β-Cell Mass and Type 1 Diabetes

Abstract

OBJECTIVE— β-Cell regeneration is a fundamental but elusive goal for type 1 diabetes research. Our objective is to review newer human and animal studies of β-cell destruction and regeneration and consider the implications for treatment of type 1 diabetes. RESEARCH DESIGN AND METHODS— Recent human and animal studies of β-cell destruction and regeneration in type 1 diabetes are reviewed. RESULTS— The loss of β-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 β-cell dynamics in humans. Islet inflammation stimulates β-cell replication that produces new insulin-positive cells. The regenerative process may tide the loss of overall β-cell function, but it also may enhance the autoimmune attack on β-cells by providing new epitopes. The highest rates of β-cell replication are at the time of diagnosis of diabetes in NOD mice, and if autoimmunity and islet inflammation are arrested, new β-cells are formed. However, the majority of β-cells after treatment with immune modulators such as anti-CD3 monoclonal antibody, and most likely during the “honeymoon” in human disease, are recovered β-cells that had been degranulated but present at the time of diagnosis of diabetes. CONCLUSIONS— Residual β-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 β-cells.

β-Cell regeneration: the pancreatic intrinsic faculty

“…This versatility could be used to trigger cell reprogramming in diabetes, but more mechanistic information will be required before the endogenous capacity of the pancreas to generate new b-cells can be exploited. For example, diverse molecules including circulating gut hormones and local growth factors, or cytokines in autoimmune or inflammatory conditions, can modulate regeneration [78,79] (Box 2).…”

Detection of β cell death in diabetes using differentially methylated circulating DNA

“…In T1D, killing of β cells and subsequent presentation with hyperglycemia takes weeks in the nonobese diabetic (NOD) mouse model of T1D and possibly years in humans (1). Hyperglycemia occurs when the majority of β cells have been destroyed, providing only limited options for therapy (2,3).…”

Beta-Cell Function and Failure in Type 1 Diabetes

“…Together with an initial loss of beta-cell function, the inflammatory process found in type 1 diabetes appears to stimulate beta-cell proliferation during the first stage of the disease. An increase in beta-cell mass may maintain metabolic demands for the period before the development of hyperglycemia, but it may also expose more and new epitopes, favoring and increasing the autoimmune destruction (Akirav, E. et al 2008). Given the important role of the beta-cell during the initiating and progression stages of insulitis that may lead to type 1 diabetes, current research is being directed toward maintenance and improvement of beta-cell function and mass before and during the inflammatory process, establishing important therapeutic targets.…”

“…Given the important role of the beta-cell during the initiating and progression stages of insulitis that may lead to type 1 diabetes, current research is being directed toward maintenance and improvement of beta-cell function and mass before and during the inflammatory process, establishing important therapeutic targets. New therapeutic approaches suggest that using combinatory treatments comprising a first immune intervention, followed by stimulation of beta-cell proliferation and function (perhaps with GLP-1-receptor agonists), and maintenance of normal glucose levels, together with the already used immunomodulatory therapy, may help not only to stop the progression of the disease, but even to recover the remaining beta-cell mass and function (Akirav, E. et al 2008;Weir, G.C. & Bonner-Weir, S. 2010).…”