Sugar, Uric Acid, and the Etiology of Diabetes and Obesity

Richard J. Johnson; Takahiko Nakagawa; L. Gabriela Sanchez-Lozada; Mohamed Shafiu; Shikha Sundaram; Myphuong Le; Takuji Ishimoto; Yuri Y. Sautin; Miguel A. Lanaspa


Diabetes. 2013;62(10):3307-3315. 

In This Article

Problems With the Fructose and Uric Acid Hypothesis

Concerns With Animal Studies. The fructose-induced hyperuricemia hypothesis has been challenged. First, animal studies using fructose typically use pure fructose as opposed to sucrose or HFCS, which is the primary source of fructose in humans, and the dose of fructose administered to rodents is usually higher (50–60% of the diet) compared with humans (where it is typically 10–15% of the diet). Purified fructose is used, however, so one can separate the effects of fructose from glucose. Indeed, animals are more sensitive to the combination of fructose and glucose because both sugars accelerate the absorption of the other.[78] Combinations of free fructose and glucose, or sucrose, induce features of metabolic syndrome with levels of fructose of 20–30% dietary intake.[5,79]

Furthermore, rodents are relatively resistant to fructose in part because they generate less uric acid in response to fructose due to the presence of the uricase gene in their liver.[38] Uricase degrades uric acid to allantoin, and as a consequence, rats degrade uric acid rapidly after it is formed in their liver. When uricase is inhibited, rats show a greater metabolic response to fructose with worse fatty liver and higher blood pressure.[79] Indeed, there is evidence that the loss of uricase may have provided a survival advantage to ancestral apes living in Europe in the mid-Miocene and therefore may have acted like a thrifty gene.[80] The subsequent rise in sugar intake over the last centuries may have acted in concert with the loss of uricase to predispose us to obesity and diabetes.[80]

Clinical Studies: The Importance of the Control Group. Recently, a number of investigators have presented meta-analyses that suggest fructose does not have a causal relationship with obesity or metabolic syndrome.[81–83] Before we analyze these studies, it is important to understand the complexity related to their interpretation. First, many clinical studies use fructose alone—and often at relatively high doses—in order to evaluate the effects of fructose per se. This allows one to directly address the effects of fructose, and the use of high doses is a common experimental approach to allow one to identify metabolic effects that could otherwise take much longer periods to show. Indeed, the fact that metabolic syndrome could be induced de novo in 25% of healthy men with high doses of fructose in just 2 weeks is a statement of how strong this approach can be.[63] Although studies involving HFCS or sucrose might be clinically more relevant, these types of studies will have trouble distinguishing whether the metabolic effects observed are from the fructose or the high glycemic content of these added sugars.

Nevertheless, the administration of fructose alone can be very difficult to interpret because the absorption of fructose when given alone is quite variable. As many as two-thirds of children and one-third of adults malabsorb fructose.[84,85] This is likely because of variable expression of the fructose transporter GLUT5 in the gut. Expression of GLUT5 and the enzyme KHK, however, are enhanced with repeated exposure to fructose. It is interesting that studies in children have found an inverse relationship between fructose malabsorption and obesity.[86] Consistent with this data, the metabolic response to fructose in children with NAFLD is greater compared with lean control subjects.[87] The importance of fructose absorption has recently been highlighted in African Americans because they commonly malabsorb fructose and also have a lower frequency of NAFLD.[88] The observation that NAFLD subjects may absorb fructose more efficiently is further supported by our observation of higher KHK expression in liver biopsies of NAFLD compared with other liver disease[36] and could be the reason why ATP depletion in response to fructose is greater in NAFLD subjects with a higher prior exposure to dietary fructose.[37] Our observation that hyperuricemia may regulate KHK[35] also provides an explanation for why studies in which fructose is given to young athletic lean individuals are often negative and why they may not carry over to older and heavier individuals.

Another key issue is whether studies evaluating fructose should include fructose from natural fruits. One can argue that fructose is fructose regardless of source, but natural fruits also contain numerous substances that block fructose effects, including potassium, vitamin C, and antioxidants such as resveratrol, quercetin, and other flavonols. We found, for example, that whereas fructose from added sugars is associated with hypertension, fructose from natural fruits is not.[89] We further showed that caloric restriction involving a reduction in fructose intake from added sugars could markedly improve metabolic syndrome in obese Mexican adults, and that this occurred even if natural fruits were administered.[90]

Another important issue is whether glucose itself is the right control for fructose. Outwardly it would seem true, but we recently discovered that glucose may act to induce obesity and insulin resistance by being converted to fructose in the liver.[91] Specifically, high concentrations of glucose, such as occurs in soft drinks, can induce the activation of the polyol pathway in the liver, resulting in the generation of fructose. In turn, the fructose is then metabolized by KHK, resulting in fructose-dependent effects. Indeed, glucose-induced weight gain, fat accumulation, fatty liver, and insulin resistance are all dependent on KHK. While some visceral fat and weight gain occur in glucose-fed mice lacking KHK, the development of fatty liver and hyperinsulinemia are almost entirely dependent on glucose-induced fructose metabolism.[91] Hence, although fructose itself will have more metabolic effects than glucose, the glucose itself may also be inducing metabolic changes via fructose.

Meta-analyses That Argue Fructose Is Not a Risk Factor for Metabolic Syndrome

Weight Gain. A meta-analysis recently reported that fructose intake does not cause weight gain compared with other sugars in short-term studies if both groups are given the same number of total calories (isocaloric diets).[81] However, no food will cause weight gain under these conditions, as weight gain is driven primarily by increased energy intake as opposed to a reduction in metabolic rate, at least in the short-term. Indeed, the mechanism by which fructose increases weight is likely via its ability to stimulate hunger and block satiety responses,[7,9] so if food intake is controlled this would not be observed.

Blood Pressure. It is a scientific fact that the administration of clinically relevant doses (60 g) of fructose acutely raises blood pressure in humans,[92] and similar increases in blood pressure have been observed following ingestion of 24 ounces of HFCS or sucrose-containing beverages.[68] It has also been reported that high doses of fructose raises 24-h ambulatory blood pressure in humans and can be blocked by lowering uric acid with allopurinol.[63] However, the recent meta-analysis by Ha et al.[82] addressed whether short-term isocaloric fructose diets can increase blood pressure after an overnight fast. Since the acute effects of fructose to raise blood pressure occur during the ingestion of fructose (and are likely mediated by uric acid), it is not surprising that the authors did not show an effect on blood pressure; indeed, a similarly designed study would conclude that glucose-rich diets do not increase insulin levels.

An important question is whether chronic fructose ingestion may be responsible for persistent elevations in blood pressure. It is known that the greatest risk for persistent hypertension is borderline hypertension in which intermittent blood pressure elevations occur. There is also evidence that fructose causes microvascular disease in the kidney, which is known to predispose to persistent salt-sensitive hypertension. Indeed, persistent hypertension can be induced with fructose and high-salt diet in rats. Furthermore, chronic fructose ingestion over time is associated with elevations in fasting uric acid levels,[58,93] in part because fructose also stimulates uric acid synthesis. Epidemiological studies have also linked fructose intake with hypertension and elevated serum uric acid levels.[94] Reduction in sugar intake is also strongly associated with a reduction in blood pressure.[95] Indeed, the DASH (Dietary Approaches to Stop Hypertension) diet is in essence a diet low in fructose from added sugars (while containing natural fruits, see above).

Uric Acid. Wang et al.[83] also reported that short-term isocaloric trials do not show an effect of fructose on fasting uric acid levels. Again, the design of the study would not be expected to show a rise in uric acid because the initial rise in uric acid is transient and occurs within minutes of the ingestion of fructose. However, as mentioned, there is some evidence that over time continued ingestion of fructose will result in chronic elevations of uric acid. A more detailed discussion is provided elsewhere.

Another issue with all three metanalyses is that they included control groups that ingested sucrose, which can be questioned because sucrose is a disaccharide that contains fructose.[81–83]

Other Issues Related to Uric Acid. Other aspects of the uric acid studies have also been questioned. One paradox is that the acute elevation of serum uric acid by infusion often results in an improvement in endothelial function.[96] However, while uric acid is an antioxidant in the extracellular environment, it has prooxidative effects inside the cell.[28,29] Several investigators have also suggested that it is not uric acid that is driving metabolic syndrome, but rather xanthine oxidase, since this enzyme generates oxidants in addition to uric acid, and it may be the former that is responsible for the metabolic syndrome. For example, high-dose allopurinol improves endothelial dysfunction in subjects with heart failure whereas the lowering of uric acid with probenecid was ineffective.[97] However, this could simply relate to the relative superiority of allopurinol to lower intracellular uric acid as it blocks synthesis. Although xanthine oxidase–induced oxidants could be important, the observation that raising intracellular uric acid, even in the presence of allopurinol, can increase hepatic fat suggests that it is the uric acid that is responsible.[35]

Genetic Studies. A final argument relates to the genetics of uric acid and fructose metabolism. While some genetic polymorphisms in various enzymes involved in fructose metabolism and urate transport have been linked with metabolic syndrome and hypertension,[98–100] several genome-wide association studies (GWAS) could not show such associations.[101,102] However, the primary polymorphism driving serum uric acid in the GWAS studies is SLC2A9; this polymorphism mediates the transport of uric acid out of tubular cells, and so it may not predict the development of diabetes because it is likely to dissociate the serum from intracellular uric acid levels, the latter of which may be more important in driving insulin resistance.