RIBOZYME-MEDIATED ATTENUATION OF PANCREATIC BETA-CELL GLUCOKINASE EXPRESSION IN TRANSGENIC MICE RESULTS IN IMPAIRED GLUCOSE-INDUCED INSULIN-SECRETION

Phosphorylation of glucose to glucose 6-phosphate by glucokinase (GK; EC 2.7.1.2) serves as a glucose-sensing mechanism for regulating insul in secretion in beta cells. Recent findings of heterozygous GK gene mu tations in patients with maturity-onset diabetes of the young (MODY), a form of type II (non-insulin-dependent) diabetes characterized by au tosomal dominant inheritance, have raised the possibility that a decre ase in beta-cell GK activity may impair the insulin secretory response of these cells to glucose. To generate an animal model for MODY we ha ve expressed in transgenic mice a GK antisense RNA with a ribozyme ele ment under control of the insulin promoter. Mice in two independent li neages had about 30% of the normal islet GK activity. Insulin release in response to glucose from in situ-perfused pancreas was impaired; ho wever, the plasma glucose and insulin levels of the mice remained norm al. These mice are likely to be predisposed to type II diabetes and ma y manifest increased susceptibility to genetic and environmental diabe togenic factors. They provide an animal model for studying the interac tion of such factors with the reduced islet GK activity.