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Fructose: A Key Factor in the Development of Metabolic Syndrome and Hypertension

Fructose: A Key Factor in the Development of Metabolic Syndrome and Hypertension Hindawi Publishing Corporation Journal of Nutrition and Metabolism Volume 2013, Article ID 682673, 12 pages http://dx.doi.org/10.1155/2013/682673 Review Article Fructose: A Key Factor in the Development of Metabolic Syndrome and Hypertension 1,2 1 Zeid Khitan and Dong Hyun Kim Marshall University’s Joan C. Edwards School of Medicine, 1600 Medical Center Drive, Huntington, WV 25701-3655, USA Department of Medicine, Marshall University Joan Edwards School of Medicine, 1600 Medical Center Drive, Huntington, WV 25701-3655, USA Correspondence should be addressed to Zeid Khitan; zkhitan@marshall.edu Received 7 March 2013; Revised 14 May 2013; Accepted 14 May 2013 Academic Editor: Peter M. Clifton Copyright © 2013 Z. Khitan and D. H. Kim. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Diabetes mellitus and the metabolic syndrome are becoming leading causes of death in the world. Identifying the etiology of diabetes is key to prevention. Despite the similarity in their structures, fructose and glucose are metabolized in different ways. Uric acid, a byproduct of uncontrolled fructose metabolism is known risk factor for hypertension. In the liver, fructose bypasses the two highly regulated steps in glycolysis, glucokinase and phosphofructokinase, both of which are inhibited by increasing concentrations of their byproducts. Fructose is metabolized by fructokinase (KHK). KHK has no negative feedback system, and ATP is used for phosphorylation. This results in intracellul ar phosphate depletion and the rapid generation of uric acid due to activation of AMP deaminase. Uric acid, a byproduct of this reaction, has been linked to endothelial dysfunction, insulin resistance, and hypertension. We present possible mechanisms by which fructose causes insulin resistance and suggest actions based on this association that have therapeutic implications. 1. Background that other risk factors besides obesity might play a role in the epidemic of type 2 diabetes. Type 2 diabetes mellitus is characterized by hyperglycemia, insulin resistance, and an impairment in insulin secretion. 2. Fructose: Sources and Metabolism In the late nineteenth century, William Osler described diabetes as a rare disorder more likely to develop in obese Fructose is a simple sugar present in fruits and honey and is people and patients with gout. He estimated its prevalence responsible for their sweet taste. However, the major source as approximately two to nine cases per 100,000 population of fructose worldwide is sucrose or table sugar, which is in the USA and Europe being more common in the latter derived from sugar cane and sugar beets. It is man-made, [1]. Diabetes, one of the leading causes of death in the rfi st developedinNew Guinea andinthe Indian subcon- United States, aeff cts over 200 million people worldwide. eTh tinent and was a rare and expensive commodity that was estimated prevalence of diabetes among adults in the United introduced into Europe via Venice, Italy, and other trading States ranges from 4.4 to 17.9 percent [2]. The community- ports during the Middle Ages. Sucrose is a disaccharide based Framingham Heart Study, in a predominantly non- that is comprised of fructose and glucose. After ingestion, Hispanic white population, found a doubling in the incidence sucrose is degraded in the gut by sucrase, releasing fructose of type 2diabetesoverthe last 30 years[3]. Identifying and glucose that are then absorbed. In addition to sucrose, the etiology of type 2 diabetes is a key to its prevention. theother majorsourceoffructoseishighfructosecorn Obesity and intra-abdominal fat accumulation induce insulin syrup (HFCS), which was introduced in the early 1970s as an resistance [4]. Studies have documented high rates of type 2 additional sweetener. HFCS consists of fructose and glucose diabetes in the absence of classic obesity [5]. This suggests mixed in a variety of concentrations, but most commonly as 2 Journal of Nutrition and Metabolism 55% fructose and 45% glucose. In the United States, HFCS it phosphorylates fructose poorly at physiological concen- andsucrose arethe majorsources of fructose in thediet, trations [23]. Recently, it was found that adiposity and and HFCS is a major ingredient in soft drinks, pastries, metabolic syndrome were prevented in mice lacking both desserts, and various processed foods [6, 7]. Despite the KHK isoforms but exacerbated in mice lacking KHK-A similarity in their chemical structures, fructose and glucose [24]. It was also demonstrated that neither KHK isoform is are metabolized in completely different ways and utilize dif- required for normal growth and development in rats [25]. ferent GLUT transporters [8]. In the liver, fructose bypasses Serum leptin, triglycerides, and fasting blood glucose levels the two highly regulated steps of glycolysis, catalyzed by arehigherinhumansplacedonahigh fructosedietfor four glucokinase/hexokinase and phosphofructokinase both of weeks compared with those on a starch-based diet [26]. which are inhibited by increasing concentrations of their Deficiency of KHK-C, an autosomal recessive inborn byproducts. Instead, fructose enters the pathway at a level that error of metabolism, results in essential fructosuria with an is not regulated and is metabolized to fructose-1-phosphate estimated incidence of 1 : 130,000 [27]. This condition was primarily by fructokinase or ketohexokinase (KHK) (Figures first recognized in 1876 [ 23]. It is an anomaly rather than 1 and 2). Fructose may also be metabolized by hexokinase; a disease, since it does not lead to any outward signs or however, theKmfor fructoseismuchhigherthanglucose, symptoms. Most cases of fructosuria have been described and hence minimal amounts of fructose are metabolized in Jewish families [28]. It has no metabolic or morbid via this pathway [6]. Fructokinase has no negative feedback manifestations other than having transient fructosuria aer ft system,andATPisusedforthephosphorylationprocess.Asa meals containing either sucrose or fructose. This condition result, continued fructose metabolism results in intracellular used to be detected during routine medical examination phosphate depletion, activation of AMP deaminase, and uric when tests based on reducing properties of glucose like acid generation which is harmful at the cellular level [6, 9, 10]. Benedict’s solution and Clini test were used to diagnose Fructose-1-phosphate is subsequently converted to diabetes. es Th e tests have since been replaced by the more dihydroxyacetone-phosphate and D-glyceraldehyde by the specific glucose oxidase method which does not react with action of the aldolase B. D-glyceraldehyde is phosphorylated fructose; therefore, patients with essential fructosuria are no and continued downstream in the glycolysis pathway to longer being identified [ 28]. Moreover, the lack of treatment form pyruvate. Two of the most energetic reactions of all consideration and counseling for aeff cted individuals and organophosphates are in the pathway of fructose metabolism, their family members, the absence of screening recommen- catalyzed by phosphoglycerate and pyruvate kinases. Two dations, and the lack of serum KHK assay makes it dicffi ult ATP molecules as well as free energy, approximately to identify subjects with this anomaly. This is in contrast to 12 kcal/mole, are released [12]. Fructose controls the activity hereditary fructose intolerance, a disease characterized by of glucokinase, the principle enzyme of glucose metabolism the deficiency of fructose-1-phosphate aldolase which has in theliver.Fructoseisapotent andacute regulatorof significant metabolic and developmental complications that liver glucose uptake and glycogen synthesis. Inclusion manifest themselves as early as in the neonatal period. In of catalytic quantities of fructose in a carbohydrate meal a well-characterized family, in which three of eight siblings improves glucose tolerance. This improvement is primarily have fructosuria, all aeff cted individuals are compound het- mediated by the activation of hepatic glucokinase resulting erozygotes for the mutations Gly40Arg and Ala43Thr [ 29]. in improved liver glucose uptake [13]. Uric acid, a byproduct of fructose degradation, stimulates 3. Epidemiological Evidence KHK expression through the activation of the transcription factor ChREBP, which in turn results in the transcriptional Since1970, thetotal availability of sugars hasdramatically activation of KHK by the binding to a specific sequence increased. Comparison of the 1977–1978 NFCS analysis with within its promoter [14]. Uric acid inhibits endothelial NO the analyses of NHANES for the period 1999–2004 indicated both in vivo and in vitro,[15] and directly induces adipocyte that, over the intervening period, mean individual intake of dysfunction [16]. Serum uric acid increases rapidly aeft r total fructose increased by∼32% [30]. HFCS now represents ingestion of fructose, resulting in increases as high as 2 mg/dL nearly 50% of caloric sweeteners use in the United States [30, within 1 hour [17–19]. Uncontrolled fructose metabolism 31].Increasedtotalfructoseconsumptionhasbeenimplicated leads to postprandial hypertriglyceridemia, which increases in the development of the obesity epidemic in the United visceral adipose deposition. Visceral adiposity contributes to States with the consumption of HFCS increased >1000% hepatic triglyceride accumulation, protein kinase C activa- between 1970 and 1990, far exceeding the changes in intake tion, and hepatic insulin resistance by increasing the portal of any other food or food group [32]. delivery of free fatty acids to the liver [20]. Several reviews have concluded that intake of both fruc- Anumberofother furanose sugars canalsoact as tose and HFCS by children and adults was associated with KHK substrates [21]. KHK is expressed as two isoforms, an increased risk of obesity and metabolic syndrome [33– KHK-C and KHK-A. KHK-C is primarily expressed in 37]. However, not all published meta-analyses have reported the liver, kidney, pancreas, and duodenum, while KHK-A a statistically significant link [ 38–41]. Recently, Sievenpiper is expressed more widely including adipose tissue, heart, and colleagues concluded in a meta-analysis of controlled and the adrenal gland [22]. The exact biologic function of feeding trials that fructose does not cause weight gain when KHK-A is unknown. KHK-A has a higher Km for fructose substituted for other carbohydrates in isocaloric trials [42]. (7 mmol/L) than does KHK-C (0.8 mmol/L) suggesting that This was criticized on the basis of fructose causing weight Journal of Nutrition and Metabolism 3 Hexokinase Glucose-6-phosphate Glucose + ATP Isomerase Hexokinase Fructose + ATP Fructose-6-phospate Cytosol KHK PFK Inosine ADP Adenosine Hypoxanthine Xanthine Uric acid Fructose-1-phosphate Fructose-1,6-diphosphate DHAP Glyceraldehyde Glyceraldehyde-3-P Figure 1: Fructose metabolism. Fructose is primarily metabolized to fructose-1-phosphate by KHK due to its lower Km for fructose compared with hexokinase. Uncontrolled consumption of ATP leads to intracellular phosphate depletion and activation of AMP deaminase leading to the increased production of uric acid. Fructose-1-phosphate is further metabolized by aldolase B and triokinase to glyceraldehyde-3- phosphate. Glyceraldehyde-3-P 2ATP NADH Pyruvate Mitochondria Acetyl-CoA Pyruvate dehydrogenase Pyruvate Increase fatty acid Citric acid synthesis cycle Figure 2: Role of fructose in lipogenesis. Glyceraldehyde-3-P continues downstream in the glycolysis pathway forming pyruvate which enters the mitochondria and is further metabolized to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA enters the citric acid cycle by combining with oxaloacetate to form citrate. In the well fed state, citrate can be transported to the cytosol, providing CoA necessary for lipogenesis. gain by altering appetite resulting in increased food intake, by among nondiabetic women in the Nurses’ Health Study II inducing leptin resistance and by a direct effect on the brain concluded that higher consumption of sugar-sweetened bev- indicating that isocaloric trials do not show a difference in erages was associated with greater magnitude of weight gain weight gain between groups. Moreover, the use of weight gain and an increased risk for the development of type 2 diabetes as a marker is subject to debate, since other fructose eeff cts, [45]. On the other hand, a recent analysis of NHANES beyond body weight as central fat accumulation and insulin 1999–2006 databases comparing data from>25,000 subjects resistance, can be more important [43]. showed no relation between daily fructose intake and the In children, intake of artificially sweetened beverages indicators of metabolic syndrome, uric acid, and BMI [46]. was found to be positively associated with adiposity [44]. Thisstudy wasbased on asnapshotofone-ortwo-days A prospective cohort analyses conducted from 1991 to 1999 recalls. u Th s, the intake data may not truly represent the long 4 Journal of Nutrition and Metabolism term, consistent consumption of food. Moreover, due to no fructose intake data being available in NHANES databases and a lack of fructose content data for many food items in the Mesenchymal stem cell USDA National Nutrient Database for Standard Reference, the fructose intake of individuals was indirectly estimated using several databases. Interpretation of cross-sectional studies examining the relationship of sugar intake to obesity can be misleading due to the fact that subjects who become obese may well reduce their sugar intake, since sugar is widely recognized to cause Preadipocyte weight gain. er Th efore, examining the relationship of sugar Fructose to obesity is best performed with well controlled, long-term longitudinal studies. It is also important to recall that leptin Early stage resistance leading to liporegulatory failure, and, subsequently, insulin resistance can be perpetuated once obesity and Ang II inhibitor intracellular lipid accumulation are manifest, especially in Late stage sites other than adipose tissue including pancreatic B cells and cardiomyocytes. u Th s, reducing fructose intake may not fully reverse insulin resistance and diabetes. This further adds to the complexity and clouds the interpretation of these epidemiological data [6, 47, 48]. The relationship between fructose intake and hyperten- Mature adipocyte sion was also examined in several clinical studies. In a ran- domized controlled trial, high dose fructose (200 gm/24 h) Figure 3: Overview of stages of adipocyte differentiation and the increasedambulatoryblood pressure andelevatedfasting impact of angiotensin II inhibitors and elevated fructose levels. insulin levels. In this study, allopurinol prevented the increase in mean arterial blood pressure [49]. In an analysis of the NHANES 2003–2006 data, fructose intake, in the form of which, on its own and among other dairy products, has been added sugar, was independently associated with higher blood showntoenhance weight loss [43, 56, 57]. pressure levels [50]. Fructose consumption in the form of There is mounting evidence from studies looking at sugar-sweetened beverages was associated with hypertension the association between fructose and obesity and metabolic andelevateduricacidlevel in USA adolescents[51]but not syndrome that primary fructose malabsorption in children in adults [52]. Uric acid may raise systemic blood pressure was negatively associated with obesity [58]. In obese African- by increasing inflammation, activating the renin-angiotensin Americans, high rates of fructose malabsorption were asso- system, and decreasing nitric oxide production contributing ciated with reduced liver fat thought to be protective against to renal vasoconstriction that results in salt insensitive hyper- fatty liver disease [59]. tension [53]. Persistent vasoconstriction may contribute to In conclusion, it is evident that there is a need for clinical arteriosclerosis and the subsequent development of salt- trials with variable amounts of fructose intake to determine sensitive hypertension, even if the hyperuricemia is corrected effects on metabolic outcomes rather than depending on [54]. This may explain the different results in the preceding meta-analyses of existing studies of mixed design and dura- two studies that looked at two different age groups. A tion. recent meta-analysis of controlled feeding trials found that isocaloric substitution of fructose with other carbohydrates did not adversely affect blood pressure in humans suggesting 4. Effect of Fructose on Adipocyte that there is a need for long-term and large trials to clarify Differentiation these ndin fi gs [ 40]. Few studies have examined the role of naturally occurring Adipocyte development in mice and humans follows a well- sugars, for example, 100% fruit juice, in the origin of obesity den fi ed pathway that begins with a common stem cell medi- andrelated endpoints. It is believed that fructosefrom ated adipocyte regeneration and is referred to as adipogenesis natural sources can be less harmful because the presence of [60]. The first step of adipogenesis is the generation and additional nutrients and antioxidants. On the other hand, commitment of mesenchymal stem cells (MSCs) to adipocyte crystalline fructose, as in table sugar, and HFCS are regarded lineage. The effect of fructose-mediated renin-Ang II activa- as less safe, since glucose present in these sugars can acceler- tion is on the stages of cell dieff rentiation (“commitment”) ate fructose absorption. 100% fruit juice consumption among and involves local and systemic effects. USA adults is associated with lower insulin resistance [55] Figure 3 showsthe mechanismofAng II inhibition and lower odds of obesity and metabolic syndrome. Obesity during adipogenesis. MSCs or preadipocytes differentiate remained an independent factor aeft r adjusting to other into lipid-laden and insulin-sensitive adipocytes [61]. lifestyle factors. What is interesting in this study is that 100% Briefly, the stages of adipocyte differentiation are aeff cted juice consumers had significantly higher white milk intake by increasesinthe levels of fructoseand AngIIwhich cause Journal of Nutrition and Metabolism 5 MSC-derived adipocyte growth arrest, clonal expansion, and Lean diets increase small adipocytes (1) Lipid synthesis, uptake, and storage early differentiation. Ang II blockade can prevent terminal differentiation leading to the development of the mature adipocyte phenotype [62, 63]. Normal diets result in the activation of PPAR𝛾 fol- (2) Hepatic and peripheral glucose lowed by adipose expansion through adipocyte hyperplasia, homeostasis, ↑ adiponectin, and IL-10 resulting in an increased number of new preadipocytes. eTh resulting adipocytes are small in size and eeff ctively Fructose rich diets store lipids, thereby reducing lipotoxicity in the liver and increase the large adipocytes adiposetissueand releaseadiponectin [64, 65]. Activation of these genes leads to repartitioning of lipids resulting in an increased triglyceride content of adipose tissue, a lowered free fatty acid content in circulation and availability for ↑ (MCP-1, IL-6, TNF-𝛼 , PAI-1, IL-1, and IL-8) liver and muscle use, thereby improving insulin sensitiv- ity. Methylisobutylxanthine (MIX), an phosphodiesterases inhibitor, increases intracellular cAMP, activating adipocyte differentiation in a PKA-independent manner [ 66]. MIX Figure 4: Enlargement of adipocytes causes alterations in secretion also increased the expression of C/EBP-𝛽 ,requiredfor the of adipokines. Under normal conditions, adipocyte is a site of subsequent expression of PPAR-𝛾 [62]. lipid synthesis, uptake, and storage. Secreted adipokines function as Although, the mechanisms by which fructose controls endocrine, paracrine, or autocrine mediators. Increased adipocyte adipogenesis in vivo are largely unknown, there are a number size can lead to deleterious alterations in insulin sensitivity caused of candidates that mediate adipocyte differentiation in culture by a decrease in adiponectin secretion and the induction of inflam- and are thought to control adipocyte accumulation and matory mediators. Modified from [ 11]. function in vivo. Two main factors tfi this criterion: (1) high fructose diets, (2) increases in ROS. eTh y have been implicated as the link between adipogenesis and metabolic Mitochondria play an important role in adipocyte dif- diseases including T2DM. ferentiation and function [68]. During the early stages of Recent studies demonstrated that the induction of oxida- preadipocyte development, an increased number of mito- tive stress by high fructose or glucose increased NAD(P)H chondria are required, resulting in small mature adipocytes, oxidase and the mitochondrial respiratory chain which is highly sensitive to insulin, and secreting high levels of associated with diabetic complications [67]. eTh refore, fruc- adiponectin [69]. By contrast, mitochondrial dysfunction tose diets may lead to adipocyte differentiation associated has also been linked to T2DM complications in fructose with adipocyte dysfunction and formation of adipocytes diets. The results of impaired mitochondrial function include external to normal adipocyte depots, that is, muscle, liver, and increased FFA levels resulting in the accumulation of mito- pancreas leading to advanced diabetic complications. chondrial products including fatty acyl coenzyme A (CoA) The fructose-mediated increase in ROS via activation of and reduced insulin sensitivity [69]. the adipocyte renin-Ang II system may lead to adipocyte Insummary,fructosediets,inactivity,andgluttonyresults dysfunction and insulin resistance. Adipose tissue is a key in adipocyte expansion with the resultant detrimental pertur- endocrine organ, the function of which, via interaction with bations in the renin-Ang II system and in mitochondria, both the vascular endothelium system, regulates lipid uptake, of which undergo cellular changes that result in the increased storage, synthesis, and secretion of paracrine and autocrine generation of ROS and TNF-𝛼 ,IL-1, andIL-6and adecrease factors that regulate insulin sensitivity. However, fructose- in adiponectin levels. Adiponectin is synthesized and released mediated vascular dysfunction may have a negative eeff ct on only by theadipocyte andhas an essentialroleinvascularand adipocyte function and the secretion of anti-inflammatory renal function. molecules such as adiponectin, IL-1, and IL-10. eTh glucose Increases in adipocyte release of adiponectin inhibits or fructose-mediated decrease in vascular function increases both the expression of hepatic gluconeogenic enzymes and adipocytesizeresulting in decreasedlevelsofadiponectin, the rate of endogenous glucose production in diabetic mice but increased levels of MCP-1, IL-6, and TNF-𝛼 that have [70]. In adiponectin transgenic mice, adiponectin reduced systemic effects on 𝛽 cells (Figure 4). the expression of phosphoenolpyruvate carboxylase and The adipocyte-mediated increase in adipokine release glucose-6-phosphatase, which are associated with elevated plays a critical role in the regulation of blood pressure phosphorylation of hepatic AMPK and decreased glucose (angiotensinogen), vascular haemostasis, and angiogene- production [70, 71]. sis. The release of these cytokines by adipocytes suggest that fructose-mediated diabetes may be related to systemic effects which include altered adiposity and insulin resis- 5. Prohypertensive Effects of Fructose and tance. Adipocyte dysfunction occurs as a consequence of Putative Mechanisms chronic overfeeding of fructose leading to adipocyte enlarge- ment and inflammation and mitochondrial dysfunction Hypertension, diabetes, and obesity were originally docu- (Figure 5). mented in England and France where sugar rfi st became 6 Journal of Nutrition and Metabolism Fructose diets or (over nutrition) Preadipocyte number and enlargement AngII inhibitor Mitochondria AngII system dysfunction Small adipocyte ROS ROS Large adipocyte Inflammatory cytokines: Adiponectin IL-1𝛼 , IL-6, TNF𝛼 , MCP-1··· Insulin resistance Figure 5: Molecular mechanisms by which fructose diets, inactivity, and gluttony increase preadipocyte number and enlargement via increases in ROS generated by the renin-AngII system and mitochondrial dysfunction leading to obesity, insulin resistance, and diabetes. Hyperglycemia results in increased ROS production within the mitochondria via a number of mechanisms including a reduction in the glutathione/glutathione disulfide ratio. ROS generation mediates a pro inflammatory cascade resulting in increase of adipogenesis, release of inflammatory cytokines, and decrease in adiponectin leading to insulin resistance. 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0 1919 1939 1975 1990 2004 1890 1900 1976 1988 1999 (Year) (Year) (a) (b) Figure 6: Changing prevalence of hypertension over 100 years in the USA (a). Increasing prevalence of obesity in the USA over 100 years. Obesity defined as body mass index (BMI Kg/m )>30 (b). available to the public. eTh rise in sugar intake in the United theprevalenceofhypertensioninthe United States [72–74] Kingdom and the United States also correlated with the (Figure 6(a)). This was paralleled by an increase in the rates rise in obesity rates observed in these countries [7]. In the of obesity and diabetes. Body mass index (BMI; in kg/m )>30 early 1900s, blood pressure in over 140,000 healthy adults was observed in only 3.4% of 50- to 59-year-old male veterans who applied for life insurance in the New York region in 1890, compared with 30.4% in 1999–2002 [7](Figure 6(b)). suggested that a blood pressure of 140 (systolic)/90 (diastolic) This is paralleled by the epidemic of sugar consumption that mm Hg was abnormal because it reflected only 5-6% of the hasworsenedoverthe past 300years. population in the United States [7]. Subsequent studies over During the last decade, emerging data have altered our the past century showed a significant and dramatic rise in perspective on the link between fructose, uric acid, and Prevalence (%) Prevalence (%) Journal of Nutrition and Metabolism 7 hypertension. Epidemiologic data, in the form of large, expression of the fructose transporter GLUT5 in pancreatic longitudinal studies strengthened the link between elevated 𝛽 -cells [87]. Consumption of fructose-sweetened beverages uric acid and hypertension [50, 75–79]. In animals, mild with meals produced a rapid and prolonged elevation of hyperuricemia induced by the uricase inhibitor oxonic acid, plasma triglycerides compared with glucose-sweetened bev- mimicking levels in humans, increased blood pressure by erages. Because insulin, leptin, and possibly ghrelin function crystal-independent mechanism resulting in stimulation of as key signals to the central nervous system in the long-term the renin-angiotensin system and inhibition of nitric oxide regulation of energy balance, decreases of circulating insulin synthase [80]. Two-thirds of adolescents with newly diag- and leptin and increased ghrelin concentrations could lead to nosed essential hypertension and elevated uric acid normal- increased caloric intake and ultimately contribute to weight ized their blood pressure when treated with the xanthine gain and obesity during chronic consumption of diets high in oxidase inhibitor allopurinol [81]. This study could not fructose [88]. Apolipoprotein B levels were found to be higher excludethe possibilitythatsomeorall of theobservedeeff ct following fructose consumption compared with isocaloric couldhavebeenmediatedbyareductioninsuperoxide amount of glucose [89]. production, a byproduct of xanthine oxidase function. A Fructose increases the incidence of hypertension, NAFL, more recent study done by the same group confirmed and diabetes [90]. In fact,countries electing to useHFCSin these results by using two differently acting urate lowering their food supply have a 20% higher prevalence of diabetes drugs, allopurinol, and probenecid [82]. This study clearly compared to countries that did not use HFCS independent implicated uric acid as the biochemical mediator of increased of obesity [91]. Uric acid stimulates fructokinase and the blood pressure. Animal data suggested that uric acid induced development of NAFL [14] via an increase in fructose hypertension has two phases. eTh rfi st is salt insensitive metabolism thereby increasing the development of type 2 which is likely to be managed by urate lowering drugs, diabetes in children. This may be related to an increase while the second phase is salt sensitive. Due to a paucity of in SREBP-1c and reduced acyl-CoA oxidase during preg- outcome data, recommendations on how to treat uric acid nancy [92]. Body size at birth is related to food intake and associatehypertensioncannotbemadeatthistimealthough the content of fructose [93] or an elevation of estrogen the mechanism appears clear, especially in the early stages during pregnancy in women with a family history of type before the development of salt sensitivity. Future clinical trials 2diabetes[94, 95]. Genetic morphism in the glucokinase are required to include different levels of hypertension and regulatory protein, which binds to glucokinase and inhibits different age groups before recommending urate lowering its activity in the presence of fructose-6-phosphate (F6P) agents especially as they have an inferior efficacy profile is associated with ethnicityand mayberesponsible for when compared with antihypertensive medications presently different response rates to obesity and diabetes in different in clinical use. populations [96]. An increase of fructose-1,6-biophosphatase Consumption of high-fructose chow by mice produced [97], or in angiotensin 1–7 [98] decreases fructose-mediated nocturnal hypertension and autonomic imbalance which diabetes by an increase in pancreatic islet metabolism may be related to activation of the sympathetic and RAS [99]. systems [83]. Subsequent data suggested that changes in auto- nomic modulation may be an initiating mechanism underly- ing the cluster of symptoms associated with cardiometabolic 7. Prospective and Therapeutic Implications disease [84]. eTh addition of clonidine to drinking water inhibited fructose-induced hypertension in rats [85]. Based on the present knowledge of fructose and its detrimen- tal metabolic effects when in excess and the unique nature of KHK, it is clear that fructose is, at least, partially responsible for the pandemic of diabetes and the metabolic syndrome that 6. Effect of Fructose on Dyslipidemia and is presently occurring. A number of therapeutic approaches Insulin Resistance appear viable as a result of the data outlined previously. The earliest recorded metabolic perturbation resulting from (1) Assessing KHK activity in human blood samples fructose consumption is postprandial hypertriglyceridemia, opensanewapproachtothe diagnosisaswellasthe which increased visceral adipose deposition. Visceral adipos- treatment of type 2 diabetes. We hypothesize that individuals ity contributes to hepatic triglyceride accumulation, protein either completely or partially deficient in KHK activity are kinase C activation, and hepatic insulin resistance by increas- immune at variable levels from developing type 2 diabetes ing the portal delivery of free fatty acids to the liver. With mellitus. In order to test this hypothesis, the following insulin resistance, VLDL production is upregulated and this, require clarification: (a) KHK-C is primarily expressed in along with systemic free fatty acids, increase lipid delivery to the liver and kidney. u Th s, the in vivo handling of fruc- muscle.Itisalsopossiblethatfructoseinitiateshepaticinsulin tose to assess enzyme expression and efficiency would be resistance independently of visceral adiposity and free fatty difficult to monitor. We propose that PMN expression will acid delivery [20]. Splanchnic perfusion studies have shown parallel hepatic expression, a series of pilot clinical studies that hepatic production of triglycerides is much greater with in individuals selected across populations at varying risk fructose compared with equimolar concentrations of glucose for type 2 diabetes mellitus is required. (b) Once this [86]. Unlike glucose, fructose does not stimulate insulin association has been demonstrated, measurement of KHK- secretion, due to its hepatic metabolism and the low level of C activity in PMN’s in young adults with type 2 diabetes 8 Journal of Nutrition and Metabolism and age/sex matched controls is required. If results support [114, 115]. Plasma Ang II is associated with markers of insulin the hypothesis, new approach to the prediction as well as a resistance and obesity [116]. Renin angiotensin expression therapeutic approach to treat type 2 diabetes mellitus is at regulates mouse and human adipocyte dieff rentiation [ 117, hand. 118]. (2) Interference with fructose transport at the GLUT (5)Uricacidcan be abyproduct of uncontrolled fructose transporter level diminishes the availability of fructose. Due metabolism due to the rapid consumption of ATP as noted to their hydrophilic nature, sugars must rst fi traverse lipid previously. Uric acid has been linked to endothelial and bilayer membranes via carrier-mediated transport mecha- adipocytes dysfunction. In contrast, uric acid also functions nisms. Several transporters have been identified, and these as an antioxidant [119]. Treating hyperuricemia in the absence include the facilitative glucose transporter (GLUT) which of gout is not recommended at this time due to the lack of primarily regulates the clearance of blood glucose along sucffi ient data. a concentration gradient and the sodium-coupled glucose (6)Theideal andlogical,but most dicffi ult, approach cotransporter (SGLT) family members that are distinct at wouldbetomodifyfructosecontent in food.Thereason both the primary and secondary structural levels from the that KHK is a poorly regulated enzyme may be due to the GLUT proteins. Expression of SGLT proteins is restricted high levels of physical activity and limited fructose intake that to the gut and kidney, where their role is energy-dependent was prevalent in humans before the introduction of ren fi ed reabsorption of glucosefromlumen.TheGLUTtransporter cane sugar and high fructose corn syrup (HFCS). Negative family comprises 13 members that exhibit tissue distribution, feedback was unnecessary due to the limited supply of substrate specificity, and transport kinetics that reflect their fructose. This does not exist today where calorie sweeteners, physiologic role. These have not been fully defined for all including HFCS, are part of the normal diet. Moreover, and 13 isoforms [100]. Fructose gains access to the circulation of grave concern, is the increased consumption of sugar- and hepatocytes via GLUT 5, GLUT 7, and GLUT 11 [8]. sweetened beverages, and fresh and processed juices which Interference with fructose transport at the level of these provideaneasyvehicle forexcessive sugarintake, over very transporters represents a therapeutic approach to prevent a short period of time and have been directly linked to fructose-induced adiposity and insulin resistance. obesity [35, 120]and type 2diabetes[45, 121]. At the end (3)Interferenceatthe levelofKHK is an attractive of the day, we might conclude that “only drinking “milk approach to modify the metabolism of fructose and, pos- and water” can prevent diabetes.” eTh present choice is sibly, alleviating adiposity and vascular dysfunction. This either to continue with the currently high rates of fructose canbeimplemented in twoways. (a) An inhibitoriscur- consumption which lead to adipocyte expansion, obesity, and rently being developed (Richard Johnson, patent number hypertension or to minimize fructose intake and alleviate WO/2012/019188, public knowledge). It remains unclear how health care cost and the cost of managing hypertension and eecti ff ve this approach will be, and if this intervention its complications, thereby improving the lots of health care will be dependent on an individual’s KHK activity profile professional, patients, and their families and the well-being as suggested previously. (b) eTh use of certain furanose of millions of individuals. sugars, which can also be substrates for KHK and compete with fructose for its metabolism to hexose-1-phosphate [21]. 8. Conclusion D-Tagatose, a furanose sugar metabolized by KHK, when compared with fructose, caused markedly higher levels of Fructose metabolism is very unique in a sense that it is serumuricacidand lowerofPi[101]. This highlights the not regulated. eTh consequences of uncontrolled fructose importance of the poorly regulated KHK in this pathway and metabolism can be harmful at the cellular level resulting in necessitates further study. intracellular ATP depletion, increased uric acid production, (4) era Th peutic agents that decrease the effect of high endothelial dysfunction, oxidative stress, and increased lipo- fructose diets on diabetes and insulin resistance include genesis. High fructose consumption induces insulin resis- statins [102], metformin [103], and renin inhibitor attenuated tance and other manifestations of metabolic syndrome in a diabetes and insulin resistance [104]. The latter is due to a series of animal models. es Th e eeff cts are not seen in animals decrease in lipid peroxidation. In support of these obser- fed either glucose or starch. Human epidemiological data are vations, candesartan cilexetil [105]and losartan improve generally of poor quality due to the lack of consistency in renal hemodynamic and insulin resistance [106]and lower study design, methodology, and length. It remains unclear blood pressure in diabetic rodents fed a high fructose diet if targeting fructose by interfering with its transport or [107] presumably by the activation of AMP-activated protein metabolism canbeofany clinical benetfi . kinase [108]. Infusion of Ang II decreased adiponectin and potentiated fructose-mediated insulin resistance in fructose- fed rats [109]. The presence of renin-angiotensin aldosterone Acknowledgments in adipose tissue has been described [110–112]inwhich Ang II increased NADPH oxidase activity and WAT mediated This work was supported by National Institutes of Health inflammation and blocked RAAS thereby preventing the Grant HL-55601 (N.G.A.) and by the BrickStreet Foundation onsetofdiabetes. 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Fructose: A Key Factor in the Development of Metabolic Syndrome and Hypertension

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Copyright © 2013 Zeid Khitan and Dong Hyun Kim. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Hindawi Publishing Corporation Journal of Nutrition and Metabolism Volume 2013, Article ID 682673, 12 pages http://dx.doi.org/10.1155/2013/682673 Review Article Fructose: A Key Factor in the Development of Metabolic Syndrome and Hypertension 1,2 1 Zeid Khitan and Dong Hyun Kim Marshall University’s Joan C. Edwards School of Medicine, 1600 Medical Center Drive, Huntington, WV 25701-3655, USA Department of Medicine, Marshall University Joan Edwards School of Medicine, 1600 Medical Center Drive, Huntington, WV 25701-3655, USA Correspondence should be addressed to Zeid Khitan; zkhitan@marshall.edu Received 7 March 2013; Revised 14 May 2013; Accepted 14 May 2013 Academic Editor: Peter M. Clifton Copyright © 2013 Z. Khitan and D. H. Kim. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Diabetes mellitus and the metabolic syndrome are becoming leading causes of death in the world. Identifying the etiology of diabetes is key to prevention. Despite the similarity in their structures, fructose and glucose are metabolized in different ways. Uric acid, a byproduct of uncontrolled fructose metabolism is known risk factor for hypertension. In the liver, fructose bypasses the two highly regulated steps in glycolysis, glucokinase and phosphofructokinase, both of which are inhibited by increasing concentrations of their byproducts. Fructose is metabolized by fructokinase (KHK). KHK has no negative feedback system, and ATP is used for phosphorylation. This results in intracellul ar phosphate depletion and the rapid generation of uric acid due to activation of AMP deaminase. Uric acid, a byproduct of this reaction, has been linked to endothelial dysfunction, insulin resistance, and hypertension. We present possible mechanisms by which fructose causes insulin resistance and suggest actions based on this association that have therapeutic implications. 1. Background that other risk factors besides obesity might play a role in the epidemic of type 2 diabetes. Type 2 diabetes mellitus is characterized by hyperglycemia, insulin resistance, and an impairment in insulin secretion. 2. Fructose: Sources and Metabolism In the late nineteenth century, William Osler described diabetes as a rare disorder more likely to develop in obese Fructose is a simple sugar present in fruits and honey and is people and patients with gout. He estimated its prevalence responsible for their sweet taste. However, the major source as approximately two to nine cases per 100,000 population of fructose worldwide is sucrose or table sugar, which is in the USA and Europe being more common in the latter derived from sugar cane and sugar beets. It is man-made, [1]. Diabetes, one of the leading causes of death in the rfi st developedinNew Guinea andinthe Indian subcon- United States, aeff cts over 200 million people worldwide. eTh tinent and was a rare and expensive commodity that was estimated prevalence of diabetes among adults in the United introduced into Europe via Venice, Italy, and other trading States ranges from 4.4 to 17.9 percent [2]. The community- ports during the Middle Ages. Sucrose is a disaccharide based Framingham Heart Study, in a predominantly non- that is comprised of fructose and glucose. After ingestion, Hispanic white population, found a doubling in the incidence sucrose is degraded in the gut by sucrase, releasing fructose of type 2diabetesoverthe last 30 years[3]. Identifying and glucose that are then absorbed. In addition to sucrose, the etiology of type 2 diabetes is a key to its prevention. theother majorsourceoffructoseishighfructosecorn Obesity and intra-abdominal fat accumulation induce insulin syrup (HFCS), which was introduced in the early 1970s as an resistance [4]. Studies have documented high rates of type 2 additional sweetener. HFCS consists of fructose and glucose diabetes in the absence of classic obesity [5]. This suggests mixed in a variety of concentrations, but most commonly as 2 Journal of Nutrition and Metabolism 55% fructose and 45% glucose. In the United States, HFCS it phosphorylates fructose poorly at physiological concen- andsucrose arethe majorsources of fructose in thediet, trations [23]. Recently, it was found that adiposity and and HFCS is a major ingredient in soft drinks, pastries, metabolic syndrome were prevented in mice lacking both desserts, and various processed foods [6, 7]. Despite the KHK isoforms but exacerbated in mice lacking KHK-A similarity in their chemical structures, fructose and glucose [24]. It was also demonstrated that neither KHK isoform is are metabolized in completely different ways and utilize dif- required for normal growth and development in rats [25]. ferent GLUT transporters [8]. In the liver, fructose bypasses Serum leptin, triglycerides, and fasting blood glucose levels the two highly regulated steps of glycolysis, catalyzed by arehigherinhumansplacedonahigh fructosedietfor four glucokinase/hexokinase and phosphofructokinase both of weeks compared with those on a starch-based diet [26]. which are inhibited by increasing concentrations of their Deficiency of KHK-C, an autosomal recessive inborn byproducts. Instead, fructose enters the pathway at a level that error of metabolism, results in essential fructosuria with an is not regulated and is metabolized to fructose-1-phosphate estimated incidence of 1 : 130,000 [27]. This condition was primarily by fructokinase or ketohexokinase (KHK) (Figures first recognized in 1876 [ 23]. It is an anomaly rather than 1 and 2). Fructose may also be metabolized by hexokinase; a disease, since it does not lead to any outward signs or however, theKmfor fructoseismuchhigherthanglucose, symptoms. Most cases of fructosuria have been described and hence minimal amounts of fructose are metabolized in Jewish families [28]. It has no metabolic or morbid via this pathway [6]. Fructokinase has no negative feedback manifestations other than having transient fructosuria aer ft system,andATPisusedforthephosphorylationprocess.Asa meals containing either sucrose or fructose. This condition result, continued fructose metabolism results in intracellular used to be detected during routine medical examination phosphate depletion, activation of AMP deaminase, and uric when tests based on reducing properties of glucose like acid generation which is harmful at the cellular level [6, 9, 10]. Benedict’s solution and Clini test were used to diagnose Fructose-1-phosphate is subsequently converted to diabetes. es Th e tests have since been replaced by the more dihydroxyacetone-phosphate and D-glyceraldehyde by the specific glucose oxidase method which does not react with action of the aldolase B. D-glyceraldehyde is phosphorylated fructose; therefore, patients with essential fructosuria are no and continued downstream in the glycolysis pathway to longer being identified [ 28]. Moreover, the lack of treatment form pyruvate. Two of the most energetic reactions of all consideration and counseling for aeff cted individuals and organophosphates are in the pathway of fructose metabolism, their family members, the absence of screening recommen- catalyzed by phosphoglycerate and pyruvate kinases. Two dations, and the lack of serum KHK assay makes it dicffi ult ATP molecules as well as free energy, approximately to identify subjects with this anomaly. This is in contrast to 12 kcal/mole, are released [12]. Fructose controls the activity hereditary fructose intolerance, a disease characterized by of glucokinase, the principle enzyme of glucose metabolism the deficiency of fructose-1-phosphate aldolase which has in theliver.Fructoseisapotent andacute regulatorof significant metabolic and developmental complications that liver glucose uptake and glycogen synthesis. Inclusion manifest themselves as early as in the neonatal period. In of catalytic quantities of fructose in a carbohydrate meal a well-characterized family, in which three of eight siblings improves glucose tolerance. This improvement is primarily have fructosuria, all aeff cted individuals are compound het- mediated by the activation of hepatic glucokinase resulting erozygotes for the mutations Gly40Arg and Ala43Thr [ 29]. in improved liver glucose uptake [13]. Uric acid, a byproduct of fructose degradation, stimulates 3. Epidemiological Evidence KHK expression through the activation of the transcription factor ChREBP, which in turn results in the transcriptional Since1970, thetotal availability of sugars hasdramatically activation of KHK by the binding to a specific sequence increased. Comparison of the 1977–1978 NFCS analysis with within its promoter [14]. Uric acid inhibits endothelial NO the analyses of NHANES for the period 1999–2004 indicated both in vivo and in vitro,[15] and directly induces adipocyte that, over the intervening period, mean individual intake of dysfunction [16]. Serum uric acid increases rapidly aeft r total fructose increased by∼32% [30]. HFCS now represents ingestion of fructose, resulting in increases as high as 2 mg/dL nearly 50% of caloric sweeteners use in the United States [30, within 1 hour [17–19]. Uncontrolled fructose metabolism 31].Increasedtotalfructoseconsumptionhasbeenimplicated leads to postprandial hypertriglyceridemia, which increases in the development of the obesity epidemic in the United visceral adipose deposition. Visceral adiposity contributes to States with the consumption of HFCS increased >1000% hepatic triglyceride accumulation, protein kinase C activa- between 1970 and 1990, far exceeding the changes in intake tion, and hepatic insulin resistance by increasing the portal of any other food or food group [32]. delivery of free fatty acids to the liver [20]. Several reviews have concluded that intake of both fruc- Anumberofother furanose sugars canalsoact as tose and HFCS by children and adults was associated with KHK substrates [21]. KHK is expressed as two isoforms, an increased risk of obesity and metabolic syndrome [33– KHK-C and KHK-A. KHK-C is primarily expressed in 37]. However, not all published meta-analyses have reported the liver, kidney, pancreas, and duodenum, while KHK-A a statistically significant link [ 38–41]. Recently, Sievenpiper is expressed more widely including adipose tissue, heart, and colleagues concluded in a meta-analysis of controlled and the adrenal gland [22]. The exact biologic function of feeding trials that fructose does not cause weight gain when KHK-A is unknown. KHK-A has a higher Km for fructose substituted for other carbohydrates in isocaloric trials [42]. (7 mmol/L) than does KHK-C (0.8 mmol/L) suggesting that This was criticized on the basis of fructose causing weight Journal of Nutrition and Metabolism 3 Hexokinase Glucose-6-phosphate Glucose + ATP Isomerase Hexokinase Fructose + ATP Fructose-6-phospate Cytosol KHK PFK Inosine ADP Adenosine Hypoxanthine Xanthine Uric acid Fructose-1-phosphate Fructose-1,6-diphosphate DHAP Glyceraldehyde Glyceraldehyde-3-P Figure 1: Fructose metabolism. Fructose is primarily metabolized to fructose-1-phosphate by KHK due to its lower Km for fructose compared with hexokinase. Uncontrolled consumption of ATP leads to intracellular phosphate depletion and activation of AMP deaminase leading to the increased production of uric acid. Fructose-1-phosphate is further metabolized by aldolase B and triokinase to glyceraldehyde-3- phosphate. Glyceraldehyde-3-P 2ATP NADH Pyruvate Mitochondria Acetyl-CoA Pyruvate dehydrogenase Pyruvate Increase fatty acid Citric acid synthesis cycle Figure 2: Role of fructose in lipogenesis. Glyceraldehyde-3-P continues downstream in the glycolysis pathway forming pyruvate which enters the mitochondria and is further metabolized to acetyl-CoA by pyruvate dehydrogenase. Acetyl-CoA enters the citric acid cycle by combining with oxaloacetate to form citrate. In the well fed state, citrate can be transported to the cytosol, providing CoA necessary for lipogenesis. gain by altering appetite resulting in increased food intake, by among nondiabetic women in the Nurses’ Health Study II inducing leptin resistance and by a direct effect on the brain concluded that higher consumption of sugar-sweetened bev- indicating that isocaloric trials do not show a difference in erages was associated with greater magnitude of weight gain weight gain between groups. Moreover, the use of weight gain and an increased risk for the development of type 2 diabetes as a marker is subject to debate, since other fructose eeff cts, [45]. On the other hand, a recent analysis of NHANES beyond body weight as central fat accumulation and insulin 1999–2006 databases comparing data from>25,000 subjects resistance, can be more important [43]. showed no relation between daily fructose intake and the In children, intake of artificially sweetened beverages indicators of metabolic syndrome, uric acid, and BMI [46]. was found to be positively associated with adiposity [44]. Thisstudy wasbased on asnapshotofone-ortwo-days A prospective cohort analyses conducted from 1991 to 1999 recalls. u Th s, the intake data may not truly represent the long 4 Journal of Nutrition and Metabolism term, consistent consumption of food. Moreover, due to no fructose intake data being available in NHANES databases and a lack of fructose content data for many food items in the Mesenchymal stem cell USDA National Nutrient Database for Standard Reference, the fructose intake of individuals was indirectly estimated using several databases. Interpretation of cross-sectional studies examining the relationship of sugar intake to obesity can be misleading due to the fact that subjects who become obese may well reduce their sugar intake, since sugar is widely recognized to cause Preadipocyte weight gain. er Th efore, examining the relationship of sugar Fructose to obesity is best performed with well controlled, long-term longitudinal studies. It is also important to recall that leptin Early stage resistance leading to liporegulatory failure, and, subsequently, insulin resistance can be perpetuated once obesity and Ang II inhibitor intracellular lipid accumulation are manifest, especially in Late stage sites other than adipose tissue including pancreatic B cells and cardiomyocytes. u Th s, reducing fructose intake may not fully reverse insulin resistance and diabetes. This further adds to the complexity and clouds the interpretation of these epidemiological data [6, 47, 48]. The relationship between fructose intake and hyperten- Mature adipocyte sion was also examined in several clinical studies. In a ran- domized controlled trial, high dose fructose (200 gm/24 h) Figure 3: Overview of stages of adipocyte differentiation and the increasedambulatoryblood pressure andelevatedfasting impact of angiotensin II inhibitors and elevated fructose levels. insulin levels. In this study, allopurinol prevented the increase in mean arterial blood pressure [49]. In an analysis of the NHANES 2003–2006 data, fructose intake, in the form of which, on its own and among other dairy products, has been added sugar, was independently associated with higher blood showntoenhance weight loss [43, 56, 57]. pressure levels [50]. Fructose consumption in the form of There is mounting evidence from studies looking at sugar-sweetened beverages was associated with hypertension the association between fructose and obesity and metabolic andelevateduricacidlevel in USA adolescents[51]but not syndrome that primary fructose malabsorption in children in adults [52]. Uric acid may raise systemic blood pressure was negatively associated with obesity [58]. In obese African- by increasing inflammation, activating the renin-angiotensin Americans, high rates of fructose malabsorption were asso- system, and decreasing nitric oxide production contributing ciated with reduced liver fat thought to be protective against to renal vasoconstriction that results in salt insensitive hyper- fatty liver disease [59]. tension [53]. Persistent vasoconstriction may contribute to In conclusion, it is evident that there is a need for clinical arteriosclerosis and the subsequent development of salt- trials with variable amounts of fructose intake to determine sensitive hypertension, even if the hyperuricemia is corrected effects on metabolic outcomes rather than depending on [54]. This may explain the different results in the preceding meta-analyses of existing studies of mixed design and dura- two studies that looked at two different age groups. A tion. recent meta-analysis of controlled feeding trials found that isocaloric substitution of fructose with other carbohydrates did not adversely affect blood pressure in humans suggesting 4. Effect of Fructose on Adipocyte that there is a need for long-term and large trials to clarify Differentiation these ndin fi gs [ 40]. Few studies have examined the role of naturally occurring Adipocyte development in mice and humans follows a well- sugars, for example, 100% fruit juice, in the origin of obesity den fi ed pathway that begins with a common stem cell medi- andrelated endpoints. It is believed that fructosefrom ated adipocyte regeneration and is referred to as adipogenesis natural sources can be less harmful because the presence of [60]. The first step of adipogenesis is the generation and additional nutrients and antioxidants. On the other hand, commitment of mesenchymal stem cells (MSCs) to adipocyte crystalline fructose, as in table sugar, and HFCS are regarded lineage. The effect of fructose-mediated renin-Ang II activa- as less safe, since glucose present in these sugars can acceler- tion is on the stages of cell dieff rentiation (“commitment”) ate fructose absorption. 100% fruit juice consumption among and involves local and systemic effects. USA adults is associated with lower insulin resistance [55] Figure 3 showsthe mechanismofAng II inhibition and lower odds of obesity and metabolic syndrome. Obesity during adipogenesis. MSCs or preadipocytes differentiate remained an independent factor aeft r adjusting to other into lipid-laden and insulin-sensitive adipocytes [61]. lifestyle factors. What is interesting in this study is that 100% Briefly, the stages of adipocyte differentiation are aeff cted juice consumers had significantly higher white milk intake by increasesinthe levels of fructoseand AngIIwhich cause Journal of Nutrition and Metabolism 5 MSC-derived adipocyte growth arrest, clonal expansion, and Lean diets increase small adipocytes (1) Lipid synthesis, uptake, and storage early differentiation. Ang II blockade can prevent terminal differentiation leading to the development of the mature adipocyte phenotype [62, 63]. Normal diets result in the activation of PPAR𝛾 fol- (2) Hepatic and peripheral glucose lowed by adipose expansion through adipocyte hyperplasia, homeostasis, ↑ adiponectin, and IL-10 resulting in an increased number of new preadipocytes. eTh resulting adipocytes are small in size and eeff ctively Fructose rich diets store lipids, thereby reducing lipotoxicity in the liver and increase the large adipocytes adiposetissueand releaseadiponectin [64, 65]. Activation of these genes leads to repartitioning of lipids resulting in an increased triglyceride content of adipose tissue, a lowered free fatty acid content in circulation and availability for ↑ (MCP-1, IL-6, TNF-𝛼 , PAI-1, IL-1, and IL-8) liver and muscle use, thereby improving insulin sensitiv- ity. Methylisobutylxanthine (MIX), an phosphodiesterases inhibitor, increases intracellular cAMP, activating adipocyte differentiation in a PKA-independent manner [ 66]. MIX Figure 4: Enlargement of adipocytes causes alterations in secretion also increased the expression of C/EBP-𝛽 ,requiredfor the of adipokines. Under normal conditions, adipocyte is a site of subsequent expression of PPAR-𝛾 [62]. lipid synthesis, uptake, and storage. Secreted adipokines function as Although, the mechanisms by which fructose controls endocrine, paracrine, or autocrine mediators. Increased adipocyte adipogenesis in vivo are largely unknown, there are a number size can lead to deleterious alterations in insulin sensitivity caused of candidates that mediate adipocyte differentiation in culture by a decrease in adiponectin secretion and the induction of inflam- and are thought to control adipocyte accumulation and matory mediators. Modified from [ 11]. function in vivo. Two main factors tfi this criterion: (1) high fructose diets, (2) increases in ROS. eTh y have been implicated as the link between adipogenesis and metabolic Mitochondria play an important role in adipocyte dif- diseases including T2DM. ferentiation and function [68]. During the early stages of Recent studies demonstrated that the induction of oxida- preadipocyte development, an increased number of mito- tive stress by high fructose or glucose increased NAD(P)H chondria are required, resulting in small mature adipocytes, oxidase and the mitochondrial respiratory chain which is highly sensitive to insulin, and secreting high levels of associated with diabetic complications [67]. eTh refore, fruc- adiponectin [69]. By contrast, mitochondrial dysfunction tose diets may lead to adipocyte differentiation associated has also been linked to T2DM complications in fructose with adipocyte dysfunction and formation of adipocytes diets. The results of impaired mitochondrial function include external to normal adipocyte depots, that is, muscle, liver, and increased FFA levels resulting in the accumulation of mito- pancreas leading to advanced diabetic complications. chondrial products including fatty acyl coenzyme A (CoA) The fructose-mediated increase in ROS via activation of and reduced insulin sensitivity [69]. the adipocyte renin-Ang II system may lead to adipocyte Insummary,fructosediets,inactivity,andgluttonyresults dysfunction and insulin resistance. Adipose tissue is a key in adipocyte expansion with the resultant detrimental pertur- endocrine organ, the function of which, via interaction with bations in the renin-Ang II system and in mitochondria, both the vascular endothelium system, regulates lipid uptake, of which undergo cellular changes that result in the increased storage, synthesis, and secretion of paracrine and autocrine generation of ROS and TNF-𝛼 ,IL-1, andIL-6and adecrease factors that regulate insulin sensitivity. However, fructose- in adiponectin levels. Adiponectin is synthesized and released mediated vascular dysfunction may have a negative eeff ct on only by theadipocyte andhas an essentialroleinvascularand adipocyte function and the secretion of anti-inflammatory renal function. molecules such as adiponectin, IL-1, and IL-10. eTh glucose Increases in adipocyte release of adiponectin inhibits or fructose-mediated decrease in vascular function increases both the expression of hepatic gluconeogenic enzymes and adipocytesizeresulting in decreasedlevelsofadiponectin, the rate of endogenous glucose production in diabetic mice but increased levels of MCP-1, IL-6, and TNF-𝛼 that have [70]. In adiponectin transgenic mice, adiponectin reduced systemic effects on 𝛽 cells (Figure 4). the expression of phosphoenolpyruvate carboxylase and The adipocyte-mediated increase in adipokine release glucose-6-phosphatase, which are associated with elevated plays a critical role in the regulation of blood pressure phosphorylation of hepatic AMPK and decreased glucose (angiotensinogen), vascular haemostasis, and angiogene- production [70, 71]. sis. The release of these cytokines by adipocytes suggest that fructose-mediated diabetes may be related to systemic effects which include altered adiposity and insulin resis- 5. Prohypertensive Effects of Fructose and tance. Adipocyte dysfunction occurs as a consequence of Putative Mechanisms chronic overfeeding of fructose leading to adipocyte enlarge- ment and inflammation and mitochondrial dysfunction Hypertension, diabetes, and obesity were originally docu- (Figure 5). mented in England and France where sugar rfi st became 6 Journal of Nutrition and Metabolism Fructose diets or (over nutrition) Preadipocyte number and enlargement AngII inhibitor Mitochondria AngII system dysfunction Small adipocyte ROS ROS Large adipocyte Inflammatory cytokines: Adiponectin IL-1𝛼 , IL-6, TNF𝛼 , MCP-1··· Insulin resistance Figure 5: Molecular mechanisms by which fructose diets, inactivity, and gluttony increase preadipocyte number and enlargement via increases in ROS generated by the renin-AngII system and mitochondrial dysfunction leading to obesity, insulin resistance, and diabetes. Hyperglycemia results in increased ROS production within the mitochondria via a number of mechanisms including a reduction in the glutathione/glutathione disulfide ratio. ROS generation mediates a pro inflammatory cascade resulting in increase of adipogenesis, release of inflammatory cytokines, and decrease in adiponectin leading to insulin resistance. 35 35 30 30 25 25 20 20 15 15 10 10 5 5 0 0 1919 1939 1975 1990 2004 1890 1900 1976 1988 1999 (Year) (Year) (a) (b) Figure 6: Changing prevalence of hypertension over 100 years in the USA (a). Increasing prevalence of obesity in the USA over 100 years. Obesity defined as body mass index (BMI Kg/m )>30 (b). available to the public. eTh rise in sugar intake in the United theprevalenceofhypertensioninthe United States [72–74] Kingdom and the United States also correlated with the (Figure 6(a)). This was paralleled by an increase in the rates rise in obesity rates observed in these countries [7]. In the of obesity and diabetes. Body mass index (BMI; in kg/m )>30 early 1900s, blood pressure in over 140,000 healthy adults was observed in only 3.4% of 50- to 59-year-old male veterans who applied for life insurance in the New York region in 1890, compared with 30.4% in 1999–2002 [7](Figure 6(b)). suggested that a blood pressure of 140 (systolic)/90 (diastolic) This is paralleled by the epidemic of sugar consumption that mm Hg was abnormal because it reflected only 5-6% of the hasworsenedoverthe past 300years. population in the United States [7]. Subsequent studies over During the last decade, emerging data have altered our the past century showed a significant and dramatic rise in perspective on the link between fructose, uric acid, and Prevalence (%) Prevalence (%) Journal of Nutrition and Metabolism 7 hypertension. Epidemiologic data, in the form of large, expression of the fructose transporter GLUT5 in pancreatic longitudinal studies strengthened the link between elevated 𝛽 -cells [87]. Consumption of fructose-sweetened beverages uric acid and hypertension [50, 75–79]. In animals, mild with meals produced a rapid and prolonged elevation of hyperuricemia induced by the uricase inhibitor oxonic acid, plasma triglycerides compared with glucose-sweetened bev- mimicking levels in humans, increased blood pressure by erages. Because insulin, leptin, and possibly ghrelin function crystal-independent mechanism resulting in stimulation of as key signals to the central nervous system in the long-term the renin-angiotensin system and inhibition of nitric oxide regulation of energy balance, decreases of circulating insulin synthase [80]. Two-thirds of adolescents with newly diag- and leptin and increased ghrelin concentrations could lead to nosed essential hypertension and elevated uric acid normal- increased caloric intake and ultimately contribute to weight ized their blood pressure when treated with the xanthine gain and obesity during chronic consumption of diets high in oxidase inhibitor allopurinol [81]. This study could not fructose [88]. Apolipoprotein B levels were found to be higher excludethe possibilitythatsomeorall of theobservedeeff ct following fructose consumption compared with isocaloric couldhavebeenmediatedbyareductioninsuperoxide amount of glucose [89]. production, a byproduct of xanthine oxidase function. A Fructose increases the incidence of hypertension, NAFL, more recent study done by the same group confirmed and diabetes [90]. In fact,countries electing to useHFCSin these results by using two differently acting urate lowering their food supply have a 20% higher prevalence of diabetes drugs, allopurinol, and probenecid [82]. This study clearly compared to countries that did not use HFCS independent implicated uric acid as the biochemical mediator of increased of obesity [91]. Uric acid stimulates fructokinase and the blood pressure. Animal data suggested that uric acid induced development of NAFL [14] via an increase in fructose hypertension has two phases. eTh rfi st is salt insensitive metabolism thereby increasing the development of type 2 which is likely to be managed by urate lowering drugs, diabetes in children. This may be related to an increase while the second phase is salt sensitive. Due to a paucity of in SREBP-1c and reduced acyl-CoA oxidase during preg- outcome data, recommendations on how to treat uric acid nancy [92]. Body size at birth is related to food intake and associatehypertensioncannotbemadeatthistimealthough the content of fructose [93] or an elevation of estrogen the mechanism appears clear, especially in the early stages during pregnancy in women with a family history of type before the development of salt sensitivity. Future clinical trials 2diabetes[94, 95]. Genetic morphism in the glucokinase are required to include different levels of hypertension and regulatory protein, which binds to glucokinase and inhibits different age groups before recommending urate lowering its activity in the presence of fructose-6-phosphate (F6P) agents especially as they have an inferior efficacy profile is associated with ethnicityand mayberesponsible for when compared with antihypertensive medications presently different response rates to obesity and diabetes in different in clinical use. populations [96]. An increase of fructose-1,6-biophosphatase Consumption of high-fructose chow by mice produced [97], or in angiotensin 1–7 [98] decreases fructose-mediated nocturnal hypertension and autonomic imbalance which diabetes by an increase in pancreatic islet metabolism may be related to activation of the sympathetic and RAS [99]. systems [83]. Subsequent data suggested that changes in auto- nomic modulation may be an initiating mechanism underly- ing the cluster of symptoms associated with cardiometabolic 7. Prospective and Therapeutic Implications disease [84]. eTh addition of clonidine to drinking water inhibited fructose-induced hypertension in rats [85]. Based on the present knowledge of fructose and its detrimen- tal metabolic effects when in excess and the unique nature of KHK, it is clear that fructose is, at least, partially responsible for the pandemic of diabetes and the metabolic syndrome that 6. Effect of Fructose on Dyslipidemia and is presently occurring. A number of therapeutic approaches Insulin Resistance appear viable as a result of the data outlined previously. The earliest recorded metabolic perturbation resulting from (1) Assessing KHK activity in human blood samples fructose consumption is postprandial hypertriglyceridemia, opensanewapproachtothe diagnosisaswellasthe which increased visceral adipose deposition. Visceral adipos- treatment of type 2 diabetes. We hypothesize that individuals ity contributes to hepatic triglyceride accumulation, protein either completely or partially deficient in KHK activity are kinase C activation, and hepatic insulin resistance by increas- immune at variable levels from developing type 2 diabetes ing the portal delivery of free fatty acids to the liver. With mellitus. In order to test this hypothesis, the following insulin resistance, VLDL production is upregulated and this, require clarification: (a) KHK-C is primarily expressed in along with systemic free fatty acids, increase lipid delivery to the liver and kidney. u Th s, the in vivo handling of fruc- muscle.Itisalsopossiblethatfructoseinitiateshepaticinsulin tose to assess enzyme expression and efficiency would be resistance independently of visceral adiposity and free fatty difficult to monitor. We propose that PMN expression will acid delivery [20]. Splanchnic perfusion studies have shown parallel hepatic expression, a series of pilot clinical studies that hepatic production of triglycerides is much greater with in individuals selected across populations at varying risk fructose compared with equimolar concentrations of glucose for type 2 diabetes mellitus is required. (b) Once this [86]. Unlike glucose, fructose does not stimulate insulin association has been demonstrated, measurement of KHK- secretion, due to its hepatic metabolism and the low level of C activity in PMN’s in young adults with type 2 diabetes 8 Journal of Nutrition and Metabolism and age/sex matched controls is required. If results support [114, 115]. Plasma Ang II is associated with markers of insulin the hypothesis, new approach to the prediction as well as a resistance and obesity [116]. Renin angiotensin expression therapeutic approach to treat type 2 diabetes mellitus is at regulates mouse and human adipocyte dieff rentiation [ 117, hand. 118]. (2) Interference with fructose transport at the GLUT (5)Uricacidcan be abyproduct of uncontrolled fructose transporter level diminishes the availability of fructose. Due metabolism due to the rapid consumption of ATP as noted to their hydrophilic nature, sugars must rst fi traverse lipid previously. Uric acid has been linked to endothelial and bilayer membranes via carrier-mediated transport mecha- adipocytes dysfunction. In contrast, uric acid also functions nisms. Several transporters have been identified, and these as an antioxidant [119]. Treating hyperuricemia in the absence include the facilitative glucose transporter (GLUT) which of gout is not recommended at this time due to the lack of primarily regulates the clearance of blood glucose along sucffi ient data. a concentration gradient and the sodium-coupled glucose (6)Theideal andlogical,but most dicffi ult, approach cotransporter (SGLT) family members that are distinct at wouldbetomodifyfructosecontent in food.Thereason both the primary and secondary structural levels from the that KHK is a poorly regulated enzyme may be due to the GLUT proteins. Expression of SGLT proteins is restricted high levels of physical activity and limited fructose intake that to the gut and kidney, where their role is energy-dependent was prevalent in humans before the introduction of ren fi ed reabsorption of glucosefromlumen.TheGLUTtransporter cane sugar and high fructose corn syrup (HFCS). Negative family comprises 13 members that exhibit tissue distribution, feedback was unnecessary due to the limited supply of substrate specificity, and transport kinetics that reflect their fructose. This does not exist today where calorie sweeteners, physiologic role. These have not been fully defined for all including HFCS, are part of the normal diet. Moreover, and 13 isoforms [100]. Fructose gains access to the circulation of grave concern, is the increased consumption of sugar- and hepatocytes via GLUT 5, GLUT 7, and GLUT 11 [8]. sweetened beverages, and fresh and processed juices which Interference with fructose transport at the level of these provideaneasyvehicle forexcessive sugarintake, over very transporters represents a therapeutic approach to prevent a short period of time and have been directly linked to fructose-induced adiposity and insulin resistance. obesity [35, 120]and type 2diabetes[45, 121]. At the end (3)Interferenceatthe levelofKHK is an attractive of the day, we might conclude that “only drinking “milk approach to modify the metabolism of fructose and, pos- and water” can prevent diabetes.” eTh present choice is sibly, alleviating adiposity and vascular dysfunction. This either to continue with the currently high rates of fructose canbeimplemented in twoways. (a) An inhibitoriscur- consumption which lead to adipocyte expansion, obesity, and rently being developed (Richard Johnson, patent number hypertension or to minimize fructose intake and alleviate WO/2012/019188, public knowledge). It remains unclear how health care cost and the cost of managing hypertension and eecti ff ve this approach will be, and if this intervention its complications, thereby improving the lots of health care will be dependent on an individual’s KHK activity profile professional, patients, and their families and the well-being as suggested previously. (b) eTh use of certain furanose of millions of individuals. sugars, which can also be substrates for KHK and compete with fructose for its metabolism to hexose-1-phosphate [21]. 8. Conclusion D-Tagatose, a furanose sugar metabolized by KHK, when compared with fructose, caused markedly higher levels of Fructose metabolism is very unique in a sense that it is serumuricacidand lowerofPi[101]. This highlights the not regulated. eTh consequences of uncontrolled fructose importance of the poorly regulated KHK in this pathway and metabolism can be harmful at the cellular level resulting in necessitates further study. intracellular ATP depletion, increased uric acid production, (4) era Th peutic agents that decrease the effect of high endothelial dysfunction, oxidative stress, and increased lipo- fructose diets on diabetes and insulin resistance include genesis. High fructose consumption induces insulin resis- statins [102], metformin [103], and renin inhibitor attenuated tance and other manifestations of metabolic syndrome in a diabetes and insulin resistance [104]. The latter is due to a series of animal models. es Th e eeff cts are not seen in animals decrease in lipid peroxidation. In support of these obser- fed either glucose or starch. Human epidemiological data are vations, candesartan cilexetil [105]and losartan improve generally of poor quality due to the lack of consistency in renal hemodynamic and insulin resistance [106]and lower study design, methodology, and length. It remains unclear blood pressure in diabetic rodents fed a high fructose diet if targeting fructose by interfering with its transport or [107] presumably by the activation of AMP-activated protein metabolism canbeofany clinical benetfi . kinase [108]. Infusion of Ang II decreased adiponectin and potentiated fructose-mediated insulin resistance in fructose- fed rats [109]. The presence of renin-angiotensin aldosterone Acknowledgments in adipose tissue has been described [110–112]inwhich Ang II increased NADPH oxidase activity and WAT mediated This work was supported by National Institutes of Health inflammation and blocked RAAS thereby preventing the Grant HL-55601 (N.G.A.) and by the BrickStreet Foundation onsetofdiabetes. 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