Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity.

The compensatory proliferation of insulin-producing beta cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of beta cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between beta cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LOL receptor-related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in beta cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of beta cells. The diminished insulin signaling was partly contributed to by the hypersensitivity to glucose-induced, Ca2+-dependent activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid metabolism, mediated at least in part by the master transcriptional regulator PPAR gamma 2. Acute overexpression of PPAR gamma 2 in beta cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired beta cell function in a similar fashion. In summary, our results uncover the double-edged effects of intracellular lipid metabolism on beta cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes.