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, Raghavendra G.

doi:10.1074/jbc.m116.741694

Cited by 22 publications

(9 citation statements)

References 63 publications

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“…Treatment of NOD mice with ML351 led to improved glycemic control and significantly reduced insulitis. The reduction of β-cell death in NOD mice has been suggested to lead to reductions in insulitis, likely by mitigating the chemotactic signals released by dying β-cells ( 4 , 5 ). On the other hand, we observed that galectin 3–positive anti-inflammatory macrophages make up a greater percentage of the insulitic infiltrate, which points to a possible direct effect of the drug on macrophages.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

et al. 2017

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Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.

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Section: Discussionmentioning

confidence: 99%

Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

et al. 2017

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“…Maganti et al. reported an increase in β cell mass of pioglitazone-treated non-obese diabetic mice, possibly through induction of ATF4 and BiP and prevention of CHOP upregulation [184] .…”

Section: Therapeutic Modulation Of β Cell Er Stress and Er Stress Sigmentioning

confidence: 99%

Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells

Cnop¹,

Toivonen²,

Igoillo-Esteve³

et al. 2017

Molecular Metabolism

221

179

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BackgroundPancreatic β cell dysfunction and death are central in the pathogenesis of most if not all forms of diabetes. Understanding the molecular mechanisms underlying β cell failure is important to develop β cell protective approaches.Scope of reviewHere we review the role of endoplasmic reticulum stress and dysregulated endoplasmic reticulum stress signaling in β cell failure in monogenic and polygenic forms of diabetes. There is substantial evidence for the presence of endoplasmic reticulum stress in β cells in type 1 and type 2 diabetes. Direct evidence for the importance of this stress response is provided by an increasing number of monogenic forms of diabetes. In particular, mutations in the PERK branch of the unfolded protein response provide insight into its importance for human β cell function and survival. The knowledge gained from different rodent models is reviewed. More disease- and patient-relevant models, using human induced pluripotent stem cells differentiated into β cells, will further advance our understanding of pathogenic mechanisms. Finally, we review the therapeutic modulation of endoplasmic reticulum stress and signaling in β cells.Major conclusionsPancreatic β cells are sensitive to excessive endoplasmic reticulum stress and dysregulated eIF2α phosphorylation, as indicated by transcriptome data, monogenic forms of diabetes and pharmacological studies. This should be taken into consideration when devising new therapeutic approaches for diabetes.

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“…Results of a Mendelian randomization study refuted a causal role for adiponectin in CV disease (88), which may explain why pure PPARγ agonists, such as rosiglitazone, are not cardioprotective. Finally, PPARγ activation improves pancreatic β cell function and survival by preventing FA-induced impairment of insulin secretion (77) and enhancing the unfolded protein response (89). Thus, whereas PPARα activation leads to energy dissipation, activation of PPARγ stimulates energy storage in WAT, thereby sensitizing liver and peripheral tissues to insulin.…”

Section: R E V I E W S E R I E S : N U C L E a R R E C E P T O R Smentioning

confidence: 99%

Distinct but complementary contributions of PPAR isotypes to energy homeostasis

Dubois¹,

Eeckhoute²,

Lefèbvre³

et al. 2017

Journal of Clinical Investigation

301

215

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Peroxisome proliferator-activated receptors (PPARs) regulate energy metabolism and hence are therapeutic targets in metabolic diseases such as type 2 diabetes and non-alcoholic fatty liver disease. While they share anti-inflammatory activities, the PPAR isotypes distinguish themselves by differential actions on lipid and glucose homeostasis. In this Review we discuss the complementary and distinct metabolic effects of the PPAR isotypes together with the underlying cellular and molecular mechanisms, as well as the synthetic PPAR ligands that are used in the clinic or under development. We highlight the potential of new PPAR ligands with improved efficacy and safety profiles in the treatment of complex metabolic disorders.

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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

Cited by 22 publications

References 63 publications

Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells

Distinct but complementary contributions of PPAR isotypes to energy homeostasis

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