Bone morphogenetic protein 6 (BMP6) as a regulator of pancreatic islet a -cell mass

Central to the pathogenesis of diabetes mellitus (DM) is the failure of pancreatic b-cells to produce adequate insulin to maintain glucose homeostasis. In type I DM, this is due to autoimmune destruction of b-cells, whereas in type II DM, this is due to loss of both b-cell number and function in the setting of insulin resistance, hyperglycemia, and oxidative stress. Pancreatic a-cells also play an important role in the pathogenesis of DM and as a potential therapeutic target. Long recognized as the source glucagon that stimulates hepatic glucose production and contributes to hyperglycemia in DM, a-cells have recently been reported to play an important role in the promotion and regeneration of b-cells, including the ability to transdifferentiate into b-cells. Understanding the factors that control a-cell mass therefore holds the promise to open up new therapeutic approaches for DM.

Bone morphogenetic proteins (BMPs) are a subfamily of the TGF- b superfamily of signaling molecules that were initially characterized by their ability to induce ectopic bone formation, but have subsequently been shown to regulate the development and homeostasis of many tissues. We will present preliminary data suggesting that BMP6 may function as a b -cell-derived secreted factor that regulates a - cell proliferation. Rat islets overexpressing the homeodomain transcription factor Pdx-1 under the control of an insulin promoter stimulated both rat and human a -cell proliferation. RNA-seq analysis identified BMP6 as one of the most highly upregulated transcripts. Treatment of human islets in culture with BMP6 stimulated a -cell proliferation, effects that were blocked by a small molecule BMP type I receptor inhibitor. Here, we propose to use our milligram quantities of recombinant BMP6 protein, Bmp6 global KO mice, and Bmp6 floxed mice to test the hypothesis that BMP6 is a b -cell derived factor that functions as a regulator of a -cell mass in vivo.

Public Health Relevance: Diabetes mellitus is a significant public health problem affecting more than 30 million people in the US alone. The long-term goals of this proposal are to understand the factors that govern islet cell mass and ultimately to develop new therapeutic avenues for diabetes.