Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice

Journal article


Millar, P., Pathak, N., Parthsarathy, V., Bjourson, A.J., O'Kane, M., Pathak, V., Moffett, R.C., Flatt, P.R. and Gault, V.A. 2017. Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. The Journal of Endocrinology. 234 (3), pp. 255-267. https://doi.org/10.1530/joe-17-0263
AuthorsMillar, P., Pathak, N., Parthsarathy, V., Bjourson, A.J., O'Kane, M., Pathak, V., Moffett, R.C., Flatt, P.R. and Gault, V.A.
Abstract

This study assessed the metabolic and neuroprotective actions of the sodium glucose cotransporter-2 inhibitor dapagliflozin in combination with the GLP-1 agonist liraglutide in dietary-induced diabetic mice. Mice administered low-dose streptozotocin (STZ) on a high-fat diet received dapagliflozin, liraglutide, dapagliflozin-plus-liraglutide (DAPA-Lira) or vehicle once-daily over 28 days. Energy intake, body weight, glucose and insulin concentrations were measured at regular intervals. Glucose tolerance, insulin sensitivity, hormone and biochemical analysis, dual-energy X-ray absorptiometry densitometry, novel object recognition, islet and brain histology were examined. Once-daily administration of DAPA-Lira resulted in significant decreases in body weight, fat mass, glucose and insulin concentrations, despite no change in energy intake. Similar beneficial metabolic improvements were observed regarding glucose tolerance, insulin sensitivity, HOMA-IR, HOMA-β, HbA1c and triglycerides. Plasma glucagon, GLP-1 and IL-6 levels were increased and corticosterone concentrations decreased. DAPA-Lira treatment decreased alpha cell area and increased insulin content compared to dapagliflozin monotherapy. Recognition memory was significantly improved in all treatment groups. Brain histology demonstrated increased staining for doublecortin (number of immature neurons) in dentate gyrus and synaptophysin (synaptic density) in stratum oriens and stratum pyramidale. These data demonstrate that combination therapy of dapagliflozin and liraglutide exerts beneficial metabolic and neuroprotective effects in diet-induced diabetic mice. Our results highlight important personalised approach in utilising liraglutide in combination with dapagliflozin, instead of either agent alone, for further clinical evaluation in treatment of diabetes and associated neurodegenerative disorders.

Keywordsdapagliflozin; diabetes; GLP-1; glucagon; liraglutide
Year2017
JournalThe Journal of Endocrinology
Journal citation234 (3), pp. 255-267
Publisherbioscientifica
ISSN1479-6805
0022-0795
Digital Object Identifier (DOI)https://doi.org/10.1530/joe-17-0263
Web address (URL)http://europepmc.org/abstract/med/28611211
https://pure.ulster.ac.uk/en/publications/metabolic-and-neuroprotective-effects-of-dapagliflozin-and-liragl-2
Output statusPublished
Publication dates13 Jun 2017
Publication process dates
Deposited26 May 2022
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