Mechanisms of β-Cell Death in Type 2 Diabetes

  1. Marc Y. Donath1,
  2. Jan A. Ehses1,
  3. Kathrin Maedler1,
  4. Desiree M. Schumann1,
  5. Helga Ellingsgaard1,
  6. Elisabeth Eppler2 and
  7. Manfred Reinecke2
  1. 1Division of Endocrinology and Diabetes, University Hospital Zurich, Zurich, Switzerland
  2. 2Division of Neuroendocrinology, Institute of Anatomy, University of Zurich, Zurich, Switzerland
  1. Address correspondence and reprint requests to Marc Y. Donath, MD, Division of Endocrinology and Diabetes, Department of Medicine, University Hospital, CH-8091 Zurich, Switzerland. E-mail: marc.donath{at}usz.ch

Abstract

A decrease in the number of functional insulin-producing β-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in β-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of β-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K+ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-κB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of β-cell secretory function and cell turnover. Thus, the mechanisms regulating β-cell proliferation, apoptosis, and function are inseparable processes.

Footnotes

  • 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 5, 2005.
    • Received March 2, 2005.
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