Function, Regeneration, and Proliferation of Pancreatic β-Cells Centered on NAD

The author retired from Iwate Medical University in March 2025 upon reaching mandatory retirement age. On this milestone occasion, I was given the opportunity to write a review article for Yakugaku Zasshi. This review primarily outlines research conducted under Professor Hiroshi Okamoto (now Professor Emeritus, Tohoku University) at the Department of Biochemistry, Graduate School of Medicine, Tohoku University, where I was affiliated before joining the Faculty of Pharmaceutical Sciences at Iwate Medical University. CD38 synthesizes cyclic adenosine diphosphate (ADP)-ribose using nicotinamide adenine dinucleotide (NAD) as a substrate, inducing insulin secretion from pancreatic β-cells via an increase in cytoplasmic calcium ion (Ca²⁺) concentration. Conversely, DNA damage to pancreatic β-cells activates poly (ADP-ribose) polymerase (PARP), promoting poly (ADP-ribosyl) ation. This depletes intracellular NAD, leading to pancreatic β-cell necrosis. Here, inhibiting PARP activity allows PARP to function as a transcription factor, enhancing the expression of the regeneration/proliferation factor RegI, leading to pancreatic β-cell regeneration and proliferation. Thus research findings from the Okamoto Laboratory suggest that in pancreatic β-cells, cell death, function, and regeneration/proliferation are closely interlinked, with NAD at the center. While NAD's role as a coenzyme is well-established, its physiological significance as a substrate for proteins such as sirtuins, CD38, and PARP, and its link to aging, have also been proposed. The Okamoto Laboratory's research on pancreatic β-cell function, death, and regeneration/proliferation centered on NAD represents pioneering work demonstrating NAD's critical importance in the living organism.