Cellular catabolism is the cell capacity to generate energy from various substrates to sustain its function. To optimize this energy production, cells are able to switch between various metabolic pathways in accordance to substrate availability via a modulation of several regulatory
enzymes. This metabolic flexibility is essential for the healthy heart, an organ requiring large quantities of
ATP to sustain its contractile function. In
type 2 diabetes, excess of non-glucidic nutrients such as
fatty acids,
branched-chain amino-acids, or
ketones bodies, induces cardiac metabolic inflexibility. It is characterized by a preferential use of these alternative substrates to the detriment of
glucose, this participating in cardiomyocytes dysfunction and development of
diabetic cardiomyopathy. Identification of the molecular mechanisms leading to this metabolic inflexibility have been scrutinized during last decades. In 1963, Randle demonstrated that accumulation of some metabolites from
fatty acid metabolism are able to allosterically inhibit regulatory steps of
glucose metabolism leading to a preferential use of
fatty acids by the heart. Nevertheless, this model does not fully recapitulate observations made in diabetic patients, calling for a more complex model. A new piece of the puzzle emerges from recent evidences gathered from different laboratories showing that metabolism of the non-glucidic substrates induces an increase in acetylation levels of
proteins which is concomitant to the perturbation of
glucose transport. The purpose of the present review is to gather, in a synthetic model, the different evidences that demonstrate the role of acetylation in the inhibition of the
insulin-stimulated
glucose uptake in cardiac muscle.