How Does Glucose Enter The Liver Cells?

Is Liver A Primary Target For Insulin Action?

I am looking into the possible causes of metabolic syndrome. I have noticed on the web that some people consider a liver to be a primary target for the action of insulin, and as such, when it becomes insulin resistant, it can cause disruption in the glucose homeostasis in the whole body - in contrary with the traditional adipocentric view, by which it is the accumulation of excess fat that leads to inflammation and a whole cascade of biochemical and physiological events. Can insulin resistant liver produce enough glucose via gluconeogenesis to cause hyperinsulinemia and hyperglycemia in humans? I have read some studies, they did this in mice, dogs, humans... they reported hyperglycemia and hyperinsulinemia, but is this the same as in hyperinsulinemic people? Glucagon has been told to mediate gluconeogenesis. It cannot act on the tissues when insulin levels are high, but the lack of insulin mediation due to insulin resistant tissues, this can lead to gluconeogenesis. To what extend - in comparison to the action of glucagon? I have also read that in the portal vein there can be three times higher insulin concentration than in the systemic circulation. Is the regulation of insulin concentrations in these two compartments dependent on the pancreas, or how do these differ? When liver becomes insulin resistant, is it blind to the insulin in the portal vein as well? I personally believe that it is mainly the muscles that determine whether a person will become hyperglycemic and hyperinsulinemic, because these are the biggest organ that needs insulin to take glucose in on the every day basis. When people remain bed bound or physically inactive and overeat, the glucose and fat content of the muscles is mostly full and cannot take in anymore. Liver glycogen is also easily replenis Continue reading >>

How Fat Cells Work

In the last section, we learned how fat in the body is broken down and rebuilt into chylomicrons, which enter the bloodstream by way of the lymphatic system. Chylomicrons do not last long in the bloodstream -- only about eight minutes -- because enzymes called lipoprotein lipases break the fats into fatty acids. Lipoprotein lipases are found in the walls of blood vessels in fat tissue, muscle tissue and heart muscle. Insulin When you eat a candy bar or a meal, the presence of glucose, amino acids or fatty acids in the intestine stimulates the pancreas to secrete a hormone called insulin. Insulin acts on many cells in your body, especially those in the liver, muscle and fat tissue. Insulin tells the cells to do the following: The activity of lipoprotein lipases depends upon the levels of insulin in the body. If insulin is high, then the lipases are highly active; if insulin is low, the lipases are inactive. The fatty acids are then absorbed from the blood into fat cells, muscle cells and liver cells. In these cells, under stimulation by insulin, fatty acids are made into fat molecules and stored as fat droplets. It is also possible for fat cells to take up glucose and amino acids, which have been absorbed into the bloodstream after a meal, and convert those into fat molecules. The conversion of carbohydrates or protein into fat is 10 times less efficient than simply storing fat in a fat cell, but the body can do it. If you have 100 extra calories in fat (about 11 grams) floating in your bloodstream, fat cells can store it using only 2.5 calories of energy. On the other hand, if you have 100 extra calories in glucose (about 25 grams) floating in your bloodstream, it takes 23 calories of energy to convert the glucose into fat and then store it. Given a choice, a fat cell w Continue reading >>

Dynamic Adaptation Of Nutrient Utilization In Humans

Most cells use glucose for ATP synthesis, but there are other fuel molecules equally important for maintaining the body's equilibrium or homeostasis. Indeed, although the oxidation pathways of fatty acids, amino acids, and glucose begin differently, these mechanisms ultimately converge onto a common pathway, the TCA cycle, occurring within the mitochondria (Figure 1). As mentioned earlier, the ATP yield obtained from lipid oxidation is over twice the amount obtained from carbohydrates and amino acids. So why don't all cells simply use lipids as fuel? In fact, many different cells do oxidize fatty acids for ATP production (Figure 2). Between meals, cardiac muscle cells meet 90% of their ATP demands by oxidizing fatty acids. Although these proportions may fall to about 60% depending on the nutritional status and the intensity of contractions, fatty acids may be considered the major fuel consumed by cardiac muscle. Skeletal muscle cells also oxidize lipids. Indeed, fatty acids are the main source of energy in skeletal muscle during rest and mild-intensity exercise. As exercise intensity increases, glucose oxidation surpasses fatty acid oxidation. Other secondary factors that influence the substrate of choice for muscle include exercise duration, gender, and training status. Another tissue that utilizes fatty acids in high amount is adipose tissue. Since adipose tissue is the storehouse of body fat, one might conclude that, during fasting, the source of fatty acids for adipose tissue cells is their own stock. Skeletal muscle and adipose tissue cells also utilize glucose in significant proportions, but only at the absorptive stage - that is, right after a regular meal. Other organs that use primarily fatty acid oxidation are the kidney and the liver. The cortex cells of the Continue reading >>

Diabetes Care Management Teams Did Not Reduce Utilization When Compared With Traditional Care: A Randomized Cluster Trial

How Is Glucose Transported In The Circulatory System?

Simple sugars and starches are both carbohydrates, and both contain the molecule glucose, which is also called blood sugar. Glucose is a very important biological molecule, as it is the brain's primary source of energy and a significant source of energy for all body cells. The circulatory system helps move glucose out of the digestive tract and into the body cells. Video of the Day The major function of the biomolecule glucose is to provide energy to cells. Body cells take up glucose from the blood and chemically burn it, yielding energy molecules that they can use to fulfill cellular functions. Some cells, such as those of the liver and muscles, store glucose and release it under fasting conditions. In their book "Biochemistry," Drs. Mary Campbell and Shawn Farrell describe glucose as the most ubiquitous of the carbohydrate molecules. Transport Problems To move glucose from the digestive tract, where it is located after a meal, into the body cells, where it's utilized, the glucose has to cross several cell membranes. Since glucose is water soluble while cell membranes are made of fatty material, glucose can't move across cell membranes on its own. Instead, explains Dr. Lauralee Sherwood in her text, "Human Physiology," transporter molecules must ferry it in and out of cells. Glucose does dissolve readily in the bloodstream, however. Glucose first moves into the bloodstream upon absorption from the intestine. Specialized cellular transporters called sodium-dependent hexose transporters shuttle glucose across the cells that line the intestinal tract, explain Drs. Campbell and Farrell. Once through the intestinal lining, glucose is free to dissolve in the blood, and travels around the body. The intestinal transporters act quickly, such that blood glucose rises rapidly aft Continue reading >>

C2006/f2402 '11 -- Outline For Lecture #6

Handouts: 6A-- Transport of glucose through body (gif) 6A-- pdf 6B -- RME (gif) 6B --RME (pdf) 6C -- Structure of Capillaries & Transcytosis (Posted on Courseworks). Here are links for a diagram of a capillary, a diagram of transcytosis, and an electron micrograph of a capillary. I. Putting all the Methods of Transport of Small Molecules Together or What Good is All This? A. How glucose gets from lumen of intestine → muscle and adipose cells. An example of how the various types of transport are used. (Handout 6A) Steps in the process: 1. How glucose exits lumen. Glucose crosses apical surface of epithelial cells primarily by Na+/Glucose co-transport. (2o act. transport). 2. Role of Na+/K+ pump. Pump in basolateral (BL) surface keeps Na+ in cell low, so Na+ gradient favors entry of Na+. (1o act. transport) 3. How glucose exits epithelial cells. a. Glucose (except that used for metabolism of epithelial cell) exits BL surface of cell by facilitated diffusion = carrier mediated transport. b. Transporter protein = GLUT2 (more details on GLUT family of proteins below). c. When glucose leaves cells it enters the interstitial fluid = IF = fluid in between body cells. 4. How glucose enters and leaves capillaries -- by simple diffusion through spaces between the cells. Cells surrounding capillaries in most of body are not joined by tight junctions. a. Material does NOT enter capillaries by diffusion across a membrane. Material diffuses through liquid in spaces (pores) between the cells. b. For structure of capillaries, see handout 6C, bottom. (Also see links at start of lecture.)Pictures are provided on handout since function is hard to understand without the anatomy. Picture shows how endothelial cells surround capillary lumen, forming pores between cells. Pores allow diffusio Continue reading >>

The Liver And Blood Glucose Levels

Tweet Glucose is the key source of energy for the human body. Supply of this vital nutrient is carried through the bloodstream to many of the body’s cells. The liver produces, stores and releases glucose depending on the body’s need for glucose, a monosaccharide. This is primarily indicated by the hormones insulin - the main regulator of sugar in the blood - and glucagon. In fact, the liver acts as the body’s glucose reservoir and helps to keep your circulating blood sugar levels and other body fuels steady and constant. How the liver regulates blood glucose During absorption and digestion, the carbohydrates in the food you eat are reduced to their simplest form, glucose. Excess glucose is then removed from the blood, with the majority of it being converted into glycogen, the storage form of glucose, by the liver’s hepatic cells via a process called glycogenesis. Glycogenolysis When blood glucose concentration declines, the liver initiates glycogenolysis. The hepatic cells reconvert their glycogen stores into glucose, and continually release them into the blood until levels approach normal range. However, when blood glucose levels fall during a long fast, the body’s glycogen stores dwindle and additional sources of blood sugar are required. To help make up this shortfall, the liver, along with the kidneys, uses amino acids, lactic acid and glycerol to produce glucose. This process is known as gluconeogenesis. The liver may also convert other sugars such as sucrose, fructose, and galactose into glucose if your body’s glucose needs not being met by your diet. Ketones Ketones are alternative fuels that are produced by the liver from fats when sugar is in short supply. When your body’s glycogen storage runs low, the body starts conserving the sugar supplies fo Continue reading >>

Metabolic Functions Of The Liver

Hepatocytes are metabolic overachievers in the body. They play critical roles in synthesizing molecules that are utilized elsewhere to support homeostasis, in converting molecules of one type to another, and in regulating energy balances. If you have taken a course in biochemistry, you probably spent most of that class studying metabolic pathways of the liver. At the risk of damning by faint praise, the major metabolic functions of the liver can be summarized into several major categories: Carbohydrate Metabolism It is critical for all animals to maintain concentrations of glucose in blood within a narrow, normal range. Maintainance of normal blood glucose levels over both short (hours) and long (days to weeks) periods of time is one particularly important function of the liver. Hepatocytes house many different metabolic pathways and employ dozens of enzymes that are alternatively turned on or off depending on whether blood levels of glucose are rising or falling out of the normal range. Two important examples of these abilities are: Excess glucose entering the blood after a meal is rapidly taken up by the liver and sequestered as the large polymer, glycogen (a process called glycogenesis). Later, when blood concentrations of glucose begin to decline, the liver activates other pathways which lead to depolymerization of glycogen (glycogenolysis) and export of glucose back into the blood for transport to all other tissues. When hepatic glycogen reserves become exhaused, as occurs when an animal has not eaten for several hours, do the hepatocytes give up? No! They recognize the problem and activate additional groups of enzymes that begin synthesizing glucose out of such things as amino acids and non-hexose carbohydrates (gluconeogenesis). The ability of the liver to synthe Continue reading >>

Facilitated Diffusion And Active Transport Of Glucose

Concept 4 Review Whether a cell uses facilitated diffusion or active transport depends on the specific needs of the cell. For example, the sugar glucose is transported by active transport from the gut into intestinal epithelial cells, but by facilitated diffusion across the membrane of red blood cells. Why? Consider how different these two environments are. Epithelial cells lining the gut need to bring glucose made available from digestion into the body and must prevent the reverse flow of glucose from body to gut. We need a mechanism to ensure that glucose always flows into intestinal cells and gets transported into the bloodstream, no matter what the gut concentration of glucose. Imagine what would happen if this were not so, and intestinal cells used facilitated diffusion carriers for glucose. Immediately after you ate a candy bar or other food rich in sugar, the concentration of glucose in the gut would be high, and glucose would flow "downhill" from the gut into your body. But an hour later, when your intestines were empty and glucose concentrations in the intestines were lower than in your blood and tissues, facilitated diffusion carriers would allow the glucose in blood and tissues to flow "downhill," back into the gut. This would quickly deplete your short-term energy reserves. Because this situation would be biologically wasteful and probably lethal, it is worth the additional energy cost of active transport to make sure that glucose transport is a one-way process. By contrast, erythrocytes (red blood cells) and most other tissues in your body move glucose by facilitated diffusion carriers, not by active transport. Facilitated diffusion makes sense in this context because the environment is different for red blood cells and the gut. Whereas the gut experiences Continue reading >>

Physiologic Effects Of Insulin

Stand on a streetcorner and ask people if they know what insulin is, and many will reply, "Doesn't it have something to do with blood sugar?" Indeed, that is correct, but such a response is a bit like saying "Mozart? Wasn't he some kind of a musician?" Insulin is a key player in the control of intermediary metabolism, and the big picture is that it organizes the use of fuels for either storage or oxidation. Through these activities, insulin has profound effects on both carbohydrate and lipid metabolism, and significant influences on protein and mineral metabolism. Consequently, derangements in insulin signalling have widespread and devastating effects on many organs and tissues. The Insulin Receptor and Mechanism of Action Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane. The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins. Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor. The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response. Several intracellular proteins have been identified as phosphorylation substrates for the insulin receptor, the best-studied of which is insulin receptor substrate 1 or IRS-1. When IRS-1 is activa Continue reading >>

The Process Of Glucose Entering The Cell

Transcript of The process of glucose entering the cell photo credit Nasa / Goddard Space Flight Center / Reto Stöckli Glucose and how it enters the cell Digestion Bibliography It all begins when food enters the body. Sugars are broken down into glucose. They prepare to go into the blood stream Glucose in the blood stream Insulin is a hormone produced in the pancreas. It causes cells in the liver, skeletal muscles, and fat tissues to take in glucose from the blood. In the liver and skeletal muscles, glucose is stored as glycogon. Insulin Glucose travels through the bloodstream and prepares itself to enter cells. Insulin opens up the cell Insulin travels to the cell receptor. Here it sends a chain link reaction known as signal transduction cascade. The signal transduction cascade causes more glucose transport proteins (glut) to be present. These glut open the membrane and allow a passage for glucose to enter the cell. Glut Recap 1. CareClub, Diabetes. "How Can Diabetes Affect the Digestion?" DiabetesCareClub. DiabetesCareClub, 24 Apr. 2012. Web. 16 Oct. 2012. <2. Media, Demand. "About Diabetes." LIVESTRONG.COM. LiveStrong, 10 Oct. 2012. Web. 16 Oct. 2012. <3. Times, Dreams. "Royalty Free Illustration: Glucose Molecule." Dreamstime. DreamsTime, 13 Mar. 2012. Web. 16 Oct. 2012. <4. Hoelzer, Mark. "Insulin and the Regulation of Glucose in the Blood." YouTube. YouTube, 08 Mar. 2011. Web. 16 Oct. 2012. 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 >>

Glucose Uptake

Method of glucose uptake differs throughout tissues depending on two factors; the metabolic needs of the tissue and availability of glucose. The two ways in which glucose uptake can take place are facilitated diffusion (a passive process) and secondary active transport (an active process which depends on the ion-gradient which is established through the hydrolysis of ATP, known as primary active transport). Facilitated diffusion[edit] There are over 10 different types of glucose transporters; however, the most significant for study are GLUT1-4. GLUT1 and GLUT3 are located in the plasma membrane of cells throughout the body, as they are responsible for maintaining a basal rate of glucose uptake. Basal blood glucose level is approximately 5mM (5 millimolar). The Km value (an indicator of the affinity of the transporter protein for glucose molecules; a low Km value suggests a high affinity) of the GLUT1 and GLUT3 proteins is 1mM; therefore GLUT1 and GLUT3 have a high affinity for glucose and uptake from the bloodstream is constant. GLUT2 in contrast has a high Km value (15-20mM) and therefore a low affinity for glucose. They are located in the plasma membranes of hepatocytes and pancreatic beta cells (in mice, but GLUT1 in human beta cells; see Reference 1). The high Km of GLUT2 allows for glucose sensing; rate of glucose entry is proportional to blood glucose levels. GLUT4 transporters are insulin sensitive, and are found in muscle and adipose tissue. As muscle is a principal storage site for glucose and adipose tissue for triglyceride (into which glucose can be converted for storage), GLUT4 is important in post-prandial uptake of excess glucose from the bloodstream. Moreover, several recent papers show that GLUT 4 is present in the brain also. The drug Metformin phosphor Continue reading >>

Liver Glucose Metabolism In Humans

Information about normal hepatic glucose metabolism may help to understand pathogenic mechanisms underlying obesity and diabetes mellitus. In addition, liver glucose metabolism is involved in glycosylation reactions and connected with fatty acid metabolism. The liver receives dietary carbohydrates directly from the intestine via the portal vein. Glucokinase phosphorylates glucose to glucose 6-phosphate inside the hepatocyte, ensuring that an adequate flow of glucose enters the cell to be metabolized. Glucose 6-phosphate may proceed to several metabolic pathways. During the post-prandial period, most glucose 6-phosphate is used to synthesize glycogen via the formation of glucose 1-phosphate and UDP–glucose. Minor amounts of UDP–glucose are used to form UDP–glucuronate and UDP–galactose, which are donors of monosaccharide units used in glycosylation. A second pathway of glucose 6-phosphate metabolism is the formation of fructose 6-phosphate, which may either start the hexosamine pathway to produce UDP-N-acetylglucosamine or follow the glycolytic pathway to generate pyruvate and then acetyl-CoA. Acetyl-CoA may enter the tricarboxylic acid (TCA) cycle to be oxidized or may be exported to the cytosol to synthesize fatty acids, when excess glucose is present within the hepatocyte. Finally, glucose 6-phosphate may produce NADPH and ribose 5-phosphate through the pentose phosphate pathway. Glucose metabolism supplies intermediates for glycosylation, a post-translational modification of proteins and lipids that modulates their activity. Congenital deficiency of phosphoglucomutase (PGM)-1 and PGM-3 is associated with impaired glycosylation. In addition to metabolize carbohydrates, the liver produces glucose to be used by other tissues, from glycogen breakdown or from de n Continue reading >>

Glucose Homeostasis

Glucose Homeostasis Most animals, are obliged to catabolize food and use the freed energy to drive anabolic synthesis. In other words, we consume complex substances, break them down to release energy and we use that energy to fuel, build and repair our own cellular components. From molds to mammals, glucose is quantitatively the most important fuel source for life on earth. It is the primary fuel for our nervous system and the preferred energy source during initial physical activity. Glucose is also an important building block for cellular structures. When the body needs to produce lactose, glycoproteins and glycolipids, they are all synthesized using glucose. We have two sources of glucose: 1) food, 2) products of metabolism. Food contains carbohydrates, lipids, proteins etc. Dietary carbohydrates are digested to yield simple sugar molecules in the gut. Simple sugars like glucose, galactose and fructose pass from the intestinal lumen to the liver via the portal circulation. Glucose makes up about 80% of absorbed dietary sugars. Galactose and fructose make up the difference. In addition to dietary carbohydrates, we can synthesize glucose from non carbohydrate products of metabolism (gluconeogenesis). Gluconeogenesis is particularly important during fasting and starvation because the testes, erythrocytes, kidney, lens and cornea are dependant upon glucose as their sole energy source. Glucose is also the primary fuel for the brain but if glucose is low it can use ketone bodies to replace about 20% of the its glucose requirement. Gluconeogenesis can provide the nervous system with a steady supply of glucose even during prolonged fasting. The activities of daily life require us to consume more nutrients at each meal than we can use immediately. However, the body can store o Continue reading >>

Cell Signalling

4 Glucose metabolism: an example of integration of signalling pathways 4.1 Glucose metabolism We are now in a position to draw together the major concepts and components of signalling, and show how they operate in one well-understood system, namely the regulation of the storage or release of glucose in the human body. From this, you will be able to recognize archetypal pathways represented in specific examples, you will be able to appreciate how the same basic pathways can be stimulated by different hormones in different tissues, and you will see how opposing hormones activate separate pathways that affect the same targets but in opposite ways. Following a meal, insulin is released into the bloodstream by pancreatic β cells. The overall systemic effects of insulin are to increase uptake of blood glucose into cells, and to promote its storage as glycogen in muscle and liver cells. (Note that glycogen is a polysaccharide consisting of repeated units of glucose used for shortterm energy storage by animal cells.) A rise in the concentration of blood glucose, such as that following the consumption of food, stimulates insulin production, which signals through the insulin RTK. The insulin RTK phosphorylates various substrate proteins, which link to several key signalling pathways such as the Ras–MAP kinase pathway. There are, however, two major pathways that control glycogen synthesis and breakdown in animal cells (Figure 47). Figure 47 The control of glycogen synthesis by insulin. Several proteins bind, and are phosphorylated by, the activated insulin receptor. Cbl activates a pathway that is implicated in the translocation of the glucose transporter GLUT4 to the membrane, allowing glucose transport into the cell. Meanwhile, IRS-1 serves as a docking protein for PI 3-kinas Continue reading >>