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Single-cell RNA Sequencing and Analysis of Human Pancreatic Islets
Published on: July 18, 2019
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Interindividual Heterogeneity of SGLT2 Expression and Function in Human Pancreatic Islets
Chiara Saponaro1,2,3, Markus Mühlemann1,2,3, Ana Acosta-Montalvo1,2,3
1INSERM, U1190, Lille, France.
Diabetes
|January 4, 2020
Summary
Interindividual differences in sodium-glucose cotransporter 2 (SGLT2) expression affect glucagon secretion in response to SGLT2 inhibitors. This variability explains differing patient responses to these diabetes medications.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Molecular Biology
Background:
- Controversial findings exist regarding sodium-glucose cotransporter 2 (SGLT2) inhibitors' effect on pancreatic alpha-cell glucagon secretion.
- Interindividual variability in SGLT2 expression and regulation may underlie these discrepancies.
Purpose of the Study:
- To investigate the heterogeneity of SGLT2 expression and its impact on human alpha-cell glucagon secretion in response to SGLT2 inhibitors.
- To explore the correlation between SGLT2 protein levels and dapagliflozin-induced glucagon secretion.
Main Methods:
- RNA-sequencing of 207 donors to assess SLC5A2 (SGLT2) gene expression heterogeneity.
- Western blot and immunofluorescence analysis of human islets from multiple donors to evaluate SGLT2 protein expression.
- Measurement of glucagon secretion from human islets in response to low glucose and dapagliflozin.
Main Results:
- Significant heterogeneity in SGLT2 gene and protein expression was observed across human donors.
- SGLT2 protein colocalized with glucagon in human islets.
- Glucagon secretion at low glucose and in response to dapagliflozin showed interindividual variability and correlation.
- A subset of donors exhibited impaired glucose sensing and non-responsive glucagon secretion to SGLT2 inhibition.
Conclusions:
- Heterogeneous SGLT2 protein expression and variable glucagon secretory responses contribute to interindividual differences in SGLT2 inhibitor efficacy.
- Understanding this variability is crucial for predicting patient responses to SGLT2 inhibitors.
- Further research is needed to elucidate the mechanisms behind SGLT2-mediated glucagon secretion regulation.
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