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Here’s the short answer: From a legal standpoint either one is sufficient to be considered dead. If you’re interested in some background about how this came to be, keep reading.Death is easy to define as the end of life. But that raises a question, “What is life?” Surprisingly, there is no firm consensus about the definition of life. It is, however, generally agreed that life has certain characteristics, among them are the ability to: 1) grow and change; 2) respond to stimuli from the environment; 3) maintain a complex chemistry within cells (homeostasis); and 4) produce offspring, to whom traits are passed. You may notice some things that are missing from this list. For example, things like sentience or other things that we normally associate with a functioning brain.For humans, death has traditionally been diagnosed by the cessation of the heartbeat and of breathing, but in the late 1960s a new definition of death was put forward, namely death as defined by neurologic criteria, something called “brain death.”The concept of brain death developed in parallel with the rise of organ transplantation. The organ transplantation era began in 1954 with the transplant of a kidney from one identical twin into another. Since we have two kidneys, and since one can live perfectly well with a single kidney, this was not a major ethical problem. However, in the 1960’s techniques were developed for transplanting organs like the liver or the heart— organs that we only have one of, organs that we can’t live without.Of course, it’s widely considered wrong to kill one person in order to save the life of another. Thus, donors need to be dead before vital organs are removed. However, they can’t have been dead for very long. Once circulation fails, the organs begin to deteriorate. As the demand for transplantable organs grew, what was needed was, somewhat paradoxically, a vital organ that could be taken from the living body of a dead donor.In 1968, an Ad Hoc Committee at Harvard proposed that a person could be diagnosed as dead when there was irreversible cessation of the function of the entire brain. Observational studies at the time indicated that, when brain death was diagnosed using strict clinical criteria, both respiratory and cardiac arrest inevitably followed, usually within a few days.By the 1980s, the concept of brain death was legally adopted across the country. The Uniform Determination of Death Act declared that death could be diagnosed by either of two routes: (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem.The act indicated that the determination of death must be made in accordance with “accepted medical standards” but it did not specify those standards. That was left up to medical organizations.For brain death, the agreed-upon diagnostic criteria were entirely clinical. That is, examination of the patient showed no evidence of activity in the brain or the brainstem. For example, there was no purposeful response to pain; the pupils didn’t react to light; and there was no effort to breathe when temporarily disconnected from the ventilator. No ancillary diagnostic tests were required. If a physical exam, performed twice over a 24-hour period, showed no evidence of brain or brainstem function, the patient was clinically and legally dead.You might ask, “What could cause irreversible cessation of all brain and brainstem functions?” The most common mechanism is the failure of circulation to the brain. More than any other organ, the brain depends on a constant flow of oxygen and energy sources.Here are two common scenarios. 1) If the heart stops beating but is subsequently re-started after more than 10-15 minutes have passed, the brain may be irreversibly damaged. 2) If something damages the brain and causes massive swelling, there may be a rise in intracranial pressure to a level above the blood pressure, and that causes blood flow to the brain to cease.Organ donation has saved many lives, and the need for donors continues to grow. As of this month, there are more that 100k people on a transplant waiting list. Yet, only about 3 in 1000 people die in a way that allows for organs to be harvested. Most of these are brain-dead donors. Thus, on balance, the concept of brain death has been a positive development. It saves lives through organ donation, and it saves money that might otherwise be spent supporting the breathing of someone who will never recover. However, some concerns have been raised, as noted below.There have been instances of people diagnosed as brain dead when they were not. Some of these people even recovered significant neurological function. In most of those cases, the cause of the misdiagnosis was taken to be a lack of strict adherence to the guidelines for diagnosis brain death.Recall that the acceptance of brain death as equivalent to cardio-respiratory death rested in part on the 1960’s observation that one couldn’t keep the heart and lungs of brain-dead person going, no matter how hard one tried. That is not so true today. The ability to support breathing and cardiac function has advanced since the 1960s.When a death certificate is issued, the date and time of death are noted. Historically, the time given is the time that the heartbeat and breathing finally stopped. For brain death, it’s more complicated. Brain cells don’t die all at once. Brain death is a process, not an instantaneous event. It evolves over time. There is no test, be it clinical or high tech, that determines whether every single one of the billions of the cells in the brain has ceased to function.Moreover, the criteria for determination of brain death do not mandate testing all brain functions. The law assumed that one could ascertain, by clinical exam alone, that all functions of the brain and brainstem had irreversibly ceased. But consider this: One function of the brain is to regulate the hormonal system. This is done in the part of the brain called the hypothalamus, which has direct connections with the master gland, the pituitary. Guidelines for diagnosing brain death do not mandate a check of the hormonal system. Yet, in people declared dead by neurological criteria, hormonal function may be normal. How is that possible if brain death really does mean “cessation of all functions of the entire brain”?To make matters more complicated, there have been recent reports that activity in brain cells can be restored even after profound and prolonged circulatory failure. In one experiment, the brains of slaughtered pigs were removed. Hours later, these brains were hooked up to a system that pumped an experimental solution into brain, and much to the surprise and delight of the researchers, this caused a resumption of electrical activity in nerve cells. After six hours of perfusion, they were reportedly able to restore full metabolic function in most of the brain. That is, the cells took oxygen and glucose and converted them into metabolites that are essential to living cells. (see link)‘Partly Alive’: Scientists Revive Cells in Brains From Dead Pigs (Published 2019)Here’s a quote from a reference linked below: “…our definition of death is man-made. In the spectrum between alive and dead, we set the threshold, and we can do so in response to biological, ethical and even practical considerations. Death is not a binary state or a simple biological fact but a complex social choice.”Opinion | What Is Death? (Published 2019)Finally, here is some food for thought: 1) Is life without a functioning brain worth living? 2) Yet, are we not more than just our brains? 3) For humans, what does it mean to be alive?

I nominate the writer and Harvard MD Dr. Michael Chrichton as the most famous skeptic of the so called climate change fear mongering. I add key studies by leading climate scientists that support Crichton in is skepticism.Michael Crichton13,786 followersMichael Crichton (1942-2008) was one of the most successful novelists of his generation, admired for his meticulous scientific research and fast-paced narrative. He graduated summa cum laude and earned his MD from Harvard Medical School in 1969.HIS famous bestseller book, STATE OF FEAR is his case for skepticism on global warming in fictional form.Reviews“Provocative and controversial. [Crichton] marries compelling subject matter with edge-of-your-seat storytelling.” (USA Today)“In STATE OF FEAR, Michael Crichton delivers a lightning-paced technopolitical thriller...every bit as informative as it is entertaining.” (Wall Street Journal)“Fascinating for how Crichton was trying to make the very absence of fear spooky.” (San Francisco Chronicle)“There’s no one else like him…a fast, fun read.” (Weekly Standard)“This is definitely one for the Christmas list.” (National Review)“He imparts science while entertaining readers.” (Denver Post)“STATE OF FEAR is a valuable education in the guise of entertainment. Do yourself a favor and buy it.” (Pittsburgh Post-Gazette)“The thrills of Crichton’s latest are interspersed with fascinating facts and data. Perhaps his most serious and important book yet.” (Booklist)“STATE OF FEAR is Michael Crichton’s best.” (http://Bookreporter.com)“Michael Crichton’s new book will appeal to your inner techie.” (Washington Post Book World)About the AuthorMichael Crichton (1942-2008) was the author of the bestselling novels The Terminal Man, The Great Train Robbery, Jurassic Park, Sphere, Disclosure, Prey, State of Fear, Next and Dragon Teeth, among many others. His books have sold more than 200 million copies worldwide, have been translated into forty languages, and have provided the basis for fifteen feature films. He wrote and directed Westworld, The Great Train Robbery, Runaway, Looker, Coma and created the hit television series ER. Crichton remains the only writer to have a number one book, movie, and TV show in the same year.Michael Crichton's 'Author's Message' from the book State of Fear:AUTHOR'S MESSAGEA novel such as State of Fear, in which so many divergent views are expressed, may lead the reader to wonder where, exactly, the author stands on these issues. I have been reading environmental texts for three years, in itself a hazardous undertaking. But I have had an opportunity to look at a lot of data, and to consider many points of view. I conclude:- We know astonishingly little about every aspect of the environment, from its past history, to its present state, to how to conserve and protect it. In every debate, all sides overstate the extent of existing knowledge and its degree of certainty.- Atmospheric carbon dioxide is increasing, and human activity is the probable cause.- We are also in the midst of a natural warming trend that began about 1850, as we emerged from a four-hundred-year cold spell known as the "Little Ice Age."- Nobody knows how much of the present warming trend might be a natural phenomenon.- Nobody knows how much of the present warming trend might be man-made.- Nobody knows how much warming will occur in the next century. The computer models vary by 400 percent, de facto proof that nobody knows. But if I had to guess-- the only thing anyone is doing, really-- I would guess the increase will be 0.812436 degrees C. There is no evidence that my guess about the state of the world one hundred years from now is any better or worse than anyone else's. (We can't "assess" the future, nor can we "predict" it. These are euphemisms. We can only guess. An informed guess is just a guess.)- I suspect that part of the observed surface warming will ultimately be attributable to human activity. I suspect that the principal human effect will come from land use, and that the atmospheric component will be minor.- Before making expensive policy decisions on the basis of climate models, I think it is reasonable to require that those models predict future temperatures accurately for a period of ten years. Twenty would be better.- I think for anyone to believe in impending resource scarcity, after two hundred years of such false alarms, is kind of weird. I don't know whether such a belief today is best ascribed to ignorance of history, sclerotic dogmatism, unhealthy love of Malthus, or simple pigheadedness, but it is evidently a hardy perennial in human calculation.- There are many reasons to shift away from fossil fuels, and we will do so in the next century without legislation, financial incentives, carbon-conservation programs, or the interminable yammering of fearmongers. So far as I know, nobody had to ban horse transport in the early twentieth century.- I suspect the people of 2100 will be much richer than we are, consume more energy, have a smaller global population, and enjoy more wilderness than we have today. I don't think we have to worry about them.- The current near-hysterical preoccupation with safety is at best a waste of resources and a crimp on the human spirit, and at worst an invitation to totalitarianism. Public education is desperately needed.- I conclude that most environmental "principles" (such as sustainable development or the precautionary principle) have the effect of preserving the economic advantages of the West and thus constitute modern imperialism toward the developing world. It is a nice way of saying, "We got ours and we don't want you to get yours, because you'll cause too much pollution."- The "precautionary principle," properly applied, forbids the precautionary principle. It is self-contradictory. The precautionary principle therefore cannot be spoken of in terms that are too harsh.- I believe people are well intentioned. But I have great respect for the corrosive influence of bias, systematic distortions of thought, the power of rationalization, the guises of self-interest, and the inevitability of unintended consequences.- I have more respect for people who change their views after acquiring new information than for those who cling to views they held thirty years ago. The world changes. Ideologues and zealots don't.- In the thirty-five-odd years since the environmental movement came into existence, science has undergone a major revolution. This revolution has brought new understanding of nonlinear dynamics, complex systems, chaos theory, catastrophe theory. It has transformed the way we think about evolution and ecology. Yet these no-longer-new ideas have hardly penetrated the thinking of environmental activists, which seems oddly fixed in the concepts and rhetoric of the 1970s.- We haven't the foggiest notion how to preserve what we term "wilderness," and we had better study it in the field and learn how to do so. I see no evidence that we are conducting such research in a humble, rational, and systematic way. I therefore hold little hope for wilderness management in the twenty-first century. I blame environmental organizations every bit as much as developers and strip miners. There is no difference in outcomes between greed and incompetence.- We need a new environmental movement, with new goals and new organizations. We need more people working in the field, in the actual environment, and fewer people behind computer screens. We need more scientists and many fewer lawyers.- We cannot hope to manage a complex system such as the environment through litigation. We can only change its state temporarily-- usually by preventing something-- with eventual results that we cannot predict and ultimately cannot control.- Nothing is more inherently political than our shared physical environment, and nothing is more ill served by allegiance to a single political party. Precisely because the environment is shared it cannot be managed by one faction according to its own economic or aesthetic preferences. Sooner or later, the opposing faction will take power, and previous policies will be reversed. Stable management of the environment requires recognition that all preferences have their place: snowmobilers and fly fishermen, dirt bikers and hikers, developers and preservationists. These preferences are at odds, and their incompatibility cannot be avoided. But resolving incompatible goals is a true function of politics.- We desperately need a nonpartisan, blinded funding mechanism to conduct research to determine appropriate policy. Scientists are only too aware whom they are working for. Those who fund research-- whether a drug company, a government agency, or an environmental organization-- always have a particular outcome in mind. Research funding is almost never open-ended or open-minded. Scientists know that continued funding depends on delivering the results the funders desire. As a result, environmental organization "studies" are every bit as biased and suspect as industry "studies." Government "studies" are similarly biased according to who is running the department or administration at the time. No faction should be given a free pass.- I am certain there is too much certainty in the world.- I personally experience a profound pleasure being in nature. My happiest days each year are those I spend in wilderness. I wish natural environments to be preserved for future generations. I am not satisfied they will be preserved in sufficient quantities, or with sufficient skill. I conclude that the "exploiters of the environment" include environmental organizations, government organizations, and big business. All have equally dismal track records.- Everybody has an agenda. Except me.AMAZONDavid W. Wildeboer4.0 out of 5 starsRead this book - no matter what side of the debate you're onReviewed in Canada on May 6, 2005Verified PurchaseOne of the masters of the science type thriller (the Jurassic Park books, Timeline, etc.) returns with this compelling and well researched thriller that challenges the bedrock upon which the environmental movement and the global warming debate stand. Using well thought out and documented arguments, Crichton questions the present infatuation with the fear of global warming. As the thriller suggests, anyone with a view contrary to the media and environmental elite is instantly discredited. Using a radical environmental organization's (one that really exists) plans to further their agenda allows the author to expound in laymen's terms on the arguments for (very little reliable and reproducible evidence) global warming and those against it.Crichton also gives the reader a lesson on the pervasiveness of the media in our society and how it can drive opinion even when the evidence isn't there. Dr. Crichton has written an engrossing thriller that can be enjoyed for the thrills alone, yet he's also made an important argument about not blindly believing "everything" but instead, checking the evidence for oneself.No matter what side of the debate about the theory of "global warming" (remember, it is only a theory, it's not a proven scientific fact) and climate change one is on, this book deserves a read. I challenge everyone, no matter how set in your beliefs you are, to read this with skepticism, check out the references and do the research yourself and prove Crichton wrong. Go for it!AMAZONPopular opinions are almost always wrong. That's the theme of this book. The point is made in the context of describing how global warming, as perceived by the public and media, is different from what scientists are describing. Dr. Crichton argues through his story that we can waste a lot of time and resources on popular delusions, and we need to get our facts right. His appendix I on the dangers of politicized science is something everyone should read. The eugenics example is a chilling one.AMAZONMay 24, 2008Brian rated it it was amazing · review of another editionShelves: fiction, 2009"So what [we:] need is to structure the information so that whatever kind of weather occurs, it always confirms your message. That's the virtue of shifting the focus to abrupt climate change. It enables [us:] to use everything that happens. There will always be floods, and freezing storms, and cyclones, and hurricanes. These events will always get airtime. And in every instance, [we:] can claim it is an example of global warming. So the message gets reinforced. The urgency is increased."This from a PR person in the book that works for a large and mainstream environmentalist group. But it could have been spoken by any of the ideologues of the movement as they switch from just global warming to climate change, and try to capitalize on every disaster as a reason for their existence.As I mentioned in one of my updates, this is my first try at a Michael Crichton book and I found it well-informed and fast-paced. The plot is plausible enough (at least until the end) and serves as a rebuttal to the claims of the power hungry environmentalist crowd. It is his case for skepticism on global warming in fictional form.A key graph:"Has it occurred to you how astonishing the culture of Western society really is? Industrialized nations provide their citizens with unprecedented safety, health, and comfort. Average life spans increased fifty percent in the last century. Yet modern people live in abject fear. They are afraid of strangers, of disease, of crime, of the environment. They are afraid of the homes they live in, the food they eat, the technology that surrounds them. They are in a particular panic over the things they can't even see--germs, chemicals, additives, pollutants. They are timid, nervous, fretful, and depressed. And even more amazingly, they are convinced that the environment of the entire plant is being destroyed around them. Remarkable!"State of Fear GOODREADSSpiritual Ecology Versus ScienceEnvironmentalism as Religion by Michael CrichtonOne of the defining features of religion is that your beliefs are not troubled by facts, because they have nothing to do with facts.Michael CrichtonIn 2003 Michael Crichton sent the Ecology industry into a rage by exposing them as a religion. He can get away with it because he has both the science background and enough money not to be silenced by the eco-lobby. In fact environmentalism is as much a fundamentalist' religion as that of Pat Robertson. He is correct about the religious undertones, but it's also a political movement as he points out.In 2008 global warming has fallen off the radar as the presidential election, high energy costs, and the Wall Street meltdown have dominated the news. But this one article seems to have been left out of the discussion. Besides reports of such record cold in Mongolia killing people and livestock, the December 19, 2007 Washington Times reports:"In Buenos Aires (Argentina), snow fell for the first time since the year 1918. Dozens of homeless people died from exposure. In Peru, 200 people died from the cold...(in 2007) Johannesburg, South Africa, had the first significant snowfall in 26 years. Australia...New Zealand...weather turned so cold..."Remarks to the Commonwealth Club by Michael Crichton San Francisco September 15, 2003 (Extract)I have been asked to talk about what I consider the most important challenge facing mankind, and I have a fundamental answer. The greatest challenge facing mankind is the challenge of distinguishing reality from fantasy, truth from propaganda. Perceiving the truth has always been a challenge to mankind, but in the information age (or as I think of it, the disinformation age) it takes on a special urgency and importance.We must daily decide whether the threats we face are real, whether the solutions we are offered will do any good, whether the problems we're told exist are in fact real problems, or non-problems. Every one of us has a sense of the world, and we all know that this sense is in part given to us by what other people and society tell us; in part generated by our emotional state, which we project outward; and in part by our genuine perceptions of reality. In short, our struggle to determine what is true is the struggle to decide which of our perceptions are genuine, and which are false because they are handed down, or sold to us, or generated by our own hopes and fears.As an example of this challenge, I want to talk today about environmentalism. And in order not to be misunderstood, I want it perfectly clear that I believe it is incumbent on us to conduct our lives in a way that takes into account all the consequences of our actions, including the consequences to other people, and the consequences to the environment. I believe it is important to act in ways that are sympathetic to the environment, and I believe this will always be a need, carrying into the future.I believe the world has genuine problems and I believe it can and should be improved. But I also think that deciding what constitutes responsible action is immensely difficult, and the consequences of our actions are often difficult to know in advance. I think our past record of environmental action is discouraging, to put it mildly, because even our best intended efforts often go awry. But I think we do not recognize our past failures, and face them squarely. And I think I know why.I studied anthropology in college, and one of the things I learned was that certain human social structures always reappear. They can't be eliminated from society. One of those structures is religion. Today it is said we live in a secular society in which many people---the best people, the most enlightened people---do not believe in any religion. But I think that you cannot eliminate religion from the psyche of mankind. If you suppress it in one form, it merely re-emerges in another form. You can not believe in God, but you still have to believe in something that gives meaning to your life, and shapes your sense of the world. Such a belief is religious.Today, one of the most powerful religions in the Western World is environmentalism. Environmentalism seems to be the religion of choice for urban atheists. Why do I say it's a religion? Well, just look at the beliefs. If you look carefully, you see that environmentalism is in fact a perfect 21st century remapping of traditional Judeo-Christian beliefs and myths.There's an initial Eden, a paradise, a state of grace and unity with nature, there's a fall from grace into a state of pollution as a result of eating from the tree of knowledge, and as a result of our actions there is a judgment day coming for us all. We are all energy sinners, doomed to die, unless we seek salvation, which is now called sustainability. Sustainability is salvation in the church of the environment. Just as organic food is its communion, that pesticide-free wafer that the right people with the right beliefs, imbibe.Eden, the fall of man, the loss of grace, the coming doomsday---these are deeply held mythic structures. They are profoundly conservative beliefs. They may even be hard-wired in the brain, for all I know. I certainly don't want to talk anybody out of them, as I don't want to talk anybody out of a belief that Jesus Christ is the son of God who rose from the dead. But the reason I don't want to talk anybody out of these beliefs is that I know that I can't talk anybody out of them. These are not facts that can be argued. These are issues of faith.And so it is, sadly, with environmentalism. Increasingly it seems facts aren't necessary, because the tenets of environmentalism are all about belief. It's about whether you are going to be a sinner, or saved. Whether you are going to be one of the people on the side of salvation, or on the side of doom. Whether you are going to be one of us, or one of them.Am I exaggerating to make a point? I am afraid not. Because we know a lot more about the world than we did forty or fifty years ago. And what we know now is not so supportive of certain core environmental myths, yet the myths do not die. Let's examine some of those beliefs.There is no Eden. There never was. What was that Eden of the wonderful mythic past? Is it the time when infant mortality was 80%, when four children in five died of disease before the age of five? When one woman in six died in childbirth? When the average lifespan was 40, as it was in America a century ago. When plagues swept across the planet, killing millions in a stroke. Was it when millions starved to death? Is that when it was Eden?...In short, the romantic view of the natural world as a blissful Eden is only held by people who have no actual experience of nature. People who live in nature are not romantic about it at all. They may hold spiritual beliefs about the world around them, they may have a sense of the unity of nature or the aliveness of all things...If Eden is a fantasy that never existed, and mankind wasn't ever noble and kind and loving, if we didn't fall from grace, then what about the rest of the religious tenets? What about salvation, sustainability, and judgment day? What about the coming environmental doom from fossil fuels and global warming, if we all don't get down on our knees and conserve every day?Well, it's interesting. You may have noticed that something has been left off the doomsday list, lately. Although the preachers of environmentalism have been yelling about population for fifty years, over the last decade world population seems to be taking an unexpected turn. Fertility rates are falling almost everywhere.As a result, over the course of my lifetime the thoughtful predictions for total world population have gone from a high of 20 billion, to 15 billion, to 11 billion (which was the UN estimate around 1990) to now 9 billion, and soon, perhaps less. There are some who think that world population will peak in 2050 and then start to decline. There are some who predict we will have fewer people in 2100 than we do today.Is this a reason to rejoice, to say halleluiah? Certainly not. Without a pause, we now hear about the coming crisis of world economy from a shrinking population. We hear about the impending crisis of an aging population. Nobody anywhere will say that the core fears expressed for most of my life have turned out not to be true...Okay, so, the preachers made a mistake. They got one prediction wrong; they're human. So what. Unfortunately, it's not just one prediction. It's a whole slew of them. We are running out of oil. (Note: oil has fallen to $45 a barrel June 2017) We are running out of all natural resources. Paul Ehrlich: 60 million Americans will die of starvation in the 1980s. Forty thousand species become extinct every year. (Ehrlich is still at it in 2017. See There's No Man-Made Global Mass Extinction.)Half of all species on the planet will be extinct by 2000. And on and on and on. With so many past failures, you might think that environmental predictions would become more cautious. But not if it's a religion. Remember, the nut on the sidewalk carrying the placard that predicts the end of the world doesn't quit when the world doesn't end on the day he expects.He just changes his placard, sets a new doomsday date, and goes back to walking the streets. One of the defining features of religion is that your beliefs are not troubled by facts, because they have nothing to do with facts....I can cite the appropriate journal articles not in whacko magazines, but in the most prestigious science journals, such as Science and Nature. But such references probably won't impact more than a handful of you, because the beliefs of a religion are not dependant on facts, but rather are matters of faith. Unshakeable belief.See part 2 Religious Fundamentalism Explained by Michael Crichton.Common Sense Environmentalism (Archive)Spiritual Ecology Versus ScienceDr. James Hansen Paid EnvironmentalistGreen Religion Won't Save AppalachiaHow Ecological Homeostasis and Hysteresis Regulate ClimateMichael Crichton Speech - Environmentalism as ReligionDissecting Al Gore's Book Earth in the BalancePostmodernism Attacks Reason, Science, and CultureAges of Gaia Writer James Lovelock Sounds an AlarmWriter James Lovelock Backtracks on Revenge of GaiaHypsithermal Warming Spreads CivilizationShockingly Rapid Climatic Shifts are RealBikini Atoll Recovery From Nuclear BlastsNASA says Earth Going GreenerClimate change changes history:Fall of the Late Roman EmpireEnd of the Vikings in GreenlandLost Colony of Roanoke IslandWhale Fossils Unlock the History of the North[ Challenge to Atheists 1 ] [ Challenge to Atheists 2 ][ Challenge to Atheists 3 ] [ Challenge to Atheists 4 ][ Challenge to Atheists 5 ]Environmental Religion by Michael CrichtonEnvironmental Religion by Michael Crichton“The Climate Scientists' Register“We, the undersigned, having assessed the relevant scientific evidence, do not find convincing support for the hypothesis that human emissions of carbon dioxide are causing, or will in the foreseeable future cause, dangerous global warming."Click on country name in the following list to see endorsers from that nation:Algéria (1 endorser), Australia (8), Bulgaria (1), Canada (17), Denmark (1),Estonia (1), Finland(1), France (1), Germany (4), Greece (1), India (3),Italy (3), Luxembourg (1), Mexico (1), New Zealand (6), Norway (5),Poland (3), Russia (5), South Africa (1), Sweden(8), United Kingdom (6),United States of America (64).CAMILLE PAGLIAOCTOBER 10, 2007 11:19AM (UTC)I too grew up in upstate New York. I am an environmental groundwater geologist (who almost majored in fine arts). Your take on the Al Gore/global warming pseudo-catastrophe was right on target. Anyone can read up on Holocene geology and see that climate changes are caused by polar wandering and magnetic reversals. It is entertaining, yet sad to read bloviage from Leonardo DiCaprio, who is so self-centered that he thinks the earth's history and climate is a function of his short personal stay on this planet. Still he, Al Gore, Prince Charles and so on, ad nauseam, continue with their jet-set lifestyles. What hypocrisy!Thank you for your input on the mass hysteria over global warming. The simplest facts about geology seem to be missing from the mental equipment of many highly educated people these days. There is far too much credulity placed in fancy-pants, speculative computer modeling about future climate change. Furthermore, hand-wringing media reports about hotter temperatures in the Northern Hemisphere are rarely balanced by acknowledgment of the recent cold waves in South Africa and Australia, the most severe in 30 years.Where are the intellectuals in this massive attack of groupthink? Inert, passive and cowardly, the lot of them. True intellectuals would be alarmed and repelled by the heavy fog of dogma that now hangs over the debate about climate change. More skeptical voices need to be heard. Why are liberals abandoning this issue to the right wing, which is successfully using it to contrast conservative rationality with liberal emotionalism? The environmental movement, whose roots are in nature-worshipping Romanticism, is vitally important to humanity, but it can only be undermined by rampant propaganda and half-truths.https://www.salon.com/2007/10/10/britney/Camille Paglia is a second-wave feminist and an American academic specializing in literature and culture, particularly topics around gender, sex, and sexuality. She has taught at the University of the Arts in Philadelphia since 1984, but is better known for her books and journalism. In 2005 she was voted #20 on a list of top public intellectuals by Prospect and Foreign Policy magazines.[Here are details of leading climate scientists skeptical of Anthropogenic Global Warming as a valid hypothesis. The list includes peer reviewed papers in major science journals. I AM UNAWARE OF ANY ANY PEER REVIEWED RESEARCH SUPPORTING THE IPCC AGW HYPOTHESIS. For example, here is very recent published research in the Environment Pollution Climate Change Journal“Hence, there are no greenhouse gases in reality – as in, gases that can cause warming,” Nikolov said when asked to explain the paper in layman’s terms.“Humans cannot in principle affect the global climate through industrial emissions of CO2, methane and other similar gases or via changes in land use,” he added. “All observed climatic changes have natural causes that are completely outside of human control.”For the first time, Nikolov said, there is now empirical evidence from NASA data that the greenhouse effect of the atmosphere is not caused by the trapping of heat, but by the force of atmospheric pressure.The pressure is the weight of the atmosphere, he added.Citation: Nikolov N, Zeller K (2017) New Insights on the Physical Nature of the Atmospheric Greenhouse Effect Deduced from an Empirical Planetary Temperature Model. Environment Pollution Climate Change Journal 1: 112.See more detail below.The Chinese scholars have addressed the issue head on in research published by the prestigious NATURE JOURNALinstrumental temperature recordNew research confirms the view of leading climate scientists and scholars that trace amounts of Co2 emissions are not destabilizing the planet. Co2 is essential plant food and therefore green energy.The authors Geli Wang & Peicai Yang and Xiuji Zhou are scientists at the CHINESE ACADEMY OF SCIENCE andChinese Academy of Meteorological Sciences, Beijing, China 中国气象科学研究院ANTHROPOGENIC (human activity). The driving forces are“the El Niño–Southern Oscillation cycle and the Hale sunspot cycle, respectively.”The title of the study published in the prestigious NATURE Journal is: Identification of the driving forces of climate change using the longest instrumental temperature recordhttps://www.nature.com/articles/...Their study confirms THE DRIVING FORCES OF GLOBAL WARMING AND CLIMATE CHANGE ARE NATURALThe “driving forces” of climate change are natural and not Co2 plant food emissions. A new Chinese study confirms climate change comes from natural cycles. This research is based on the longest actual temperature data of more than 400 years from 1659 to 2013, including the period of anthropogenic warming.AbstractThe identification of causal effects is a fundamental problem in climate change research. Here, a new perspective on climate change causality is presented using the central England temperature (CET) dataset, the longest instrumental temperature record, and a combination of slow feature analysis and wavelet analysis. The driving forces of climate change were investigated and the results showed two independent degrees of freedom —a 3.36-year cycle and a 22.6-year cycle, which seem to be connected to the El Niño–Southern Oscillation cycle and the Hale sunspot cycle, respectively. [Emphasis added]. Moreover, these driving forces were modulated in amplitude by signals with millennial timescales.MY PUBLISHED COMMENTJames Matkin 
This Chinese research is very relevant and should make climate alarmists pause in their crusade against Co2 emissions from fossil fuels. Far too much focus on Co2 like a one trick pony in a big tent circus where solar radiation is a more compelling show. The thrust of recent research has demonstrated that climate changes continually and is determined by natural forces that humans have no significant control over. Many leading scientists have presented research of other "driving forces" and cautioned against the arrogance of many that "the science is settled." See Judith Curry of the Georgia Institute of Technology and blogger at Climate Etc. talks with EconTalk host Russ Roberts about climate change. Curry argues that climate change is a "wicked problem" with a great deal of uncertainty surrounding the expected damage as well as the political and technical challenges of dealing with the phenomenon. She emphasizes the complexity of the climate and how much of the basic science remains incomplete. The conversation closes with a discussion of how concerned citizens can improve their understanding of climate change and climate change policy.
http://www.econtalk.org/arc...https://www.nature.com/articles/...This peer reviewed from German scientists demolishs the false idea of a greenhouse effect heating the planet with minute amounts of Co2 plant food emissions from fossil fuels.GERMAN CLIMATE RESEARCH PAPERFalsification Of The Atmospheric CO2 Greenhouse Effects Within The Frame Of PhysicsGerhard Gerlich, Ralf D. Tscheuschner(Submitted on 8 Jul 2007 (v1), last revised 4 Mar 2009 (this version, v4))The atmospheric greenhouse effect, an idea that many authors trace back to the traditional works of Fourier (1824), Tyndall (1861), and Arrhenius (1896), and which is still supported in global climatology, essentially describes a fictitious mechanism, in which a planetary atmosphere acts as a heat pump driven by an environment that is radiatively interacting with but radiatively equilibrated to the atmospheric system. According to the second law of thermodynamics such a planetary machine can never exist. Nevertheless, in almost all texts of global climatology and in a widespread secondary literature it is taken for granted that such mechanism is real and stands on a firm scientific foundation. In this paper the popular conjecture is analyzed and the underlying physical principles are clarified. By showing that (a) there are no common physical laws between the warming phenomenon in glass houses and the fictitious atmospheric greenhouse effects, (b) there are no calculations to determine an average surface temperature of a planet, (c) the frequently mentioned difference of 33 degrees Celsius is a meaningless number calculated wrongly, (d) the formulas of cavity radiation are used inappropriately, (e) the assumption of a radiative balance is unphysical, (f) thermal conductivity and friction must not be set to zero, the atmospheric greenhouse conjecture is falsified.115 pages, 32 figures, 13 tables (some typos corrected)Atmospheric and Oceanic Physics (http://physics.ao-ph)Journal reference: Int.J.Mod.Phys.B23:275-364,2009DOI: 10.1142/S021797920904984XCite as: arXiv:0707.1161 [http://physics.ao-ph](or arXiv:0707.1161v4 [http://physics.ao-ph] for this version)PEER REVIEWIzvestiya, Atmospheric and Oceanic Physics is a peer reviewed journal. We use a double blind peer review format. Our team of reviewers includes 75 reviewers, both internal and external (90%). The average period from submission to first decision in 2017 was 30 days, and that from first decision to acceptance was 30 days. The rejection rate for submitted manuscripts in 2017 was 20%. The final decision on the acceptance of an article for publication is made by the Editorial Board.Henrik Svensmark: While the Sun Sleeps“In fact global warming has stopped and a cooling is beginning. No climate model has predicted a cooling of the Earth – quite the contrary. And this means that the projections of future climate are unreliable,” writes Henrik Svensmark.A brilliant Danish scientist PROF HENRIK SVENSMARK explained this reality as follows:Svensmark: “global warming stopped and a cooling is beginning” – “enjoy global warming while it lasts”Anthony Watts / September 10, 2009While the sun sleepsTranslation approved by Henrik SvensmarkWhile the Sun sleepsHenrik Svensmark, Professor, Technical University of Denmark, CopenhagenThe star that keeps us alive has, over the last few years, been almost free of sunspots, which are the usual signs of the Sun’s magnetic activity. Last week [4 September 2009] the scientific team behind the satellite SOHO (Solar and Heliospheric Observatory) reported, “It is likely that the current year’s number of blank days will be the longest in about 100 years.” Everything indicates that the Sun is going into some kind of hibernation, and the obvious question is what significance that has for us on Earth.If you ask the Intergovernmental Panel on Climate Change (IPCC) which represents the current consensus on climate change, the answer is a reassuring “nothing”. But history and recent research suggest that is probably completely wrong. Why? Let’s take a closer look.2. Scrutinizing the atmospheric greenhouse effect and its climatic impactDOI: 10.4236/ns.2011.312124 15,065 Downloads 36,460 Views CitationsGerhard Kramm, Ralph DlugiABSTRACTIn this paper, we scrutinize two completely different explanations of the so-called atmospheric greenhouse effect: First, the explanation of the American Meteorological Society (AMS) and the World Meteorological Organization (W?MO) quan- tifying this effect by two characteristic temperatures, secondly, the explanation of Ramanathan et al. [1] that is mainly based on an energy-flux budget for the Earth-atmosphere system. Both explanations are related to the global scale. In addition, we debate the meaning of climate, climate change, climate variability and climate variation to outline in which way the atmospheric greenhouse effect might be responsible for climate change and climate variability, respectively. In doing so, we distinguish between two different branches of climatology, namely 1) physical climatology in which the boundary conditions of the Earth-atmosphere system play the dominant role and 2) statistical climatology that is dealing with the statistical description of fortuitous weather events which had been happening in climate periods; each of them usually comprises 30 years. Based on our findings, we argue that 1) the so-called atmospheric greenhouse effect cannot be proved by the statistical description of fortuitous weather events that took place in a climate period, 2) the description by AMS and W?MO has to be discarded because of physical reasons, 3) energy-flux budgets for the Earth-atmosphere system do not provide tangible evidence that the atmospheric greenhouse effect does exist. Because of this lack of tangible evidence it is time to acknowledge that the atmospheric greenhouse effect and especially its climatic impact are based on meritless conjectures. [Emphasis added]KEYWORDSPhysical Climatology; Statistical Climatology; Atmospheric Greenhouse Effect; Earth-Atmosphere SystemCite this paperKramm, G. and Dlugi, R. (2011) Scrutinizing the atmospheric greenhouse effect and its climatic impact. Natural Science, 3, 971-998. doi: 10.4236/ns.2011.312124.“In fact global warming has stopped and a cooling is beginning. No climate model has predicted a cooling of the Earth – quite the contrary. And this means that the projections of future climate are unreliable,” writes Henrik Svensmark.Environment Pollution andClimate Change JOURNALNew Insights on the Physical Nature of the Atmospheric GreenhouseEffect Deduced from an Empirical Planetary Temperature ModelNed Nikolov* and Karl ZellerAbstractA recent study has revealed that the Earth’s natural atmospheric greenhouse effect is around 90 K or about 2.7 times stronger than assumed for the past 40 years. A thermal enhancement of such a magnitude cannot be explained with the observed amount of outgoing infrared long-wave radiation absorbed by the atmosphere (i.e. ≈ 158 W m-2), thus requiring a re-examination of the underlying Greenhouse theory. We present here a new investigation into the physical nature of the atmospheric thermal effect using a novel empirical approach toward predicting the Global Mean Annual near-surface equilibrium Temperature (GMAT) of rocky planets with diverse atmospheres. Our method utilizes Dimensional Analysis (DA) applied to a vetted set of observed data from six celestial bodies representing a broad range of physical environments in our Solar System, i.e. Venus, Earth, the Moon, Mars, Titan (a moon of Saturn), and Triton (a moon of Neptune). Twelve relationships (models) suggested by DA are explored via non-linear regression analyses that involve dimensionless products comprised of solar irradiance, greenhouse-gas partial pressure/density and total atmospheric pressure/density as forcing variables, and two temperature ratios as dependent variables. One non-linear regression model is found to statistically outperform the rest by a wide margin. Our analysis revealed that GMATs of rocky planets with tangible atmospheres and a negligible geothermal surface heating can accurately be predicted over a broad range of conditions using only two forcing variables: top-of-the-atmosphere solar irradiance and total surface atmospheric pressure. The hereto discovered interplanetary pressure-temperature relationship is shown to be statistically robust while describing a smooth physical continuum without climatic tipping points. This continuum fully explains the recently discovered 90 K thermal effect of Earth’s atmosphere. The new model displays characteristics of an emergent macro-level thermodynamic relationship heretofore unbeknown to science that has important theoretical implications. A key entailment from the model is that the atmospheric ‘greenhouse effect’ currently viewed as a radiative phenomenon is in fact an adiabatic (pressure-induced) thermal enhancement analogous to compression heating and independent of atmospheric composition. Consequently, the global down-welling long-wave flux presently assumed to drive Earth’s surface warming appears to be a product of the air temperature set by solar heating and atmospheric pressure. In other words, the so-called ‘greenhouse back radiation’ is globally a result of the atmospheric thermal effect rather than a cause for it. Our empirical model has also fundamental implications for the role of oceans, water vapour, and planetary albedo in global climate. Since produced by a rigorous attempt to describe planetary temperatures in the context of a cosmic continuum using an objective analysis of vetted observations from across the Solar System, these findings call for a paradigm shift in our understanding of the atmospheric ‘greenhouse effect’ as a fundamental property of climate.Received November 11, 2016;Accepted February 06, 2017;Citation: Nikolov N, Zeller K (2017) New Insights on the Physical Nature of the Atmospheric Greenhouse Effect Deduced from an Empirical Planetary Temperature Model. Environment Pollution Climate Change Journal 1: 112.https://www.researchgate.net/pro...STUDY BLOWS 'GREENHOUSE THEORY OUT OF THE WATER''All observed climatic changes have natural causes completely outside of human control'Published: 07/08/2017 at 8:53 PMRead more at Study blows ‘greenhouse theory out of the water’ - WNDBOZEMAN, Mont. – A new scientific paper contends the entire foundation of the man-made global-warming theory – the assumption that greenhouse gases warm the atmosphere by trapping heat – is wrong.If confirmed, the study’s findings would crush the entire “climate change” movement to restrict CO2 emissions, the authors assertSome experts contacted by WND criticized the paper, while others advised caution.Still others suggested that the claimed discovery represents a massive leap forward in human understanding – a “new paradigm.”The paper argues that concentrations of CO2 and other supposed “greenhouse gases” in the atmosphere have virtually no effect on the earth’s temperature.They conclude the entire greenhouse gas theory is incorrect.Instead, the earth’s “greenhouse” effect is a function of the sun and atmospheric pressure, which results from gravity and the mass of the atmosphere, rather than the amount of greenhouse gases such as CO2 and water vapor in the atmosphere.The same is true for other planets and moons with a hard surface, the authors contend, pointing to the temperature and atmospheric data of various celestial bodies collected by NASA.So precise is the formula, the authors of the paper told WND, that, by using it, they were able to correctly predict the temperature of other celestial bodies not included in their original analysis.The paperThe paper, published recently in the journal “Environment Pollution and Climate Change,” was written by Ned Nikolov, a Ph.D. in physical science, and Karl Zeller, retired Ph.D. research meteorologist.The prevailing theory on the earth’s temperature is that heat from the sun enters the atmosphere, and then greenhouse gases such as CO2, methane and water vapor trap part of that energy by preventing it from escaping back into space.That theory, which underpins the anthropogenic global-warming hypothesis and the climate models used by the United Nations, was first proposed and developed in the 19th century.However, the experiments on which it was based involved glass boxes that retain heat by preventing the mixing of air inside the box with air outside the box.The truth about global warming is no further than the WND Superstore, where “Climategate,” “The Greatest Hoax,” and more publications are available.The experiment is not analogous to what occurs in the real atmosphere, which does not have walls or a lid, according to Nikolov and Zeller.The new paper, headlined “New Insights on the Physical Nature of the Atmospheric Greenhouse Effect Deduced from an Empirical Planetary Temperature Model,” argues that greenhouse theory is incorrect.“This was not a pre-conceived conclusion, but a result from an objective analysis of vetted NASA observations,” Nikolov told WND.The real mechanisms that control the temperature of the planet, they say, are the sun’s energy and the air pressure of the atmosphere. The same applies to other celestial bodies, according to the scientists behind the paper.To understand the phenomena, the authors used three planets – Venus, Earth and Mars – as well as three natural satellites: the Moon of Earth, Titan of Saturn and Triton of Neptune.They chose the celestial bodies based on three criteria: having a solid surface, representation of a broad range of environments, and the existence of reliable data on temperature, atmospheric composition and air pressure.“Our analysis revealed a poor relationship between global mean annual temperature] and the amount of greenhouse gases in planetary atmospheres across a broad range of environments in the Solar System,” the paper explains.“This is a surprising result from the standpoint of the current Greenhouse theory, which assumes that an atmosphere warms the surface of a planet (or moon) via trapping of radiant heat by certain gases controlling the atmospheric infrared optical depth,” the study continues.image:The paper outlines four possible explanations for those observations, and concludes that the most plausible was that air pressure is responsible for the greenhouse effect on a celestial body.In essence, what is commonly known as the atmospheric “greenhouse” effect is in fact a form of compression heating caused by total air pressure, the authors told WND in a series of e-mails and phone interviews, comparing the mechanics of it to the compression in a diesel engine that ignites the fuel.”And that effect is completely independent of the so-called “greenhouse gases” and the chemical composition of the atmosphere, they added.“Hence, there are no greenhouse gases in reality – as in, gases that can cause warming,” Nikolov said when asked to explain the paper in layman’s terms.“Humans cannot in principle affect the global climate through industrial emissions of CO2, methane and other similar gases or via changes in land use,” he added. “All observed climatic changes have natural causes that are completely outside of human control.”For the first time, Nikolov said, there is now empirical evidence from NASA data that the greenhouse effect of the atmosphere is not caused by the trapping of heat, but by the force of atmospheric pressure.The pressure is the weight of the atmosphere, he added.And the combination of gravity and the mass of the atmosphere explains why the Earth, for example, is warmer than the moon.“The moon receives about the same amount of heat from the sun as Earth, yet it is 90 degrees [Celsius] colder than the Earth, because it has no atmosphere,” Nikolov explained.Read more at https://www.wnd.com/2017/07/study-blows-greenhouse-theory-out-of-the-water/#FPuf1lW59KOtRBxu.99“In fact global warming has stopped and a cooling is beginning. No climate model has predicted a cooling of the Earth – quite the contrary. And this means that the projections of future climate are unreliable,” writes Henrik Svensmark.Leading climate scientists who doubt the science of the IPCC and Al Gore alarmism.Nobel Laureate in Physics Dr. Ivar Giaever; "Global Warming is Pseudoscience"MIT Professor Richard Lindzen and his recent lecture:ConclusionSo there you have it. An implausible conjecture backed by false evidence and repeated incessantly has become politically correct ‘knowledge,’ and is used to promote the overturn of industrial civilization. What we will be leaving our grandchildren is not a planet damaged by industrial progress, but a record of unfathomable silliness as well as a landscape degraded by rusting wind farms and decaying solar panel arrays. False claims about 97% agreement will not spare us, but the willingness of scientists to keep mum is likely to much reduce trust in and support for science. Perhaps this won’t be such a bad thing after all – certainly as concerns ‘official’ science.There is at least one positive aspect to the present situation. None of the proposed policies will have much impact on greenhouse gases. Thus we will continue to benefit from the one thing that can be clearly attributed to elevated carbon dioxide: namely, its effective role as a plant fertilizer, and reducer of the drought vulnerability of plants. Meanwhile, the IPCC is claiming that we need to prevent another 0.5◦C of warming, although the 1◦C that has occurred so far has been accompanied by the greatest increase in human welfare in history.Notes1. ‘This is the first time in the history of mankind that we are setting ourselves the task of intentionally, within a defined period of time, to change the economic development model that has been reigning for at least 150 years, since the Industrial Revolution.’PDF version of this lecture: https://www.thegwpf.org/content/...

More than you ever wanted to know about fructose metabolism! Basically, even that amount of fructose probably wouldn’t overwhelm the liver’s ability to store it. Extreme oral fructose loads overwhelm the absorptive capacity of the small bowel and produce an osmotic diarrhea.Sun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usFructose metabolism in humans – what isotopic tracer studies tell usREVIEW Open AccessSam Z Sun* and Mark W EmpieAbstractFructose consumption and its implications on public health are currently under study. This work reviewed the metabolic fate of dietary fructose based on isotope tracer studies in humans. The mean oxidation rate of dietary fructose was 45.0% ± 10.7 (mean ± SD) in non-exercising subjects within 3–6 hours and 45.8% ± 7.3 in exercising subjects within 2–3 hours. When fructose was ingested together with glucose, the mean oxidation rate of the mixed sugars increased to 66.0% ± 8.2 in exercising subjects. The mean conversion rate from fructose to glucose was 41% ± 10.5 (mean ± SD) in 3–6 hours after ingestion. The conversion amount from fructose to glycogen remains to be further clarified. A small percentage of ingested fructose (<1%) appears to be directly converted to plasma TG. However, hyperlipidemic effects of larger amounts of fructose consumption are observed in studies using infused labeled acetate to quantify longer term de novo lipogenesis. While the mechanisms for the hyperlipidemic effect remain controversial, energy source shifting and lipid sparing may play a role in the effect, in addition to de novo lipogenesis. Finally, approximately a quarter of ingested fructose can be converted into lactate within a few of hours. The reviewed data provides a profile of how dietary fructose is utilized in humans.Keywords: Fructose, Glucose, Isotope tracer, MetabolismIntroductionFructose has been a part of the human diet for many thousands of years, and it is found in highest concentra- tions in fruits and to a lesser degree in vegetables. Cane, beet, and corn sugars are produced industrially, and their use results in significant quantities of added sugars entering the diet, about half of which is fructose [1]. Cane and beet sugars are comprised of the disaccharide sucrose (glucose bonded to fructose) and are commonly called table sugar or simple sugar. Corn sugars come from corn starch, and mainly consist of high fructose corn syrup 55 (HFCS 55; 55% fructose-41% glucose), HFCS 42 (42% fructose-52% glucose), and corn syrup (glucose and oligoglucose with trace amounts of fruc- tose). During the last several decades, the prevalence of obesity and metabolic syndrome has risen dramatically on a global basis, but more so in the U.S. population. Because the prevalence is chronologically and statisti- cally correlated with the increase of added sugar intakes,* Correspondence: [email protected], Archer Daniels Midland Company, 1001 North Brush College Road, Decatur, IL 62521, USAparticularly HFCS in the U.S. (HFCS is not consumed significantly outside the U.S.), some have proposed the intake of HFCS or fructose as a free monosaccharide may be a cause of various adverse health consequences [2]. Conventional clinical trials and ecological studies have been conducted to assess the hypotheses, but not all results are found to be supportive. Conventional studies often cannot reveal details of interconnecting metabolic pathways when testing fructose or fructose- containing sugars, but they also cannot clearly distin- guish a mechanistic cause associated with an observed physiological consequence linked to the sugar con- sumed. This is because the ordinary diet contains mul- tiple forms of saccharides which are inter-convertible in the body and share many steps of the carbohydrate me- tabolism pathways.Over the last decade, a series of controversies have arisen regarding fructose consumption. In 2004, a com- mentary was written hypothesizing that the “high” fruc- tose content in HFCS was the cause of the obesity rise in America [3]. This was based on the association of the obesity prevalence rise with the replacement of cane and beet sugar by HFCS, even though the fructose content© 2012 Sun and Empie; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (Creative Commons - Attribution 2.0 Generic - CC BY 2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Sun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usof these two sweetener sources is essentially the same. Later, several dietary studies using calorically high doses of fructose were published to investigate fructose modu- lation of leptin hormone status, with a suggestion that chronic changes in this hormone level could lead to weight gain [4,5]. However, other studies and evidence based reviews do not always support these findings [6-13]. Recently, Welsh et al. [14] reported that the in- take of added sugar has significantly decreased between 1999 and 2008 while the obesity prevalence has contin- ued to rise. The current view is that obesity is a matter of energy balance [15,16]. Next, the fructose moiety in sugars was hypothesized to cause high serum uric acid which could lead to the development of Type-2 diabetes [17]. There is currently no direct proof for a cause and effect relation of urate with diabetes, and NHANES data suggests no relation of serum urate with fructose intake at ordinary dietary consumption levels [18]. Then, another hypothesis has been raised that dietary fructose may potentially lead to Non Alcoholic Fatty Liver Disease (NAFLD) and augmented de-novo trigly- ceride synthesis, based on an analysis of hormonePage 2 of 15regulated lipid pathways in the liver [19,20]. It is known that high dietary levels of fructose can increase serum triglycerides. However, all the factors linked to the de- velopment of fatty liver disease are not well understood and can include, insulin resistance, inflammation, fat re- deposition, abnormalities in control of reactive oxygen species [21] and uncoupling proteins in mitochondria [22]. NAFLD is currently an important and actively researched field relative to dietary sugar intakes.Additionally, it is important to understand the prac- tical significance of testing an effect from a single sugar using an unrepresentative dose compared to the true population sugar intake, a question which is currently under debate [23-26]. In many of the intervention stud- ies involved with studying the various hypotheses men- tioned above, very high doses of sugars over short term were often applied, the study designs were more similar to toxicological studies, and the studies were only able to draw associative conclusions between applied dose and observed health-related outcomes in the subjects studied. The observed biological changes, although sta- tistically significant by a P-value ruling, were often onlyGlucoseGlycogenGlucose-6-PFructose1532Fructose-6-P 46Fructose-1,6-bis-PFructose-1-PExtrahepatic metabolismExtrahepatic metabolismGlyceraldehyde-3-P 10Pyruvate1178Dihydroxyacetone-PGlycerol-3-P79GlyceraldehydeGluconeogenesis (via Cori cycle)12Lactate17Acyl-CoA Acyl-glycerolFatty acids CoA-SH-oxidation 13 15 1618Lipoprotein (VLDL)Acetyl-CoAMalonyl- CoAApolipoprotein (B-100, C and E)Extrahepatic metabolismKetone 14 bodiesExtrahepatic metabolismCitric Acid CycleCO2 + ATPFigure 1 Major metabolic pathways and flux of dietary glucose and fructose. P = phosphate. For enzymes numbered in circles:1 = hexokinase/glucokinase or Glucose-6-phosphatase, 2 = phosphoglucose isomerase, 3 = hexokinase, 4 = fructokinase, 5 = glycogen synthase or phosphorylase, 6 = phosphofructokinase, 7 = aldolase, 8 = triose phosphate isomerase, 9 = triose kinase, 10 = several enzymes including pyruvate kinase, 11 = pyruvate dehydrogenase complex,12 = lactate dehydrogenase,13 = ketothiolase and other 3 enzymes,14 = enzyme group related to citric acid cycle, 15 = acetyl CoA carboxylase,16 = multienzyme complexes, 17 = acyl CoA synthase, 18 = glycerol-phosphate acyl transferase and triacylglycerol synthase complex. The dashed-line and arrow represents minor pathways or will not occur under a healthy condition or ordinary sugar consumption. The compound names in bold would be major metabolic intermediates or end products of glucose or fructose metabolism.Sun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usfluctuations within normal ranges. These studies rarely measured actual development of disease or the inter- mediate metabolites characterizing mechanism-based reactions. To begin to prove true effect of a diet compo- nent, it is useful to study the component disposal through the common central pathways at the molecular level. These studies are facilitated and detailed by the use of isotope tracer labeled precursors, and this concept is the stimulus for this review.The questions raised by the above hypotheses reach into the broader metabolome and fluxome. Our under- standing of the metabolism of glucose and fructose as separate sugars is founded upon many years of study, and detailed anabolic and catabolic pathways are known [27]. Recently, the extended metabolism of glucose and fructose has been reviewed by Tappy and Le [28]. Glu- cose and fructose carbons are utilized through the gly- colysis, gluconeogenesis, glycogenolysis, tricarboxylic acid (TCA) cycle, lactate production (Cori cycle), pen- tose phosphate shunt, and lipid synthesis pathways in various physiological compartments to provide sub- strates for glycogen homeostasis, amino acids, other sugars, fats and energy (e.g. ATP). Glucose and fructose enter the metabolic pathways differently (Figure 1), with glucose being converted to 1,6-diphosphorylated fruc- tose before being cleaved into the three carbon meta- bolic intermediates, dihydroxy acetone phosphate and glyceraldehyde 3-phosphate. Absorbed fructose is only mono-phosphorylated before being cleaved into glyceral- dehyde and dihydroxy acetone phosphate, which is the common intermediate with the glucose pathway. Glu- cose utilization can be regulated before cleavage, whereas fructose is less regulated. This initial difference has prompted some to hypothesize that, because fruc- tose cleavage by-passes key feedback regulatory steps in the glucose metabolic pathway, this bypass may lead to increases of fatty acid synthesis, which may contribute to causes of obesity [4]. This hypothesis relies on a sim- plified metabolic pathway analysis and on studies using pure fructose in comparison to pure glucose, a situation which rarely occurs in the American diet [29,30].In nature, fructose commonly occurs together with glucose, and composition values for some foods have been tabulated by the USDA on its website: http://www. Welcome to the USDA Food Composition Database. The metabolism of food derived sucrose, fruit sugars, honey, and high fruc- tose corn syrup, major sources of fructose and glucose in the diet, are currently under study, and the biological effects resulting from the use of experimentally formu- lated mixtures of glucose and fructose are relevant to our understanding. The use of mixed sugars are more metabolically predictive of dietary consequences than that from single monosaccharides studied individually, as metabolism of each type of sugar is not independentPage 3 of 15from the other (discussed below). Metabolic interactions between glucose and fructose significantly impact gen- eral sugar metabolism.Owing to the complexity of fructose and glucose me- tabolism, conventional feeding study approaches are usually less informative than isotope tracer studies for obtaining a clear picture of mechanisms for utilization of dietary fructose or glucose. It is known that carbon moieties in fructose and glucose can be inter-converted in the liver [31], and thus studying the disposal and metabolic effects of these dietary sugars with respect to one another is most definitively conducted using isotope-labeled sugars as tracers. A number of these iso- topic tracer studies exist, and many are found in the lit- erature dated before the year 2000. Although all pathways have not been completely studied for fructose disposal and metabolism under different physiological conditions, a significant number of reports on fructose isotope tracer studies are published. In this work, we have reviewed fructose disposal and metabolism in humans based on isotope tracer studies to better under- stand from a molecular stand point fructose oxidation, fructose conversion into glucose, fructose conversion into lipids, and fructose conversion into lactate.MethodPubmed and Scopus websites were searched using 2 or more key word combinations of fructose, glucose, su- crose, tracer, 13C, 14C, and isotope with limitation of using human studies. When reviewing the metabolic fate of dietary fructose (including oxidation, glucose conver- sion, glycogen synthesis, lipid conversion and lactate production), the data were obtained from publications that met the following criteria: adult subjects, unbound or bound fructose studied, isotope-tracer used, in Eng- lish, and with metabolic-related study purposes. In total, 34 papers met the criteria. Other conditions related to study design were not used as exclusion criteria, such as subject fasting status, ways of fructose administration, and sample size. Many of the studies on fructose oxida- tion were conducted by researchers interested in exer- cise and athletic performance enhancement. In some studies, fructose ingestions were combined with glucose or with other nutrient intravenous infusion. Dose levels of fructose and administration methods (bolus or several small portions) also varied between studies. As a result, there is significant heterogeneity between studies and the protocol, and quality among the tracer studies cited in this review may not be similar. The expired CO2 re- covery coefficients, correction factors (k factor) for the collection loss of expired CO2, were not identical in the studies investigating fructose oxidation. This may ac- count for some of the observed variations in oxidation rates of ingested fructose [32].Sun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usThe following sections will review what tracer studies tell us about the disposal and metabolism of dietary fruc- tose as a single sugar or as a mixture with glucose, either bound or free. In this way, the origins and fate of specific carbons in these sugars may be determined in relation to their partition among metabolic pathways and how the presence of one sugar influences the metabolism of the other. In two sections, studies are included which use non-labeled fructose together with labeled pathway com- pounds to assess the impact of ingested fructose on meta- bolites or pool intermediates leading to alterations in relevant end points, such as glucose production or de novo lipogenesis. In this way, fructose carbons themselves are not followed, but broader anabolic responses affected by the fructose load can be measured. This isotopic method makes use of Mass Isotopomer Distribution Ana- lysis (MIDA), a technique reviewed by Hellerstein and Neese (1999) [33]. Although these studies investigate a number of other important physiological parameters, we report here only the results which are directly measured by the tracer itself.Fructose absorptionTo place the metabolism of labeled sugars in context, it is helpful to briefly discuss what is known about the up- take of fructose, glucose and sucrose from the gut, inter- dependencies, and entry into the circulation. These considerations should be taken into account when designing studies. A number of the studies discussed in this section do not use tracer labeled sugars, but are included to provide a comprehensive description. The absorption rate of fructose alone from the small intestine is slower than that of glucose. This is partly due to the differences in the absorption process between the two monosaccharides. Glucose is absorbed from the intestine into the plasma via more than one active glucose co- transporter protein. SGLT1 transports glucose from the intestinal lumen through the apical membrane into the intestinal epithelial cells. Exit from the epithelial cells through the basolateral membrane to the blood is facili- tated by GLUT2. Fructose is absorbed at a slower rate from the lower part of duodenum and jejunum both passively and actively by the brush-border membrane transporter 5 (GLUT-5) and transported into blood also by GLUT2 [34,35]. GLUT transporters are primarily made up of 13 multiple homologous proteins (GLUT 1– 12 and 14) and they are located throughout the body often exhibiting tissue specificities [36]. The capacity for fructose absorption in humans is not completely clear, but early studies suggested that fructose absorption is quite efficient, though it is less efficient than that of glu- cose or sucrose [34]. The slower absorption and pro- longed contact time with the luminal intestinal wall would be expected to result in the stimulation ofPage 4 of 15regulatory and satiety signals and release of hormones from enteroendocrine cells [37,38].When fructose is consumed as the sole carbohydrate source, it can be incompletely absorbed, and as a result, produces a hyperosmolar environment in the intestine. A high concentration of solute within the gut lumen draws fluid into the intestine which can produce feelings of malaise, stomachache or diarrhea [39], and results in decreased food intake. However, when glucose is also present, malabsorption is significantly attenuated [40]. Riby et al. [34] compiled data from five studies compar- ing glucose, fructose and mixtures of the two for degree of absorption, by measurement of breath hydrogen as an indicator of malabsorption. Pure fructose alone pro- duced dose-dependent evidence of malabsorption start- ing from12 gram ingestion loads, while glucose and sucrose individually produced no intolerance up to 50 gram ingestion loads. Incremental amounts of added free glucose to a 50 gram fructose load dose-dependently attenuated malabsorption symptoms, and at the equimo- lar mixture of the two (up to 100 grams total sugars), no malabsorption was observed. Thus, how studies are designed to deliver the various sugars can have an im- pact on sugar uptake and appearance in the blood.Sucrose is a valid comparison for glucose-fructose mixtures, as the disaccharide is cleaved by the enzyme sucrase into the mono sugars before being absorbed into the circulation. Comparison of sucrose absorption rates in 32 normal subjects with an equivalent amount of monosaccharide mixture containing glucose and fruc- tose, infused intralumenally to avoid gastric hydrolysis, resulted in the similar absorption rates for each glucose and fructose component of the test [41]. In another study, type-2 diabetic patients were fed sucrose or HFCS with a background diet, resulting in plasma glucose AUC’s not being different between sucrose and the HFCS, nor were mean plasma insulin values [42]. It was also shown that mucosal-to-serosal glucose flux was similar between sucrose and glucose + fructose mixture solution, but rates depended on sucrase and sodium- dependent glucose transport in an in vitro study [43]. Other comparison studies in normal men and women [44] and in diabetics [45,46] produced no differences in intestinal uptake between sucrose and honey (a glucose- fructose mixture). Thus, the body appears to handle oral free glucose-fructose mixtures or HFCS similarly as su- crose and that hydrolysis of sucrose does not appear to be rate limiting for uptake.Once absorbed, glucose is delivered to the liver then to peripheral organs for utilization, and its entrance into muscle and fat cells is insulin dependent. Fructose is pri- marily delivered to and metabolized in the liver for en- ergy and for two and three carbon precursor production without dependence on insulin. Bolus or divided dosesSun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usof 50–150 g fructose produce plasma concentrations of 3–11 mg/dl of this sugar [47-52], while glucose can spike upwards of 150 mg/dl and more. Although little dietary fructose appears in the circulation, it can influ- ence plasma glucose concentrations via sugar inter- conversion. In man, studies indicate fructose to glucose conversion may occur to a highly significant degree (reviewed below) and that this conversion occurs via the 3-carbon intermediate pathways. The extent of inter- conversion may be species dependent.Key points: 1) Fructose is readily absorbed and its ab- sorption is facilitated by the presence of co-ingested glu- cose. Sucrose, honey, 50:50 glucose-fructose mixtures and HFCS all appear to be similarly absorbed. 2) Fructose itself is retained by the liver, while glucose is mainly released into the circulation and utilized peripherally. And, 3) Plasma levels of fructose are an order of magnitude (10–50 folds) lower than circulating glucose, and fruc- tose elicits only a modest insulin response. This lower glucose and insulin response by the body to fructose in- take has been considered desirable for diabetic diets.Fructose and glucose metabolic fluxFructose and glucose metabolic flux is briefly described in Figure 1. The important point of distinction between glucose and fructose metabolism resides in two areas. Absorbed fructose is extracted by, held, and processed in the liver, with little fructose circulating in the blood stream or delivered to peripheral tissues. Absorbed glu- cose or that produced in the liver from fructose or other precursors is either metabolized in the liver or exported to the blood stream and further to extrahepatic tissues. Most absorbed fructose is cleaved in the liver into gly- ceraldehyde and dihydroxy acetone phosphate, and these trioses further go to glycerol phosphate and pyruvate metabolic pathways, respectively. With both fructose and glucose, lactate conversion plays an important role in distributing carbohydrate potential energy between gluconeogenesis and acetyl CoA, with entry into the TCA cycle or use in lipid synthesis (Figure 1) [53,54]. Lactate discharge is also a means for fructose carbons to escape the liver and be transported to peripheral tissues. Fructose cleavage to glyceraldehyde can result in the production of glycerol via reduction. It was observed that blood glycerol concentration increased after fruc- tose ingestion in exercise subjects [55,56]. The noted glycerol increases after fructose ingestion are either greater or similar compared with the values after glucose ingestion, and the produced glycerol can be oxidized for energy. However, the metabolic balance between glycerol produced from fructose and central pathway trioses has not been clearly determined.Given the complexity and interdependencies of energy metabolism and biochemical synthesis arising fromPage 5 of 15sugars, consideration of the flux of carbons among these pathways is critical to understanding the health conse- quences of consuming these nutrients. Single sugar dis- tribution and fluxes between pathways are not easily studied without isotopic labels. Classically, a limited number of metabolites are characterized in a study and some disposal points can be missed. More recently, a computational technique is being employed utilizing. Nuclear Magnetic Resonance (NMR) or mass spectral analyses of the 13C isotopomer distribution of metabo- lites, following administration of labeled precursors. These precursors may be uniformly labeled compounds or labeled at specific carbons, depending on the question to be answered. An empirical metabolic flux analysis profile is generated which can be mathematically mod- eled without being constrained by physical chemistry rigor, as reviewed by Selivanoc and Lee [57,58]. This technique allows one to model metabolite fluxes which may not be well characterized or understood from direct enzymatic or physical chemistry data. A second method is under development to mathematically model general metabolism and interdependencies of pathways using known thermodynamic free energy and kinetic constant parameters for each reaction in the pathway sequences [59], but there is currently insufficient data to apply to fructose metabolism questions.Each method has advantages and disadvantages, and likely the combination of both is needed for optimal pre- dictive power. In the future, with these tools one should be able to predict outcomes from sugars supply as a function of the organism’s energy (ATP) status, oxida- tion/reduction potential (NADH/NADPH) and nutrient dependent cofactors. Metabolic differences among com- partments and their interactions as a whole should be included. Experimentation should account for metabo- lome interactions, and study results should be inter- preted carefully with respect to the experimental conditions employed.Key points: 1) Fructose is observed to enter all the pathways of disposal as found for glucose glycolysis and the TCA cycle. 2) Three carbon intermediates provide a means for fructose to be released from the liver and to be utilized peripherally, which suggests that physio- logical effects observed should be integrated with the co-effect and metabolic fluxes arising from all sugars using these pathways.Metabolic fate of dietary fructoseThe following reviews the data as presented in the papers. As depicted in Figure 1, the interdependence of metabolic pathways of fructose and glucose can influ- ence the flow of metabolites and their temporal appear- ance as other compounds. Thus, in discussing the disposal of fructose carbons, e.g. through oxidation, oneSun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell uscannot accurately distinguish if the labeled CO2 arose directly from the fructose itself, or from fructose which had undergone conversion to neoformed glucose, neo- formed lactate, or other neoformed compounds. Where the conversions occur, these metabolites can be readily transported out of the liver to other tissues, altering the temporal appearance of metabolites. Further complicat- ing the analysis, some studies used fructose labeled with 13C at different positions of its carbon backbone, uni- formly labeled fructose, or 13C naturally enriched fruc- tose. The different labeling may also influence the appearance of the isotope tracer in various metabolites. Using uniformly labeled fructose would limit the poten- tial complications from different labeling positions on isotope tracer appearance in its metabolites. It should also be noted that most of the tracer studies described in the following sections are short-term dietary studies (monitored periods shorter than 8 hours) and may not reflect longer term effects of fructose, such as on de novo lipogenesis, VLDL TG production, or other meta- bolic specificities.Fructose oxidationMultiple studies have been conducted to observe how much fructose and other sugars can be oxidized follow- ing ingestion. Table 1 summarizes fructose and other sugar oxidation data reported from tracer studies in humans under different experimental designs. In all, 19 relevant studies were found which met the inclusion cri- teria of this review. The first 4 studies cited in Table 1 used resting subjects with fructose ingestion levels from 0.5-1.0 g/kg body weight (bw). Within the study moni- toring periods, the ingested fructose was oxidized from 30.5% to 59%. The study by Chong and colleagues [48] showed fructose was oxidized faster than glucose (30.5% vs 24.5%). This effect may be due to less regulation of phosphorylation for fructose or to a wider tissue distri- bution of glucose. Oxidation rates increase as the dose increases but would be attenuated by its rate of absorp- tion when intake amounts are large. Delarue et al. [49] indicated when the fructose administration dose increased from 0.5 to 1 g/kg bw, the oxidation amount of fructose correspondingly increased, such that a simi- lar percent of the given fructose dosage was oxidized (56% and 59%, respectively). However, there is a differ- ence in oxidation rates between normal and diabetic subjects, in that normal subjects could more efficiently oxidize fructose than type-2 diabetics (38.5% vs 31.3% of given dosage) [52].The other studies in the Table 1 were conducted under conditions of exercise where workloads corresponded to 50-75% of max VO2 uptake. The oxidized amounts of ingested fructose ranged from 37.5% to 62.0%. Except in one study [60] which showed that fructose and glucosePage 6 of 15had similar oxidation rates (38.8% and 40.5%, respect- ively), the other studies all observed that glucose was oxidized faster than fructose under the exercise condi- tions [47,50,55,56,61-65]. A very interesting pheno- menon noted is that when fructose and glucose are ingested together (including fructose-containing su- crose), the oxidation rates of the mixed sugars were fas- ter than that of either one of them ingested alone at the same dosage. Adopo et al. reported that, given 100 g fructose, glucose, or fructose + glucose, 73.6% of the mixed sugars were oxidized while the data of fructose and glucose were 43.8% and 48.1% as ingested separately [61]. The series of studies by Jentjens and colleagues [66-69] also reported that fructose plus glucose or su- crose plus glucose consumed together were oxidized fas- ter than glucose alone.A summary of the sugar oxidation data is shown in Figure 2. The data of obese or diabetic subjects are not included in this figure. In non-exercise subjects, the mean of the oxidized fructose amount was 45.0% ± 10.7 (mean ± SD, range 30.5-59%) of ingested dose within a period of 3–6 hours. Under exercise conditions, this mean was 45.8% ± 7.3 (mean ± SD, range 37.5-62%) within 2–3 hours. When fructose and glucose are ingested in combination, either as fructose plus glucose, as sucrose, or as sucrose plus one of the 2 mono-sugars, the mean oxidized amount of the mixed sugars increased to 66.0% ± 8.2 (mean ± SD, range 52.2-73.6%). The oxida- tion data of glucose alone is 58.7% ± 12.9 (mean ± SD, range 37.1-81.0%).Key points: 1) A significant amount of ingested fruc- tose is oxidized by the body to produce energy. 2) Under resting conditions, fructose may be preferentially or similarly utilized to produce energy as glucose, and under exercise, glucose appeared to be more preferen- tially used to produce energy by the body. 3) When fruc- tose and glucose are ingested together, the mixed sugars will be oxidized significantly faster than either one of the sugars ingested alone. And, 4) Fructose metabolism could be very different between normal and obese/ diabetic subjects. A potential consideration with these oxidation studies is that with shorter time frames of measurement or incomplete oxidation and with only partial labeling, position of the isotope label can influ- ence the rate of appearance of the isotope in the exhaled carbon dioxide (CO2). Temporal isotope appearance in CO2 can be altered if some of the fructose carbons are not completely oxidized in the time frame of measure- ment due to diversion to non-oxidative pathways.Fructose-glucose conversionThe disposal pathway for fructose is not solely by direct oxidation, as some absorbed fructose will be converted to glucose. A number of studies have determined theSun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usTable 1 Oxidation of Dietary Fructose, Glucose, and Other Sugars in Tracer Studies(1)Page 7 of 15Reference[70] (2) [48] [49] (2) [52] (2)[82][60][47][62] [61] (2,3)[50] [65][64] (3) [55] [63] (3) [56] [68] (3,4) [67] (4)Subjects9M9F8M +68M +6M+ 3F3M +34M +47 obese F8 type-2 (4 M) 10 M10 M 10 M 10 M 6M 6M 6M 6M 6M 6M 6M 18 M 18 M 6M 6M 6M 6M 6M 5M 5M 5 M3 5 M3 6M 6M 6M 6M 7M 7M 10 M 10 M 8M 8M 8M 8MExercise HoursNo 6 No 6 No 6 No 6 No 6 No 6 No 3 No 3 No 3 yes 2 yes 2 yes 2 yes 2 Yes 2 Yes 2 Yes 2 yes 2 yes 2 yes 2 yes 2 yes 2 yes 2 yes 2 yes 2 yes 2 yes 3 yes 3 yes 2 yes 2 yes 2 yes 2 yes 2 yes 2 yes 2 yes 2 yes 3 yes 3 yes 2 yes 2 yes 2 yes 2 yes 2 yes 2Sugar dosage (g)0.9 fru/kg bw0.9 fru/kg bw0.75 glu/kg bw0.75 fru/kg bw0.5 fru/kg bw1.0 fru/kg bw0.9 fru/kg bw0.9 fru/kg bw0.9 fru/kg bw0.6 malt/min0.3 fru + 0.6 malt/min 0.5 fru + 0.6 malt/min 0.7 fru + 0.6 malt/min 100 galactose100 fru100 glu100 fru100 glu100 fru + 120 sucr 100 glu + 120 sucr 1.33 fru/kg bw 1.33 glu/kg bw 100 fru100 glu 50fru+50glu150 fru150 glu1.33 fru/kg bw1.33 glu/kg bw1.33 fru/kg bw1.33 glu/kg bw1.33 fru/kg bw1.33 glu/kg bw100 fru100 glu140 fru140 glu1.0 fru/kg bw1.0 glu/kg bw0.5 fru + 1.0 glu/min 1.5 glu/min1.2 sucr/min1.2 glu/minTracer13C-fru(L1)13C-fru 13C-glu(L1)13C-fru(L1) 13C-fru(L2)13C-fru 13C-fru(L3)13C-fru13C-fru 13C-glu(L4)13C-fru(L4)13C-fru 13C-fru13C-galactose(L1) 13C-fru(L1)13C-glu(L1)13C-fru(L1) 13C-glu(L1)13C-fru13C-glu 13C-fru(L1)13C-glu(L1) 13C-fru(L1) 13C-glu(L1)13C-fru + 13C-glu 13C-fru(L2)13C-glu(L2) 13C-fru(L4)13C-glu(L4) 13C-fru13C-glu 13C-fru(L4)13C-glu(L4)13C-fru(L4)13C-glu(L4) 13C-fru(L4)13C-glu(L4) 13C-fru(L2)13C-glu(L2)13C-fru + 13C-glu(L2)13C-glu13C-sucr(L1) 14C-glu(L1)Oxidation42.9%43%24.5%30.5%56%59%38.5%34.9%31.3%81.7% (0.49 g/min) 62.0% (0.18 g/min) 54.0% (0.27 g/min) 52.0% (0.36 g/min) 23.7%38.8%40.5%43.8%48.1%42.0% (42 g) 50.2% (50.2 g) 36.7% (35.7 g) 57.2% (56.1 g) 45.8%58.3%73.6%38.0%54.0%51.0% (49 g) 60.4% (58 g) 37.5% (36 g) 58.3% (56 g) 54.0% (53 g) 72.0% (70 g) 54%67%56%75%43.0% (30 g) 37.1% (26 g) 72.7% (1.09 g/min) 50.7% (0.76 g/min) 78.3% (0.94 g/min) 58.3% (0.70 g/min)F FF FSun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usTable 1 Oxidation of Dietary Fructose, Glucose, and Other Sugars in Tracer Studies(1) (Continued)Page 8 of 15[69] (4)[66] (4)8M yes 2 9M yes 2.5 9M yes 2.5 9M yes 2.5 8M yes 2 8M yes 20.6 sucr + 0.6 glu/min 1.8 glu/min0.6 sucr + 1.2 glu/min 0.6 malt + 1.2 glu/min 1.8 glu /min0.6 fru + 1.2 glu/min13C-sucr + 14C-glu 13C-glu(L2)13C-sucr + 13C-glu(L2)13C-malt + 13C-glu(L2) 14C-glu(L1)13C-fru + 14C-glu(L1)70.8% (0.85 g/min) 53.3% (0.96 g/min) 62.2% (1.12 g/min) 52.2% (0.94 g/min) 38.7% (0.75 g/min) 64.4% (1.16 g/min)(1): hours = study monitoring hours, fru = fructose, glu = glucose, sucr = sucrose, malt = maltose; bw = body weight; M = male, F = female; type-2 = type-2 diabetes. In the reference column, (2) = with glucose infusion. (3) = non-fasting subjects. (4) = oxidation data of the 2nd hour or the last 1.5 hours. In the column of “Tracer”, superscripted L1 = labeled uniformly, L2 = naturally enriched, L3 = labeled at position 1, and L4 = 13C position not indicated.extent of the conversion, which can only be clearly done using tracers. Table 2 tabulates the data from various studies with different experimental conditions. Tran and colleagues [70] studied the conversion of fructose to glu- cose as compared between men and women. After a 3 times ingestion of a fructose-containing beverage (3x0.3 g/kg bw), 37.4% of the fructose was converted to glucose in men during 6 hours. This value is significantly higher than the conversion rate of 28.9% observed in women. Similarly, using an equal fructose dosage, Paquot et al. [52] noted the conversion percent from fructose to glucose was 36.4% in 8 normal subjects (4 M + 4 F), which is comparable with Tran’s data. How- ever, the conversion proportion appeared to be lower in obese and diabetic subjects (29.5% and 30.2%, respect- ively). In a dosing study monitored over a period of 6 hours, using 0.5 and 1 gram/kg bw, the conversion from fructose to glucose was reported to be 54% and 50.7% of given dosages, respectively [49]. Surmely et al. [71] infused fructose at 3 mg/kg bw per minute for the first 3 hours, followed by doubling the infusion dosage for the next 3 hours. It was noted that the subsequent higher infusion dose level somewhat slowed the fructose conversion percentage, 22% and 28% for high and low dose levels respectively. Under exercise conditions, Lecoultre et al. [51] reported that 29% of ingested fruc- tose (96 g) is converted to glucose when a steady state of carbohydrate flux was reached (1.7-2 hrs from the begin- ning of study). With repeated administration to achieve a high dose level and under exercise, Jandrian et al. [50] reported that 55-60% of circulating glucose comes from fructose conversion during the latter half of the monitor- ing period. This data is similar to that observed by Delarue et al. [49] who reported the amount of glucose synthesized from fructose was 57% of overall glucose ap- pearance in the circulation after an ingestion of fructose at dosage of 1 g/kg bw, while the subjects were not under exercise. These data suggest that 41% ±10.5 (mean ± SD, range 29-54%) of fructose can be converted to glucose within 2–6 hours after ingestion in normal non-exercise subjects. This conversion may be lower inwomen compared to men, and obese and diabetic sub- jects may also have lower conversion capability.For the conversion from dietary fructose to glycogen, data are very limited. Nilsson et al. [72] reported that a significantly higher amount of glycogen was determined in the liver (274.6 mmol glycosyl unit per kg wet tissue) after fructose infusion than that (76.2 mmol glycosyl unit) after glucose infusion; and no difference of glyco- gen increase in muscle was noted (23.0 and 24.4 mmol glycosyl units per kg after fructose and glucose infu- sions, respectively). Another fructose infusion study (non-exercise) by Dirlewanger et al. [73] noted that fruc- tose stimulates total glucose output, glucose cycling and intrahepatic UDP galactose turnover, which was used as a marker for increased glycogen synthesis. Blom and col- leagues [74] reported that dietary fructose could be about half as efficient as glucose or sucrose to replenishFigure 2 Dietary fructose and glucose oxidation (in normal subjects, mean + SD). On horizontal axis, ‘studies = number’ means that how many studies the bar data averaged from. In the Figure, 3–6 hours and 2–3 hours represent study monitoring period. The noted data variations between studies could be due to the differences of sugar dosages, tracer labeling forms, sugar administration methods, subject characteristics, and/or measurement errors. Also, the produced CO2 from labeled sugar oxidation can arise directly from sugar molecules themselves, or other compounds converted from the sugars, such as glucose, lactate, or fatty acid from fructose.Sun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usTable 2 Conversion from Fructose to Glucose, Tracer Studies in Adults(1)Page 9 of 15Reference[70][52] [49][71] [51] [50]Subjects9M9F4M+4F7 obese F8 type-2 (4 M) 3M+3F3M+3FExercise HoursNo 6 No 6 No 3 No 3 No 3 No 6 No 6 No 0-3 No 4-6Fru dosages3x0.3 g/kg bw 3x0.3 g/kg bw 3x0.3 g/kg bw 3x0.3 g/kg bw 3x0.3 g/kg bw 0.5 g/kg bw 1.0 g/kg bw3 mg/kg/min46 mg/kg/min4 96 g fru+144 g glu 6x25 gTracer13C-fru(L1)13C-fru 13C-fru(L3)13C-fru13C-fru 13C-fru(L2)13C-fru 13C-fru(L1)13C-fru 13C-fru(L1)13C-fru(L2)Blood glu (mmol/L)5.94%(2) 4.87%(2) 5.2 5.3 7.7 4.56 4.66 NA NA 6.2 NAFru to glu conversion37.4%28.9% 36.4%(3) 29.5%(3) 30.2%(3) 54.0% 50.7% 28.0%(4) 22.0%(4) 29%(5) 55-60%(6)7M Yes 2 6M Yes 3For superscript numbers: (1), except Jandrain’s study [50], the subjects in the other studies were under glucose infusion; Hours = study monitoring hours,fru = fructose, glu = glucose; bw = body weight; M = male, F = female; type-2 = type-2 diabetes; NA = not available. (2), increases from baseline. (3), data were calculated based on reported parameters. (4), fructose administrated by infusion. (5), under steady state of carbohydrate flux. (6), percent of circulating glucose in the 2nd half of study hours. In the column of “Tracer”, superscripted L1 = labeled uniformly, L2 = naturally enriched, and L3 = labeled at position 1.muscle glycogen after exercise. In that study, healthy young subjects exhaustively exercised on bicycle erg- ometers, and ingested 0.7 g/kg bw of fructose, glucose, or sucrose divided in 3 doses. The rates of glycogen syn- thesis in muscle corresponding to each sugar treatment were observed as 0.32, 0.58, and 0.62 mmol/kg per hour, respectively. The data indicate that energy status plays a role in how the body handles fructose distribution and conversion to glycogen. A more recent study reported that a part of dietary fructose was converted to glycogen based on surge of blood 13C-glucose concentration fol- lowing a glucagon administration after 4 hours of 13C- labeled fructose intake (0.72 g/kg-bw) [75].Although it was reported that a significant amount of fructose in the circulation could be used to produce glycogen in liver via first conversion to glucose, no iso- tope tracer studies were found to directly quantitate 13C-carbons from dietary fructose incorporated into glycogen in humans. Considering that most of absorbed fructose is extracted and metabolized in liver, the data from the fructose infusion studies noted above may not be representative for orally administered fructose.Lastly, a number of studies using labeled glucose have examined how dietary fructose loads affect glu- cose production and disposal [76-78]. In these three studies, 6,6-deuterium labeled glucose was infused as a glucose metabolism tracer into male subjects after a 4–7 day fructose feeding, with fructose representing >25% energy in the diet. Results indicated that hepatic glucose production in normal subjects did not change [76], or had no effect on whole-body insulin-mediated glucose disposal [78]. Using a 2-step hyperinsulinemic euglycemic clamp, healthy offspring of Type 2 diabetics fed a high fructose diet exhibited higher fasting hepatic glucose levels compared to controls [77].Key points: 1) Fructose is converted to glucose to vari- able extents, depending on exercise condition, gender, and health status. This interconversion occurs at the tri- ose phosphate intersection of the glucose-fructose path- ways. 2) A portion of fructose is incorporated into glycogen after conversion to glucose, but the extent is not known. 3) Fructose feeding has an effect on hepatic glucose production and whole body glucose disposal. And, 4) Fructose may be processed differently in obese population or population with higher diabetes risk.Fructose-lactate conversionAnother significant and perhaps underappreciated meta- bolic pathway of dietary fructose is its conversion to lac- tate. Earlier tracer studies observed that blood lactate concentration was increased after fructose or fructose+ glucose ingestion compared to that after glucose inges- tion alone [56,66,68,79,80]. It was also observed that su- crose ingestion also caused a higher blood lactate response than did glucose [67,81]. However, no detailed data were reported to clarify how much of the ingested fructose was converted into the lactate in these studies.Recently, Lecoultre et al. [51] conducted a tracer study in 7 men while under exercise. Within 100 minutes, 96 g fructose with 144 g glucose were co-ingested. The lactate conversion from 13C-labeled fructose was calcu- lated using the parameters between 100 and 120 minutes when steady state of carbohydrate flux was assumed. As a result, 28% of fructose ingested was converted to lac- tate (35 micromol/kg-bw/min). Most of the converted lactate (25/28 or 89.3%) from fructose was oxidized mainly by working skeletal muscle (31 micromol/kg-bw/ min). The non-oxidative fructose disposal was 0.52 grams per minute accounting for about 40% of the fruc- tose ingested. The rate of appearance of glucose fromSun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usfructose conversion was 19.8 micromol/kg-bw/min or 29% of the fructose dose. The authors also indicated that the increased lactate production and oxidation would be an essential explanation of faster oxidation of fructose +glucose co-ingested than glucose ingested alone.In the tracer study by Rowland and colleagues [82], blood lactate concentration changes were compared in 10 men under exercise using oral test solutions of 13C-labeled glucose + 14C-labeled fructose (at 0.6 g/min glucose + 0, 0.3, 0.5, or 0.7 g/min fructose). During the 2-hour study period and compared to glucose alone, plasma lactate amount increased 31% and 24% under the glucose + fructose ingestions at 0.6 + 0.5 g/min and 0.6 + 0.7 g/min, respectively. However, the study did not indicate conversion percentage from the labeledfructose or glucose dosages.Key points: 1) Clearly, a significant amount of fructosecan be converted to lactate, but quantitative metabolic data of dietary fructose to lactate conversion is very lim- ited. The effects of fructose dose, administration method, physical activity, and subject characteristics on fructose-lactate metabolism remain to be further stud- ied. 2) Labeling patterns of isotope tracer in fructose will have an influence on the measured isotope appearance in lactate, if the studied sugar is not uniformly labeled.Fructose-lipids conversionA significant number of clinical studies have been per- formed to investigate the influence of fructose intake on blood triglyceride (TG) concentrations. However, tracer studies aimed at revealing metabolic conversion from la- beled fructose carbons to TG are extremely limited. In contrast to the conversion from fructose to glucose, the metabolic pathway from fructose to TG conversion can be much more complicated due to the complex distribu- tion and diversity of blood lipid compositions in the body. De novo lipogenesis from sugars can occur in the liver and end up as packaged VLDL TG and/or as intra- hepatocellular lipids. There are currently no convenient methods to quantitate overall DNL and intrahepatic lipid deposition. The fractional contribution of sugars to de novo lipogenesis and VLDL TG are commonly deter- mined using tracer enrichment data of blood samples. The time periods of liver de novo lipogenesis from sugars and the factors influencing it are not completely understood, and are impacted by the concentrations and tracer characteristics of the various substrates drawn from lipid precursor pools. De novo lipogenesis may also occur in adipose tissue or muscles, but there are no adequate methods available to quantitate it. A more expansive discussion of de novo lipogenesis and meth- odological considerations is an appropriate subject for a separate review.Page 10 of 15Perhaps because of these difficulties, only two tracer studies were found that investigated conversion of la- beled dietary fructose carbons into plasma lipids. Chong et al. [48] studied the effect of fructose on postprandial lipidemia in fourteen adults (8 men) who were orally administrated 13C-labeled fructose or 13C-labeled glu- cose at a dose of 0.75 g/kg bw, together with an 2 H- labeled oil mix (85% palm oil and 15% sunflower oil) at 0.5 g/kg bw. Blood lipid changes were monitored in a 6-hour period. It was observed that plasma TG con- centration rose more significantly after fructose inges- tion (from baseline 1240 μmol/L (%110 mg/dl) to its plateau of 2350 μmol/L (%208 mg/dl)) than that after glucose ingestion (from baseline 1240 μmol/L to its plateau of 1700 μmol/L(%150 mg/dl)). However, the concentration increases of 13C-enriched TG-fatty acids and TG-glycerol from the labeled fructose in the Sf 20–400 lipid fraction (including VLDL) were very small within the monitoring period. The plateau value of 13C-palmitate concentration was about 0.022 μmol/L (%0.002 mg/dl), 13C-myristate was about 0.0015 μmol/L (%0.0001 mg/dl), and 13C-TG-glycerol was about 1.4 μmol/L (%0.124 mg/dl), suggesting that fructose car- bons were not substantially transferred into plasma TG molecules during the time period monitored. The authors indicated that the lipogenic potential of fructose seems to be small, since the results showed that only 0.05% and 0.15% of fructose were converted to de novo fatty acids and TG-glycerol at 4 hour, respectively. The reported data should be viewed in the context of the 4- hour time period and whether further conversion would be observed at extended times was not illustrated. It was observed by Vedala and colleagues [83], using labeled fatty acids, acetate and glycerol as precursors, that a meaningful portion of de novo synthesized triglyceride would appear in blood at later times, and rates of this delayed secretion were significantly different among nor- mal, hypertriglyceridemic, and diabetic subjects. How- ever, this study did not specifically measure fructose conversion using labeled sugars.In another study, Tran et al. [70] reported that 13C- labeled fructose consumption at 3x0.3 g/kg body weight caused a small but significant increase of 13C- enrichment in VLDL palmitate in 8 men compared with that found in 9 women (no increase) during a 6-hour monitoring period. However, compared to baselines, plasma TG and non-esterified fatty acid concentrations decreased 5.3% and 32.9% in men and 3.3% and 24.4% in women, respectively. The data indicate that the conver- sion from fructose to fatty acid occurred, however, no blood lipid concentrations increased. Although the authors reported that 42.9% and 43% of the ingested fructose was oxidized and 37.4% and 28.9% was con- verted into glucose in men and women during theSun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell us6-hour monitoring period, conversion rate or percent from fructose into fatty acid or triglyceride was not reported. This study also noted that men processed dietary fructose differently than women, and the given fructose lowered postprandial plasma lipids. It was dis- cussed that although fructose is a potent lipogenic sub- strate, the observed fat synthesis arising from fructose carbons appeared to be quantitatively minor compared with other pathways of fructose disposal, but it may nevertheless have a significant impact on plasma and tissue lipids. In this same study, respiratory quotient (RQ) measurements found differences between genders, with male subjects increasing their RQ by 3% and females maintaining theirs. This data suggest that the increase of blood TG frequently observed in men com- pared to women after high dose fructose ingestion could be due to fat sparing during energy utilization.There are several studies which used labeled acetate, administered by intravenous infusion as a precursor of lipid synthesis, to assess the fructose stimulation of de novo lipogenesis (DNL). This technique uses the ap- proach of Mass Isotopomer Distribution Analysis (MIDA) to estimate the infused subunit (acetate) appear- ance in newly synthesized fatty acids and further predict the effect of dietary fructose on fractional DNL. The advantages and limitations of the method were well reviewed by Hellerstein in 1996 [84]. Parks et al. [85] investigated the influence of fructose-containing drinks on blood lipid changes using infused 13C-acetate. Six healthy subjects were randomly administrated 86 grams (mean) of glucose, glucose + fructose (50:50) or glucose +fructose (25:75) in drinks by a crossover-designed trial. Four hours after fructose ingestion, a standard lunch was consumed. Compared to glucose, more palmitate synthesis in triglyceride-rich lipoprotein (TRL) TG was noted after fructose-containing drinks, but not after the lunch. No significant differences were observed for TRL- TG concentrations between glucose and fructose- containing drink arms after baseline correction. Plasma TG concentration was decreased after glucose preload and stayed constant after fructose-containing drink pre- loads. Following the lunch, TG concentrations increased for all treatments. The authors reported that the after lunch TG-AUC data from fructose-containing drink treatments were significantly larger than that of glucose drink treatment. However, this AUC data was calculated over the entire study time period. Due to the negative TG rise during the glucose preload phase, the difference between the glucose and fructose arms was accentuated.Similarly, in Stanhope and colleagues’ study [86], 13C- labeled acetate infusion was used to measure fractional DNL in a 10-week intervention involving 18 overweight or obese subjects consuming either glucose (n = 8) or fructose beverages (n=10) delivering 25% of dailyPage 11 of 15energy. The percent changes of fractional hepatic DNL were not significantly different from baseline following 9-week glucose consumption for both fasting and post- prandial measurements. In the fructose beverage group, the percent changes of fractional hepatic DNL were also not significantly different between baseline and following 9-weeks for fasting data, but were significantly increased for postprandial data (2-7% during 11-hour monitoring). The actual amount of the DNL was not reported.Faeh et al. conducted a shorter term crossover study using a 6-day intervention [78]. Seven men were fed hypercaloric (+800-1000 kcal/d) diets, with the add- itional 25% of energy provided through a fructose solution. Fractional hepatic DNL was measured via 13C- labeled acetate infusion. The % changes from baseline for plasma TG and hepatic DNL were found to be sig- nificantly increased for the hypercaloric fructose diet compared to isocaloric control diets. The authors noted that the results could not truly differentiate the effects of the high-fructose intake per se and that of the total carbohydrate energy overfeeding. This study also found that fish oil added to the diets containing fructose atte- nuated this hyperlipidemic response somewhat [78].Clearly, the 3 studies discussed above [78,85,86] assess effects of dietary fructose with or without over energy intakes on the utilization of acetate in the circulation, which is designed to feed directly into lipid synthesis. In humans, acetate concentrations in blood are fairly low. As indicated in the Human Metablome Database [87], normal blood concentrations of acetate are 41.9 ± 15.1 (SD) μmol/ L in adults aged 18 years and over. For earlier data, Richards et al. [88] reported in 1976 that the normal value of blood acetate was 25 ± 2 μmol/L. Beyond alcohol con- sumption, common dietary intakes have no or limited in- fluence on blood acetate concentration [89,90]. In the studies of Parks, Stanhope, and Faeh, acetate was con- stantly infused at 0.5-0.55 g/hr (about 7000 μmol/hr) for 25, 26 and 9.5 hours, respectively. Although the data of blood acetate concentration were not reported in those studies, it would be important to determine whether the acetate infusion significantly raised blood acetate concen- trations such that this could have a meaningful impact on metabolic response to the fructose challenge. The coexist- ence of the infused acetate and intermediate metabolites of fructose, including regulatory elements of citrate, mal- ate, and lactate, could prime the pathway of DNL. As detailed above, dietary fructose (up to 25% of daily energy and 3 g/day-kg in these studies) can metabolically be con- verted into lactate and further result in blood lactate con- centration increases. Beynen and colleagues’ hepatic cell study [91] indicated that lactate and acetate both stimulate fatty acid synthesis, and lactate can induce activation of acetyl-CoA carboxylase, a key enzyme for fatty acid syn- thesis. Thus, the meaning of stimulation of de novoSun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell uslipogenesis observed from use of infused intermediate me- tabolite tracer and its interaction with the sugars studied should be considered carefully, along with the study meth- odologies being validated for the dosage of infused tracer. Additionally, how the infused acetate can truly represent intrahepatocellular acetyl-CoA pool is another key point to be clarified.Key points: 1) The above tracer studies indicate the com- plex relationship between dietary fructose and lipid synthe- sis. The observed increases in plasma TG and DNL in these studies can arise from both increased lipid synthesis and decreased lipid clearance, and the relative contributions were not addressed in any detail. And, 2) The intake levels, health status, and gender of subjects are all important fac- tors influencing sugar-lipid relationships. The influence of fructose consumption on plasma lipids and de novo lipo- genesis remains controversial and understudied.Influence of exogenous sugars on utilization of endogenous energy sourcesAfter sugar ingestion, body utilization of energy sources will change. As exogenous carbohydrate is used as a fuel source, the oxidation rates of stored energy, typically, endogenous carbohydrates and fat, will decrease. The extent of the decrease is usually driven by ingested sugar type, intake amount, and status of body energy need (such as vigorous exercise or screen watching). Under exercise, glucose is more likely to be preferentially oxi- dized than fructose, and this scenario will go in the op- posite direction under a resting state. Although data are limited related to detailed shifting of energy sources under different conditions, some studies using subjects under exercise may provide a basic concept of energy source shifting after sugar ingestion. Jentjens and collea- gues conducted a series of studies [66-69,80] using exer- cise subjects under somewhat comparable conditions, and reported some data related to the energy source shifting. The subjects were given drinks containing glu- cose, sucrose, glucose+fructose, or glucose+sucrose at dosage 0 (control), 1.2, 1.5, 1.8, or 2.4 g/min and under exercise workloads around 50% VO2 max uptake. For controls (0 gram of sugar intake), the oxidation rates of fat and endogenous carbohydrate were between 0.77- 0.95 g/min and 1.43-1.85 g/min, respectively. Compared to the control, glucose-containing drinks decreased fat oxidation rates by 21.6-41.7% (calculated based on reported data) and endogenous carbohydrate oxidation rates by 8.5-31.5%, except that one of the 5 studies noted endogenous carbohydrate oxidation rates increased (3.8% for medium and 14.1% for high glucose intake). For fructose-containing drink arms, either for glucose+fructose, sucrose, or glucose+sucrose, the fat oxidation rates were lowered by 19.5-47.4% and endogenous carbohydrate oxidation rates were lowered by 13.0-Page 12 of 1531.6%. These percent decreases appeared to be positively correlated to the sugar intake levels and the ratios of fructose in the mixed sugar drinks. The other two stud- ies [60,79] with similar settings as Jentjens and collea- gues’ work also reported comparable data of decreasing fat and endogenous carbohydrate oxidation after sugar preloads.Key points: 1) Together with other sugar inter- conversion data and the RQ data of Tran et al. [70], the shifting of energy sources after sugar ingestion may indi- cate that the utilization of exogenous and endogenous energy is closely regulated according to the energy bal- ance of body. 2) Beyond specific health and physiological conditions, physical activity, over energy consumption, dietary macronutrient composition, and other lifestyle factors would also play critical roles in the body’s utilization of dietary sugars. In view of these factors, how energy is quantitatively balanced with fructose load- ing is an area yet to be delineated.SummaryFigure 3 summarizes the major metabolic fates of dietary fructose based on the data obtained from the reviewed isotope tracer studies. The mean oxidation rate of diet- ary fructose was 45.0% (ranged 30.5-59%) of ingested doses in normal subjects within a period of 3–6 hours. With exercise conditions, the mean oxidation rate of fructose came to 45.8% (ranged 37.5-62%) within 2–3 hours. When fructose was ingested together with glucose, the mean oxidation rate of the mixed sugars increased to 66.0% (ranged 52.2-73.6%) under similar ex- ercise conditions. Secondly, the mean conversion rate from fructose to glucose was 41% (ranged 29-54%) ofFigure 3 Metabolic fate of dietary fructose carbons. The data are obtained within study periods less than or equal to 6 hours. After 50–150 gm fructose ingestion, the peak of fructose concentration in plasma would be between 3–11 mg/dL. The percent data above arrow lines or under box are the estimated amounts of ingested fructose doses via the pathway, and the question mark represents that the data remain to be further confirmed. The dash-line represents presumably minor pathways.Sun and Empie Nutrition & Metabolism 2012, 9:89 Fructose metabolism in humans – what isotopic tracer studies tell usingested dose in 3–6 hours after ingestion in normal non-exercise subjects. This value may be higher in sub- jects under exercise. The conversion amount from fruc- tose to glycogen remains to be further clarified. Thirdly, at short time periods (≤ 6 hours), it appeared that only a small percent of fructose carbons enter the pathway of liponeogenesis after fructose ingestion. The hyperlipid- emic effect of dietary fructose observed in both tracer and non-tracer studies may involve other metabolic mechanisms and this could relate to energy source shift- ing and lipid sparing. Lastly, fructose can be catabolized into lactate and cause an increase of blood lactate con- centrations. Approximately a quarter of ingested fruc- tose could be converted into lactate within a few of hours and this is a means to release fructose-derived car- bons from the liver for extrahepatic utilization. Even though the reviewed tracer studies may not be fully rep- resentative of real-life diets and the obtained data are limited, this review provides a basic outline how fructose is utilized after it is consumed by humans.Competing interestsThe authors are employed full time by Archer Daniels Midland Company (ADM). ADM is a major oilseed and grain commodity processor and produces, among other products, fructose-containing sweeteners.Authors’ contributionsThe two authors, SZS and MWE, have made similar contributions to the review. Both authors have read and approved the final manuscript.AcknowledgementsThe authors kindly thank Drs. 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