Inhibition of the Glucose Transporter SGLT2 with Dapagliflozin in Pancreatic Alpha Cells Triggers Glucagon Secretion
Abstract
Type 2 diabetes (T2D) is characterized by chronic hyperglycemia resulting from a deficiency in insulin signaling, because of insulin resistance and/or defects in insulin secretion; it is also associated with increases in glucagon and endogenous glucose production (EGP). Gliflozins, including dapagliflozin, are a new class of approved oral antidiabetic agents that specifically inhibit sodium-glucose co-transporter 2 (SGLT2) function in the kidney, thus preventing renal glucose reabsorption and increasing glycosuria in diabetic individuals while reducing hyperglycemia. However, gliflozin treatment in subjects with T2D increases both plasma glucagon and EGP by unknown mechanisms. In spite of the rise in EGP, T2D patients treated with gliflozin have lower blood glucose levels than those receiving placebo, possibly because of increased glycosuria; however, the resulting increase in plasma glucagon levels represents a possible concerning side effect, especially in a patient population already affected by hyperglucagonemia. Here we demonstrate that SGLT2 is expressed in glucagon-secreting alpha cells of the pancreatic islets. We further found that expression of SLC5A2 (which encodes SGLT2) was lower and glucagon (GCG) gene expression was higher in islets from T2D individuals and in normal islets exposed to chronic hyperglycemia than in islets from non-diabetics. Moreover, hepatocyte nuclear factor 4-α (HNF4A) is specifically expressed in human alpha cells, in which it controls SLC5A…
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Increased expression of intestinal glucose transporters post-surgery may facilitate rapid nutrient absorption.
“In addition, increased expression of intestinal glucose transporters post-surgery may facilitate rapid nutrient absorption [52].”
From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [52]
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Ipragliflozin improves the hepatic outcomes of patients with diabetes with NAFLD
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- Authors
- Bonner, C., Kerr-Conte, J., Gmyr, V., Queniat, G., Moerman, E., Thévenet, J., Beaucamps, C., Delalleau, N., Popescu, I., Malaisse, W. J., Sener, A., Deprez, B., Abderrahmani, A., Staels, B., & Pattou, F.
- Affiliations
- Inserm (FR)
- Université Libre de Bruxelles (BE)
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Staels, Bart
- Pattou, François
- ORCID
- Venue
- Nature Medicine
- Published
- 2015-04-20
- Volume
- 21
- Issue
- 5
- Pages
- 512-517
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2021517048
- Cited by
- 670
- References
- 7
- Citations by year
- 2026: 31 · 2025: 37 · 2024: 46 · 2023: 37 · 2022: 41 · 2021: 61 · 2020: 100 · 2019: 64 · 2018: 60 · 2017: 72 · 2016: 78 · 2015: 42 · 2014: 1
- FWCI
- 73.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
- Funders
- Bristol-Myers Squibb
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- dapagliflozin, SGLT2 inhibition, glucagon secretion, alpha cells, type 2 diabetes, SLC5A2, HNF4α, ATP-sensitive potassium channels, hepatic gluconeogenesis, endogenous glucose production, hyperglycemia
- MeSH terms
- Administration, Oral, Adult, Animals, Benzhydryl Compounds, Blood Glucose, Cell Separation, Female, Flow Cytometry, Gene Expression Regulation, Glucagon, Gluconeogenesis, Glucosides, Humans, Insulin Resistance, Male, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Gene Silencing, Gene Expression Profiling, RNA, Small Interfering, Glucagon-Secreting Cells, Sodium-Glucose Transporter 1, Sodium-Glucose Transporter 2, Mice, Hepatocyte Nuclear Factor 4
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