The Adiponectin Paradox for All-Cause and Cardiovascular Mortality

Abstract

Basic science studies have shown beneficial effects of adiponectin on glucose homeostasis, chronic low-grade inflammation, apoptosis, oxidative stress, and atherosclerotic processes, so this molecule usually has been considered a salutary adipokine. It was therefore quite unexpected that large prospective human studies suggested that adiponectin is simply a marker of glucose homeostasis, with no direct favorable effect on the risk of type 2 diabetes and cardiovascular disease. But even more unforeseen were data addressing the role of adiponectin on the risk of death. In fact, a positive, rather than the expected negative, relationship was reported between adiponectin and mortality rate across many clinical conditions, comprising diabetes. The biology underlying this paradox is unknown. Several explanations have been proposed, including adiponectin resistance and the confounding role of natriuretic peptides. In addition, preliminary genetic evidence speaks in favor of a direct role of adiponectin in increasing the risk of death. However, none of these hypotheses are based on robust data, so further efforts are needed to unravel the elusive role of adiponectin on cardiometabolic health and, most important, its paradoxical association with mortality rate.

Figure 1

The adiponectin paradox. Quite unexpectedly, given its salutary effects on glucose metabolism, inflammation, and several atherosclerotic processes reported by basic science studies, adiponectin seems to be a mere marker of reduced insulin resistance and type 2 diabetes, with no pathogenic role on these metabolic abnormalities (as stressed by the dashed arrow). Even more unexpected are reports showing that adiponectin exerts a neutral effect on nonfatal cardiovascular events and, paradoxically, a deleterious role on both all-cause and cardiovascular mortality.