The role of candidate transport proteins in β‐cell long‐chain fatty acid uptake: Where are we now?

Type 2 diabetes (T2D) in humans is typically preceded by elevated levels of circulatory long‐chain free fatty acids (LC‐FFA). These excess LC‐FFA are widely thought to be taken up by pancreatic β‐cells, contributing to their dysfunction and death during the development of T2D; a process that has been termed lipotoxicity. Depending on their degree of saturation and carbon chain length, LC‐FFA can exert different effects on pancreatic β‐cells viability and function in vitro. Long‐chain saturated fatty acids (LC‐SFA) are thought to be toxic, whereas monounsaturated fatty acids are not and may even offer protection against the toxic effects of LC‐SFAs. However, the mechanism of LC‐FFA uptake into pancreatic β‐cells is poorly understood, partly because it has been an understudied area of research. Determining how LC‐FFA are taken up into β‐cells is crucial for later formulation of therapies to prevent potential cellular overload of LC‐FFA, thereby slowing the onset of T2D. In this work, we detail more than 40 years of literature investigating the role of membrane‐associated transport proteins in LC‐FFA uptake. By focussing on what is known in other cell types, we highlight where we can extrapolate our current understanding of protein‐mediated transport to β‐cells and uncover where further understanding is required.