Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes?

Abstract

We propose that excessive fructose intake (>50 g/d) may be one of the underlying etiologies of metabolic syndrome and type 2 diabetes. The primary sources of fructose are sugar (sucrose) and high fructose corn syrup. First, fructose intake correlates closely with the rate of diabetes worldwide. Second, unlike other sugars, the ingestion of excessive fructose induces features of metabolic syndrome in both laboratory animals and humans. Third, fructose appears to mediate the metabolic syndrome in part by raising uric acid, and there are now extensive experimental and clinical data supporting uric acid in the pathogenesis of metabolic syndrome. Fourth, environmental and genetic considerations provide a potential explanation of why certain groups might be more susceptible to developing diabetes. Finally, we discuss the counterarguments associated with the hypothesis and a potential explanation for these findings. If diabetes might result from excessive intake of fructose, then simple public health measures could have a major impact on improving the overall health of our populace.

Figure 1

Fructose metabolism. Fructose enters cells via a transporter (typically Glut 5, Glut 2, or SLC2A9) where it is preferentially metabolized by fructokinase (KHK) to generate fructose-1-phosphate. Unlike phosphofructokinase, which is involved in glucose metabolism, fructokinase has no negative feedback system to prevent it from continuing to phosphorylate substrate, and as a consequence ATP can be depleted, causing intracellular phosphate depletion, activation of AMP deaminase, and uric acid generation. In addition, fructose is lipogenic and can generate both glycerol phosphate and acyl coenzyme A, resulting in triglyceride formation that is both secreted and stored in hepatocytes. IMP, Inosine monophosphate; TCA, trichloroacetic acid.

Figure 2

Effect of fructose on various organ systems. Table sugar, HFCS, and natural sources provide fructose, which in excess has numerous effects on the brain, liver, vasculature, kidney, and adipocyte. The net effects induce all features of the metabolic syndrome and ultimately type 2 diabetes.

Figure 3

Potential mechanisms by which fructose and uric acid may induce insulin resistance. Fructose enters cell via a transporter (primarily Glut 5) where it is acted on by fructokinase (KHK). As part of this metabolism, ATP depletion may occur, generating uric acid with systemic effects that block insulin-dependent NO-mediated vascular dilation as well as direct cellular effects on the adipocyte. Fructose also causes de novo lipogenesis that can lead to intracellular triglycerides that can also induce insulin resistance. DAG, Diacylglycerol; PKC, protein kinase C; VLDL, very low-density lipoprotein.

Figure 4

Parallel epidemic of diabetes and sugar consumption. Sugar intake has been increasing steadily over the last 200 yr (33,310,318,319). In parallel, there has been a rise in diabetes (first described based on death certificates of diabetes-related deaths per 100,000 population) (4) and later by diabetes prevalence rates (268). [The data showing sugar consumption are adapted with permission from R.J. Johnson, et al.: Am J Clin Nutr 86:899–906, 2007 (27) © The American Society for Nutrition.]