Peroxisome proliferator-activated receptor-γ activation augments the β-Cell unfolded protein response and rescues early glycemic deterioration and β cell death in non-obese diabetic mice

Aarthi V. Maganti, Sarah A. Tersey, Farooq Syed, Jennifer B. Nelson, Stephanie C. Colvin, Bernhard Maier, Raghu Mirmira

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Type 1 diabetes is an autoimmune disorder that is characterized by a failure of the unfolded protein response in islet β cells with subsequent endoplasmic reticulum stress and cellular death. Thiazolidinediones are insulin sensitizers that activate the nuclear receptor PPAR-γ and have been shown to partially ameliorate autoimmune type 1 diabetes in humans and non-obese diabetic (NOD) mice. We hypothesized that thiazolidinediones reduce β cell stress and death independently of insulin sensitivity. To test this hypothesis, female NOD mice were administered pioglitazone during the pre-diabetic phase and assessed for insulin sensitivity and β cell function relative to controls. Pioglitazone-treated mice showed identical weight gain, body fat distribution, and insulin sensitivity compared with controls. However, treated mice showed significantly improved glucose tolerance with enhanced serum insulin levels, reduced β cell death, and increased β cell mass. The effect of pioglitazone was independent of actions on T cells, as pancreatic lymph node T cell populations were unaltered and T cell proliferation was unaffected by pioglitazone. Isolated islets of treated mice showed a more robust unfolded protein response, with increases in Bip and ATF4 and reductions in spliced Xbp1 mRNA. The effect of pioglitazone appears to be a direct action on β cells, as islets from mice treated with pioglitazone showed reductions in PPAR-γ (Ser-273) phosphorylation. Our results demonstrate that PPAR-γ activation directly improves β cell function and survival in NOD mice by enhancing the unfolded protein response and suggest that blockade of PPAR-γ (Ser-273) phosphorylation may prevent type 1 diabetes.

Original languageEnglish (US)
Pages (from-to)22524-22533
Number of pages10
JournalJournal of Biological Chemistry
Volume291
Issue number43
DOIs
StatePublished - Oct 21 2016

Fingerprint

pioglitazone
Unfolded Protein Response
Inbred NOD Mouse
Peroxisome Proliferator-Activated Receptors
Cell death
Deterioration
Cell Death
Chemical activation
Type 1 Diabetes Mellitus
T-cells
Insulin
Medical problems
Insulin Resistance
Thiazolidinediones
Phosphorylation
Proteins
T-Lymphocytes
Islets of Langerhans
Body Fat Distribution
Endoplasmic Reticulum Stress

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Peroxisome proliferator-activated receptor-γ activation augments the β-Cell unfolded protein response and rescues early glycemic deterioration and β cell death in non-obese diabetic mice. / Maganti, Aarthi V.; Tersey, Sarah A.; Syed, Farooq; Nelson, Jennifer B.; Colvin, Stephanie C.; Maier, Bernhard; Mirmira, Raghu.

In: Journal of Biological Chemistry, Vol. 291, No. 43, 21.10.2016, p. 22524-22533.

Research output: Contribution to journalArticle

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abstract = "Type 1 diabetes is an autoimmune disorder that is characterized by a failure of the unfolded protein response in islet β cells with subsequent endoplasmic reticulum stress and cellular death. Thiazolidinediones are insulin sensitizers that activate the nuclear receptor PPAR-γ and have been shown to partially ameliorate autoimmune type 1 diabetes in humans and non-obese diabetic (NOD) mice. We hypothesized that thiazolidinediones reduce β cell stress and death independently of insulin sensitivity. To test this hypothesis, female NOD mice were administered pioglitazone during the pre-diabetic phase and assessed for insulin sensitivity and β cell function relative to controls. Pioglitazone-treated mice showed identical weight gain, body fat distribution, and insulin sensitivity compared with controls. However, treated mice showed significantly improved glucose tolerance with enhanced serum insulin levels, reduced β cell death, and increased β cell mass. The effect of pioglitazone was independent of actions on T cells, as pancreatic lymph node T cell populations were unaltered and T cell proliferation was unaffected by pioglitazone. Isolated islets of treated mice showed a more robust unfolded protein response, with increases in Bip and ATF4 and reductions in spliced Xbp1 mRNA. The effect of pioglitazone appears to be a direct action on β cells, as islets from mice treated with pioglitazone showed reductions in PPAR-γ (Ser-273) phosphorylation. Our results demonstrate that PPAR-γ activation directly improves β cell function and survival in NOD mice by enhancing the unfolded protein response and suggest that blockade of PPAR-γ (Ser-273) phosphorylation may prevent type 1 diabetes.",
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