Highly selective SGLT2 inhibitors suppress glucose uptake in alpha-TC1 cells, while glucagon secretion is not affected

Heerspink HJL, Stefánsson BV, Correa-Rotter R et al (2020) Dapagliflozin in patients with chronic kidney disease. N Engl J Med 383:1436–1446. https://doi.org/10.1056/NEJMoa2024816

Article  CAS  PubMed  Google Scholar 

Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373:2117–2128. https://doi.org/10.1056/NEJMoa1504720

Article  CAS  PubMed  Google Scholar 

Kanai Y, Lee WS, You G et al (1994) The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J Clin Invest 93:397–404. https://doi.org/10.1172/JCI116972

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sabolić I, Vrhovac I, Eror DB et al (2012) Expression of Na+-d-glucose cotransporter SGLT2 in rodents is kidney-specific and exhibits sex and species differences. Am J Physiol Cell Physiol 302:C1174–C1188. https://doi.org/10.1152/ajpcell.00450.2011

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vrhovac I, Balen Eror D, Klessen D et al (2015) Localizations of Na+-d-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflug Arch Eur J Physiol 467:1881–1898. https://doi.org/10.1007/s00424-014-1619-7

Article  CAS  Google Scholar 

Chen J, Williams S, Ho S et al (2010) Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diabetes Ther 1:57–92. https://doi.org/10.1007/s13300-010-0006-4

Article  CAS  PubMed  PubMed Central  Google Scholar 

Wright EM, Loo DDF, Hirayama BA (2011) Biology of human sodium glucose transporters. Physiol Rev 91:733–794. https://doi.org/10.1152/physrev.00055.2009

Article  CAS  PubMed  Google Scholar 

Merovci A, Solis-Herrera C, Daniele G et al (2014) Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 124:509–514. https://doi.org/10.1172/JCI70704

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ferrannini E, Muscelli E, Frascerra S et al (2014) Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 124:499–508. https://doi.org/10.1172/JCI72227

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhu X, Lin C, Li L et al (2021) SGLT2i increased the plasma fasting glucagon level in patients with diabetes: A meta-analysis. Eur J Pharmacol 903:174145. https://doi.org/10.1016/j.ejphar.2021.174145

Article  CAS  PubMed  Google Scholar 

Bonner C, Kerr-Conte J, Gmyr V et al (2015) Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med 21:512–517. https://doi.org/10.1038/nm.3828

Article  CAS  PubMed  Google Scholar 

Pedersen MG, Ahlstedt I, El Hachmane MF, Göpel SO (2016) Dapagliflozin stimulates glucagon secretion at high glucose: experiments and mathematical simulations of human A-cells. Sci Rep 6:31214. https://doi.org/10.1038/srep31214

Article  CAS  PubMed  PubMed Central  Google Scholar 

Solini A, Sebastiani G, Nigi L et al (2017) Dapagliflozin modulates glucagon secretion in an SGLT2-independent manner in murine alpha cells. Diabetes Metab 43:512–520. https://doi.org/10.1016/j.diabet.2017.04.002

Article  CAS  PubMed  Google Scholar 

Kuhre RE, Ghiasi SM, Adriaenssens AE et al (2019) No direct effect of SGLT2 activity on glucagon secretion. Diabetologia 62:1011–1023. https://doi.org/10.1007/s00125-019-4849-6

Article  CAS  PubMed  PubMed Central  Google Scholar 

Saponaro C, Mühlemann M, Acosta-Montalvo A et al (2020) Interindividual heterogeneity of SGLT2 expression and function in human pancreatic islets. Diabetes 69:902–914. https://doi.org/10.2337/db19-0888

Article  CAS  PubMed  Google Scholar 

Chae H, Augustin R, Gatineau E et al (2020) SGLT2 is not expressed in pancreatic α- and β-cells, and its inhibition does not directly affect glucagon and insulin secretion in rodents and humans. Mol Metab 42:101071. https://doi.org/10.1016/j.molmet.2020.101071

Article  CAS  PubMed  PubMed Central  Google Scholar 

Suga T, Kikuchi O, Kobayashi M et al (2019) SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels. Mol Metab 19:1–12. https://doi.org/10.1016/j.molmet.2018.10.009

Article  CAS  PubMed  Google Scholar 

Powers AC, Efrat S, Mojsov S et al (1990) Proglucagon processing similar to normal islets in pancreatic α-like cell line derived from transgenic mouse tumor. Diabetes 39:406–414. https://doi.org/10.2337/diab.39.4.406

Article  CAS  PubMed  Google Scholar 

Toyoda T, Hayashi T, Miyamoto L et al (2004) Possible involvement of the α1 isoform of 5′AMP-activated protein kinase in oxidative stress-stimulated glucose transport in skeletal muscle. Am J Physiol Endocrinol Metab 287:E166–E173. https://doi.org/10.1152/ajpendo.00487.2003

Article  CAS  PubMed  Google Scholar 

Miyamoto L, Toyoda T, Hayashi T et al (2007) Effect of acute activation of 5’-AMP-activated protein kinase on glycogen regulation in isolated rat skeletal muscle. J Appl Physiol 102:1007–1013. https://doi.org/10.1152/japplphysiol.01034.2006

Article  CAS  PubMed  Google Scholar 

Miyamoto L, Yamane M, Tomida Y et al (2017) Nitrite activates 5’AMP-activated protein kinase-endothelial nitric oxide synthase pathway in human glomerular endothelial cells. Biol Pharm Bull 40:1866–1872. https://doi.org/10.1248/bpb.b17-00316

Article  CAS  PubMed  Google Scholar 

Han S, Hagan DL, Taylor JR et al (2008) Dapagliflozin, a selective SGLT2 inhibitor, improves glucose homeostasis in normal and diabetic rats. Diabetes 57:1723–1729. https://doi.org/10.2337/db07-1472

Article  CAS  PubMed  Google Scholar 

Meng W, Ellsworth BA, Nirschl AA et al (2008) Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 51:1145–1149. https://doi.org/10.1021/jm701272q

Article  CAS  PubMed  Google Scholar 

Grempler R, Thomas L, Eckhardt M et al (2012) Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 14:83–90. https://doi.org/10.1111/j.1463-1326.2011.01517.x

Article  CAS  PubMed  Google Scholar 

Zhang Q, Ramracheya R, Lahmann C et al (2013) Role of KATP channels in glucose-regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab 18:871–882. https://doi.org/10.1016/j.cmet.2013.10.014

Article  CAS  PubMed  PubMed Central  Google Scholar 

MacDonald PE, Marinis YZD, Ramracheya R et al (2007) A KATP channel-dependent pathway within α cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol 5:e143. https://doi.org/10.1371/journal.pbio.0050143

Article  PubMed  PubMed Central  Google Scholar 

Basco D, Zhang Q, Salehi A et al (2018) α-cell glucokinase suppresses glucose-regulated glucagon secretion. Nat Commun 9:546. https://doi.org/10.1038/s41467-018-03034-0

Article  CAS 

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