Improved mitochondrial function is linked with improved insulin sensitivity through reductions in FFA.

Abstract

Diabetes 2014;63:2611–2612 | DOI: 10.2337/db14-0277 Skeletal muscle insulin resistance (IR) is inextricably linked with the etiology of type 2 diabetes (T2D) and is a key target for prevention and treatment strategies. IR likely has many mechanistic origins, but the primary causes remain elusive, particularly in humans. Of the many possible mediators of IR, a considerable body of work has debated the potential roles of mitochondria (1–3), lipid oversupply (i.e., “lipotoxicity”) (4,5), and the association between mitochondria, fatty acid metabolism, and intramyocellular lipid accumulation—the subject of this article. Indeed, substantial evidence exists to both support and refute a role for mitochondria in skeletal muscle insulin resistance (6,7). In this issue, Daniele et al. (8) examined the associations among chronic free fatty acid (FFA) levels, intramyocellular lipids, the capacity for skeletal muscle mitochondrial ATP production and IR in human obesity and T2D. These investigators used a 2-week, single-arm, open-label acipimox treatment, which, consistent with this group’ sp revious studies (9,10), significantly reduced circulating FFA levels and presumably availability to muscle and improved insulin sensitivity. The authors’ central hypothesis was that chronic reduction in FFA would increase insulin sensitivity and that this would occur despite any change in the capacity for mitochondrial ATP production measured ex vivo in mitochondria isolated from muscle biopsy specimens. Their inherent argument was that this would rule out a role for mitochondria in FFA-induced IR. Daniele et al. conducted a series of elegant ex vivo and in vivo studies in obese insulin-resistant subjects either with or without T2D. Contrary to their initial hypothesis, they found that reduction in elevated FFA in individuals with both T2D and normal glucose tolerance resulted in an