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Functional Maturation of Fetal Porcine ß-Cells by Glucagon-Like Peptide 1 and Cholecystokinin

Diabetes Transplant Unit, Prince of Wales Hospital and University of New South Wales, Sydney, New South Wales 2031, Australia

Address all correspondence and requests for reprints to: Bernard E. Tuch, M.D., Ph.D., Diabetes Transplant Unit, Prince of Wales Hospital, High Street, Randwick, New South Wales 2031, Australia. E-mail: b.tuch{at}unsw.edu.au.

Fetal ß-cells are immature in their responsiveness to glucose, and maturation occurs after oral feeding commences at birth. The incretin hormones glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are known to be released from the gut in response to oral feeding and enhance insulin secretion from pancreatic ß-cells. We hypothesized that these fetal ß-cells would mature in their glucose responsiveness if they were previously exposed to incretins. We exposed fetal pig islet-like cell clusters (ICCs) to 100 nM GLP-1, 5 µM CCK, or 10 mM nicotinamide (NIC; a positive control) for 6 h and demonstrated 3- and 1.7-fold increases in glucose-induced insulin secretion for GLP-1 and CCK, respectively. This effect did not reach statistical significance if the ICCs were exposed to the incretins for 3 d. However, exposure for 4 d enhanced formation of ß-cells from undifferentiated cells, from 8 ± 1% (controls) to 17 ± 3% for GLP-1, 20 ± 4% for CCK, and 15 ± 1 for NIC (P < 0.001). ICCs exposed to GLP-1 for 3 d also showed a 1.9-fold increase in the intensity of PDX-1⁺ cells, as assessed by semiquantitative fluorescent immunocytochemistry. Exposure of ICCs to incretins for 3 d did not show any increase in size of the islet clusters. ICCs exposed to either incretin as well as controls were transplanted into severe combined immunodeficient mice and examined at 1 and 2 months. We found a significant increase in the number of ß-cells in the GLP-1- and NIC-treated groups compared with the untreated controls or CCK. Perfusion of these grafts at 2 months showed that ICCs previously exposed to GLP-1, CCK, and NIC (but not controls), were functional and mature. In conclusion, GLP-1 and CCK have a dual effect on fetal pig ICCs, causing maturation of glucose-induced insulin secretion from ß-cells as well as enhancement of differentiation from undifferentiated precursors.

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