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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.

Author information

1
Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern (UTSW) Medical Center, Dallas, Texas, USA.
2
Department of Medical Education, Texas Tech University Health Sciences Center Paul L. Foster School of Medicine, El Paso, Texas, USA.
3
Center for the Genetics of Host Defense, UTSW Medical Center, Dallas, Texas, USA.
4
Department of Biochemistry, University of Wisconsin, Madison, Wisconsin, USA.
5
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, New York, USA.
6
Departments of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics, and Center for Translational Neurodegeneration Research, UTSW Medical Center, Dallas, Texas, USA.
7
Center for Neuroscience, Department of Neuroanatomy, Albert Ludwig University, Freiburg, Germany.

Abstract

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.

KEYWORDS:

Beta cells; Diabetes; Endocrinology; Metabolism; Obesity

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