International collaborative studies undertaken by the Hundal Group (Division of Cell Signalling & Immunology) alongside researchers in Germany and Poland have provided new insight into the mechanisms by which over-supply of saturated fatty acids induce metabolic defects in skeletal muscle – the principal target tissue for the hormone insulin.
The research published in the journal Diabetes demonstrates the deleterious impact that nutrient (fuel) overload has upon the integrity and function of mitochondria; organelles that function as cellular “energy generators”. The study reveals that limiting glucose availability causes a profound reduction in the ability of saturated fatty acids to promote obesity-induced insulin resistance and inflammation within muscle by helping to preserve mitochondrial function. Strikingly, a non-metabolisable glucose analogue that competitively inhibits glucose utilisation within cells is just as effective as glucose starvation in negating the pathogenic potential of fatty acid over-provision. This sugar analogue also functions as a calorie restriction mimetic and the current study shows that its administration improves muscle insulin sensitivity and inflammatory status in an in vivo model of obesity. Importantly, these beneficial effects occur despite the intramuscular accumulation of toxic lipid-derived intermediates (such as diacylglycerols and ceramides), which, hitherto, have been presented as major determinants of fat-induced insulin resistance in skeletal muscle.
The study highlights that strategies designed to reduce the cellular supply of carbohydrate fuel (for example, via calorie restriction), may not only help maintain the integrity and function of mitochondria, but also improve their “fat burning” capacity and thereby help combat fat-induced insulin resistance and other obesity-associated metabolic disorders.
The research has been supported by Diabetes UK.
Christopher Lipina, Katherine Macrae, Tamara Suhm, Cora Weigert, Agnieszka Blachnio-Zabielska, Marcin Baranowski, Jan Gorski, Karl Burgess, and Harinder S Hundal
Mitochondrial Substrate Availability and its Role in Lipid-Induced Insulin Resistance and Proinflammatory Signalling in Skeletal Muscle