Increased glucose production in mice overexpressing human fructose-1,6-bisphosphatase in the liver

Increased endogenous glucose production (EGP) predominantly from the liver is a characteristic feature of Type 2 diabetes, which positively correlates with fasting hyperglycemia. Gluconeogenesis is the biochemical pathway shown to significantly contribute to increased EGP in diabetes. Fructose-1,6-bisphosphatase (FBPase) is a regulated enzyme in gluconeogenesis that is increased in animal models of obesity and insulin resistance. However whether a specific increase in liver FBPase can result in increased EGP has not been shown. The objective of this study was to determine the role of upregulated liver FBPase in glucose homeostasis. To achieve this goal, we generated human liver FBPase transgenic mice under the control of the transthyretin promoter, using insulator sequences to flank the transgene and protect it from site-of-integration effects. This resulted in a liver-specific model as transgene expression was not detected in other tissues. Mice were studied under the following conditions - 1) at two ages (24 weeks and 1 year old); 2) following a 60 high-fat (HF) diet; and 3) when bred to homozygosity. Hemizygous transgenic mice had an approximately 3-fold increase in total liver FBPase mRNA with concomitant increases in FBPase protein and enzyme activity levels. Following HF feeding, hemizygous transgenics were glucose intolerant compared to negative littermates (p