title: Replicative capacity of β-cells and type 1 diabetes.
abstract: Efforts to restore β-cell number or mass in type 1 diabetes (T1D) must combine an intervention to stimulate proliferation of remaining β-cells and an intervention to mitigate or control the β-cell-directed autoimmunity. This review highlights features of the β-cell, including it being part of a pancreatic islet, a mini-organ that is highly vascularized and highly innervated, and efforts to promote β-cell proliferation. In addition, the β-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 β-cell's capacity for replication. Physiologic β-cell proliferation occurs in human and rodents in the neonatal period and early in life, after which there is an age-dependent decline in β-cell proliferation, and also as part of the β-cell's compensatory response to the metabolic challenges of pregnancy and insulin resistance. This review reviews the molecular pathways involved in this β-cell proliferation and highlights recent work in two areas: 1) Investigators, using high-throughput screening to discover small molecules that promote human β-cell proliferation, are now focusing on the dual-specificity tyrosine-regulated kinase-1a and cell cycle-dependent kinase inhibitors CDKN2C/p18 or CDKN1A/p21as targets of compounds to stimulate adult human β-cell proliferation. 2) Local inflammation, macrophages, and the local β-cell microenvironment promote β-cell proliferation. Future efforts to harness the responsible mechanisms may lead to new approaches to promote β-cell proliferation in T1D.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Diane
authors.initials: D
authors.lastname: Saunders
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, United States; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, United States; VA Tennessee Valley Healthcare System, Nashville, TN, United States. Electronic address: al.powers@vanderbilt.edu.
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Powers
mesh_terms: D000818:Animals; D015551:Autoimmunity; D049109:Cell Proliferation / Q000187:drug effects; D060833:Cellular Microenvironment; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000378:metabolism* / Q000628:therapy; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D058990:Molecular Targeted Therapy; D012038:Regeneration; D015398:Signal Transduction / Q000187:drug effects
keywords: Autoimmune; Cell proliferation; Diabetes; Islet