Natural history of β-cell adaptation and failure in type 2 diabetes

Emilyn U. Alejandro, Brigid Gregg, Manuel Blandino-Rosano, Corentin Cras-Méneur, Ernesto Bernal-Mizrachi

Research output: Contribution to journalReview articlepeer-review

172 Scopus citations


Type 2 diabetes mellitus (T2D) is a complex disease characterized by β-cell failure in the setting of insulin resistance. The current evidence suggests that genetic predisposition, and environmental factors can impair the capacity of the β-cells to respond to insulin resistance and ultimately lead to their failure. However, genetic studies have demonstrated that known variants account for less than 10% of the overall estimated T2D risk, suggesting that additional unidentified factors contribute to susceptibility of this disease. In this review, we will discuss the different stages that contribute to the development of β-cell failure in T2D. We divide the natural history of this process in three major stages: susceptibility, β-cell adaptation and β-cell failure, and provide an overview of the molecular mechanisms involved. Further research into mechanisms will reveal key modulators of β-cell failure and thus identify possible novel therapeutic targets and potential interventions to protect against β-cell failure.

Original languageEnglish (US)
Pages (from-to)19-41
Number of pages23
JournalMolecular Aspects of Medicine
StatePublished - Apr 1 2015

Bibliographical note

Funding Information:
The authors apologize to the many authors whose important publications were not cited because of lack of space. The authors wish to acknowledge funding resources for this essential contribution to this work. E.B-M. is supported by the National Institutes of Health (NIH) Grant RO1-DK073716 , DK084236 , and MERIT award IBX002728A and Juvenile Diabetes Research Foundation (JDRF) grant 17-2013-416 . E.U.A was supported by an NIH training grant ( 2T32DK071212-06 ), Post-Doctoral Fellowship from the Hartwell Foundation , and a Career Development Award from NIH ( K01-DK-103823 ). C.C-M was supported by a Junior Faculty Award from the American Diabetes Foundation ( N013797 ). We thank Ronald Mark Ygona for assistance in preparing Fig. 3 .


  • Glucolipotoxicity
  • Insulin resistance
  • Islet biology
  • β-cell development
  • β-cell failure
  • β-cell programming


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