An islet in distress: β cell failure in type 2 diabetes - PubMed (original) (raw)

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An islet in distress: β cell failure in type 2 diabetes

Takeshi Ogihara et al. J Diabetes Investig. 2010.

Abstract

Over 200 million people worldwide suffer from diabetes, a disorder of glucose homeostasis. The majority of these individuals are diagnosed with type 2 diabetes. It has traditionally been thought that tissue resistance to the action of insulin is the primary defect in type 2 diabetes. However, recent longitudinal and genome-wide association studies have shown that insulin resistance is more likely to be a precondition, and that the failure of the pancreatic β cell to meet the increased insulin requirements is the triggering factor in the development of type 2 diabetes. A major emphasis in diabetes research has therefore shifted to understanding the causes of β cell failure. Collectively, these studies have implicated a complex network of triggers, which activate intersecting execution pathways leading to β cell dysfunction and death. In the present review, we discuss these triggers (glucotoxicity, lipotoxicity, amyloid and cytokines) with respect to the pathways they activate (oxidative stress, inflammation and endoplasmic reticulum stress) and propose a model for understanding β cell failure in type 2 diabetes. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00021.x, 2010).

Keywords: Diabetes; Insulin resistance; Islet.

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Figures

Figure 1

Figure 1

Trajectories of β cell function, insulin sensitivity and post‐prandial glucose during the progression from normal glucose tolerance to diabetes. The general trajectories depicted and the relative timelines with respect to one another are taken from data from the Whitehall II study.

Figure 2

Figure 2

Triggers of β cell dysfunction impinge on intercommunicating pathways. β cell dysfunction is depicted as emanating from specific extracellular (glucotoxicity, cytokines and lipotoxicity) and intracellular (IAPP) signals, which then activate an intercommunicating network of pathways (oxidative stress, ER stress and inflammatory stress) leading to β cell dysfunction and demise. The figure is intended to be descriptive of the events observed in models in vitro and in vivo, and is not intended to suggest that those mechanisms depicted are the only mechanisms that occur. FFA, free fatty acid.

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