Problem

The two main forms of diabetes mellitus are T1D and T2D. They are a major cause of morbidity and mortality, decreasing both life quality and life expectancy of nearly 30 million affected individuals in Europe.

T1D is characterized by a near complete lack of insulin production due to specific destruction of the pancreatic beta cells that typically develops over several years. Although some immune-related biomarkers can identify individuals at risk to develop T1D, the process by which the beta cells are destroyed is not well understood. As a consequence, there are no adequate strategies for preservation of beta cell mass and prevention of the disease. Accumulating evidence suggests that beta cell loss in T1D is the result of an autoimmune mediated process, where a chronic inflammation called insulitis causes beta cell destruction. This is mediated by cytokines and other mediators released by the activated immune cells invading the islets, which activate secondary pathways of cell death in the target beta cells.

T2D results from a reduced ability of the pancreatic beta cells to secrete enough insulin to stimulate glucose utilization by peripheral tissues. Initially, this causes impaired glucose tolerance, i.e. a reduced capacity to clear glucose from the blood following a glucose load. As beta cell mass decreases and beta cell secretory capacity further deteriorates, there is a progressive increase in the fasting glucose concentration, eventually culminating in overt hyperglycaemia. Defects in both insulin secretion and action contribute to the pathogenesis of T2D, but it is now acknowledged that T2D is an insulin deficiency syndrome  associated with a progressive reduction in beta cell mass. The loss of beta cell mass in T2D is probably secondary to chronic exposure to high glucose and free fatty acid (FFA) levels (glucolipotoxicity).

In conclusion, a reduction in beta cell mass is a key component of diabetes mellitus and the molecular mechanisms underlying beta cell loss remain to be clarified.