Role of $\beta$-cell serotonin in the proliferation of $\beta$-cell during perinatal period and the development of diabetes

Abstract

Part I. The Role of Serotonin in Perinatal $\beta$-cell Proliferation and Proper Mass AchievementThe physiological role of serotonin in adult $\beta$-cell has been well known during the last decade. It amplifies $\beta$-cell proliferation during pregnancy, and intensifies insulin secretion in pregnancy and an insulin resistance state. It has been known that serotonin appears in $\beta$-cell during perinatal period. However, the physiological role of serotonin in that period has not been clarified yet. Here, I proved the role of serotonin in perinatal $\beta$-cell proliferation. First, I confirmed the up-and-down change pattern of serotonin in $\beta$-cell and Tph1 in pancreas during perinatal period. Next, I generated $\beta$-cell-specific Tph1 and Htr2b knockout mice. Both of them showed decreased $\beta$-cell proliferation and mass without any change in pancreas weight at perinatal day 0. The effect of $\beta$-cell specific Tph1 and Htr2b knockout continued till adulthood to have lower $\beta$-cell mass. It was clear that definite upstream of Tph1 was Stat5 while it was not with respect to prolactin receptor. Taken together, Tph1 and its product serotonin increases to proliferate $\beta$-cell during perinatal period through downstream signal, Htr2b, given the upstream signal from Stat5.Part II. Lack of Serotonin in $\beta$-cell and the Development of Diabetes in AdulthoodHere, I proved that the lack of serotonin or its downstream Htr2b during perinatal period lingers till adulthood and leads glucose intolerance. The glucose intolerance was not combined with insulin resistance or weight gain. Insulin secretion was decreased in mice of $\beta$-cell specific Tph1 or Htr2b knockout. Individual islet insulin secretion was not different from normal islet in $\beta$-cell specific Tph1 knockout, which means that the decreased insulin secretion in a mouse depends on the decreased $\beta$-cell mass. Both of knockout did not show any immaturities of $\beta$-cell. Both of knockout also showed normal islet structure. In human, absence of serotonin signal was related with the occurrence of type 2 diabetes in old female. Collectively, serotonin proliferates $\beta$-cell during perinatal period thorough Htr2b which lingers till adulthood.