2037-P: Islet ß-Cell Dedifferentiation Is Involved in Progression of Type 2 Diabetes

T2D is associated with deficits of β-cell function and number. But it remains unclear how these processes interact during disease progression. It has been described that islet cell plasticity, i.e., β-cell dedifferentiation and conversion into other islet cells, is implicated to β-cell failure in murine diabetes of insulin resistance. We aimed to examine it in human T2D and to elucidate its involvement in disease progression.

Methods: We evaluated pancreata obtained during pancreatectomy from Japanese subjects who had been over-weighed during adulthood and had no diabetic family history and analyzed patient’s clinical information. The diabetics in the early- and the advanced-stage that were defined by combining clinical information on disease duration, microvascular complications and insulin replacement were evaluated. The islet area was determined by measuring ChgA- positive area. We detected islet major 4 hormones-negative/ChgA-positive cells as dedifferentiated cells.

Results: There was a diversity in relative β-, α- and islet area to pancreatic area in the T2D subjects, suggesting metabolic heterogeneity associated with various capabilities of islet compensation in response to insulin resistance. We found that a decreased relative β-cell number and an increased relative α-cell number to entire ChgA-positive cell number in individual T2D islets. But there was no further increase in α-cells along disease progression despite progressive β-cell loss, and only little INS/GCG double positive cells. Instead, a strikingly elevated number of the dedifferentiated cells in T2D islets compared to control subjects and its significant increase with disease progression was observed. Importantly, there was a significant inverse correlation between increasing dedifferentiated cells and declining C-peptide index among the groups. These finding indicates that islet cells exert plasticity during diabetes progression and that β-cell dedifferentiation is a pathologic process leading β-cell failure.