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Targeting sphingolipid metabolism in the treatment of obesity/type 2 diabetes

Lara Bellini1, Mélanie Campana, Rana Mahfouz

  • 1Université PARIS-DIDEROT (7), Unité Biologie Fonctionnelle et Adaptative - UMR CNRS 8251, Équipe Régulation de la glycémie par le système nerveux central (REGLYS) , 4, rue Marie-Andrée Lagroua Weill-Halle, 75205 PARIS Cedex 13 , France +01 57 27 77 97 ; +01 57 27 77 96 ; herve.le-stunff@univ-paris-diderot.fr.

Expert Opinion on Therapeutic Targets
|March 28, 2015
PubMed
Abstract

Insights

Obesity-induced lipotoxicity, driven by fatty acids and ceramides, promotes type 2 diabetes (T2D). Counteracting ceramide accumulation or balancing sphingolipids may offer therapeutic strategies for T2D linked to obesity.

Area of Science:

  • Metabolic disease
  • Endocrinology
  • Lipid metabolism

Background:

  • Obesity is a primary driver of type 2 diabetes (T2D).
  • Excess circulating fatty acids (FAs) in obesity cause insulin resistance, steatosis, and pancreatic beta-cell dysfunction, a process termed lipotoxicity.
  • Ceramides, a class of lipids, are key mediators of FA-induced lipotoxicity.

Purpose of the Study:

  • To review the role of ceramides in obesity-associated T2D.
  • To examine ceramide action in key tissues like muscle, liver, adipose tissue, and pancreatic beta-cells.
  • To explore the potential counter-regulatory effects of sphingoid base phosphates.

Main Methods:

  • Literature review focusing on ceramide metabolism and function in T2D.
  • Analysis of ceramide's impact on insulin resistance and beta-cell apoptosis.
  • Evaluation of sphingoid base phosphates as potential antagonists of lipotoxicity.

Main Results:

  • Ceramides are critical mediators in the development of T2D linked to obesity.
  • Directly targeting proteins in ceramide signaling is challenging due to their broad involvement in cellular pathways.
  • Specific ceramide species accumulation contributes to insulin resistance and beta-cell dysfunction.

Conclusions:

  • Preventing the accumulation of specific lipotoxic ceramide species is a potential therapeutic avenue.
  • Modulating the balance between ceramides and sphingoid base phosphates may counteract T2D development.
  • Targeting lipid metabolism offers novel strategies for managing obesity-related T2D.
Keywords:
adipose tissueapoptosisceramideinsulinislet of Langerhanslipotoxicitylivermuscleobesitypancreatic β cellssphingolipidssphingosine-1-phosphatetype 2 diabetes

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