4.7 Article

No direct effect of SGLT2 activity on glucagon secretion

期刊

DIABETOLOGIA
卷 62, 期 6, 页码 1011-1023

出版社

SPRINGER
DOI: 10.1007/s00125-019-4849-6

关键词

Alpha cells; Endogenous glucose production; Glucagon secretion; SGLT2; Sodium-glucose cotransporter 2 inhibitors; Sodium-glucose cotransporter-2; Type 2 diabetes

资金

  1. Lundbeck foundation (Lundbeckfonden) [R264-2017-3492]
  2. AstraZeneca postdoc programme
  3. Lundbeck foundation [R289-2018-1026]
  4. Novo Nordisk Center for Basic Metabolic Research (Novo Nordisk Foundation, Denmark)
  5. Novo Nordisk Foundation [NNF15OC0016574]
  6. European Research Council [695069]
  7. European Union's Seventh Framework Programme for Research, Technological Development, and Demonstration Activities [266408]
  8. Swedish Research Council [2009-1039, 349-2006-237, 2017-00862]
  9. Swedish Foundation for Strategic Research [IRC15-0067]
  10. MRC [MRC_MC_UU_12012/3]
  11. Wellcome [106262/Z/14/Z, 106263/Z/14/Z]
  12. MRC [MC_UU_00014/3, MC_UU_12012/3] Funding Source: UKRI

向作者/读者索取更多资源

Aims/hypothesis Sodium-glucose cotransporter (SGLT) 2 inhibitors constitute a new class of glucose-lowering drugs, but they increase glucagon secretion, which may counteract their glucose-lowering effect. Previous studies using static incubation of isolated human islets or the glucagon-secreting cell line alpha-TC1 suggested that this results from direct inhibition of alpha cell SGLT1/2-activity. The aim of this study was to test whether the effects of SGLT2 on glucagon secretion demonstrated in vitro could be reproduced in a more physiological setting. Methods We explored the effect of SGLT2 activity on glucagon secretion using isolated perfused rat pancreas, a physiological model for glucagon secretion. Furthermore, we investigated Slc5a2 (the gene encoding SGLT2) expression in rat islets as well as in mouse and human islets and in mouse and human alpha, beta and delta cells to test for potential inter-species variations. SGLT2 protein content was also investigated in mouse, rat and human islets. Results Glucagon output decreased three- to fivefold within minutes of shifting from low (3.5 mmol/l) to high (10 mmol/l) glucose (4.0 +/- 0.5 pmol/15min vs 1.3 +/- 0.3 pmol/15min, p < 0.05). The output was unaffected by inhibition of SGLT1/2 with dapagliflozin or phloridzin or by addition of the SGLT1/2 substrate alpha-methylglucopyranoside, whether at low or high glucose concentrations (p = 0.29-0.99). Insulin and somatostatin secretion (potential paracrine regulators) was also unaffected. Slc5a2 expression and SGLT2 protein were marginal or below detection limit in rat, mouse and human islets and in mouse and human alpha, beta and delta cells. Conclusions/interpretation Our combined data show that increased plasma glucagon during SGLT2 inhibitor treatment is unlikely to result from direct inhibition of SGLT2 in alpha cells, but instead may occur downstream of their blood glucose-lowering effects.

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