Diabetes mellitus and the metabolic syndrome are becoming leading causes of death in the world. Identifying the etiology of diabetes is key to prevention. Despite the similarity in their structures, fructose and glucose are metabolized in different ways. Uric acid, a byproduct of uncontrolled fructose metabolism is known risk factor for hypertension. In the liver, fructose bypasses the two highly regulated steps in glycolysis, glucokinase and phosphofructokinase, both of which are inhibited by increasing concentrations of their byproducts. Fructose is metabolized by fructokinase (KHK). KHK has no negative feedback system, and ATP is used for phosphorylation. This results in intracellular phosphate depletion and the rapid generation of uric acid due to activation of AMP deaminase. Uric acid, a byproduct of this reaction, has been linked to endothelial dysfunction, insulin resistance, and hypertension. We present possible mechanisms by which fructose causes insulin resistance and suggest actions based on this association that have therapeutic implications. 1. Background Type 2 diabetes mellitus is characterized by hyperglycemia, insulin resistance, and an impairment in insulin secretion. In the late nineteenth century, William Osler described diabetes as a rare disorder more likely to develop in obese people and patients with gout. He estimated its prevalence as approximately two to nine cases per 100,000 population in the USA and Europe being more common in the latter [1]. Diabetes, one of the leading causes of death in the United States, affects over 200 million people worldwide. The estimated prevalence of diabetes among adults in the United States ranges from 4.4 to 17.9 percent [2]. The community-based Framingham Heart Study, in a predominantly non-Hispanic white population, found a doubling in the incidence of type 2 diabetes over the last 30 years [3]. Identifying the etiology of type 2 diabetes is a key to its prevention. Obesity and intra-abdominal fat accumulation induce insulin resistance [4]. Studies have documented high rates of type 2 diabetes in the absence of classic obesity [5]. This suggests that other risk factors besides obesity might play a role in the epidemic of type 2 diabetes. 2. Fructose: Sources and Metabolism Fructose is a simple sugar present in fruits and honey and is responsible for their sweet taste. However, the major source of fructose worldwide is sucrose or table sugar, which is derived from sugar cane and sugar beets. It is man-made, first developed in New Guinea and in the Indian subcontinent and was a rare and
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