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

Mol Aspects Med. 2015 Apr;42:19-41. doi: 10.1016/j.mam.2014.12.002. Epub 2014 Dec 24.


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.

Keywords: Glucolipotoxicity; Insulin resistance; Islet biology; β-cell development; β-cell failure; β-cell programming.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cell Differentiation
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology*
  • Endoplasmic Reticulum Stress
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Insulin Resistance* / genetics
  • Insulin-Secreting Cells / pathology*
  • Insulin-Secreting Cells / physiology
  • Oxidative Stress
  • Pancreas / cytology
  • Pancreas / growth & development
  • Pregnancy
  • Rodentia