Impaired regulation of hepatic fructose-1,6-bisphosphatase in the New Zealand obese mouse: An acquired defect

• Published in: Metabolism, clinical and experimental clinical and experimental, 1996, Vol.45 (5), p.622-626
• Main Authors: Andrikopoulos, Sofianos, Rosella, Gennaro, Kaczmarczyk, Stan J., Zajac, Jeffrey D., Proietto, Joseph
• Format: Article
• Language: English
• Subjects: age differences; Biological and medical sciences; diabetes mellitus; Diabetes. Impaired glucose tolerance; elevated protein levels; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; enzyme activity; enzyme inhibitors; Etiopathogenesis. Screening. Investigations. Target tissue resistance; fructose-2,6-bisphosphate; fructose-bisphosphatase; genetic models; gluconeogenesis; liver; Medical sciences; messenger RNA; mice; noninsulin-dependent diabetes mellitus; obesity; polygenic models; regulation; sugar phosphates
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/S0026-0495(96)90034-7

Increased hepatic glucose production, a feature of (non—insulin-dependent diabetes mellitus [NIDDM] is present at an early age in the New Zealand Obese (NZO) mouse and is associated with impaired suppression of the gluconeogenic enzyme, fructose-1,6-bisphosphatase (FBPase). The aim of this study was to further characterize the abnormality in the regulation of hepatic FBPase in NZO mice versus New Zealand Chocolate (NZC) control mice. At 20 weeks of age, NZO mice have elevated FBPase activity (65.3 ± 7.9 v 46.7 ± 5.0 μmol/min/mg protein, P = .07) and protein levels (31.7 ± 3.1 v 22.5 ± 2.8 arbitrary units, P < .05), but not mRNA levels (0.18 ± 0.03 v 0.16 ± 0.03 arbitrary units). Elevated FBPase activity and protein levels in NZO mice were also shown at 4 to 6 weeks of age, but not in 1-day-old mice, suggesting that the increase occurs between birth and weaning. The K m of the enzyme was the same in NZO and NZC mice (3.7 ± 0.5 v 5.0 ± 0.9 μmol/L, NZO v NZC). The regulation of FBPase by the competitive inhibitor, fructose-2,6-bisphosphate ([Fru(2,6)P z] 5 μmol/L) measured over a range of substrate concentrations (2.5 to 80 μmol/L) was similar between NZO and control mice ( K m in the presence of Fru(2,6)P z, 10.8 ± 1.9 v 13.2 ± 3.3 μmol/L, NZO v NZC). It is concluded that increased FBPase activity in the NZO mouse is due to elevated protein levels, and that this appears to be due to a failure of the normal decrease that occurs following birth in control animals.