ANALYSIS OF THE PANCREATIC BETA-CELL IN THE MOUSE WITH TARGETED DISRUPTION OF THE PANCREATIC BETA-CELL-SPECIFIC GLUCOKINASE GENE

This is the first systematic study on the pancreatic beta cell functio n in the heterozygous mouse with targeted disruption of the beta cell glucokinase gene. The hetetrozygotes' beta cell displayed the followin g characteristics: (1) impaired glucose sensitivity with normal glucos e responsiveness, (2) poor discrimination of alpha and beta glucose an omers, and (3) normal response to glucose in the presence of 25 mM Kand 150 mu M diazoxide. Both the first and the second phases of glucos e-stimulated insulin release were depressed, Although the heterozygote s were mildly hyperglycemic, insulin treatment further suppressed beta cell function, implying the beta cell glucose toxicity is not the cau se of impaired glucose sensitivity. The data are compatible with the g lucokinase glucose sensor concept inasmuch as glucose sensitivity is r educed in the heterozygotes' beta cell. The anomeric malaise and prese rvation of the ATP-sensitive K+ channel-independent glucose action wer e considered due to chronic hyperglycemia. (C) 1996 Academic Press, In c.