Adipocytes induce insulin secretion and glucokinase gene transcription in pancreatic beta-cells through the Wnt-signalling pathway

Objectives: Non-diabetic obesity is associated with insulin resistance and hyperinsulinemia. It is not clear which factors regulate insulin secretion in this situation to maintain normal blood glucose levels. Therefore, we investigated direct effects of human fat-cells on pancreatic beta-cells.

Methods: Isolation of human primary adipocytes to generate fat-cell conditioned-medium (FCCM). Transient transfections of insulin-producing Ins-1 cells using reporter-gene assays. Isolation of primary murine islets. Radio-immuno-assay (RIA) to measure insulin secretion.

Results: We investigated the BMI, fasting glucose, and fasting insulin levels in 1600 normoglycemic obese subjects and found an increase in insulin levels with the BMI. Insulin levels almost doubled from 12.03microU/ml (BMI<30kg/m²) to 20.42microU/ml (BMI>40kg/m²) with increasing obesity. In order to investigate direct effects of adipocytes on pancreatic beta-cell function in vitro we used human fat-cell conditioned-medium to treat Ins-1 cells and murine primary islets, respectively. In previous studies we found human adipocytes to secrete Wnt-signalling molecules (Schinner et al. Int. J. Obesity, in press). Therefore, we tested the effect of FCCM on canonical Wnt-signalling in Ins-1 cells. FCCM led to a 2.5-fold increase in the transcription of a canonical Wnt-reporter-gene (TOPFLASH). As Wnt-signalling has been shown to regulate insulin-secretion, we treated primary murine islets with FCCM. Insulin secretion increased to 195% after stimulation of islets with FCCM as compared to untreated controls. On the molecular level, beta-catenin activated glucokinase gene transcription in a PPARgamma-dependent manner, defining the glucokinase gene as a target for canonical Wnt-signalling.

Conclusions: Our data demonstrate a direct effect of adipocyte-derived Wnt-signalling molecules on pancreatic beta-cell function in vitro. This interaction might represent a novel mechanism for adipocyte deposition to lead to increased insulin secretion.