Endoplasmic Reticulum Stress in Beta Cells

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,[1] which can contribute to the development of diabetes.[2]

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 [3] and trafficking [4] or inappropriate calcium regulation [5] 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.[6]

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.[7]

References

  1. ↑ Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29:42-61
  2. ↑ Laybutt DR, Preston AM, Akerfeldt MC et al (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50:752-763
  3. ↑ Jeffrey KD, Alejandro EU, Luciani DS et al (2008) Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis. Proc Natl Acad Sci USA 105:8452–8457
  4. ↑ Preston AM, Gurisik E, Bartley C, Laybutt DR, Biden TJ (2009) Reduced endoplasmic reticulum (ER)-to-Golgi protein trafficking contributes to ER stress in lipotoxic mouse beta cells by promoting protein overload. Diabetologia 52:2369–2373
  5. ↑ Cunha DA, Hekerman P, Ladriere L et al (2008) Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. J Cell Sci 121:2308–2318
  6. ↑ Oyadomari S, Takeda K, Takiguchi M et al (2001) Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proc Natl Acad Sci USA 98:10845–10850.
  7. ↑ Pirot P, Eizirik DL, Cardozo AK (2006) Interferon-gamma potentiates endoplasmic reticulum stress-induced death by reducing pancreatic beta cell defence mechanisms. Diabetologia 49:1229–1236
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