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Journal of Endocrinological Investigation

, Volume 40, Issue 10, pp 1069–1076 | Cite as

The effect of PPARγ agonist on SGLT2 and glucagon expressions in alpha cells under hyperglycemia

  • M. KimEmail author
  • E. J. Lee
  • H. M. Shin
  • H. S. Jung
  • T. K. Kim
  • T. N. Kim
  • M. J. Kwon
  • S. H. Lee
  • B. D. Rhee
  • J. H. Park
Original Article
  • 387 Downloads

Abstract

Background

Although sodium glucose cotransporter 2 (SGLT2) inhibitors have many beneficial effects for type 2 diabetes, including decreased cardiovascular death, recent reports that they increased glucagon through SGLT2 inhibition raised some concern. Troglitazone, Peroxisome proliferator-activated receptor γ (PPAR-γ) agonist, was reported to increase SGLT2 in renal proximal tubule cells, but its role on pancreatic alpha cells have not been reported. We investigated the effect of troglitazone on SGLT2 expression in alpha cells and subsequent glucagon regulation in hyperglycemia.

Methods

An Alpha TC1-6 cell line was cultured in control (5 mM) or hyperglycemia (HG, 15 mM) for 72 h. We applied troglitazone with or without PPARγ antagonist (GW9662 10 μM). To investigate the involvement of PI3K/Akt pathway, we applied troglitazone with or without Wortmanin. We measured sodium glucose transporter 2 (SGLT2) and glucagon (GCG) mRNA and protein expression. PPAR gamma, PI3K and Akt protein were also measured.

Results

Exposure of alpha TC cells to HG for 72 h increased glucagon mRNA and protein expression. HG decreased SGLT2 mRNA and protein expression. Troglitazone significantly reversed HG-induced reduction of SGLT2 expression and increase of glucagon secretion. PPARγ antagonist (GW9662 10 μM) decreased the expression of SGLT2 and increased glucagon as HG did. Hyperglycemia increased PI3K and pAkt expression in alpha cells. Wortmanin (PI3K inhibitor, 1 μM) reversed HG-induced SGLT2 decrease and glucagon increase. Troglitazone treatment decreased PI3K and pAkt expression in HG.

Conclusion

In conclusion, PPARγ agonist, troglitazone improved glucose transport SGLT2 dysfunction and subsequent glucagon dysregulation in alpha cell under hyperglycemia. Those effects were through the involvement of PI3K/pAkt signaling pathway. This study may add one more reason for the ideal combination of PPARγ agonist and SGLT2 inhibitor in clinical practice.

Keywords

SGLT2 Glucagon PPARγ agonist PI3K/pAkt 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

For this type of study formal consent is not required.

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Copyright information

© Italian Society of Endocrinology (SIE) 2017

Authors and Affiliations

  • M. Kim
    • 1
    • 2
    Email author
  • E. J. Lee
    • 1
  • H. M. Shin
    • 2
  • H. S. Jung
    • 2
  • T. K. Kim
    • 1
  • T. N. Kim
    • 1
  • M. J. Kwon
    • 1
  • S. H. Lee
    • 1
  • B. D. Rhee
    • 1
  • J. H. Park
    • 1
    • 2
  1. 1.Division of Endocrinology and Metabolism, Department of Internal Medicine, College of MedicineInje UniversityBusanSouth Korea
  2. 2.Molecular Therapy Lab, Paik Institute for Clinical ResearchInje UniversityBusanSouth Korea

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