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Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion.

ABSTRACT: As a key regulator of the unfolded protein response, the transcription factor XBP1 activates genes in protein secretory pathways and is required for the development of certain secretory cells. To elucidate the function of XBP1 in pancreatic ?-cells, we generated ?-cell-specific XBP1 mutant mice. Xbp1(f/f);RIP-cre mice displayed modest hyperglycemia and glucose intolerance resulting from decreased insulin secretion from ?-cells. Ablation of XBP1 markedly decreased the number of insulin granules in ?-cells, impaired proinsulin processing, increased the serum proinsulin:insulin ratio, blunted glucose-stimulated insulin secretion, and inhibited cell proliferation. Notably, XBP1 deficiency not only compromised the endoplasmic reticulum stress response in ?-cells but also caused constitutive hyperactivation of its upstream activator, IRE1?, which could degrade a subset of mRNAs encoding proinsulin-processing enzymes. Hence, the combined effects of XBP1 deficiency on the canonical unfolded protein response and its negative feedback activation of IRE1? caused ?-cell dysfunction in XBP1 mutant mice. These results demonstrate that IRE1? has dual and opposing roles in ?-cells, and that a precisely regulated feedback circuit involving IRE1? and its product XBP1s is required to achieve optimal insulin secretion and glucose control.

SUBMITTER: Lee AH

PROVIDER: S-EPMC3102350 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion.

Lee Ann-Hwee AH Heidtman Keely K Hotamisligil Gökhan S GS Glimcher Laurie H LH

Proceedings of the National Academy of Sciences of the United States of America 20110509 21

As a key regulator of the unfolded protein response, the transcription factor XBP1 activates genes in protein secretory pathways and is required for the development of certain secretory cells. To elucidate the function of XBP1 in pancreatic β-cells, we generated β-cell-specific XBP1 mutant mice. Xbp1(f/f);RIP-cre mice displayed modest hyperglycemia and glucose intolerance resulting from decreased insulin secretion from β-cells. Ablation of XBP1 markedly decreased the number of insulin granules i ...[more]

PMID: 21555585

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Project description:BackgroundGrowing evidence indicates that oxidative stress (OS), a persistent state of excess amounts of reactive oxygen species (ROS) along with reactive nitrogen species (RNS), plays an important role in insulin resistance, diabetic complications, and dysfunction of pancreatic β-cells. Pancreatic β-cells contain exceptionally low levels of antioxidant enzymes, rendering them susceptible to ROS-induced damage. Induction of antioxidants has been proposed to be a way for protecting β-cells against oxidative stress. Compared to other antioxidants that act against particular β-cell damages, metallothionein (MT) is the most effective in protecting β-cells from several oxidative stressors including nitric oxide, peroxynitrite, hydrogen peroxide, superoxide and streptozotocin (STZ). We hypothesized that MT overexpression in pancreatic β-cells would preserve β-cell function in C57BL/6J mice, an animal model susceptible to high fat diet-induced obesity and type 2 diabetes.Research design and methodsThe pancreatic β-cell specific MT overexpression was transferred to C57BL/6J background by backcrossing. We studied transgenic MT (MT-tg) mice and wild-type (WT) littermates at 8 weeks and 18 weeks of age. Several tests were performed to evaluate the function of islets, including STZ in vivo treatment, intraperitoneal glucose tolerance tests (IPGTT) and plasma insulin levels during IPGTT, pancreatic and islet insulin content measurement, insulin secretion, and islet morphology assessment. Gene expression in islets was performed by quantitative real-time PCR and PCR array analysis. Protein levels in pancreatic sections were evaluated by using immunohistochemistry.ResultsThe transgenic MT protein was highly expressed in pancreatic islets. MT-tg overexpression significantly protected mice from acute STZ-induced ROS at 8 weeks of age; unexpectedly, however, MT-tg impaired glucose stimulated insulin secretion (GSIS) and promoted the development of diabetes. Pancreatic β-cell function was significantly impaired, and islet morphology was also abnormal in MT-tg mice, and more severe damage was detected in males. The unique gene expression pattern and abnormal protein levels were observed in MT-tg islets.ConclusionsMT overexpression protected β-cells from acute STZ-induced ROS damages at young age, whereas it impaired GSIS and promoted the development of diabetes in adult C57BL/6J mice, and more severe damage was found in males.

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Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion.

Publications

Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion.

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