Endocrine Reviews 2009; 30 (1): 96-116

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.

I. Introduction
II. Unique Characteristics of Fructose Metabolism
III. Fructose Causes Metabolic Syndrome in Animals
IV. Mechanism(s) for Fructose-Induced Insulin Resistance
V. Mechanism(s) by Which Fructose Induces Other Features of the Metabolic Syndrome: Role of Uric Acid
VI. Human Studies with Fructose
VII. Epidemiological Studies: Sugar Intake and Type 2 Diabetes
VIII. Epidemiological Studies: Uric Acid and Type 2 Diabetes
IX. Do Other Conditions That Modify Uric Acid Levels Affect the Development of Metabolic Syndrome or Diabetes?
X. Twelve Countering Arguments and Caveats
XI. The Thrifty Gene Revisited
XI. What Research Should Be Done to Prove Our Hypothesis?

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.

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.

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.

Am J Clin Nutr 2002;76:911–22.

This review explores whether fructose consumption might be a contributing factor to the development of obesity and the accompanying metabolic abnormalities observed in the insulin resistance syndrome. The per capita disappearance data for fructose from the combined consumption of sucrose and high-fructose corn syrup have increased by 26%, from 64 g/d in 1970 to 81 g/d in 1997. Both plasma insulin and leptin act in the central nervous system in the long-term regulation of energy homeostasis. Because fructose does not stimulate insulin secretion from pancreatic ß cells, the consumption of foods and beverages containing fructose produces smaller postprandial insulin excursions than does consumption of glucose-containing carbohydrate. Because leptin production is regulated by insulin responses to meals, fructose consumption also reduces circulating leptin concentrations. The combined effects of lowered circulating leptin and insulin in individuals who consume diets that are high in dietary fructose could therefore increase the likelihood of weight gain and its associated metabolic sequelae. In addition, fructose, compared with glucose, is preferentially metabolized to lipid in the liver. Fructose consumption induces insulin resistance, impaired glucose tolerance, hyperinsulinemia, hypertriacylglycerolemia, and hypertension in animal models. The data in humans are less clear. Although there are existing data on the metabolic and endocrine effects of dietary fructose that suggest that increased consumption of fructose may be detrimental in terms of body weight and adiposity and the metabolic indexes associated with the insulin resistance syndrome, much more research is needed to fully understand the metabolic effect of dietary fructose in humans.