Toward a unifying hypothesis of metabolic syndrome.

Pediatrics
Andrew A BremerRobert H Lustig

Abstract

Despite a lack of consistent diagnostic criteria, the metabolic syndrome (MetS) is increasingly evident in children and adolescents, portending a tsunami of chronic disease and mortality as this generation ages. The diagnostic criteria for MetS apply absolute cutoffs to continuous variables and fail to take into account aging, pubertal changes, and race/ethnicity. We attempt to define MetS mechanistically to determine its specific etiologies and to identify targets for therapy. Whereas the majority of studies document a relationship of visceral fat to insulin resistance, ectopic liver fat correlates better with dysfunctional insulin dynamics from which the rest of MetS derives. In contrast to the systemic metabolism of glucose, the liver is the primary metabolic clearinghouse for 4 specific foodstuffs that have been associated with the development of MetS: trans-fats, branched-chain amino acids, ethanol, and fructose. These 4 substrates (1) are not insulin regulated and (2) deliver metabolic intermediates to hepatic mitochondria without an appropriate "pop-off" mechanism for excess substrate, enhancing lipogenesis and ectopic adipose storage. Excessive fatty acid derivatives interfere with hepatic insulin signal transduction. R...Continue Reading

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