Lipotoxic endoplasmic reticulum stress, β cell failure, and type 2 diabetes mellitus

Failure of the unfolded protein response (UPR) to maintain optimal folding of pro-insulin in the endoplasmic reticulum (ER) leads to unresolved ER stress and β cell death. This contributes not only to some rare forms of diabetes, but also to type 2 diabetes mellitus (T2DM). Many key findings, elaborated over the past decade, are based on the lipotoxicity model, entailing chronic exposure of β cells to elevated levels of fatty acids (FAs). Here, we update recent progress on how FAs initiate ER stress, particularly via disruption of protein trafficking, and how this leads to apoptosis. We also highlight differences in how β cells are impacted by the classic UPR, versus the more selective UPR that arises as part of a broader response to lipotoxicity.