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Research and Development

Liver glucose production in type 2 diabetes - AQP9: a novel target for therapy

Type 2 diabetics suffer from an over-production of sugar within the liver, which contributes to high blood glucose levels in patients. Normally, the liver produces glucose to supply organs during hunger periods, as a response to falling blood glucose levels. In diabetes patients this mechanism is dysregulated and always active, even at already high blood glucose. Glycerol is an important substrate for liver glucose production. Apoglyx has shown in animal models that inhibition of aquaporin-9 (AQP9) can reduce hepatic glucose production and whole body blood glucose.

AQP9 in inflammatory conditions

AQP9 has been validated as a drug target in several inflammatory conditions. These include the inflammatory response following myocardial infarction, as well as skin allergic dermatitis. AQP9 is expressed in several types of leukocytes, and augments a pro-inflammatory leukocyte phenotype.

Small molecule inhibitors for AQP9

Apoglyx has developed 191 compounds in the lead series of which 46 have drug-like properties consistent with oral administration. Several of the most promising candidates have been tested in-vivo and we are continuing a program of pharmacokinetics, pharmacology, including multi-dose administration in-vivo efficacy studies. The ultimate aim is to develop a once-daily, oral therapy for diabetes patients.

Publications

Spegel P, Chawade A, Nielsen S, Kjellbom P, Rützler M: Deletion of glycerol channel aquaporin-9 (Aqp9) impairs long-term blood glucose control in C57BL/6 leptin receptor-deficient (db/db) obese mice. Physiological Reports Published 28 September 2015 Vol. 3 no. e12538

Wacker SJ, Aponte-Santamaría C, Kjellbom P, Nielsen S, de Groot BL, Rützler M: The identification of novel, high affinity AQP9 inhibitors in an intracellular binding site. Molecular Membrane Biology 2013, 30(3):246-260.

Jelen S, Parm Ulhøi B, Larsen A, Frøkiær J, Nielsen S, Rützler M. AQP9 Expression in Glioblastoma Multiforme Tumors Is Limited to a Small Population of Astrocytic Cells and CD15+/CalB+ Leukocytes. PLoS ONE 8(9): e75764.

Jelen S, Wacker S, Aponte-Santamaría C, Skott M, Rojek A, Johanson U, Kjellbom P, Nielsen S, de Groot BL, Rützler M: Aquaporin-9 Protein Is the Primary Route of Hepatocyte Glycerol Uptake for Glycerol Gluconeogenesis in Mice. Journal of Biological Chemistry 2011, 286(52):44319-44325.
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