Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice

Paul Millar, Nupur M Pathak, Vadivel Parthsarathy, Anthony Bjourson, Maurice O'Kane, R Charlotte Moffett, Peter R Flatt, Varun Pathak

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Abstract

This study assessed the metabolic and neuroprotective actions of the sodium glucose co-transporter-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.
Original languageEnglish
JournalJournal of Endocrinology
Early online date13 Jun 2017
Publication statusEarly online date - 13 Jun 2017

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Neuroprotective Agents
Glucose
Glucagon-Like Peptide 1
Insulin
Energy Intake
Sodium-Glucose Transporter 2
Insulin Resistance
Histology
Diabetic Diet
Body Weight
Symporters
Synaptophysin
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Liraglutide
Densitometry
Dentate Gyrus
Brain
High Fat Diet
Therapeutics
Streptozocin

Cite this

Millar, P., Pathak, N. M., Parthsarathy, V., Bjourson, A., O'Kane, M., Moffett, R. C., ... Pathak, V. (2017). Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. Journal of Endocrinology.
Millar, Paul ; Pathak, Nupur M ; Parthsarathy, Vadivel ; Bjourson, Anthony ; O'Kane, Maurice ; Moffett, R Charlotte ; Flatt, Peter R ; Pathak, Varun. / Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. In: Journal of Endocrinology. 2017.
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Millar, P, Pathak, NM, Parthsarathy, V, Bjourson, A, O'Kane, M, Moffett, RC, Flatt, PR & Pathak, V 2017, 'Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice', Journal of Endocrinology.

Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. / Millar, Paul; Pathak, Nupur M; Parthsarathy, Vadivel; Bjourson, Anthony; O'Kane, Maurice; Moffett, R Charlotte; Flatt, Peter R; Pathak, Varun.

In: Journal of Endocrinology, 13.06.2017.

Research output: Contribution to journalArticle

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AU - Millar, Paul

AU - Pathak, Nupur M

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AU - O'Kane, Maurice

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AU - Flatt, Peter R

AU - Pathak, Varun

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N2 - This study assessed the metabolic and neuroprotective actions of the sodium glucose co-transporter-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.

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Millar P, Pathak NM, Parthsarathy V, Bjourson A, O'Kane M, Moffett RC et al. Metabolic and neuroprotective effects of dapagliflozin and liraglutide in diabetic mice. Journal of Endocrinology. 2017 Jun 13.