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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.

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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