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Research Abstracts Online
January 2008 - March 2009

University of Minnesota Twin Cities
College of Biological Sciences and Medical School
Department of Biochemistry, Molecular Biology, and Biophysics

PI: Alex J. Lange

Comparative Gene Expression Profiles in a Mouse Model

These researchers have developed a therapy to lower blood sugar in type 1 diabetic mice by overexpressing the bifunctional enzyme (BiF) 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PFK2/FBPase2) in the liver via adenovirus vectors (Ado-BiF-BPD). They have engineered the enzyme, which normally has two activities that both make and degrade the regulatory metabolite fructose-2,6-bisphosphate (F26BP), to be kinase dominant and raise F26BP levels. This has the metabolic effect of lowering blood glucose levels in these diabetic mice. They have also discovered that this elevation of F26BP had effects beyond changes in glucose flux, namely that high F26BP, in the absence of insulin, can induce the gene expression of glucokinase. This indicates that F26BP is involved in a signaling pathway that leads to changes in gene expression. Further evidence for F26BP signaling is seen in the activation (phosphorylation) of Akt, an intermediate kinase in the insulin- signaling pathway. F26BP signaling is distinct from insulin signaling, but has common signaling proteins. Although the expression of GK is an appropriate target for F26BP or insulin signaling, the researchers hypothesize that there are many other targets, and there is differential expression of these targets by insulin and F26BP. They are conducting gene microarray analysis under the conditions: type 1 diabetic mouse (Streptozotocin [STZ]-treated); STZ-mouse treated with insulin; and STZ-mouse treated with Ado-Bif-BPD (establishes the high F26BP state). With these analyses they will be able to determine not only the metabolic and signaling targets of high F26BP, but also the differences between insulin and F26BP signaling. This analysis will demonstrate proof of principle for targeting the bifunctional enzyme and may also lead to novel candidates for anti-diabetes therapies.

Group Member

Salmaan Khan, Graduate Student