title: Natural history of β-cell adaptation and failure in type 2 diabetes.
abstract: 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.
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Emilyn U
authors.initials: EU
authors.lastname: Alejandro
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Brigid
authors.initials: B
authors.lastname: Gregg
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: Blandino-Rosano
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Corentin
authors.initials: C
authors.lastname: Cras-Méneur
authors.affiliation: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, Brehm Center for Diabetes Research, University of Michigan, Ann Arbor, MI, USA; VA Ann Arbor Healthcare System, Ann Arbor, MI, USA. Electronic address: ebernal@med.umich.edu.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Bernal-Mizrachi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000473:pathology*; D059865:Endoplasmic Reticulum Stress; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000473:pathology* / Q000502:physiology; D018384:Oxidative Stress; D010179:Pancreas / Q000166:cytology / Q000254:growth & development; D011247:Pregnancy; D012377:Rodentia
keywords: Glucolipotoxicity; Insulin resistance; Islet biology; β-cell development; β-cell failure; β-cell programming