Role of pancreatic beta-cell death and inflammation in diabetes

Abstract

Apoptosis of pancreatic beta-cells is the final step in the development of type 1 diabetes (T1D), leading to critically diminished beta-cells mass and contributing to the onset of hyperglycaemia. The spontaneous apoptosis of pancreatic beta-cells during pancreas ontogeny also induces cell death-associated inflammation, stimulates antigen-presenting cells and sensitizes naive diabetogenic T cells. The role of pancreatic beta-cells death in type 2 diabetes (T2D) is less clear. In the preclinical period of T2D, hyperinsulinaemia and beta-cells hyperplasia develop to compensate for insulin resistance, which is clearly seen in animal models of T2D. For the development of overt T2D, relative insulin deficiency is critical in addition to insulin resistance. Insulin deficiency could be due to beta-cells dysfunction and/or decreased beta-cells mass. Pancreatic beta-cells apoptosis due to lipid injury (lipoapoptosis), endoplasmic reticulum (ER) stress or JNK activation could contribute to the decreased beta-cells mass in T2D. Activation of inflammasomes by lipid injury, ER stress, human islet amyloid polypeptide, hyperglycaemia or autophagy insufficiency could also lead to beta-cells death or dysfunction. Thus, beta-cells death and cell death-associated inflammation through innate immune receptors could be important in both T1D and T2D.