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

Disclosures

Diabetes. 2013;62(10):3307-3315. 

In This Article

Role of Uric Acid in Insulin Resistance and Fatty Liver in Humans

As mentioned, fructose increases intracellular and circulating uric acid levels due to increased nucleotide turnover and nucleotide synthesis. Initially the rise in serum uric acid is best shown shortly (30–60 min) after fructose ingestion (or ingestion of HFCS or sucrose), but total 24-h levels are also elevated.[60,68] Over time, fasting serum uric acid levels increase.[58] Intake of soft drinks is also associated with increasing risk for hyperuricemia.[69]

An elevated serum uric acid is also one of the best independent predictors of diabetes and commonly precedes the development of both insulin resistance and diabetes (Table 1). An elevated uric acid also independently predicts the development of fatty liver,[41] obesity,[70] hypertension (rev. in,[71] and elevations in C-reactive protein.[72] Furthermore, metabolic syndrome is associated with a high frequency of hyperuricemia, and similarly, hyperuricemia is associated with metabolic syndrome.[73,74] Though hyperinsulinemia may contribute to hyperuricemia by blocking uric acid excretion, it cannot be the primary reason for the association because hyperuricemia has been reported to precede the development of hyperinsulinemia and/or diabetes (Table 1).

A number of conditions associated with hyperuricemia are also associated with increased risk for insulin resistance or diabetes, including chronic lead intoxication and gestational diabetes mellitus. Many drugs associated with insulin resistance are also associated with hyperuricemia, such as calcineurin inhibitors and thiazide diuretics. Indeed, lowering uric acid improves the insulin resistance induced by thiazides in rats.[75]

Evidence that lowering uric acid can improve insulin resistance in humans is limited. One small study showed that lowering uric acid with benzbromarone improves insulin resistance in subjects with congestive heart failure.[76] Another study reported that lowering uric acid improves HbA1c levels in normotensive diabetic subjects.[77] In contrast, we were not able to show an improvement of insulin resistance with allopurinol in subjects administered fructose,[63] but the doses of fructose were exceptionally high (200 g/day) raising the possibility that the doses of allopurinol we used might not have been able to block intracellular uric acid. Clearly, more studies are indicated before any definitive conclusions can be made with regards to the benefit of lowering uric acid for the treatment of insulin resistance.

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