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Intracellular lipid metabolism impairs [beta] cell compensation during diet-induced obesity
- Source :
- Journal of Clinical Investigation. March, 2018, Vol. 128 Issue 3, p1178, 12 p.
- Publication Year :
- 2018
-
Abstract
- 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 LDL 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 glucoseinduced, [Ca.sup.2+]-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.<br />Introduction At early stages of type 2 diabetes, [beta] cells increase insulin production by hyperplasia as a compensatory response to insulin resistance in peripheral tissues (I). At that stage, the [...]
Details
- Language :
- English
- ISSN :
- 00219738
- Volume :
- 128
- Issue :
- 3
- Database :
- Gale General OneFile
- Journal :
- Journal of Clinical Investigation
- Publication Type :
- Academic Journal
- Accession number :
- edsgcl.530360232
- Full Text :
- https://doi.org/10.1172/JCI97702