Abstract
Recently, mutations in the glucokinase gene have been found in patients with maturity-onset diabetes of the young (MODY), which has raised the possibility that a decrease in glucokinase activity may impair the glucose-stimulated insulin secretion in β cells, leading to diabetes. To test the effect of a reduced glucokinase activity in β cells on β-cell function and their ability to maintain glucose homeostasis, we generated transgenic mice expressing an anti-sense glucokinase mRNA in β cells. The transgene construct contains the human insulin promoter linked to a 5' part of glucokinase cDNA of -280 by long including the start codon and is designed to produce an RNA that hybridizes specifically to glucokinase mRNA molecules, resulting in reduced levels of glucokinase mRNA in cells expressing the transgene. Fourteen mouse lineages were generated. Their fasting blood glucose levels were significantly higher than those of negative littermates. Studies are underway to determine the glucokinase activity in islets isolated from these mice. These mice are likely to provide insights into the role of glucokinase in glucose sensing in β cells under various physiological conditions. These results also demonstrate the potential of applying anti-sense RNA for cell-specific reduction in gene expression in vivo.
