Free fatty acids accelerate β-cell death in type 1 diabetes

Type 1 diabetes (T1D) results from autoimmune destruction of the insulin-producing pancreatic beta cells. The body lipid metabolism is strongly regulated during this process but there is a need to understand how this regulation contributes to the beta-cell death. Here, we show that fatty acids are released from plasma lipoproteins in children during islet autoimmunity, prior to T1D onset. These fatty acids (FFAs) enhanced cytokine-mediated apoptosis in cultured insulin-producing cells by downregulating the production of nicotinamide adenosine dinucleotide (NAD) via its salvage pathway, as well as deregulated central carbon metabolism and impaired levels of ATP. Downregulation of the NAD salvage pathway and central carbon metabolism enzymes were further observed during T1D development, supporting that the pathways for NAD and energy production are compromised in vivo. Our findings show that fatty acids are released during islet autoimmunity, accelerating disease development through impaired NAD metabolism.