Control of pancreatic β-cell fate by insulin signaling: The sweet spot hypothesis

James D. Johnson, Emilyn U. Alejandro

Research output: Contribution to journalReview articlepeer-review

28 Scopus citations

Abstract

Diabetes results from an absolute or relative deficiency in functional pancreatic β-cell mass. Over the past few years, there has been renewed interest in the role of insulin itself in the regulation of β-cell fate. Numerous animal models point to a critical role for β-cell insulin signaling in the survival and proliferation of pancreatic β-cells. In the present article, we review new studies that elucidate the mechanism by which insulin exerts anti-apoptotic and promitogenic effects on β-cells. In particular, we highlight the emerging role for Raf-1 kinase in autocrine insulin signaling and β-cell fate decisions. We also discuss provocative evidence that the relationship between the dose of insulin and the birth and death of β-cells is not linear. We propose a new hypothesis based on these findings, called the 'sweet spot' hypothesis, that can explain how both upward and downward deviations from normal levels of autocrine/paracrine insulin signaling might play an important role in the pathogenesis of type 1 diabetes and type 2 diabetes. We also highlight the key experiments that are required to further test this hypothesis.

Original languageEnglish (US)
Pages (from-to)1343-1347
Number of pages5
JournalCell Cycle
Volume7
Issue number10
DOIs
StatePublished - May 15 2008

Bibliographical note

Funding Information:
We thank members of the UBC Diabetes Research Group for helpful discussions. Work in the author’s laboratory is supported by the Juvenile Diabetes Research Foundation (JDRF), the Canadian Diabetes Association (CDA), the Canadian Institutes for Health Research (CIHR), the Stem Cell Network, and the Natural Sciences and Engineering Research Council of Canada. J.D.J. holds scholar awards from JDRF, CIHR and CDA. E.U.A. is a National Institutes of Health National Research Service Award recipient (F31DK079346).

Keywords

  • Autocrine insulin signaling
  • Pancreatic islets
  • Raf-1 kinase

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