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J Biol Chem, Vol. 274, Issue 32, 22517-22523, August 6, 1999

Hexokinase II-deficient Mice
PRENATAL DEATH OF HOMOZYGOTES WITHOUT DISTURBANCES IN GLUCOSE TOLERANCE IN HETEROZYGOTES

Sami Heikkinen^§, Marko Pietilä^§, Maria Halmekytö^§, Suvikki Suppola^§, Eija Pirinen^§, Samir S. Deeb^¶, Juhani Jänne^§, and Markku Laakso

From the  Department of Medicine, University of Kuopio, FIN-70211 Kuopio, Finland, the ^§ A. I. Virtanen Institute and Department of Biochemistry and Biotechnology, University of Kuopio, FIN-70211 Kuopio, Finland, and the ^¶ Departments of Medicine and Genetics, University of Washington, Seattle, Washington 98195

Type 2 diabetes is characterized by decreased rates of insulin-stimulated glucose uptake and utilization, reduced hexokinase II mRNA and enzyme production, and low basal levels of glucose 6-phosphate in insulin-sensitive skeletal muscle and adipose tissues. Hexokinase II is primarily expressed in muscle and adipose tissues where it catalyzes the phosphorylation of glucose to glucose 6-phosphate, a possible rate-limiting step for glucose disposal. To investigate the role of hexokinase II in insulin action and in glucose homeostasis as well as in mouse development, we generated a hexokinase II knock-out mouse. Mice homozygous for hexokinase II deficiency (HKII^/) died at approximately 7.5 days post-fertilization, indicating that hexokinase II is vital for mouse embryogenesis after implantation and before organogenesis. HKII^+/ mice were viable, fertile, and grew normally. Surprisingly, even though HKII^+/ mice had significantly reduced (by 50%) hexokinase II mRNA and activity levels in skeletal muscle, heart, and adipose tissue, they did not exhibit impaired insulin action or glucose tolerance even when challenged with a high-fat diet.

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