Beta-cell mass and type 1 diabetes: going, going, gone?

Abstract

Objective: Beta-cell regeneration is a fundamental but elusive goal for type 1 diabetes research. Our objective is to review newer human and animal studies of beta-cell destruction and regeneration and consider the implications for treatment of type 1 diabetes.

Research design and methods: Recent human and animal studies of beta-cell destruction and regeneration in type 1 diabetes are reviewed.

Results: The loss of beta-cells that characterizes type 1 diabetes reflects the net effects of destruction and regeneration. These processes have been examined in the nonobese diabetic (NOD) mouse; uncertainty remains about beta-cell dynamics in humans. Islet inflammation stimulates beta-cell replication that produces new insulin-positive cells. The regenerative process may tide the loss of overall beta-cell function, but it also may enhance the autoimmune attack on beta-cells by providing new epitopes. The highest rates of beta-cell replication are at the time of diagnosis of diabetes in NOD mice, and if autoimmunity and islet inflammation are arrested, new beta-cells are formed. However, the majority of beta-cells after treatment with immune modulators such as anti-CD3 monoclonal antibody, and most likely during the "honeymoon" in human disease, are recovered beta-cells that had been degranulated but present at the time of diagnosis of diabetes.

Conclusions: Residual beta-cells play a significant role for the design of therapeutic trials: they not only may respond to combination therapies that include stimulants of metabolic function but are also the potential source of new beta-cells.

FIG. 1.

Changes in β-cells during progression of type 1 diabetes and the selection of interventions: the initial event that primes the adaptive immune response is not known but is postulated to involve β-cell death. Antigen-specific immune interventions (red arrow) have the greatest chance of efficacy in this early stage. With progression of the response, there are increased rates of β-cell proliferation but also a loss of β-cells and expansion of the immune response. A greater proportion of replicating β-cells is seen in the islet as insulitis progresses, and some β-cells are unable to keep up with the metabolic demands. Most likely, a broader approach to immune intervention is needed at this point, since the autoreactive repertoire is broader than at the earlier stages. Left untreated, there is continued loss of β-cells. However, interventions such as immune modulators can prevent the ongoing adaptive immune response against β-cells and, with metabolic treatment, recovery of degranulated β-cells can occur.