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Mechanisms of Glucose-Induced Secretion of Pancreatic-Derived Factor (PANDER or FAM3B) in Pancreatic ß-Cells

From the Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Pancreatic-derived factor (PANDER) is an islet-specific cytokine present in both pancreatic - and ß-cells, which, in vitro, induces ß-cell apoptosis of primary islet and cell lines. In this study, we investigated whether PANDER is secreted by pancreatic - and ß-cells and whether PANDER secretion is regulated by glucose and other insulin secretagogues. In mouse-derived insulin-secreting ß-TC3 cells, PANDER secretion in the presence of stimulatory concentrations of glucose was 2.8 ± 0.4-fold higher (P < 0.05) than without glucose. Insulin secretion was similarly increased by glucose in the same cells. The total concentration of secreted PANDER in the medium was 6–10 ng/ml (0.3–0.5 nmol/l) after a 24-h culture with glucose. L-Glucose failed to stimulate PANDER secretion in ß-TC3 cells. KCl stimulated PANDER secretion 2.1 ± 0.1-fold compared with control without glucose. An L-type Ca²⁺ channel inhibitor, nifedipine, completely blocked both glucose- or KCl-induced insulin and PANDER secretion. In rat-derived INS-1 cells, glucose (20 mmol/l) stimulated PANDER secretion 4.4 ± 0.9-fold, while leucine plus glutamine stimulated 4.4 ± 0.7-fold compared with control without glucose. In mouse islets overexpressing PANDER, glucose (20 mmol/l) stimulated PANDER secretion 3.2 ± 0.5-fold (P < 0.05) compared with basal (3 mmol/l glucose). PANDER was also secreted by -TC3 cells but was not stimulated by glucose. Mutations of cysteine 229 or of cysteines 91 and 229 to serine, which may form one disulfide bond, and truncation of the COOH-terminus or NH₂-terminus of PANDER all resulted in failure of PANDER secretion, even though these mutant or truncated PANDERs were highly expressed within the cells. In conclusion, we found that 1) PANDER is secreted from both pancreatic - and ß-cells, 2) glucose stimulates PANDER secretion dose dependently in ß-cell lines and primary islets but not in -cells, 3) PANDER is likely cosecreted with insulin via the same regulatory mechanisms, and 4) structure and conformation is vital for PANDER secretion.

Abbreviations: CCH, carbachol; FBS, fetal bovine serum; IFN, interferon; IL, interleukin; KRBB, Krebs-Ringer bicarbonate buffer; PANDER, pancreatic-derived factor (or FAM3B); TBST, Tris-buffered saline with Tween; TNF, tumor necrosis factor

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