We'd like to understand how you use our websites in order to improve them. Register your interest. The intravenous infusion of fructose 0. A decrease of the total adenine nucleotide content of the livers occurs concomitantly. In contrast to its effect upon liver tissue fructose neither effects the content of adenine nucleotides nor the incorporation of glycine into these nucleotides in skeletal muscle of rats. However, they do not as yet present clear cut evidence as to whether this is a direct effect of fructose or is secondary to the depletion of adenine nucleotides.
|Published (Last):||23 September 2017|
|PDF File Size:||3.33 Mb|
|ePub File Size:||4.61 Mb|
|Price:||Free* [*Free Regsitration Required]|
Richard J. Johnson, Santos E. Perez-Pozo, Yuri Y. The primary sources of fructose are sugar sucrose and high fructose corn syrup.
First, fructose intake correlates closely with the rate of diabetes worldwide. Second, unlike other sugars, the ingestion of excessive fructose induces features of metabolic syndrome in both laboratory animals and humans. Third, fructose appears to mediate the metabolic syndrome in part by raising uric acid, and there are now extensive experimental and clinical data supporting uric acid in the pathogenesis of metabolic syndrome.
Fourth, environmental and genetic considerations provide a potential explanation of why certain groups might be more susceptible to developing diabetes. Finally, we discuss the counterarguments associated with the hypothesis and a potential explanation for these findings.
If diabetes might result from excessive intake of fructose, then simple public health measures could have a major impact on improving the overall health of our populace.
A lthough diabetes was described by Aretaeus, Galen, and Paracelsus, by the mid to late s William Prout 1 and others recognized that diabetes could have two presentations: one manifesting as a rapidly progressive and wasting condition in a thin and feeble individual likely type 1 diabetes , and a slower and more progressive disease in an overweight or obese subject likely type 2 diabetes 1 , 2.
Both conditions were rare; indeed, Osler 3 projected a prevalence of approximately two or three cases per , population in Europe and North America. By the early s, however, a remarkable rise in the prevalence of the second type of diabetes was observed in Europe and the United States 4.
Similarly, a dramatic increase in diabetes was observed in a number of tropical countries 5. In these early reports, the type of subject developing diabetes was often wealthy, overweight, and living in an urban environment 4 , 5. However, over the last 50 yr there has been a transition such that diabetes is now increasing most rapidly among the poor and minorities 6. Although some of the increase in diabetes prevalence may be due to the increasing longevity of the population, an increase in the rate of type 2 diabetes is also being observed among the young, suggesting that an active process is driving the epidemic.
Today diabetes is present in over million individuals worldwide. Over the next few decades a remarkable increase in diabetes is projected, especially in Asia and India 8. By , over million people are projected to suffer from this condition, making it one of the most serious diseases of humankind 7 , 8.
Identifying the etiology of type 2 diabetes is key to prevention. Obesity, and in particular intraabdominal fat accumulation, has been shown to induce insulin resistance via several mechanisms, and insulin resistance is considered the central pathogenic mechanism underlying type 2 diabetes Nevertheless, studies in certain populations, such as Asians, have documented high rates of type 2 diabetes in the absence of classical obesity 11 , There are also many obese subjects that do not have diabetes.
This suggests that whereas obesity may be a risk factor, other pathogenic factors may exist that could contribute to the epidemic of type 2 diabetes.
Although insulin resistance is characteristic of the subject with type 2 diabetes, insulin resistance also precedes its development. The metabolic syndrome is currently defined as having at least three of five characteristic signs abdominal obesity, impaired fasting glucose, hypertriglyceridemia, low high-density lipoprotein HDL cholesterol, and elevated blood pressure However, other conditions are also associated with metabolic syndrome, including fatty liver nonalcoholic steatohepatitis , mild kidney disease, and the presence of endothelial dysfunction, systemic inflammation, and oxidative stress.
Today the metabolic syndrome affects over 55 million More recently there has developed a debate over whether the metabolic syndrome is clinically useful above and beyond its individual components and whether it should be considered a disease entity 23 , Some studies also suggest that the metabolic syndrome represents multiple clusters of signs On the other hand, if the syndrome represented a common pathway for the development of diabetes, as suggested by one study 26 , then considering metabolic syndrome a disease entity would be reasonable.
In this paper we present the hypothesis that many cases of metabolic syndrome, as well as type 2 diabetes, may have a single etiology. Specifically, we revisit the old hypothesis that excessive intake of sugar, and in particular fructose, may be an important cause of type 2 diabetes. The hypothesis that sugar consumption might predispose to diabetes was entertained by the famous diabetologist, Frederick Allen 28 , as well as by other investigators of the early 20th century 4 , 5 , The hypothesis was resurrected in the s, particularly by Campbell and Yudkin 30 — 34 , but it has largely been eschewed, and restriction of sugar has not been recommended as a means to prevent diabetes by the American Diabetes Association However, recent studies from our group and others have provided evidence for how sucrose, and in particular its component fructose, may cause diabetes.
Fructose intake is associated with the metabolic syndrome, thus supporting this latter condition as a disease entity. Furthermore, fructose appears to cause insulin resistance through classic adiposity based mechanisms as well as mechanisms independent of energy intake or weight gain 36 , To better understand how fructose acts, we will first review certain unique characteristics of its metabolism.
Fructose is a simple sugar that is present in fruits and honey and is responsible for their sweet taste. However, the major source of fructose worldwide is sucrose, or table sugar, which is derived from sugar cane and sugar beets. After ingestion, sucrose is degraded in the gut by sucrase, releasing free fructose and glucose that are then absorbed.
In addition to sucrose, the other major source of fructose is high fructose corn syrup HFCS , which was introduced in the early s as an additional sweetener. In the United States, HFCS and sucrose are the major source of fructose in the diet, and HFCS is often a major ingredient in soft drinks, pastries, desserts, and various processed foods. The uptake of fructose by cells is largely mediated by Glut 5 and Glut 2 transporters, followed by metabolism by fructokinase ketohexokinase, KHK Fig.
Fructokinase may exist in two isoforms, of which KHK-C appears to be the principal isoform involved in fructose metabolism The dominant sites of KHK-C expression include the liver, the intestinal epithelium, the proximal tubule of the kidney, the adipocyte, and possibly the vascular endothelium 43 — Fructose may also be metabolized by hexokinase glucokinase ; however, the Km for fructose is much higher than glucose, and hence minimal amounts of fructose are metabolized via this pathway Fructose metabolism.
Fructose enters cells via a transporter typically Glut 5, Glut 2, or SLC2A9 where it is preferentially metabolized by fructokinase KHK to generate fructosephosphate. Unlike phosphofructokinase, which is involved in glucose metabolism, fructokinase has no negative feedback system to prevent it from continuing to phosphorylate substrate, and as a consequence ATP can be depleted, causing intracellular phosphate depletion, activation of AMP deaminase, and uric acid generation. In addition, fructose is lipogenic and can generate both glycerol phosphate and acyl coenzyme A, resulting in triglyceride formation that is both secreted and stored in hepatocytes.
Fructose differs from glucose primarily due to its different transporters and the first three enzymes involved in its metabolism Fig. A key enzyme is fructokinase, which uses ATP to phosphorylate fructose to fructosephosphate. Unlike enzymes involved in glucose metabolism glucokinase and phosphofructokinase , in which downstream metabolites prevent excessive phosphorylation, fructokinase is poorly regulated and will phosphorylate all fructose rapidly with the depletion of ATP The administration of fructose rapidly depletes ATP in human liver 47 , Similarly, concentrations of fructose as low as 1.
The effect of fructose to cause ATP depletion acts like a type of ischemia and can cause transient arrest of protein synthesis 46 , 47 and the production of inflammatory proteins, endothelial dysfunction, and oxidative stress 44 , Fructose is also highly lipogenic, stimulates triglyceride synthesis, and increases fat deposition in the liver, likely mediated in part by increasing fatty acyl coenzyme A and diacylglycerol Splanchnic perfusion studies have shown that hepatic production of triglycerides is much greater with fructose compared with equimolar concentrations of glucose Fructose administration results in greater postprandial hypertriglyceridemia than that observed with isocaloric glucose, and it can also result in higher apolipoprotein B levels 49 , Fructose feeding is also an effective way to induce fatty liver 52 , 53 and may be preferentially used by hibernating mammals as a means to increase fat stores One of the more striking aspects of fructose is its ability to stimulate uric acid production Although initially the rise in uric acid is transient, studies in which high fructose or sucrose diets have been administered have found that even fasting uric acid levels will increase after several weeks 59 , Choi et al.
Another distinct characteristic of fructose is that it has a positive feedback system in which fructose up-regulates its transporter Glut 5 as well as fructokinase. Experimentally, fructose administration has been shown to up-regulate Glut 5 and fructokinase in the rat intestine, liver, and kidney 64 , Subjects administered a high fructose diet show an enhanced rise in uric acid in response to a standard fructose load We have reported that subjects with metabolic syndrome and fatty liver have a history of significantly greater fructose intake and have higher levels of fructokinase mRNA in their liver biopsies compared with control subjects with other types of liver disease Because fructose intake appears to be higher in obese subjects 53 , 66 , this could account for the greater serum triglyceride response observed in these subjects after a fructose load 51 , 67 — Finally, fructose is quite distinct from glucose because it does not signal insulin release.
Moreover, fructose can actually lower plasma glucose acutely due to stimulation of hepatic glucose uptake due to a stimulation of hexokinase 70 — This has led to the concept that catalytic amounts of fructose may be beneficial in the diabetic. However, as discussed in Section X , the other short-term and long-term effects of fructose have led societies such as the American Diabetes Association not to recommend fructose supplementation for the diabetic subject As will be seen in Section III , it is the lipogenic characteristics of fructose, in association with its ability to induce ATP depletion and uric acid generation, that are largely responsible for its ability to induce metabolic syndrome.
Beginning with studies in the s, it was recognized that diets high in sucrose can rapidly induce features of metabolic syndrome in rats, including hyperglycemia, insulin resistance, hyperlipidemia, hypertension, weight gain, and hyperuricemia 74 — Further studies documented that these metabolic changes were due to the fructose content Indeed, if rats are pair-fed equivalent amounts of fructose or glucose so that total energy intake is the same and body weight change is equivalent, only the fructose-fed rats develop features of metabolic syndrome hypertriglyceridemia, hyperuricemia, and hyperinsulinemia 37 , In addition to the ability of fructose to cause hypertriglyceridemia 37 , low HDL cholesterol 79 , weight gain 80 — 82 , blood pressure elevation 83 — 85 , and impaired glucose tolerance 37 , 78 , the administration of fructose to rats can result in other findings associated with the metabolic syndrome, including endothelial dysfunction 78 , 86 , oxidative stress 87 , sympathetic nervous system activation 85 , 88 , activation of the renin angiotensin system 89 , systemic inflammation 45 , fatty liver 52 , increased intraabdominal fat accumulation 90 , leptin resistance 82 , 91 , proteinuria 78 , renal hypertrophy 84 , glomerular hypertension 84 , and renal microvascular disease 83 , Metabolic syndrome is also recognized as a risk factor for chronic kidney disease 92 ; fructose feeding also accelerates chronic kidney disease in rats compared with dextrose-fed rats administered identical caloric intake Despite the relatively consistent ability of fructose to induce hypertriglyceridemia, weight gain is often variable in studies using rats 83 , Recent studies from our group may provide insights into this mechanism.
In this study, rats were fed fructose or starch-based diets for 6 months. Despite the fact that there was no difference in weight gain between groups, the fructose-fed rats developed leptin resistance that was not observed in starch-fed rats. When the leptin-resistant rats were placed on a classic Western, high-fat, and high-sugar diet, the rats gained weight much more rapidly than their starch-fed littermates This suggests an interaction between fructose and high-fat diet in the ability to induce obesity.
A similar interaction has been shown in the ability of a high-salt diet to increase blood pressure in fructose-fed rats There is also evidence that sucrose, and possibly fructose, may have neuropsychiatric effects. Sugar may be addicting, similar to many commonly addictive drugs 95 , Rats exposed to sugar demonstrate sugar bingeing and craving, with dopamine and opioid receptor binding, enkephalin mRNA expression, and dopamine and acetylcholine release in the nucleus accumbens 95 , Similarly, humans exposed to cake or ice cream show enhanced activation of certain areas in the brain by positron emission tomography scanning, possibly due to alteration in dopaminergic activity A summary of the effects of fructose on the various organ systems is shown in Fig.
Effect of fructose on various organ systems. Table sugar, HFCS, and natural sources provide fructose, which in excess has numerous effects on the brain, liver, vasculature, kidney, and adipocyte. The net effects induce all features of the metabolic syndrome and ultimately type 2 diabetes. Potential mechanisms by which fructose and uric acid may induce insulin resistance.
Fructose enters cell via a transporter primarily Glut 5 where it is acted on by fructokinase KHK. As part of this metabolism, ATP depletion may occur, generating uric acid with systemic effects that block insulin-dependent NO-mediated vascular dilation as well as direct cellular effects on the adipocyte.
Studies on the Mechanism of Fructose-Induced Hyperuricemia in Man
The increasing incidence of obesity and the metabolic syndrome over the past two decades has coincided with a marked increase in total fructose intake. Fructose--unlike other sugars--causes serum uric acid levels to rise rapidly. We recently reported that uric acid reduces levels of endothelial nitric oxide NO , a key mediator of insulin action. NO increases blood flow to skeletal muscle and enhances glucose uptake. Animals deficient in endothelial NO develop insulin resistance and other features of the metabolic syndrome.
Fructose-Induced Hyperuricemia Is Associated With a Decreased Renal Uric Acid Excretion in Humans
Fructose induced hyperuricemia
Ingestion of a high-fructose meal increases blood uric acid UA concentration in healthy subjects 1. Furthermore, high-fructose intake over several days is associated with increased fasting UA concentration 1. These effects are generally attributed to an increased UA production, as observed after intravenous fructose administration 2. It has not been assessed, however, whether UA also increases when fructose is administered as several small drinks instead of one single large load or whether a high-fructose diet HFrD impairs renal UA clearance UAC or fractional excretion UAFE as observed in rats 3.
Purine Metabolism in Man pp Cite as. The precise biochemical basis for many instances of hyperuricemia in man are not clearly understood. Elucidation of the mechanism by which certain normal intermediates and their structural analogs alter the serum uric acid may be useful in delineating potential pathophysiological alterations leading to hyperuricemia. The infusion of fructose in man precipitates a number of biochemical changes including hyperlacticacidemia, decrease in serum inorganic phosphate, and decrease in serum glucose. This results from the phosphorylation of fructose to fructoseP and the entrance of this compound into the glycolytic pathway. An increase in serum uric acid concentration following the infusion of fructose was initially reported by Perheentupa and Raivio in