Replicative capacity of β-cells and type 1 diabetes

Efforts to restore beta-cell number or mass in type 1 diabetes (T1D) must combine an intervention to stimulate proliferation of remaining beta-cells and an intervention to mitigate or control the beta-cell-directed autoimmunity. This review highlights features of the beta-cell, including it being part of a pancreatic islet, a mini-organ that is highly vascularized and highly innervated, and efforts to promote beta-cell proliferation. In addition, the beta-cell in T1D exists in a microenvironment with interactions and input from other islet cell types, extracellular matrix, vascular endothelial cells, neuronal projections, and immune cells, all of which likely influence the beta-cell's capacity for replication. Physiologic beta-cell proliferation occurs in human and rodents in the neonatal period and early in life, after which there is an age-dependent decline in beta-cell proliferation, and also as part of the beta-cell's compensatory response to the metabolic challenges of pregnancy and insulin resistance. This review reviews the molecular pathways involved in this beta-cell proliferation and highlights recent work in two areas: 1) Investigators, using high-throughput screening to discover small molecules that promote human beta-cell proliferation, are now focusing on the dual specificity tyrosine-regulated kinase-1a and cell cycle-dependent kinase inhibitors CDKN2C/p18 or CDKN1A/p2las targets of compounds to stimulate adult human beta-cell proliferation. 2) Local inflammation, macrophages, and the local beta-cell microenvironment promote beta-cell proliferation. Future efforts to harness the responsible mechanisms may lead to new approaches to promote beta-cell proliferation in T1D. (C) 2016 Elsevier Ltd. All rights reserved.