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Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus.

Jing Yong, James D Johnson, Peter Arvan, Jaeseok Han, Randal J Kaufman,

Diabetes mellitus is characterized by the failure of insulin-secreting pancreatic β-cells (or β-cell death) due to either autoimmunity (type 1 diabetes mellitus) or failure to compensate for insulin resistance (type 2 diabetes mellitus; T2DM). In addition, mutations of critical genes cause monogenic diabetes. The endoplasmic reticulum (ER) is the primary ... Read more >>

Nat Rev Endocrinol (Nature reviews. Endocrinology)
[2021, 17(8):455-467]

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Distinct states of proinsulin misfolding in MIDY.

Leena Haataja, Anoop Arunagiri, Anis Hassan, Kaitlin Regan, Billy Tsai, Balamurugan Dhayalan, Michael A Weiss, Ming Liu, Peter Arvan,

A precondition for efficient proinsulin export from the endoplasmic reticulum (ER) is that proinsulin meets ER quality control folding requirements, including formation of the Cys(B19)-Cys(A20) "interchain" disulfide bond, facilitating formation of the Cys(B7)-Cys(A7) bridge. The third proinsulin disulfide, Cys(A6)-Cys(A11), is not required for anterograde trafficking, i.e., a "lose-A6/A11" mutant [Cys(A6), ... Read more >>

Cell Mol Life Sci (Cellular and molecular life sciences : CMLS)
[2021, :]

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Thyroid hormone synthesis continues despite biallelic thyroglobulin mutation with cell death.

Xiaohan Zhang, Aaron P Kellogg, Cintia E Citterio, Hao Zhang, Dennis Larkin, Yoshiaki Morishita, Héctor M Targovnik, Viviana A Balbi, Peter Arvan,

Complete absence of thyroid hormone is incompatible with life in vertebrates. Thyroxine is synthesized within thyroid follicles upon iodination of thyroglobulin conveyed from the endoplasmic reticulum (ER), via the Golgi complex, to the extracellular follicular lumen. In congenital hypothyroidism from biallelic thyroglobulin mutation, thyroglobulin is misfolded and cannot advance from ... Read more >>

JCI Insight (JCI insight)
[2021, 6(11):]

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Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes

Maroof Alam, Anoop Arunagiri, Leena Haataja, Mauricio Torres, Dennis Larkin, John Kappler, Niyun Jin, Peter Arvan,

Throughout evolution, proinsulin has exhibited significant sequence variation in both C-peptide and insulin moieties. As the proinsulin coding sequence evolves, the gene product continues to be under selection pressure both for ultimate insulin bioactivity and for the ability of proinsulin to be folded for export through the secretory pathway of ... Read more >>

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Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Chien-Wen Chen, Bo-Jhih Guan, Mohammed Alzahrani, Zhaofeng Gao, Long Gao, Syrena Bracey, Leena Haataja, Ashleigh Schaffer, Hugo Lee, Thomas Laframboise, Ilya Bederman, Peter Arvan, Clayton Mathews, Ivan Gerling, Klaus Kaestner, Boaz Tirosh, Feyza Engin, Maria Hatzoglou,

Pancreatic β-cells undergo high levels of endoplasmic reticulum (ER) stress due to their role in insulin secretion. Hence, they require sustainable and efficient adaptive stress responses to cope with the stress. Whether duration and episodes of chronic ER stress directly compromises β-cell identity is largely unknown. We show that under ... Read more >>

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Distinct states of proinsulin misfolding in MIDY

Leena Haataja, Anoop Arunagiri, Anis Hassan, Kaitlin Regan, Billy Tsai, Balamurugan Dhayalan, Michael Weiss, Ming Liu, Peter Arvan,

A precondition for efficient proinsulin export from the endoplasmic reticulum (ER) is that proinsulin meets ER quality control folding requirements, including formation of the Cys(B19)-Cys(A20) “interchain” disulfide bond, facilitating formation of the Cys(B7)-Cys(A7) bridge. The third proinsulin disulfide, Cys(A6)-Cys(A11), is not required for anterograde trafficking, i.e., a “lose-A6/A11” mutant [Cys(A6), ... Read more >>

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Altered β-Cell Prohormone Processing and Secretion in Type 1 Diabetes.

Teresa Rodriguez-Calvo, Yi-Chun Chen, C Bruce Verchere, Leena Haataja, Peter Arvan, Pia Leete, Sarah J Richardson, Noel G Morgan, Wei-Jun Qian, Alberto Pugliese, Mark Atkinson, Carmella Evans-Molina, Emily K Sims,

Analysis of data from clinical cohorts, and more recently from human pancreatic tissue, indicates that reduced prohormone processing is an early and persistent finding in type 1 diabetes. In this article, we review the current state of knowledge regarding alterations in islet prohormone expression and processing in type 1 diabetes ... Read more >>

Diabetes (Diabetes)
[2021, 70(5):1038-1050]

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Pathological β-Cell Endoplasmic Reticulum Stress in Type 2 Diabetes: Current Evidence.

Neha Shrestha, Elisa De Franco, Peter Arvan, Miriam Cnop,

The notion that in diabetes pancreatic β-cells express endoplasmic reticulum (ER) stress markers indicative of increased unfolded protein response (UPR) signaling is no longer in doubt. However, what remains controversial is whether this increase in ER stress response actually contributes importantly to the β-cell failure of type 2 diabetes (akin ... Read more >>

Front Endocrinol (Lausanne) (Frontiers in endocrinology)
[2021, 12:650158]

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Cell death-associated lipid droplet protein CIDE-A is a noncanonical marker of endoplasmic reticulum stress.

Yoshiaki Morishita, Aaron P Kellogg, Dennis Larkin, Wei Chen, Suryakiran Vadrevu, Leslie Satin, Ming Liu, Peter Arvan,

Secretory protein misfolding has been linked to ER stress and cell death. We expressed a TGrdw transgene encoding TG-G(2298)R, a misfolded mutant thyroglobulin reported to be linked to thyroid cell death. When the TGrdw transgene was expressed at low level in thyrocytes of TGcog/cog mice that experienced severe ER stress, ... Read more >>

JCI Insight (JCI insight)
[2021, 6(7):]

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Reduced replication fork speed promotes pancreatic endocrine differentiation and controls graft size.

Lina Sui, Yurong Xin, Qian Du, Daniela Georgieva, Giacomo Diedenhofen, Leena Haataja, Qi Su, Michael V Zuccaro, Jinrang Kim, Jiayu Fu, Yuan Xing, Yi He, Danielle Baum, Robin S Goland, Yong Wang, Jose Oberholzer, Fabrizio Barbetti, Peter Arvan, Sandra Kleiner, Dieter Egli,

Limitations in cell proliferation are important for normal function of differentiated tissues and essential for the safety of cell replacement products made from pluripotent stem cells, which have unlimited proliferative potential. To evaluate whether these limitations can be established pharmacologically, we exposed pancreatic progenitors differentiating from human pluripotent stem cells ... Read more >>

JCI Insight (JCI insight)
[2021, 6(5):]

Cited: 2 times

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Normal and defective pathways in biogenesis and maintenance of the insulin storage pool.

Ming Liu, Yumeng Huang, Xiaoxi Xu, Xin Li, Maroof Alam, Anoop Arunagiri, Leena Haataja, Li Ding, Shusen Wang, Pamela Itkin-Ansari, Randal J Kaufman, Billy Tsai, Ling Qi, Peter Arvan,

Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic β cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting β cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of β ... Read more >>

J Clin Invest (The Journal of clinical investigation)
[2021, 131(2):]

Cited: 1 time

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GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer.

Wei Zhou, Ben Brumpton, Omer Kabil, Julius Gudmundsson, Gudmar Thorleifsson, Josh Weinstock, Matthew Zawistowski, Jonas B Nielsen, Layal Chaker, Marco Medici, Alexander Teumer, Silvia Naitza, Serena Sanna, Ulla T Schultheiss, Anne Cappola, Juha Karjalainen, Mitja Kurki, Morgan Oneka, Peter Taylor, Lars G Fritsche, Sarah E Graham, Brooke N Wolford, William Overton, Humaira Rasheed, Eirin B Haug, Maiken E Gabrielsen, Anne Heidi Skogholt, Ida Surakka, George Davey Smith, Anita Pandit, Tanmoy Roychowdhury, Whitney E Hornsby, Jon G Jonasson, Leigha Senter, Sandya Liyanarachchi, Matthew D Ringel, Li Xu, Lambertus A Kiemeney, Huiling He, Romana T Netea-Maier, Jose I Mayordomo, Theo S Plantinga, Jon Hrafnkelsson, Hannes Hjartarson, Erich M Sturgis, Aarno Palotie, Mark Daly, Cintia E Citterio, Peter Arvan, Chad M Brummett, Michael Boehnke, Albert de la Chapelle, Kari Stefansson, Kristian Hveem, Cristen J Willer, Bjørn Olav Åsvold,

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional ... Read more >>

Nat Commun (Nature communications)
[2020, 11(1):3981]

Cited: 2 times

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Biological behaviors of mutant proinsulin contribute to the phenotypic spectrum of diabetes associated with insulin gene mutations.

Heting Wang, Cécile Saint-Martin, Jialu Xu, Li Ding, Ruodan Wang, Wenli Feng, Ming Liu, Hua Shu, Zhenqian Fan, Leena Haataja, Peter Arvan, Christine Bellanné-Chantelot, Jingqiu Cui, Yumeng Huang,

Insulin gene mutation is the second most common cause of neonatal diabetes (NDM). It is also one of the genes involved in maturity-onset diabetes of the young (MODY). We aim to investigate molecular behaviors of different INS gene variants that may correlate with the clinical spectrum of diabetes phenotypes. In ... Read more >>

Mol Cell Endocrinol (Molecular and cellular endocrinology)
[2020, 518:111025]

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Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling.

Neha Shrestha, Tongyu Liu, Yewei Ji, Rachel B Reinert, Mauricio Torres, Xin Li, Maria Zhang, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, Chengyang Liu, Ali Naji, Ming Liu, Jiandie D Lin, Sander Kersten, Peter Arvan, Ling Qi,

β Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying β cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while ... Read more >>

J Clin Invest (The Journal of clinical investigation)
[2020, 130(7):3499-3510]

Cited: 9 times

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Abnormalities in proinsulin processing in islets from individuals with longstanding T1D.

Emily K Sims, Farooq Syed, Julius Nyalwidhe, Henry T Bahnson, Leena Haataja, Cate Speake, Margaret A Morris, Appakalai N Balamurugan, Raghavendra G Mirmira, Jerry Nadler, Teresa L Mastracci, Peter Arvan, Carla J Greenbaum, Carmella Evans-Molina,

We recently described the persistence of detectable serum proinsulin in a large majority of individuals with longstanding type 1 diabetes (T1D), including individuals with undetectable serum C-peptide. Here, we sought to further explore the mechanistic etiologies of persistent proinsulin secretion in T1D at the level of the islet, using tissues ... Read more >>

Transl Res (Translational research : the journal of laboratory and clinical medicine)
[2019, 213:90-99]

Cited: 11 times

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The type 2 diabetes gene product STARD10 is a phosphoinositide binding protein that controls insulin secretory granule biogenesis

Gaelle Carrat, Elizabeth Haythorne, Alejandra Tomas, Leena Haataja, Andreas Müller, Peter Arvan, Alexandra Piunti, Kaiying Cheng, Mutian Huang, Timothy Pullen, Eleni Georgiadou, Theodoros Stylianides, Nur Shabrina Amirruddin, Victoria Salem, Walter Distaso, Andrew Cakebread, Kate Heesom, Philip Lewis, David Hodson, Linford Briant, Annie C.H. Fung, Richard Sessions, Fabien Alpy, Alice P.S. Kong, Peter Benke, Federico Torta, Adrian Kee Keong Teo, Isabelle Leclerc, Michele Solimena, Dale Wigley, Guy Rutter,

<h4>Objective</h4> Risk alleles for type 2 diabetes at the STARD10 locus are associated with lowered STARD10 expression in the β-cell, impaired glucose-induced insulin secretion and decreased circulating proinsulin:insulin ratios. Although likely to serve as a mediator of intracellular lipid transfer, the identity of the transported lipids, and thus the pathways ... Read more >>

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In vivo imaging of individual islets across the mouse pancreas reveals a heterogeneous insulin secretion response to glucose

Henriette Frikke-Schmidt, Peter Arvan, Randy Seeley, Corentin Cras-Méneur,

While numerous techniques can be used to measure and analyze insulin secretion in isolated islets in culture, assessments of insulin secretion in vivo are typically indirect and only semiquantitative. The CpepSfGFP reporter mouse line allows the in vivo imaging of insulin secretion from individual islets after a glucose challenge, in ... Read more >>

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Unbiased Profiling of the Human Proinsulin Biosynthetic Interaction Network Reveals a Role for Peroxiredoxin 4 in Proinsulin Folding.

Duc T Tran, Anita Pottekat, Saiful A Mir, Salvatore Loguercio, Insook Jang, Alexandre Rosa Campos, Kathleen M Scully, Reyhaneh Lahmy, Ming Liu, Peter Arvan, William E Balch, Randal J Kaufman, Pamela Itkin-Ansari,

The β-cell protein synthetic machinery is dedicated to the production of mature insulin, which requires the proper folding and trafficking of its precursor, proinsulin. The complete network of proteins that mediate proinsulin folding and advancement through the secretory pathway, however, remains poorly defined. Here we used affinity purification and mass ... Read more >>

Diabetes (Diabetes)
[2020, 69(8):1723-1734]

Cited: 2 times

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SUN-669 The G209R Mutant Mouse as a Model for Human PCSK1 Polyendocrinopathy

Manita Shakya, Surbhi Gahlot, Anoop Arunagiri, Anis Hassan, Peter Arvan, Malcolm James Low, Iris Lindberg,

Abstract A striking number of SNPs and rare mutations have been identified in PCSK1, the gene that codes for the enzyme proprotein convertase 1/3 (PC1/3) which proteolytically activates prohormones within the secretory pathway. All infants bearing two copies of catalytically inactivating mutations, including G209R, exhibit severe neonatal malabsorption requiring parenteral ... Read more >>

J Endocr Soc (Journal of the Endocrine Society)
[2020, 4(Suppl 1):]

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p.L571P in the linker domain of rat thyroglobulin causes intracellular retention.

Cintia E Citterio, Sofia Siffo, Christian M Moya, Mauricio Gomes Pio, Maricel F Molina, Karen G Scheps, Osvaldo A Rey, Peter Arvan, Carina M Rivolta, Héctor M Targovnik,

Thyroglobulin (TG), a large glycosylated protein secreted by thyrocytes into the thyroid follicular lumen, plays an essential role in thyroid hormone biosynthesis. Rattus norvegicus TG (rTG) is encoded by a large single copy gene, 186-kb long, located on chromosome 7 composed of 48 exons encoding a 8461-kb mRNA. Although the ... Read more >>

Mol Cell Endocrinol (Molecular and cellular endocrinology)
[2020, 505:110719]

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Establishing cell-intrinsic limitations in cell cycle progression controls graft growth and promotes differentiation of pancreatic endocrine cells

Lina Sui, Yurong Xin, Daniela Georgieva, Giacomo Diedenhofen, Leena Haataja, Qi Su, Yong Wang, Michael Zuccaro, Jinrang Kim, Jiayu Fu, Yuan Xing, Danielle Baum, Robin Goland, Jose Oberholzer, Fabrizio Barbetti, Peter Arvan, Sandra Kleiner, Dieter Egli,

Limitations in cell proliferation are a key barrier to reprogramming differentiated cells to pluripotent stem cells, and conversely, acquiring these limitations may be important to establish the differentiated state. The pancreas, and beta cells in particular have a low proliferative potential, which limits regeneration, but how these limitations are established ... Read more >>

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Epitope-tagging of the endogenous murine BiP/GRP78/Hspa5locus allows direct analysis of the BiP interactome and protein misfoldingin vivo

Yunqian Peng, Zhouji Chen, Peter Arvan, Randal Kaufman,

<h4>ABSTRACT</h4> BiP/GRP78, encoded by the Hspa5 gene, is the major HSP70 family member in the endoplasmic reticulum (ER) lumen, and controls ER protein folding. BiP’s essential functions in facilitating proper protein folding are mainly mediated through its dynamic interaction with unfolded or misfolded client proteins, and by serving as a ... Read more >>

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Requirement for translocon-associated protein (TRAP) α in insulin biogenesis.

Xin Li, Omar A Itani, Leena Haataja, Kathleen J Dumas, Jing Yang, Jeeyeon Cha, Stephane Flibotte, Hung-Jen Shih, Colin E Delaney, Jialu Xu, Ling Qi, Peter Arvan, Ming Liu, Patrick J Hu,

The mechanistic basis for the biogenesis of peptide hormones and growth factors is poorly understood. Here, we show that the conserved endoplasmic reticulum membrane translocon-associated protein α (TRAPα), also known as signal sequence receptor 1, plays a critical role in the biosynthesis of insulin. Genetic analysis in the nematode Caenorhabditis ... Read more >>

Sci Adv (Science advances)
[2019, 5(12):eaax0292]

Cited: 4 times

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Role of Proinsulin Self-Association in Mutant INS gene-induced Diabetes of Youth

Jinhong Sun, Yi Xiong, Xin Li, Leena Haataja, Wei Chen, Saiful Mir, Rachel Madley, Dennis Larkin, Arfah Anjum, Balamurugan Dhayalan, Nischay Rege, Nalinda Wickramasinghe, Michael Weiss, Pamela Itkin-Ansari, Randal Kaufman, David Ostrov, Peter Arvan, Ming Liu,

Abnormal interactions between misfolded mutant and wild-type (WT) proinsulin in the endoplasmic reticulum (ER) drive the molecular pathogenesis of Mutant- INS -gene induced Diabetes of Youth (MIDY). How these abnormal interactions are initiated remains unknown. Normally, proinsulin-WT dimerizes in the ER. Here, we suggest that the normal proinsulin-proinsulin contact surface, ... Read more >>

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A reference map of the human proinsulin biosynthetic interaction network

Duc Tran, Anita Pottekat, Saiful Mir, Insook Jang, Salvatore Loguercio, Alexandre Rosa Campos, Reyhaneh Lahmy, Ming Liu, Peter Arvan, William Balch, Randal Kaufman, Pamela Itkin-Ansari,

The beta-cell protein synthetic machinery is dedicated to the production of insulin, which plays a critical role in organismal homeostasis. Insulin synthesis requires the proper folding and trafficking of its precursor, proinsulin, yet the precise network of proinsulin protein interactions in the secretory pathway remains poorly defined. In the present ... Read more >>

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