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

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 beta 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 beta cell proliferation in rats and humans of both sexes. In rats, beta cell proliferation correlated with a rise in growth hormone (GH) levels. Serum from pubertal rats and humans promoted beta 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 beta cell proliferation in pubertal islets ex vivo and in vivo. Peripubertal metabolic stress blunted beta 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 beta cell mass expansion during puberty and identifies a mechanistic link between pubertal obesity and the risk of developing type 2 diabetes.

Automated summary

Puberty is associated with transient insulin resistance, and beta cell proliferation is related to the rise in growth hormone levels. Changes in gene expression of the 5-hydroxytryptamine pathway are consistent with the proliferative effect. Inhibition of 5-HT receptor blocks the increase in beta cell proliferation during puberty.