Liver X Receptor Activation Stimulates Insulin Secretion via Modulation of Glucose and Lipid Metabolism in Pancreatic Beta-Cells

  1. Alexander M. Efanov,
  2. Sabine Sewing,
  3. Krister Bokvist and
  4. Jesper Gromada
  1. From the Lilly Research Laboratories, Hamburg, Germany
  1. Address correspondence and reprint requests to Dr. Alexander M. Efanov, Lilly Research Laboratories, Essener Strasse 93, D-22419 Hamburg, Germany. E-mail: efanov_alexander{at}lilly.com

Abstract

Liver X receptors (LXRs) α and β, transcription factors of a nuclear hormone receptor family, are expressed in pancreatic islets as well as glucagon-secreting and insulin-secreting cell lines. Culture of pancreatic islets or insulin-secreting MIN6 cells with a LXR specific agonist T0901317 caused an increase in glucose-dependent insulin secretion and islet insulin content. The stimulatory effect of T0901317 on insulin secretion was observed only after >72 h of islet culture with the compound. In MIN6 cells, T0901317 increased protein expression of lipogenic enzymes, fatty acid synthase, and acetyl-CoA carboxylase. LXR activation also produced an increase in glucokinase protein and pyruvate carboxylase (PC) activity levels. The PC inhibitor phenylacetic acid abolished the increase in insulin secretion in cells treated with T0901317. The results suggest that LXRs can control insulin secretion and biosynthesis via regulation of glucose and lipid metabolism in pancreatic β-cells.

Footnotes

  • A.M.E. and S.S. hold stock in Eli Lilly; K.B. holds stock in Eli Lilly and Novartis AG; and J.G. holds stock in Eli Lilly and Novo Nordisk A/S.

    This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted May 25, 2004.
    • Received January 27, 2004.
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