What is in high fructose corn syrup

Dietary Sources

High-fructose corn syrup is a major source of Fru in the United States, where this pervasive sweetener is added to many industrially produced foods, including ketchup and bread. The Fru content in this syrup is increased by conversion of its Glc during industrial processing using glucose isomerase/d-xylulose ketol-isomerase (EC5.3.1.5). A more conventional source is the disaccharide sucrose, consisting of Glc α-[1>β2] Fru.

Mixtures with equal amounts of monomeric Fru and Glc are 1.3 times sweeter than the same amount of sucrose (Stone and Oliver, 1969). Fruits and vegetables also contain significant amounts of monomeric Fru and sucrose. About half of the dry weight of peaches is sucrose.

Daily Fru intake may be as high as 100 g, especially in populations with high intakes of sucrose and high-fructose corn syrup (Ruxton et al., 1999). Per-capita disappearance of fructose was 81 g/day in the United States for 1997 (Elliott et al., 2002).

Proposed glycotoxicity mechanisms

Fructose or high-fructose corn syrup in our diet and beverages has increased dramatically in the last 40 years and may contribute to the escalation of obesity to epidemic proportions around the world during this time period. High dietary fructose/sucrose in rodents also causes obesity and hepatic steatosis development (see above for a discussion of steatosis). The steatosis mechanism likely results from fructose bypassing the glucose regulatory enzyme phosphofructokinase causing the fructose-derived carbons to more readily undergo lipogenesis than glucose (Rutledge and Adeli, 2007). A high sucrose diet increased lipogenesis by repartitioning fatty acids to esterification away from fatty acid β-oxidation possibly by increasing malonyl-CoA, an inhibitor of carnitine palmitoyltransferase-1 (Roberts et al., 2008). Fatty acid β-oxidation would also be inhibited by methylglyoxal since it inhibits Complex III (Rosca et al., 2005). A two hit hypothesis is proposed for the progression of steatosis induced by glycotoxicity to form liver cirrhosis and rarely liver cancer with the first hit being mitochondrial toxicity caused by the endogenous dicarbonyl metabolites methylglyoxal and glyoxal whilst the second hit would be oxidative stress induced by inflammation. Methylglyoxal is formed from the glycolytic triose phosphate metabolites whereas glyoxal is formed from glycolaldehyde and glyceraldehyde metabolites during oxidative stress (Lee et al., 2008; Shangari and O’Brien, 2004; Shangari et al., 2006). These dicarbonyls are much more rapidly formed from fructose than from glucose metabolism. Glyoxylate and oxalic acid are also end products of glycolaldehyde metabolism whilst glyoxylate forms oxalomalate, a citric acid cycle inhibitor, by condensation with mitochondrial oxaloacetate whereas calcium oxalate monohydrate inhibits mitochondrial respiration and induces the mitochondrial permeability transition (McMartin and Wallace, 2005). Inflammation causes activation of immune cells which generate H2O2 and cytokines. Glyoxal cytotoxicity due to mitochondrial toxicity is also increased several orders of magnitude by low noncytotoxic doses of H2O2 (Shangari et al., 2006).

High-Fructose Corn Syrup

Several studies have shown high-fructose corn syrup (HFCS) to be a contributing factor to energy overconsumption, weight gain, and the rise in the prevalence of obesity.29–31 The fructose in sugar-sweetened beverages promotes insulin resistance.32 HFCS also promotes dyslipidemia,33 increases visceral fat deposits, and increases hepatic de novo lipogenesis.34 In patients with NAFLD, de novo synthesis of FAs from glucose and fructose is dysregulated, leading to an increase in plasma free fatty acids (FFAs) and a subsequent increase in the liver triglyceride content.35 Fructose also provokes a hepatic stress response involving activation of c-Jun N-terminal kinases (JNK) and subsequent reduced hepatic insulin signaling.36

In a small-scale study, it was observed that consumption of fructose in 49 patients with NAFLD was two- to threefold higher than in 24 control subjects, and hepatic mRNA expression of fructokinase and FA synthase was increased in patients with NAFLD.37 Another study showed that 80% of patients (25 out of 31) with NAFLD consumed an excessive amount of soft drinks, totaling more than 50 g of added sugar per day.38 In patients with NAFLD, fructose consumption was linked with lower hepatic fat content but increased hepatic fibrosis, suggesting that fructose may enhance liver inflammation.39

Starch-Based Syrups Manufacture

Common methods employed in the commercial production of corn syrups are the acid process, the acid–enzyme process, and multiple enzyme process. In the acid conversion process, a starch slurry of the appropriate dry substance is acidified to pH of about 2 and pumped to the converter. After neutralization, liquor is clarified and concentrated by evaporation to an intermediate density. The resulting syrup is further clarified, decolorized, and finally concentrated in evaporators to the final required density. Some syrups are treated with ion exchange resins for further refinement.

The acid–enzyme process is similar except that the starch slurry is only partially converted by acid to a given dextrose equivalent (DE), then treated with an appropriate enzyme or contribution of enzymes to complete the conversion.

In multiple enzyme processes, starch granules are gelatinized and the preliminary starch-splitting or depolymerization is brought about by an α-amylase enzyme, rather than by means of acid.

Various intermediate syrups of differing composition may be further converted with enzymes having specific modes of action or providing particular types of end product, such as high-maltose syrups, high-fermentable syrups, and others.

Dietary Fats and Sugars

High intake of fructose present in table sugar and high fructose corn syrup has been correlated with the epidemics of obesity, hypertension, metabolic syndrome, and diabetes. In animals, the intake of fructose but not of glucose or starch can rapidly induce features of the metabolic syndrome. In an experimental study, an intake of 200 g fructose per day in healthy overweight adult men caused a significant increase in systolic and diastolic BP, a rise in plasma triglycerides, a fall in high-density lipoprotein (HDL) cholesterol, and an increase in relative insulin resistance. Other studies have shown that a diet rich in fructose can increase intra-abdominal fat and cause insulin resistance, particularly in subjects who are already overweight. The pathogenesis of the hypertension may be related to the unique ability of fructose as a sugar to cause intracellular ATP depletion and uric acid generation. Allopurinol has been found to block the BP rise to fructose in both humans and rats.38 These studies suggest that excessive sugar intake could have a role in the metabolic syndrome and that reduction of sugar intake could be beneficial. Interestingly, whole fruits, which also contain fructose, do not appear to cause metabolic syndrome, probably because of the lower fructose content and the presence of numerous antioxidants (such as vitamin C) that block the effect of fructose to induce insulin resistance.

In epidemiologic studies, substantial red meat intake (mean 103 g/day) is associated with a rise in systolic BP of 1.25 mm Hg.39 Red meat intake has also been associated with an increased risk for diabetes. The mechanisms are unknown but may be related to the production of oxidants, inflammatory cytokines, or uric acid.

Supplementation with omega-3 fatty acids reduces the risk of myocardial infarction and sudden cardiac death,40 but their effect on BP is small. In a recent meta-analysis, omega-3 supplementation significantly reduced diastolic BP by a mean of 1.8 mm Hg but had no effect on systolic BP, fibrinogen level, or heart rate.41 About ten portions of oily fish per week or nine or ten fish oil capsules per day are required, and this is not tolerated by most subjects because of belching and fishy taste. Concerns about the cholesterol content as well as dioxin and polychlorinated biphenyl content (environmental pollutants that have carcinogenic potential and, being fat soluble, can accumulate in the body) of some fish oil supplements also raise questions about the safety of very large doses.

7.3.2 Carbohydrate Intake and CKD

Approximately 50% of US sweetener consumption is provided by high-fructose corn syrup (HFCS) (https://fnic.nal.usda.gov/food-composition/nutritive-and-nonnutritive-sweetener-resources). HFCS is made from corn treated with glucose isomerase to convert some of the glucose to fructose. Because HFCS is less expensive than sucrose, it is widely used for sweetened beverages. Its ability to retain moisture better than other sweeteners makes HFCS an excellent additive to baked and processed foods to improve quality and texture, and to maintain a longer shelf-life. While HFCS is purported to contain 45–55% fructose, preparations that approach 65% fructose have been reported for a number of commercially available soft drinks.

Sucrose, common table sugar, is a disaccharide made up of fructose linked by a glycosidic bond to glucose. Ingested sucrose is cleaved to its monosaccharide components by the intestinal brush-border enzyme, sucrose. Whether the sweetener is sucrose or HFCS, the glucose is absorbed into the enterocyte by a sodium-dependent active transporter. In contrast, liberated fructose is rapidly taken up by facilitated diffusion, mediated by the non-energy requiring GLUT-5 enterocyte transporter. Fractional absorption of fructose is enhanced in the presence of luminal glucose, suggesting the presence of an additional, possibly glucose-specific, transporter.

Absorbed monosaccharides also differ in their metabolic pathways (Tappy and Lê, 2010). While glucose oxidation through the glycolysis pathway is highly regulated, fructose oxidation has no negative feedback system. Most absorbed fructose is phosphorylated to fructose-1-phosphate by the hepatic enzyme, fructokinase. Since this action requires ATP, excess dietary fructose maximizes fructokinase activity, leading to transient ATP depletion. The AMP produced is metabolized by AMP deaminase to inosine monophosphate and eventually to uric acid (Kretowicz et al., 2011). Emerging evidence suggests that elevated uric acid predicts kidney damage through endothelial dysfunction, increased RAAS activity as well as induction of inflammatory cascades and profibrotic cytokine activation (Hovind et al., 2011; Jalal et al., 2011). At the same time, under hyperglycemic conditions, glucose is converted to fructose by aldose reductase (AR) through the polyol pathway. This endogenous source of fructose enters the fructose pool. While several classes of drugs are known to inhibit AR, it should also be noted that many flavonoids, including quercetin and luteolin, have AR-inhibitory activities (Xiao et al., 2015) (Fig. 7.7).

Cells respond to transient ATP depletion as they do to ischemia, by arresting protein synthesis with the induction of oxidative stress and inflammation. A small fraction (~20%) of absorbed fructose escapes into the systemic circulation where it is taken up by other cell types, including endothelial cells. Fructose that remains unmetabolized is filtered and reabsorbed by the GLUT 5 transporter in the proximal tubular cells of the kidney. Thus, both dietary and endogenous fructose are metabolized by fructokinase, and have potential to generate transient ATP depletion, leading to an ischemic-like state with potential to precipitate kidney injury, glomerulosclerosis, and tubulointerstitial fibrosis.

Experimental rat models with 5/6 nephrectomy and treated with a high-fructose (60%) diet exhibited increased renal vasoconstriction, proteinuria, glomerular hypertension, and other biomarkers of renal inflammation and subsequent cell injury (Gersch et al., 2007; Johnson et al., 2009). Similarly, large human population studies have implicated high fructose and sucrose intakes with a decline in renal function and microalbuminuria (Lin and Curhan, 2011). High dietary fructose intake is also associated with depletion of essential nutrients (Douard et al., 2010). Marked depletion of active vitamin D and subsequent reduced calcium absorption were seen in rats subjected to 5/6 nephrectomy and fed high-fructose diets (Douard et al., 2013). It is also likely that the high fructose intake increased fructokinase activity in the enterocyte, reducing intracellular calcium transport as described elsewhere (refer to Essentials III: Nutrients for Bone Structure and Calcification: Calcium). Reduced serum calcium levels stimulate compensatory secretion of parathyroid hormone (PTH) and compromised bone integrity.

The high-fructose diet also increased kidney weight, elevated blood urea nitrogen, increased serum levels of creatinine, fibroblast growth factor 23, and phosphate, and increased the calcium–phosphate product. While compromised copper availability has been well described in the fructose-fed rat, human studies are less conclusive, possibly because the fructose dose was lower. The influence of copper deficiency on CKD progression (see below) has not been explored in rat models or in human subjects.

Finally, high fructose intake is associated with production of advanced glycation end-products (AGEs). Sugars can form nonenzymatic complexes with free amino groups on proteins, lipids, and nucleic acids (the Maillard reaction) and mature into irreversible molecular rearrangements (AGEs). (The Maillard reaction is named after the French chemist Louid-Camille Maillard, who described it in 1912. It is a reaction between amino acids and reducing sugars; the carbonyl group of the sugar reacts with the nucleophilic amino group of the amino acid. The Maillard reaction forms nonenzymatic browning of baked goods, meat, and other protein-rich foods.) Depending on the tissue, AGEs can form crosslinks between key molecules in the basement membrane and the ECM, alter intracellular proteins and interfere with intracellular signaling. Podocyte injury observed early in diabetic nephropathy has been attributed to hyperglycemia and RAAS activation. More recently, murine podocytes were shown to avidly bind AGE complexes with resultant hypertrophy and cell damage by a mechanism involving p27Kip1 (Rüster et al., 2008). This damage can contribute to the loss of podocytes observed in diabetic nephropathy. While AGE formation has been associated with hyperglycemia, glucose may not be the major contributor because it has a lower chemical reactivity compared with fructose. Fructose was shown to produce 10-fold more AGEs than glucose in vitro due to its more reactive, open chain form (Suárez et al., 1989; Collino, 2011). Thus, it is possible that basement membrane thickening, podocyte necrosis, and other damage associated with AGE formation and diabetic nephropathy result, in part, from exposure to high levels of simple sugars, and especially to fructose.

4 Fructose

Fructose is readily used as a sweetener in the form of high-fructose corn syrup (HFCS), frequently found in soft drinks and other sweetened foods.32 The proliferative and widespread use of fructose in the food industry as a flavor enrichment has increased free sugar intake in modern diet and has been cited by the World Health Organization (WHO) as a health concern.33

Fructose bypasses the rate limiting step of 1- or 6-phosphofructokinase in glycolysis that plays a key regulatory role in glycolysis. This results in increased hepatic uptake and a more rapid utilization of fructose compared to glucose, with profound consequences on carbohydrate and lipid metabolism.34 Pyruvate and lactate production is increased, with activation of pyruvate dehydrogenase, shifting the balance from fatty acid oxidation toward esterification of fatty acids, ensuing an increased production of hepatic very low-density lipoproteins (VLDLs). Long-term, excessive fructose intake results in enzyme adaption. Carbohydrate response element-binding protein (ChREBP), a key factor for enzymes involved in DNL, glycolysis, gluconeogenesis, and fructolysis, is increased in animal models of high-fructose feeding.35–38 Of note, without ChREBP, high-fructose diets do not increase intrahepatocellular lipid concentrations, but result in inflammation and fibrosis instead.39

High-fructose diets result in hyperinsulinemia and IR resulting in insulin-induced sterol regulatory element-binding protein 1c (SREPB1c) activation.40–43 SREPB1c is another important transcription factor involved in DNL and the onset of NAFLD.44 In addition, fructose among other monosaccharides, activate other transcription factors such as liver X receptor (LXR),45 and peroxisome, proliferator-activator receptor γ coactivator 1β (PPARGC1B),46 which have synergistic effects with ChREBP and SREPB1C-mediated lipogenesis. Lastly, fructose has also been implicated in leptin resistance, an important satiety mediator.47–51

A causal relationship has been suggested between the increased prevalence of NAFLD/MS with the increased consumption of fructose.52–56 Patients with NAFLD consume more fructose when compared with healthy individuals despite similar total energy and macronutrient composition intake.52 This increased intake also correlated with increased plasma concentrations of endotoxin, plasminogen activator inhibitor (PAI)-1 and increased hepatic expression of PAI-1, and toll-like receptor (TLR) 4 mRNA.52 Increased intrahepatic ChREBP expression has also been associated with NAFLD and IR in obese individuals.57 Moreover, in patients with NAFLD, increased fructose ingestion was associated with a higher fibrosis stage.58

A meta-analysis by Wang et al.54 (14 isocaloric trials in which fructose was exchanged isocalorically with other carbohydrates and two hypercaloric trials in which fructose supplemented the background diet) showed that while there was no significant effect in the isocaloric trials, there was a significant increase in the postprandial TG in the hypercaloric group. Limitation being the significant heterogeneity and short durations of the trials are analyzed. A separate meta-analysis comprising seven isocaloric trials and six hypercaloric trials (fructose given at an increase of 25%–35% energy) found no effect of fructose in the isocaloric trials, but fructose in the hypercaloric trials increased both intrahepatocellular lipids and serum ALT levels.59

Carbohydrate Catabolism

Various sugars, such as glucose, sucrose, lactose, and corn syrups, are commonly added to sausage batter as substrates for the LAB because the natural content of carbohydrates in meat is too low. Carbohydrate fermentation by LAB mainly produces the DL lactic acid that is responsible for the acidification of the sausages (Table 2). The acidification rate and final pH drop will depend on the nature and level of carbohydrates added (from 0.3 to 2%), the LAB inoculated, the parameters of the fermentation, and the ripening steps (temperature, humidity, time). This acidification plays a key role in the inhibition of the undesirable bacteria, in the acid taste (desired in northern sausages and not in southern ones), and in the texture and color development.

In addition to lactic acid, a small amount of acetic acid, acetoin, and diacteyl can be produced from pyruvate metabolism by certain LAB (L. plantarum, Pediococcus) and S. carnosus. These compounds contribute to flavor development (Table 2).

Summary of a Pragmatic Approach for Recommending an Elimination Diet

A number of chronic diseases are associated with inflammation and intestinal permeability, indicating that methods of reducing inflammation and intestinal permeability will be beneficial. A multimodal approach that emphasizes mind-body techniques for stress management, physical activity, emotional health, and adequate sleep and nutrition is necessary to reduce sympathetic overdrive and an associated increased inflammatory state. A focused 4R approach to reduce intestinal permeability is an example of a multimodal treatment plan. The goal of the nutrition component is to eliminate or reduce potentially inflammatory foods while encouraging antiinflammatory ones. While specific foods may worsen particular diseases, as noted in the following text, a general approach may be used for any disease with an inflammatory component. An ideal elimination diet eliminates as few healthful foods as possible to achieve improvement in symptoms and overall wellbeing. For many people, simply switching to a more healthy diet will provide adequate symptom relief.26

Diseases with an inflammatory component include autoimmune thyroiditis, vitiligo, inflammatory arthritis, lupus, asthma, allergies (food, seasonal, environmental), chronic pain, migraines, diabetes, obesity, coronary artery disease, eczema, fibromyalgia, depression, chronic obstructive pulmonary disease, and cancer.