Effects of altered glucokinase gene copy number on blood glucose homoeostasis.

Introduction Glucokinase (GK) gene expression is essential for glucose homoeostasis. This high& hexokinase is expressed in both the liver and pancreatic P-cell [l-31, as well as in other rare neuraVneuroendocrine cell types that may also play a role in the regulation of glucose homoeostasis [4,5]. In humans, coding sequence mutations in the GK gene cause maturity-onset diabetes of the young, type 2 (MODY-2), a form of non-insulin-dependent diabetes mellitus [6-81. Since MODY-2 is inherited as an autosoma1 dominant heterozygous trait, its pathogenesis is thought to be due to reduced GK activity from the loss of one functional gene copy [7,9-111. Because it is not yet clear how diminished GK activity within these cell types actually causes diabetes, we and others have studied the consequences of altering the number of functional copies of the GK gene in mice ([12-141; K. D. Niswender, M. Shiota, C. Postic, T. L. Jetton, B. Bennett, D. Piston, S. Efrat, A. D. Chemington and M. A. Magnuson, unpublished work). Analysis of these mouse models provides new insights into the effects of perturbed GK gene expression on glucose homoeostasis.