Activated PPARβ/δ Protects Pancreatic β Cells in Type 2 Diabetic Goto-Kakizaki Rats from Lipoapoptosis via GPR40

Lipids. 2019 Oct;54(10):603-616. doi: 10.1002/lipd.12182. Epub 2019 Jul 30.


GW501516-activated peroxisome proliferator-activated receptor (PPAR) β/δ and G-protein-coupled receptor (GPR) 40 were shown to protect pancreatic β cells against lipoapoptosis. Therefore, this study aimed to investigate whether activated PPARβ/δ could protect type 2 diabetic rats from lipoapoptosis through regulation of GPR40 and to compare the protective effects of activated PPARβ/δ and PPARγ. We made an animal model of type 2 diabetic lipoapoptosis by feeding spontaneously type 2 diabetic Goto-Kakizaki (GK) rats with a high-fat diet (HFD) to evaluate the effects of PPARβ/δ on islet β cell apoptosis. And, treated INS-1 cells with 0.5 mM palmitate (PAM) in the absence/presence of GW501516 (a specific agonist of PPAR β/δ) and with/without transfection of GPR40 siRNA to explore the underlying molecular mechanism. HFD aggravated GK rats' poorer INSR30, lower mass, greater apoptosis of β cells, lower mass, and lower expression of GPR40, which were similarly improved by GW501516 at 3 or 6 mg/kg day and pioglitazone. Compared with pioglitazone, GW501516 caused more weight loss and had no effect on insulin resistance. GW501516 protected INS-1 cells from PAM-induced apoptosis by upregulating GPR40 and activating Akt/Bcl-2/caspase-3. Activated extracellular regulated protein kinases (ERK) was relevant to the lipoapoptosis in INS-1 cells, but was not involved in the antilipoapoptotic effect of GW501516. These results showed that the PPARβ/δ agonist GW501516 protected β cells from lipoapoptosis and improved β cell mass by upregulating GPR40 and activating the Akt/Bcl-2/caspase-3 pathway, but not the ERK-signaling pathway.

Keywords: GK rat; GPR40; Lipoapoptosis; PPARβ/δ; Pancreatic β-cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / pathology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Models, Animal
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Lipids / chemistry
  • Male
  • PPAR delta / metabolism*
  • PPAR-beta / metabolism*
  • Rats
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / metabolism*


  • G-protein-coupled receptor 40, rat
  • Lipids
  • PPAR delta
  • PPAR-beta
  • Receptors, G-Protein-Coupled