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J Clin Invest. 2018 Mar 1;128(3):1178-1189. doi: 10.1172/JCI97702. Epub 2018 Feb 19.

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

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Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern (UTSW) Medical Center, Dallas, Texas, USA.
Department of Medical Education, Texas Tech University Health Sciences Center Paul L. Foster School of Medicine, El Paso, Texas, USA.
Center for the Genetics of Host Defense, UTSW Medical Center, Dallas, Texas, USA.
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, USA.
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York, USA.
Departments of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, and Center for Translational Neurodegeneration Research, UTSW Medical Center, Dallas, Texas, USA.
Center for Neuroscience, Department of Neuroanatomy, Albert Ludwig University, Freiburg, Germany.


The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β 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 β cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of β 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 PPARγ2. Acute overexpression of PPARγ2 in β cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired β cell function in a similar fashion. In summary, our results uncover the double-edged effects of intracellular lipid metabolism on β cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes.


Beta cells; Diabetes; Endocrinology; Metabolism; Obesity

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