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Perspectives

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

James D. Johnson and Emilyn U. Alejandro

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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 pro-mitogenic 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.

Authors

James D. Johnson

University of British Columbia; Vancouver, British Columbia, Canada

Emilyn U. Alejandro

University of British Columbia; Vancouver, British Columbia, Canada

Purchase article for $19

Subscribe to this journal for $129/year