GLUCOSE REGULATION OF DIPEPTIDYL PEPTIDASE IV GENE EXPRESSION IS MEDIATED BY HEPATOCYTE NUCLEAR FACTOR‐1α IN EPITHELIAL INTESTINAL CELLS

Abstract

1. Dipeptidyl peptidase IV (DPP-IV) is a new drug target in the treatment of Type 2 diabetes. Dipeptidyl peptidase IV enzyme activity is significantly altered in Type 2 diabetic patients with hyperglycaemia, but the underlying molecular mechanisms remain unclear. 2. The first aim of the present study was to clarify whether glucose regulates DPP-IV enzyme activity. To address this, DPP-IV gene expression and enzyme activity were measured in Caco2 cells cultured in the presence of low (2.5 mmol/L) or high (16.7 mmol/L) concentrations of glucose. We observed that high glucose inhibited DPP-IV gene expression and enzyme activity. 3. The second aim of the present study was to investigate whether hepatocyte nuclear factor (HNF)-1alpha contributes to glucose regulation of DPP-IV gene expression. To explore this question, associations between the gene expression of DPP-IV and HNF-1alpha were examined in Caco-2 cells cultured in the presence of low (2.5 mmol/L) or high (16.7 mmol/L) glucose. We found that the pattern of glucose-regulated DPP-IV gene expression is similar to that of HNF-1alpha. Moreover, to elucidate whether glucose regulation of DPP-IV gene expression is affected when HNF-1alpha is inhibited, we produced two stable cell lines in which a dominant-negative mutant HNF-1alphaR271G or basic vectors were stably expressed. We found that glucose regulation of DPP-IV gene expression was compromised in HNF-1alphaR271G cells, but was well maintained in basic vector cells. 4. These results suggest that glucose regulation of DPP-IV gene expression is mediated by HNF-1alpha.