Novel Approaches to Restore Pancreatic Beta-Cell Mass and Function.

Beta-cell dysfunction and beta-cell death are critical events in the development of type 2 diabetes mellitus (T2DM). Therefore, the goals of modern T2DM management have shifted from merely restoring normoglycemia to maintaining or regenerating beta-cell mass and function. In this review we summarize current and novel approaches to achieve these goals, ranging from lifestyle interventions to N-methyl-D-aspartate receptor (NMDAR) antagonism, and discuss the mechanisms underlying their effects on beta-cell physiology and glycemic control. Notably, timely intervention seems critical, but not always strictly required, to maximize the effect of any approach on beta-cell recovery and disease progression. Conventional antidiabetic medications are not disease-modifying in the sense that the disease does not progress or reoccur while on treatment or thereafter. More invasive approaches, such as bariatric surgery, are highly effective in restoring normoglycemia, but are reserved for a rather small proportion of obese individuals and sometimes associated with serious adverse events. Finally, we recapitulate the broad range of effects mediated by peripheral NMDARs and discuss recent evidence on the potential of NMDAR antagonists to be developed as a novel class of antidiabetic drugs. In the future, a more refined assessment of disease risk or disease subtype might enable more targeted therapies to prevent or treat diabetes.