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

Cell Cycle
James D Johnson, Emilyn U Alejandro

Abstract

Diabetes results from an absolute or relative deficiency in functional pancreatic beta-cell mass. Over the past few years, there has been renewed interest in the role of insulin itself in the regulation of beta-cell fate. Numerous animal models point to a critical role for beta-cell insulin signaling in the survival and proliferation of pancreatic beta-cells. In the present article, we review new studies that elucidate the mechanism by which insulin exerts anti-apoptotic and pro-mitogenic effects on beta-cells. In particular, we highlight the emerging role for Raf-1 kinase in autocrine insulin signaling and beta-cell fate decisions. We also discuss provocative evidence that the relationship between the dose of insulin and the birth and death of beta-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.

Citations

Jan 29, 2013·Diabetologia·G E LimJ D Johnson
Jun 25, 2009·Journal of Helminthology·G EscobedoJ Morales-Montor
Sep 26, 2013·Proceedings of the National Academy of Sciences of the United States of America·Yu Hsuan Carol YangJames D Johnson
Aug 6, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Emilyn U AlejandroJames D Johnson
Nov 9, 2012·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Jinny R LavezziPaul J Rozance
Nov 7, 2014·BMC Cancer·Michelle T ChanJames D Johnson
Nov 21, 2014·Journal of Diabetes Investigation·Søs Skovsø
Dec 12, 2012·Cell Metabolism·Arya E MehranJames D Johnson
Mar 29, 2016·Royal Society Open Science·Marta SzabatJames D Johnson
Mar 2, 2013·Endocrinology·Jocelyn E Manning FoxPatrick E MacDonald
Oct 17, 2018·International Journal of Molecular Sciences·Yinan JiangXiangwei Xiao
Nov 17, 2020·Frontiers in Genetics·Shaza AsifKyoung-Han Kim
Mar 30, 2021·Diabetes & Metabolism Journal·Anni M Y ZhangJames D Johnson

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