Pharmacological strategies for protection of extrahepatic islet transplantation

Minerva Endocrinol. 2015 Jun;40(2):85-103. Epub 2015 Feb 5.

Abstract

The safety and effectiveness of islet transplantation has been proven through world-wide trials. However, acute and chronic islet loss has hindered the ultimate objective of becoming a widely used treatment option for type 1 diabetes. A large islet loss is attributed, in part, to the liver being a less-than-optimal site for transplantation. Over half of the transplanted islets are destroyed shortly after transplantation due to direct exposure to blood and non-specific inflammation. Successfully engrafted islets are continuously exposed to the liver micro-environment, a unique immune system, low oxygen tension, toxins and high glucose, which is toxic to islets, leading to premature islet dysfunction/death. Investigations have continued to search for alternate sites to transplant islets that provide a better environment for prolonged function and survival. This article gathers courses and conditions that lead to islet loss, from organ procurement through islet transplantation, with special emphasis on hypoxia, oxidative stress, and antigen non-specific inflammation, and reviews strategies using pharmacological agents that have shown effectiveness in protecting islets, including a new treatment approach utilizing siRNA. Pharmacological agents that support islet survival and promote β-cell proliferation are also included. Treatment of donor pancreata and/or islets with these agents should increase the effectiveness of islets transplanted into extrahepatic sites. Furthermore, the development of methods designed to release these agents over an extended period, will further increase their efficacy. This requires the combined efforts of both islet transplant biologists and bioengineers.

Publication types

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

MeSH terms

  • Angiogenesis Inducing Agents / pharmacology
  • Angiogenesis Inducing Agents / therapeutic use
  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Antioxidants / pharmacology
  • Antioxidants / therapeutic use
  • Cell Hypoxia / drug effects
  • Cellular Microenvironment
  • Drug Evaluation, Preclinical
  • Gene Knockdown Techniques
  • Glucagon-Like Peptide 1 / agonists
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide 1 / therapeutic use
  • Glucose / metabolism
  • Graft Survival / drug effects
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / therapeutic use
  • Intercellular Signaling Peptides and Proteins / pharmacology
  • Intercellular Signaling Peptides and Proteins / therapeutic use
  • Islets of Langerhans / drug effects
  • Islets of Langerhans Transplantation / methods*
  • Liver / cytology
  • Liver / immunology
  • Liver / metabolism
  • Liver / surgery*
  • Mice
  • Organ Specificity
  • Oxidative Stress / drug effects
  • RNA, Small Interfering / pharmacology
  • RNA, Small Interfering / therapeutic use
  • Tissue Inhibitor of Metalloproteinases / pharmacology
  • Tissue Inhibitor of Metalloproteinases / therapeutic use
  • Tissue and Organ Procurement / methods
  • Transplantation, Heterotopic / methods*

Substances

  • Angiogenesis Inducing Agents
  • Anti-Inflammatory Agents
  • Antioxidants
  • Immunosuppressive Agents
  • Intercellular Signaling Peptides and Proteins
  • RNA, Small Interfering
  • Tissue Inhibitor of Metalloproteinases
  • Glucagon-Like Peptide 1
  • Glucose