PPAR-γ activation restores pancreatic islet SERCA2 levels and prevents β-cell dysfunction under conditions of hyperglycemic and cytokine stress

Mol Endocrinol. 2012 Feb;26(2):257-71. doi: 10.1210/me.2011-1181. Epub 2012 Jan 12.


The maintenance of intracellular Ca(2+) homeostasis in the pancreatic β-cell is closely regulated by activity of the sarco-endoplasmic reticulum Ca(2+) ATPase (SERCA) pump. Our data demonstrate a loss of β-cell SERCA2b expression in several models of type 2 diabetes including islets from db/db mice and cadaveric diabetic human islets. Treatment of 832/13 rat INS-1-derived cells with 25 mm glucose and the proinflammatory cytokine IL-1β led to a similar loss of SERCA2b expression, which was prevented by treatment with the peroxisome proliferator-activated receptor (PPAR)-γ agonist, pioglitazone. Pioglitazone was able to also protect against hyperglycemia and cytokine-induced elevations in cytosolic Ca(2+) levels, insulin-secretory defects, and cell death. To determine whether PPAR-γ was a direct transcriptional regulator of the SERCA2 gene, luciferase assays were performed and showed that a -259 bp region is sufficient to confer PPAR-γ transactivation; EMSA and chromatin immunoprecipitation experiments confirmed that PPAR-γ directly binds a PPAR response element in this proximal region. We next sought to characterize the mechanisms by which SERCA2b was down-regulated. INS-1 cells were exposed to high glucose and IL-1β in time course experiments. Within 2 h of exposure, activation of cyclin-dependent kinase 5 (CDK5) was observed and correlated with increased serine-273 phosphorylation of PPAR-γ and loss of SERCA2 protein expression, findings that were prevented by pioglitazone and roscovitine, a pharmacological inhibitor of CDK5. We conclude that pioglitazone modulates SERCA2b expression through direct transcriptional regulation of the gene and indirectly through prevention of CDK5-induced phosphorylation of PPAR-γ.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Blood Glucose
  • Calcium / metabolism
  • Cell Cycle
  • Cyclin-Dependent Kinase 5 / metabolism
  • Cytokines / pharmacology
  • Cytokines / physiology*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / metabolism*
  • Down-Regulation
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • PPAR gamma / metabolism
  • PPAR gamma / physiology*
  • Phosphorylation
  • Pioglitazone
  • Protein Binding
  • Rats
  • Response Elements
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism*
  • Stress, Physiological
  • Thiazolidinediones / pharmacology


  • Blood Glucose
  • Cytokines
  • Hypoglycemic Agents
  • Insulin
  • Isoenzymes
  • PPAR gamma
  • Thiazolidinediones
  • Cyclin-Dependent Kinase 5
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium
  • Pioglitazone