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

M Kim1,2, E J Lee3, H M Shin4

  • 1Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, 875, Hauendae-ro, Hauendae-gu, Busan, 612-862, South Korea. kmkdoc@hanmail.net.

Journal of Endocrinological Investigation
|April 10, 2017
PubMed
Abstract

Insights

Troglitazone, a PPAR-γ agonist, improved sodium glucose cotransporter 2 (SGLT2) function and regulated glucagon in pancreatic alpha cells during hyperglycemia, potentially via the PI3K/Akt pathway.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Diabetes Research

Background:

  • Sodium glucose cotransporter 2 (SGLT2) inhibitors benefit type 2 diabetes but may increase glucagon.
  • Troglitazone (PPAR-γ agonist) increases SGLT2 in kidneys; its effect on pancreatic alpha cells is unknown.
  • Investigating troglitazone's impact on alpha cell SGLT2 and glucagon regulation under hyperglycemia.

Purpose of the Study:

  • To determine troglitazone's effect on SGLT2 expression in alpha cells under hyperglycemic conditions.
  • To assess troglitazone's influence on glucagon regulation in alpha cells during hyperglycemia.
  • To elucidate the role of the PI3K/Akt pathway in troglitazone's effects on alpha cells.

Main Methods:

  • Alpha TC1-6 cells were cultured in normal (5 mM) or hyperglycemic (15 mM) conditions for 72 hours.
  • Cells were treated with troglitazone, a PPARγ antagonist (GW9662), or a PI3K inhibitor (Wortmanin).
  • SGLT2, glucagon, PPARγ, PI3K, and Akt (including phosphorylated Akt) mRNA and protein levels were measured.

Main Results:

  • Hyperglycemia increased glucagon and PI3K/pAkt expression while decreasing SGLT2 expression in alpha cells.
  • Troglitazone reversed hyperglycemia-induced SGLT2 reduction and glucagon increase.
  • Troglitazone decreased PI3K/pAkt expression in hyperglycemic cells, suggesting pathway involvement.

Conclusions:

  • Troglitazone ameliorates SGLT2 dysfunction and glucagon dysregulation in alpha cells under hyperglycemia.
  • These beneficial effects are mediated through the PI3K/Akt signaling pathway.
  • Findings support combining PPARγ agonists and SGLT2 inhibitors for type 2 diabetes treatment.
Keywords:
GlucagonPI3K/pAktPPARγ agonistSGLT2

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