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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.

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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.