Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2017

Role of the sympathetic nervous system in regulation of the sodium glucose co-transporter 2. (#38)

Vance Matthews 1 2 , Rosemary Elliot 1 2 , Caroline Rudnicka 2 3 , Jana Hricova 1 2 , Lakshini Herat 1 2 , Markus Schlaich 1 2 4
  1. The University of Western Australia, Perth, WA, Australia
  2. Dobney Hypertension Centre, Perth, Western Australia, Australia
  3. Research Centre, Royal Perth Hospital, Perth, WA, Australia
  4. Royal Perth Hospital, Perth, Western Australia, Australia

Background: Sympathetic nervous system (SNS) activation is a common feature in obesity and type-2 diabetes and regulates glucose metabolism in organs including the kidneys. The sodium glucose co-transporter 2 (SGLT-2) mediates re-absorption of glucose from the renal proximal tubules in the kidney. SGLT-2 inhibitors have garnered attention due to their glucose lowering effects and may improve cardiovascular and renal outcomes.

Aims: Firstly, to investigate the hypothesis that SGLT-2 is up-regulated by norepinephrine (NE), the main neurotransmitter of the SNS. Secondly, we also aimed to determine whether SGLT-2 inhibition may limit SNS activity in vivo.

Methods: We used the human renal proximal tubule cell line, HK2. Cells were treated with NE at a range of concentrations and time-points. SGLT-2 expression in HK2 cells in response to treatment with NE was determined by immunocytochemistry and western blotting. IL-6 release was also determined by ELISA. We also performed studies to determine the influence of SGLT-2 inhibition on the SNS in vivo. Mice fed a high fat diet were oral gavaged with dapagliflozin (DAPA) and the expression of NE and the sympathetic neuron protein tyrosine hydroxylase was measured in the kidney and heart by immunohistochemistry.

Results: A marked increase in SGLT-2 and IL-6 expression in HK2 cells and translocation of SGLT2 to the cell surface could be demonstrated in response to NE treatment. In vivo, DAPA treatment resulted in marked glucosuria in high fat diet fed mice. Importantly, SGLT-2 inhibition in vivo, significantly reduced high fat diet induced elevations of NE and tyrosine hydroxylase in the kidney and heart.

Conclusions: Our in vitro and in vivo studies provide first evidence for an important cross-talk between the SNS and SGLT-2 regulation, which may not only account for SNS-induced alterations of glucose metabolism but may potentially contribute to cardiovascular and renal protection observed with SGLT2 inhibitors.   

  1. Elliott, R.H.,* Matthews, V.B.,* et al. (2016) Is it time to think about the sodium glucose co-transporter 2 sympathetically? Nephrology (Carlton). 21(4): 286-294. doi: 10.1111/nep.12620. (*R.H.E and V.B.M: equal contribution).
  2. Matthews et al. 2017. Role of the sympathetic nervous system in regulation of the sodium glucose co-transporter 2. J. Hypertension (in-press).