of the cycle. Along the way, each citrate molecule will produce one ATP, one FADH2, and three NADH.

The FADH2 and NADH will enter the oxidative phosphorylation system located in the inner mitochondrial membrane. In addition, the Krebs cycle supplies the starting materials to process and break down proteins and fats.

To start the Krebs cycle, citrate synthase combines acetyl CoA and oxaloacetate to form a six-carbon citrate molecule; CoA is subsequently released and can combine with another pyruvate molecule to begin the cycle again. The aconitase enzyme converts citrate into isocitrate.

In two successive steps of oxidative decarboxylation, two molecules of CO2 and two NADH molecules are produced when isocitrate dehydrogenase converts isocitrate into the five-carbon α-ketoglutarate, which is then catalyzed and converted into the four-carbon succinyl CoA by α-ketoglutarate dehydrogenase.

The enzyme succinyl CoA dehydrogenase then converts succinyl CoA into succinate and forms the high-energy molecule GTP, which transfers its energy to ADP to produce ATP. Succinate dehydrogenase then converts succinate into fumarate, forming a molecule of FADH2.

Oxaloacetate is then ready to combine with the next acetyl CoA to start the Krebs cycle again see Figure 4.

For each turn of the cycle, three NADH, one ATP through GTP , and one FADH2 are created. Each carbon of pyruvate is converted into CO2, which is released as a byproduct of oxidative aerobic respiration.