Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity

Masaya Oshima,Miriam Cnop,Raphaël Scharfmann,Mélanie Campana,Lara Bellini,Federica Fantuzzi,Hervé Le Stunff,Claude Rouch,Sanna Toivonen,Piero Marchetti,Julien Dairou,Sven O Göpel,Christophe Magnan,Cristina Cosentino,Séverine Pechberty

doi:10.1007/s00125-019-05046-x

Abstract

Aims/hypothesisDuring the onset of type 2 diabetes, excessive dietary intake of saturated NEFA and fructose lead to impaired insulin production and secretion by insulin-producing pancreatic beta cells. The majority of data on the deleterious effects of lipids on functional beta cell mass were obtained either in vivo in rodent models or in vitro using rodent islets and beta cell lines. Translating data from rodent to human beta cells remains challenging. Here, we used the human beta cell line EndoC-βH1 and analysed its sensitivity to a lipotoxic and glucolipotoxic (high palmitate with or without high glucose) insult, as a way to model human beta cells in a type 2 diabetes environment.MethodsEndoC-βH1 cells were exposed to palmitate after knockdown of genes related to saturated NEFA metabolism. We analysed whether and how palmitate induces apoptosis, stress and inflammation and modulates beta cell identity.ResultsEndoC-βH1 cells were insensitive to the deleterious effects of saturated NEFA (palmitate and stearate) unless stearoyl CoA desaturase (SCD) was silenced. SCD was abundantly expressed in EndoC-βH1 cells, as well as in human islets and human induced pluripotent stem cell-derived beta cells. SCD silencing induced markers of inflammation and endoplasmic reticulum stress and also IAPP mRNA. Treatment with the SCD products oleate or palmitoleate reversed inflammation and endoplasmic reticulum stress. Upon SCD knockdown, palmitate induced expression of dedifferentiation markers such as SOX9, MYC and HES1. Interestingly, SCD knockdown by itself disrupted beta cell identity with a decrease in mature beta cell markers INS, MAFA and SLC30A8 and decreased insulin content and glucose-stimulated insulin secretion.Conclusions/interpretationThe present study delineates an important role for SCD in the protection against lipotoxicity and in the maintenance of human beta cell identity.Data availabilityMicroarray data and all experimental details that support the findings of this study have been deposited in in the GEO database with the GSE130208 accession code.

Highlights

Type 2 diabetes develops as a consequence of a combination of insulin resistance of peripheral tissues and progressive decrease of functional pancreatic beta cell mass
We did not observe lipotoxicity associated with morphological changes or obvious cell death in EndoC-βH1 cells treated with 0.4 mmol/l palmitate (C16:0)
The mechanisms involved in beta cell lipotoxicity induced by saturated NEFA are the subject of active investigations because of its association with the development of type 2 diabetes [2, 3]

Summary

Introduction

Type 2 diabetes develops as a consequence of a combination of insulin resistance of peripheral tissues and progressive decrease of functional pancreatic beta cell mass. This deficit is manifested by inadequate and insufficient insulin secretion in response to increased circulating glucose levels [1, 2]. NEFA represent an important source of energy for pancreatic beta cells in the normal state but can induce beta cell dysfunction and death when present in excessive levels during a prolonged period [1,2,3]. Numerous studies have suggested different mechanisms by which NEFA mediate beta cell dysfunction and death such as endoplasmic reticulum (ER) stress [14], increased intracellular triacylglycerol [15], reactive oxygen species (ROS) [16, 17], inflammation [14] and de novo synthesis of ceramide [15]

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Results

Conclusion