FGF1 Mediates Overnutrition-Induced Compensatory β-Cell Differentiation.

Li M, Page-McCaw P, Chen W
Diabetes. 2016 65 (1): 96-109

PMID: 26420862 · PMCID: PMC4686947 · DOI:10.2337/db15-0085

Increased insulin demand resulting from insulin resistance and/or overnutrition induces a compensatory increase in β-cell mass. The physiological factors responsible for the compensation have not been fully characterized. In zebrafish, overnutrition rapidly induces compensatory β-cell differentiation through triggering the release of a paracrine signal from persistently activated β-cells. We identified Fgf1 signaling as a key component of the overnutrition-induced β-cell differentiation signal in a small molecule screen. Fgf1 was confirmed as the overnutrition-induced β-cell differentiation signal, as inactivation of fgf1 abolished the compensatory β-cell differentiation. Furthermore, expression of human FGF1 solely in β-cells in fgf1(-/-) animals rescued the compensatory response, indicating that β-cells can be the source of FGF1. Additionally, constitutive secretion of FGF1 with an exogenous signal peptide increased β-cell number in the absence of overnutrition. These results demonstrate that fgf1 is necessary and FGF1 expression in β-cells is sufficient for the compensatory β-cell differentiation. We further show that FGF1 is secreted during prolonged activation of cultured mammalian β-cells and that endoplasmic reticulum stress acts upstream of FGF1 release. Thus, the recently discovered antidiabetes function of FGF1 may act partially through increasing β-cell differentiation.

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

MeSH Terms (16)

Animals Animals, Genetically Modified Cell Differentiation Cell Line, Tumor Endoplasmic Reticulum Stress Fibroblast Growth Factor 1 Flow Cytometry Humans Insulin-Secreting Cells Overnutrition Rats Reverse Transcriptase Polymerase Chain Reaction RNA, Messenger Signal Transduction Zebrafish Zebrafish Proteins

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