β Cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood
Anne-Laure Castell, Clara Goubault, Mélanie Ethier, Grace Fergusson, Caroline Tremblay, Marie Baltz, Dorothée Dal Soglio, Julien Ghislain, Vincent Poitout
Anne-Laure Castell, Clara Goubault, Mélanie Ethier, Grace Fergusson, Caroline Tremblay, Marie Baltz, Dorothée Dal Soglio, Julien Ghislain, Vincent Poitout
View: Text | PDF
Research Article Endocrinology Metabolism

β Cell mass expansion during puberty involves serotonin signaling and determines glucose homeostasis in adulthood

Abstract

Puberty is associated with transient insulin resistance that normally recedes at the end of puberty; however, in overweight children, insulin resistance persists, leading to an increased risk of type 2 diabetes. The mechanisms whereby pancreatic β cells adapt to pubertal insulin resistance, and how they are affected by the metabolic status, have not been investigated. Here, we show that puberty is associated with a transient increase in β cell proliferation in rats and humans of both sexes. In rats, β cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted β cell proliferation, suggesting the implication of a circulating factor. In pubertal rat islets, expression of genes of the GH/serotonin (5-hydroxytryptamine [5-HT]) pathway underwent changes consistent with a proliferative effect. Inhibition of the pro-proliferative 5-HT receptor isoform HTR2B blocked the increase in β cell proliferation in pubertal islets ex vivo and in vivo. Peripubertal metabolic stress blunted β cell proliferation during puberty and led to altered glucose homeostasis later in life. This study identifies a role of GH/GH receptor/5-HT/HTR2B signaling in the control of β cell mass expansion during puberty and identifies a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.

Authors

Anne-Laure Castell, Clara Goubault, Mélanie Ethier, Grace Fergusson, Caroline Tremblay, Marie Baltz, Dorothée Dal Soglio, Julien Ghislain, Vincent Poitout

×

Figure 4

Pubertal but not prepubertal serum stimulated β cell proliferation in isolated rat and human islets.

Options: View larger image (or click on image) Download as PowerPoint
Pubertal but not prepubertal serum stimulated β cell proliferation in is...
(A and B) Male rat islets were isolated at puberty were exposed to prepubertal (Weaning), pubertal (Puberty), or adult rat serum for 72 hours, and β and α cell proliferation was assessed by flow cytometry following staining for EdU and C-peptide (CPEP) or glucagon (GCG), respectively. Both β (A) and α (B) cell proliferation were presented as the fold-change of the percentage of EdU+CPEP+ or EdU+GCG+ cells over CPEP+ or GCG+ cells, respectively, over the control condition (Weaning serum) (n = 5–8). (C and D) Adult human islets were exposed to sex-matched prepubertal (4–8 years) or pubertal (11–14 years) human male (black square) or female (red circle) serum (n = 6) or to Harmine (10 μM) in the presence of human AB serum (n = 6) for 72 hours, and β and α cell proliferation were assessed by flow cytometry following staining for EdU and insulin (INS) or GCG, respectively. Both β (C) and α (D) cell proliferation were presented as the fold-change of the percentage of EdU+INS+ or EdU+GCG+ cells over INS+ or GCG+ cells, respectively, over the control condition (prepubertal serum and AB serum, respectively). Data represent individual values and are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.005 following 1-way ANOVA with Tukey’s multiple-comparison test (A and B) or following unpaired Student’s t test (C and D).