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Inhibition of Hepatic Gluconeogenesis and Enhanced Glucose Uptake Contribute to the Development of Hypoglycemia in Mice Bearing Interleukin-1ß- Secreting Tumor

Department of Medicine (S.M., S.N., D.P., T.C.-S.), Hadassah University Hospital, Mount Scopus, and Departments of Biochemistry (V.B.) and Pathology (O.P.), Hadassah University Hospital, Jerusalem 91240, Israel; and Division of Pediatric Surgery (J.S.), Medical College of Wisconsin, Milwaukee, Wisconsin 53201

Address all correspondence and requests for reprints to: Tova Chajek-Shaul, M.D., Department of Medicine, Hadassah University Hospital, Mount Scopus, P.O. Box 24035, Jerusalem 91240, Israel. E-mail: chajek{at}hadassah.org.il.

Mice bearing IL-1ß-secreting tumor were used to study the chronic effect of IL-1ß on glucose metabolism. Mice were injected with syngeneic tumor cells transduced with the human IL-1ß gene. Serum IL-1ß levels increased exponentially with time. Secretion of IL-1ß from the developed tumors was associated with decreased food consumption, reduced body weight, and reduced blood glucose levels. Body composition analysis revealed that IL-1ß caused a significant loss in fat tissue without affecting lean body mass and water content. Hepatic phosphoenolpyruvate carboxykinase and glucose-6-phosphatase activities and mRNA levels of these enzymes were reduced, and 2-deoxy-glucose uptake by peripheral tissues was enhanced. mRNA levels of glucose transporters (Gluts) in the liver were determined by real-time PCR analysis. Glut-3 mRNA levels were up-regulated by IL-1ß. Glut-1 and Glut-4 mRNA levels in IL-1ß mice were similar to mRNA levels in pair-fed mice bearing nonsecreting tumor. mRNA level of Glut-2, the major Glut of the liver, was down-regulated by IL-1ß. We concluded that both decreased glucose production by the liver and enhanced glucose disposal lead to the development of hypoglycemia in mice bearing IL-1ß-secreting tumor. The observed changes in expression of hepatic Gluts that are not dependent on insulin may contribute to the increased glucose uptake.

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