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Editorials |
Departments of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
Correspondence: Dr. Eric G. Neilson, Department of Medicine, D-3100 Medical Center North, Vanderbilt University School of Medicine, Nashville, TN 37232-2358. Phone: 615-322-3146; Fax: 615-343-9391; E-mail: eric.neilson{at}vanderbilt.edu
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Introduction |
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Fructose is everywhere because it is highly soluble in water, more so than glucose,2 makes bread crusts browner, cookies softer, and everything sweeter. The vast majority of sweeteners are nutritive, although nonnutritive sweeteners like acesulfame and sucralose (chlorinated sucrose) are increasingly in use. The recent shortage of sucralose suggests some retreat from fructose may already be under way. Even so, concern remains that unfettered consumption of fructose is contributing to rampant obesity, metabolic syndrome, and insulin-resistant diabetes.3 It seems we have morphed insidiously into a fructose nation.
It did not start out like this. For eons, humans sweetened their food with cane or beet sugar containing sucrose. Sucrose is metabolized into dextrose and fructose by disaccharidases in the gut and is the only sweetener allowed to label as commercial sugar. By the mid-19th century, however, the use of cornstarch as a laundry stiffener ushered in a new era for agrocorn.4 Chemists figured out how to make dextrose and anhydrous sugar from cornstarch after the Civil War, and the marketplace for corn-based sweeteners became a nascent industry. Corn syrups came next. Syrup manufactured from the dregs of corn germ led to the development of commercial dextrose, which quickly became an economical competitor of natural sucrose by the early 1900s, but that is not the end. With better corn syrup technology, chemists were eventually able to isomerize dextrose into fructose, producing a commercially successful derivative known as high-fructose corn syrup.
Fructose is sweeter than sucrose,1 and high-fructose corn syrup became a main staple of the sweetener industry beginning in 1967.5 How much fructose do we eat today? A lot. Americans increased their overall consumption of nutritive sweeteners by 41% between 1959 and 1997, to an amount nearly 10 yr ago totaling 70 kg per capita per year.6 The addition of high-fructose corn syrup to the national diet during a comparable interval7 increased exposure to fructose in high-fructose corn syrup from near zero to 29 kg per capita per year3 and a few years ago represented a large fraction of our current appetite for nutritive sweeteners.1,6 In past decades, even back to Osler, fructose was also touted as a preferred sugar substitute for individuals with diabetes because its metabolism lowers blood glucose and insulin responses.8 Now this notion seems quaint and probably ill-advised.9
If sucrose has been around for centuries and is partly metabolized to fructose, why only now do we censure fructose in the epidemic of obesity10 and metabolic syndrome?3 Opinion varies. Many foods need sweetening or no one will buy or make them. Sucrose consumption a few decades ago was largely influenced by whoever did meal preparation at home.6 Today we snack more frequently and super-size what we consume, and with reliance on vending machines and fast foods for quick calories, nimble commercial interests now influence our quantity of fructose per serving. This transition has been facilitated by perverse incentives in congressional farm bills that encouraged commodity farmers to grow more corn in the past 25 yr.11 Although entrenched supply-chain economics are hard to repurpose, much of our current corn production may have alternative use in new ethanol-based fuels.
So what is the problem with fructose? Fructose is metabolized differently than glucose. Unlike glucose, which is stored as glycogen, fructose is absorbed by the gut and converted into triglycerides by the liver.12 Fructose also elevates uric acid levels through effects on an ADP-IMP pathway in hepatocytes.13 The resulting dyslipidemia and hyperuricemia facilitate insulin resistance,14 aggravate hypertension,13 and accelerate endothelial dysfunction.15 Attenuation of nitric oxide levels is an important pathogenic mechanism as a final common pathway to poor blood flow.3,16 What we end up with is a familiar caloric additive provoking a new spate of metabolic dysfunction.3
Johnson and colleagues17 have been studying this problem in rats using diets rich in fructose that produce a metabolic syndrome with glomerular hypertension. In this issue of JASN, their group moves the story a step further by showing that exposure to thiazide diuretics in fructose-consuming rats makes metabolic syndrome worse.18 It is interesting that these rats are not obese, perhaps because the study period was too short, or, as recently observed, obesity may not be the only driver of metabolic syndrome.19
Thiazide diuretics have long been linked with glucose intolerance in humans.20,21 An elevated blood glucose in this setting is largely attributable to hypokalemia that renders glucose uptake less effective. Thiazides, which are a traditional mainstay for treating hypertension in populations with metabolic syndrome and diabetes, also raise blood levels of uric acid.22 Proper attention to potassium replacement and the lowering of serum uric acid with allopurinol in rats on high-fructose diets consuming thiazides ameliorate the aggravating circumstances of metabolic syndrome.18
Where do we go from here? It is important not to reach conclusions too quickly. Some think a commercial conversion to nonnutritive sweeteners in processed foods and beverages is the answer to the fructose problem. Nonnutritive sweeteners are quite potent; sucralose, for example, is 600 times sweeter than sucrose but has a metallic aftertaste that needs abatement.23 Mixing in inulin can improve palatability,24 and nephrologists will enjoy that piece of trivia. Although a change to nonnutritive sweeteners would reduce exposure to fructose, there is a curve ball and the irony is this: Consumables laced with nonnutritive sweeteners seemingly produce less satiety and only marginal weight loss because they are not appetite suppressants.25 Although controversial, disconnecting nutritive sweeteners from free-living diets may not address passive overeating. Worse yet, low-income populations are more affected because high-energy foods and beverages cost less than low-energy consumables.26 Put another way, most of us probably cannot win for losing.
Although a proverbial stretch from current studies in rats, more attention to potassium stores27 and uric acid levels28 may hypothetically help patients with metabolic syndrome, particularly if they are taking thiazide diuretics for control of hypertension. Only further human study will tell, but the sweetener epidemic is here. There is paradoxic subtext to the meaning of sugar-free, and with apologies to Pogo, the enemy is us.
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Disclosures |
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Footnotes |
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See the related article, "Thiazide Diuretics Exacerbate Fructose-Induced Metabolic Syndrome," on pages 2724–2731.
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Related Article
This article has been cited by other articles:
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  A. S Bomback, R. Katz, K. He, D. A Shoham, G. L Burke, and P. J Klemmer Sugar-sweetened beverage consumption and the progression of chronic kidney disease in the Multi-Ethnic Study of Atherosclerosis (MESA) Am. J. Clinical Nutrition, November 1, 2009; 90(5): 1172 - 1178. [Abstract] [Full Text] [PDF]
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 M. E. Choi The Not-so-Sweet Side of Fructose J. Am. Soc. Nephrol., March 1, 2009; 20(3): 457 - 459. [Full Text] [PDF]
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