Type 1 Diabetes—Reaping the Rewards of a Targeted Research Investment

Judith E. Fradkin; Julie A. Wallace; Beena Akolkar; Griffin P. Rodgers


Diabetes. 2016;65(2):307-313. 

In This Article

Restoring β-cell Function

Another strategic goal pursued with the special funding is to identify ways to replace lost β-cells and restore insulin production. Islet transplantation has been demonstrated to be highly successful in reversing hypoglycemia unawareness.[12] The Immune Tolerance Network (ITN), with SDP support, conducted the first international, multicenter trial of islet transplantation using the Edmonton protocol.[13] Building on this trial, the Clinical Islet Transplantation (CIT) Consortium, supported by the SDP, has conducted clinical and mechanistic studies in islet transplantation, with or without accompanying kidney transplantation, with a goal of validating a process for islet cell manufacturing for submission to the FDA for licensure as a biologic product. If the licensure is approved, islet transplantation could potentially transition from an experimental treatment to a procedure covered by third-party insurers. The islet-alone phase 3 trial has been completed, and the islet-after-kidney phase 3 trial has reached its primary end point. In addition, the Collaborative Islet Transplant Registry (CITR), also supported with SDP funding, found that rates of independence from insulin administration at 3 years after islet transplant increased over time—from 27 to 37 to 44% in 1999–2002, 2003–2006, and 2007–2010, respectively.[14] The transplanted islets also functioned longer in the most recent period, and the procedure protected patients from severe episodes of hypoglycemia. In addition to demonstrating that islet transplantation can achieve insulin independence, results from the phase 3 trials and CITR show that even if insulin therapy is required, islet transplantation allows recipients previously incapacitated by hypoglycemia to achieve glycemic targets with a sustained marked decrease in severe hypoglycemic episodes. While this treatment has been life-changing for those with severe, recurring episodes of hypoglycemia, its use is limited by side effects of immunosuppressive medications and limited numbers of donor islets.

The Beta Cell Biology Consortium (BCBC) was established, with SDP support, to facilitate interdisciplinary collaborations to advance the understanding of pancreatic islet development and function with the goal of developing innovative therapies to correct the loss of β-cell mass in diabetes, including cell reprogramming, regeneration, and replacement. This team science initiative brought together more than 50 research laboratories. Their efforts contributed to one of the most important advances in stem cell biology—the recent discovery of a method for large-scale production of glucose-responsive β-cells from human pluripotent stem cells.[15] This breakthrough brings us closer to the goal of β-cell replacement through transplantation and has accelerated efforts to protect newly transplanted β-cells from the autoimmune attack through encapsulation, as well as immunomodulation. In addition, BCBC researchers discovered that δ-cells could be reprogrammed into β-cells, representing another potential way to restore lost β-cells in type 1 diabetes.[16]

Building on this progress, the newly launched Human Islet Research Network (HIRN) (http://hirnetwork.org) will pursue innovative strategies to protect and replace β-cells in people with diabetes. Four independent, but complementary, research initiatives are focused on specific goals using human cells and tissues. One consortium is focused on the discovery of highly specific biomarkers of β-cell injury that will be important for testing strategies to stop β-cell destruction early in the disease process. Another is combining advances in β-cell and stem cell biology with tissue engineering technologies to develop microdevices that will support functional human islets in vivo. A third is developing innovative approaches to model the immunobiology of type 1 diabetes, reconstructing the disease using induced pluripotent stem cell–derived β-cells and thymic epithelial cells and immune systems derived from people with type 1 diabetes implanted in immunodeficient mice. The fourth is investigating methods to increase or maintain functional β-cell mass through targeted manipulation of islet plasticity or engineered protection of β-cells.