Insulin Resistance in Metabolic Syndrome – Literature review

To provide evidence on the topic, a review of literature published since 2000 was conducted. The search for articles was done in PubMed with articles that were not available on open access being obtained via the electronic databases provided by the university. Various keywords were used including “dietary fructose”, “fructose”, “HFCS”, “metabolic syndrome”, “Insulin Resistance” and “diabetes.” Boolean operators were used to refine results to those where various combinations of keywords were present. Three pathways that could explain the link between increased fructose intake and insulin resistance were evident. First, is the fructose metabolic pathway favoring lipogenesis – a pathway that results into insulin resistance developing through obesity-related mechanisms. The other two pathways involve uric acid, one associated with systemic effects of nitric oxide – a metabolite of uric acid –  leading to endothelial dysfunction and the second, with heightened accumulation of uric acid in adipocytes (fat cells), which increases the oxidative stress [5]. The section below highlights these mechanisms.

Obesity-associated mechanisms

Obesity-related mechanisms via which fructose leads to insulin resistance arise out of unique characteristics of fructose metabolism that result into increased de-novo lipogenesis. Unlike glucose metabolism that proceeds via the glycolytic pathway in feedback-mediated enzymatic reactions such as those catalyzed by glucokinase and phosphofructokinase (PFK), metabolism of fructose favors the reaction by fructokinase, which converts it to fructose-1-phospaste, an enzyme whose feedback regulation by its products is poor [5]. Accordingly, fructokinase catalyzes the rapid phosphorylation of fructose at carbon 1 until ATP is depleted; administration of fructose thus leads to rapid depletion of ATP in the liver, the site where fructokinase expression is predominant [5].  Once fructose-1-phosphate is formed, it either undergoes a series of enzymatic reactions to form acetyly-CoA – a component of the tricarboxylic acid (TCA) cycle and a lipogenic substrate – or may be converted to adenosine monophosphate (AMP), and eventually to uric acid [5, see appendix for diagram]. The metabolism of fructose to acetyly-CoA, via the fructokinase pathway accounts for lipogenic characteristics associated with ingestion fructose-rich diets. Go to obesity-associated mechanisms.

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