title: The effect of PPARγ agonist on SGLT2 and glucagon expressions in alpha cells under hyperglycemia.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division 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.|Molecular Therapy Lab, Paik Institute for Clinical Research, Inje University, Busan, South Korea. kmkdoc@hanmail.net.
authors.forename: M
authors.initials: M
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, 875, Hauendae-ro, Hauendae-gu, Busan, 612-862, South Korea.
authors.forename: E J
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Molecular Therapy Lab, Paik Institute for Clinical Research, Inje University, Busan, South Korea.
authors.forename: H M
authors.initials: HM
authors.lastname: Shin
authors.affiliation: Molecular Therapy Lab, Paik Institute for Clinical Research, Inje University, Busan, South Korea.
authors.forename: H S
authors.initials: HS
authors.lastname: Jung
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, 875, Hauendae-ro, Hauendae-gu, Busan, 612-862, South Korea.
authors.forename: T K
authors.initials: TK
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, 875, Hauendae-ro, Hauendae-gu, Busan, 612-862, South Korea.
authors.forename: T N
authors.initials: TN
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, 875, Hauendae-ro, Hauendae-gu, Busan, 612-862, South Korea.
authors.forename: M J
authors.initials: MJ
authors.lastname: Kwon
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, 875, Hauendae-ro, Hauendae-gu, Busan, 612-862, South Korea.
authors.forename: S H
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, 875, Hauendae-ro, Hauendae-gu, Busan, 612-862, South Korea.
authors.forename: B D
authors.initials: BD
authors.lastname: Rhee
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Inje University, 875, Hauendae-ro, Hauendae-gu, Busan, 612-862, South Korea.|Molecular Therapy Lab, Paik Institute for Clinical Research, Inje University, Busan, South Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Park
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005947:Glucose / Q000494:pharmacology; D006943:Hyperglycemia / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology*; D000077288:Troglitazone
chemical_list: D002839:Chromans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D045162:Thiazolidinediones; D005934:Glucagon; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077288:Troglitazone; D005947:Glucose
keywords: Glucagon; PI3K/pAkt; PPARγ agonist; SGLT2