Beta cells are heavily engaged in the synthesis and secretion of insulin. They are therefore particularly sensitive to endoplasmic reticulum (ER) stress and the subsequent unfolded protein response(UPR). Severe or prolonged episodes of ER stress can lead to the death of beta cells, which can contribute to the development of diabetes.
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Activation of ER stress
ER stress can be activated by a variety of factors. In experimental conditions, excessive lipid (which can happen following obesity, a common condition preceding type 2 diabetes) and pro-inflammatory cytokines (which can occur following an inflammation, a common cause for type 1 diabetes) can activate ER stress in beta cells.
Causes such as defective protein processing and trafficking or inappropriate calcium regulation are likely in lipid-mediated ER stress. On the other hand, cytokines are likely to activate ER stress by decreasing the calcium pump Serca2b (also known as Atp2a2), leading to subsequent depletion in the ER calcium stores.
Resolution of ER stress
Activation of ER stress by lipids results in a typical UPR to primarily restore ER function, whereas cytokine-activated ER stress leads to an atypical UPR that preferentially activate apoptosis in beta cells.