Replicative capacity of β-cells and type 1 diabetes

J Autoimmun. 2016 Jul;71:59-68. doi: 10.1016/j.jaut.2016.03.014. Epub 2016 Apr 28.

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.

Keywords: Autoimmune; Cell proliferation; Diabetes; Islet.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Autoimmunity
  • Cell Proliferation / drug effects
  • Cellular Microenvironment
  • Diabetes Mellitus, Type 1 / etiology*
  • Diabetes Mellitus, Type 1 / metabolism*
  • Diabetes Mellitus, Type 1 / therapy
  • Energy Metabolism / drug effects
  • Humans
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / immunology*
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / immunology
  • Islets of Langerhans / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Molecular Targeted Therapy
  • Regeneration
  • Signal Transduction / drug effects