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Diabetologia. 2008 Jan;51(1):147-54. Epub 2007 Nov 10.

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules.

Author information

1
Department of Endocrinology, Diabetes and Rheumatology, University Hospital Düsseldorf, Moorenstr. 5, 40225, Dusseldorf, Germany. sven.schinner@uni-duesseldorf.de

Abstract

AIMS/HYPOTHESIS:

Adipocytes secrete signalling molecules that elicit responses from target cells, including pancreatic beta cells. Wnt signalling molecules have recently been identified as novel adipocyte-derived factors. They also regulate insulin secretion in pancreatic beta cells and the cell cycle. The aim of this study was to investigate the effect of adipocyte-derived Wnt signalling molecules on insulin secretion and beta cell proliferation.

METHODS:

Human adipocytes were isolated to generate fat cell-conditioned medium (FCCM). Ins-1 cells were stimulated with FCCM and transiently transfected with reporter genes. Proliferation assays using [3H]thymidine incorporation were carried out in Ins-1 cells and primary islet cells. Insulin secretion from primary islets was assessed by radioimmunoassay. Gene expression in primary islets was assessed by Taqman PCR.

RESULTS:

Treatment with human FCCM increased the transcription of a T cell-specific transcription factor reporter gene (TOPFLASH) in Ins-1 cells (241%, p < 0.05). FCCM induced the proliferation of Ins-1 cells (1.8 fold, p < 0.05) and primary mouse islet cells (1.6 fold, p < 0.05). Antagonizing Wnt signalling with secreted Frizzled-related protein 1 (FRP-1) inhibited the proliferative effect induced by Wnt3a and FCCM on Ins-1 cells by 49 and 41%, respectively. In addition, FCCM led to a twofold (p < 0.05) induction of cyclin D1 promoter activity in Ins-1 cells. Furthermore, FCCM stimulated insulin secretion (204% of controls, p > 0.05) in primary mouse islets, and this stimulation was inhibited by sFRP-1. At a molecular level, canonical Wnt signalling induced glucokinase gene transcription in a peroxisome proliferator-activated receptor gamma-dependent fashion, thereby defining the glucokinase gene as a novel Wnt target gene.

CONCLUSIONS/INTERPRETATION:

Taken together, these data show that adipocyte-derived Wnt signalling molecules induce beta cell proliferation and insulin secretion in vitro, suggesting a novel mechanism linking obesity to hyperinsulinaemia.

PMID:
17994217
DOI:
10.1007/s00125-007-0848-0
[Indexed for MEDLINE]
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