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Dapagliflozin Does Not Directly Affect Human α or β Cells
Chunhua Dai1, John T Walker2, Alena Shostak1
1Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Endocrinology
|May 20, 2020
Summary
Selective sodium glucose cotransporter-2 (SGLT2) inhibitors do not directly impact human pancreatic islets. Dapagliflozin treatment in vivo showed indirect effects on insulin and transient glucagon secretion, suggesting a secondary response to lower blood glucose.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Pharmacology
Background:
- Selective sodium glucose cotransporter-2 (SGLT2) inhibitors are used for type 2 diabetes, primarily acting on kidneys to lower blood glucose.
- A controversy exists regarding whether SGLT2 inhibitors affect pancreatic alpha cells, potentially increasing glucagon secretion.
Purpose of the Study:
- To investigate the direct effects of SGLT2 inhibition on human pancreatic islets.
- To analyze SGLT2 expression and hormone secretion in human islets treated with dapagliflozin (DAPA) in vitro and in vivo.
Main Methods:
- Assessed SLC5A2 transcript and SGLT2 protein expression in human islets.
- Measured insulin and glucagon secretion from human islets treated with DAPA in vitro.
- Evaluated DAPA's effects on glucose, insulin, and glucagon levels in mice with transplanted human islets.
Main Results:
- SGLT2 expression was significantly lower in human islets compared to kidneys; SGLT2 protein was undetectable.
- In vitro, DAPA did not alter insulin or glucagon secretion from human islets.
- In vivo, DAPA led to lower blood glucose and insulin, with a transient increase in glucagon after 1 week, normalizing by 4 weeks.
Conclusions:
- Dapagliflozin does not directly affect human pancreatic islet function.
- Observed hormonal changes are likely indirect effects of SGLT2 inhibition, secondary to reduced blood glucose levels.
- These findings clarify the mechanism of action of SGLT2 inhibitors on glucose homeostasis.
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