Welcome. The central focus of this laboratory is to examine molecular mechanisms involved in the folding, trafficking, and targeting of newly-synthesized endocrine secretory proteins.
Projects currently concentrate on two cell types relevant to issues of health and disease:
- pancreatic beta cells that store insulin in secretory granules for release to the bloodstream in response to an increase in blood glucose or other secretagogues, and
- thyroid epithelial cells that use thyroglobulin (Tg) as a precursor for iodination in the synthesis of thyroid hormone. In these cell types, the lab is particularly interested in protein interactions that allow the secretory pathway [comprising the endoplasmic reticulum (ER), Golgi complex, secretory vesicles, as well as organelles of the endosome-lysosome-autophagosome system] to optimize production of polypeptide-derived hormones.
Secretory Protein Folding, Sorting, and Targeting
1a). We are investigating proinsulin folding in the endoplasmic reticulum (ER). Recent evidence strongly implicates that proinsulin misfolding takes place in various genetic forms of diabetes mellitus. As a flagship example, we are investigating mutations in the coding sequence of preproinsulin, which (depending upon the particular mutant allele) trigger autosomal dominant diabetes that can begin as early as the neonatal period or as late as young adulthood. We have named this disease as Mutant INS gene-induced Diabetes of Youth (MIDY). We have been characterizing the misfolding of various MIDY mutants as well as exploring the molecular mechanisms by which the mutant proinsulin impairs production of insulin derived from the nonmutant INS allele. As a model, we examine mice bearing one of several MIDY mutations in just one or two of the four alleles encoding mouse insulin.
1b). We are interested in the most common form of diabetes known as "type 2" diabetes. We have identified misfolded isoforms of proinsulin by virtue of mispaired disulfide bonds, and examined interactions of these misfolded forms with endoplasmic reticulum (ER) molecular chaperones. Our evidence suggest that the formation of intermolecular disulfide-linked proinsulin complexes occurs even before the initial onset of diabetes in the db/db (leptin receptor-deficient) diabetic mouse. The misfolding appears to occur within the ER, and is linked to an increase in markers of ‘ER stress’.
1c). We are interested in early aspects of preproinsulin biosynthesis, including initial translation of the INS mRNA, leading to the translocation of newly-synthesized preproinsulin from the cytosol across the ER membrane to enter the secretory pathway. We have been defining the role of various accessory proteins of the ER membrane that assist in preproinsulin translocation.
1d). We are concentrating on ways to modulate the ER environment to impact on proinsulin folding, in the hope of developing small molecules that may be of benefit to insulin production, as well as manipulation of ER oxidoreductase activity. We have also developed a fluorescent proinsulin (called hPro-CpepSfGFP) and mice expressing this fluorescent proinsulin exclusively in pancreatic beta cells. The hPro-CpepSfGFP allows for production of authentic human insulin as well as stoichiometric quantities of fluorescent C-peptide, which can be followed by fluorescence microscopy in live mice as a quantifiable measure of pancreatic insulin content. The animals can then be mated to various genetic models of diabetes.
2a). We have been concentrating on humans and mice with congenital hypothyroidism caused by an Endoplasmic Reticulum Storage Disease as a consequence of expression of misfolded mutant thyroglobulin (Tg). Many human families have been described with the disease, and the thyroglobulin mutations in these families are known. We cloned the mutation causing congenital goiter in cog/cog mice, and this involves a single amino acid change contained within the carboxy-terminal cholinesterase-like (ChEL) domain of Tg. This same domain is also involved in cases of human hypothyroidism, as it functions as an intramolecular chaperone for the upstream part of the Tg protein.
2b). Congenital hypothyroidism in the rat dwarf (rdw/rdw) is also caused by a single point mutation in the ChEL domain. However, the dwarf rat develops an unusually hypoplastic (small) thyroid gland despite an increased in the blood levels of the growth promoting hormone known as "thyroid stimulating hormone" (TSH). We have been concentrating on the hypothesis that, as a consequence of expression of the mutant Tg protein, thyroid cell death from ER stress occurs in mice, rats, and humans with the disease.
2c). Congenital hypothyroidism from homozygous mutant TG gene is uncommon but heterozygotes are quite common in the human population although they routinely go undiagnosed. We find that heterozygous expression of mutant mouse Tg protein already triggers dramatic ER stress from the accumulated misfolded secretory protein. Studies indicate that the mutant Tg protein is not so easy to completely degrade. The degradation process known as ERAD (ER-associated degradation), is under active investigation in our mouse models.
2d). Each individual monomer of Tg is stabilized by a large number of intramolecular disulfide bonds. Tg is ultimately a homodimeric protein. Our recent studies suggest that Tg secretion, and some thyroid hormone synthesis, depends upon a dimeric structure. We are particularly interested in further understanding the formation and importance of various specific Tg disulfide bonds.
Peter Arvan, MD, PhD
Chief, Division of Metabolism, Endocrinology & Diabetes
Maroof Alam, PhD
Anoop Arunagiri, PhD
Cintia Citterio, PhD
Leena Haataja, PhD
Associate Research Scientist
Bhoomanyu Malik, MD
Xiaoxi Xu, MD
Visiting Research Investigator
Xiaohan Zhang, MD
- Thyrocyte Protein Transport to the Cell Surface, NIDDK
- Peptide Hormone Sorting to the Secretory/Storage Granule, NIDDK
- High Quality Proinsulin Folding Requires ERAD of Proinsulin, NIDDK
- Modifiers of Proinsulin Influence T2D Susceptibility, NIDDK
- Multidisciplinary Training Program in Basic Diabetes Research, NIDDK
The Structure of Natively Iodinated Bovine Thyroglobulin
Kim K, Kopylov M, Bobe D, Kelley K, Eng ET, Arvan P, Clarke OB. Acta Crystallogr D Struct Biol. 2021 Nov 1;77(Pt 11):1451-1459. doi: 10.1107/S2059798321010056. Epub 2021 Oct 29.PMID: 34726172
Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes
Alam M, Arunagiri A, Haataja L, Torres M, Larkin D, Kappler J, Jin N, Arvan P. Diabetes. 2021 Nov;70(11):2580-2594. doi: 10.2337/db21-0422. Epub 2021 Aug 30.PMID: 34462258
Distinct States of Proinsulin Misfolding in MIDY
Haataja L, Arunagiri A, Hassan A, Regan K, Tsai B, Dhayalan B, Weiss MA, Liu M, Arvan P. Cell Mol Life Sci. 2021 Aug;78(16):6017-6031. doi: 10.1007/s00018-021-03871-1. Epub 2021 Jul 10.PMID: 34245311
Thyroid Hormone Synthesis Continues Despite Biallelic Thyroglobulin Mutation with Cell Death
Zhang X, Kellogg AP, Citterio CE, Zhang H, Larkin D, Morishita Y, Targovnik HM, Balbi VA, Arvan P. JCI Insight. 2021 Jun 8;6(11):e148496. doi: 10.1172/jci.insight.148496.PMID: 33914707
Deficient Endoplasmic Reticulum Translocon-Associated Protein Complex Limits the Biosynthesis of Proinsulin and Insulin
Huang Y, Xu X, Arvan P, Liu M. FASEB J. 2021 May;35(5):e21515. doi: 10.1096/fj.202002774R.PMID: 33811688
Cell Death-Associated Lipid Droplet Protein CIDE-A Is a Noncanonical Marker of Endoplasmic Reticulum Stress
Morishita Y, Kellogg AP, Larkin D, Chen W, Vadrevu S, Satin L, Liu M, Arvan P. JCI Insight. 2021 Apr 8;6(7):e143980. doi: 10.1172/jci.insight.143980.PMID: 33661766
Normal and Defective Pathways in Biogenesis and Maintenance of the Insulin Storage Pool
Liu M, Huang Y, Xu X, Li X, Alam M, Arunagiri A, Haataja L, Ding L, Wang S, Itkin-Ansari P, Kaufman RJ, Tsai B, Qi L, Arvan P. J Clin Invest. 2021 Jan 19;131(2):e142240. doi: 10.1172/JCI142240.PMID: 33463547 Review
Improved In Vivo Imaging Method for Individual Islets Across the Mouse Pancreas Reveals a Heterogeneous Insulin Secretion Response to Glucose
Frikke-Schmidt H, Arvan P, Seeley RJ, Cras-Méneur C. Sci Rep. 2021 Jan 12;11(1):603. doi: 10.1038/s41598-020-79727-8.PMID: 33436691
Evolution of Insulin at the Edge of Foldability and Its Medical Implications
Rege NK, Liu M, Yang Y, Dhayalan B, Wickramasinghe NP, Chen YS, Rahimi L, Guo H, Haataja L, Sun J, Ismail-Beigi F, Phillips NB, Arvan P, Weiss MA. Proc Natl Acad Sci U S A. 2020 Nov 24;117(47):29618-29628. doi: 10.1073/pnas.2010908117. Epub 2020 Nov 5.PMID: 33154160
Unbiased Profiling of the Human Proinsulin Biosynthetic Interaction Network Reveals a Role for Peroxiredoxin 4 in Proinsulin Folding
Tran DT, Pottekat A, Mir SA, Loguercio S, Jang I, Campos AR, Scully KM, Lahmy R, Liu M, Arvan P, Balch WE, Kaufman RJ, Itkin-Ansari P. Diabetes. 2020 Aug;69(8):1723-1734. doi: 10.2337/db20-0245. Epub 2020 May 26.PMID: 32457219
Thyrocyte Cell Survival and Adaptation to Chronic Endoplasmic Reticulum Stress Due to Misfolded Thyroglobulin
Morishita Y, Kabil O, Young KZ, Kellogg AP, Chang A, Arvan P. J Biol Chem. 2020 May 15;295(20):6876-6887. doi: 10.1074/jbc.RA120.012656. Epub 2020 Apr 2.PMID: 32241916
Sel1L-Hrd1 ER-Associated Degradation Maintains β Cell Identity via TGF-β signaling
Shrestha N, Liu T, Ji Y, Reinert RB, Torres M, Li X, Zhang M, Tang CA, Hu CA, Liu C, Naji A, Liu M, Lin JD, Kersten S, Arvan P, Qi L. J Clin Invest. 2020 Jul 1;130(7):3499-3510. doi: 10.1172/JCI134874.PMID: 32182217
Role of Proinsulin Self-Association in Mutant INS Gene-Induced Diabetes of Youth
Sun J, Xiong Y, Li X, Haataja L, Chen W, Mir SA, Lv L, Madley R, Larkin D, Anjum A, Dhayalan B, Rege N, Wickramasinghe NP, Weiss MA, Itkin-Ansari P, Kaufman RJ, Ostrov DA, Arvan P, Liu M. Diabetes. 2020 May;69(5):954-964. doi: 10.2337/db19-1106. Epub 2020 Mar 5.PMID: 32139596
Reticulon Protects the Integrity of the ER Membrane During ER Escape of Large Macromolecular Protein Complexes
Chen YJ, Williams JM, Arvan P, Tsai B. J Cell Biol. 2020 Feb 3;219(2):e201908182. doi: 10.1083/jcb.201908182.PMID: 31895406
Requirement for Translocon-Associated Protein (TRAP) α in Insulin Biogenesis
Li X, Itani OA, Haataja L, Dumas KJ, Yang J, Cha J, Flibotte S, Shih HJ, Delaney CE, Xu J, Qi L, Arvan P, Liu M, Hu PJ. Sci Adv. 2019 Dec 4;5(12):eaax0292. doi: 10.1126/sciadv.aax0292. eCollection 2019 Dec.PMID: 31840061
Proinsulin Misfolding Is an Early Event in the Progression to Type 2 Diabetes
Arunagiri A, Haataja L, Pottekat A, Pamenan F, Kim S, Zeltser LM, Paton AW, Paton JC, Tsai B, Itkin-Ansari P, Kaufman RJ, Liu M, Arvan P. Elife. 2019 Jun 11;8:e44532. doi: 10.7554/eLife.44532.PMID: 31184302
Cells Deploy a Two-Pronged Strategy to Rectify Misfolded Proinsulin Aggregates
Cunningham CN, Williams JM, Knupp J, Arunagiri A, Arvan P, Tsai B. Mol Cell. 2019 Aug 8;75(3):442-456.e4. doi: 10.1016/j.molcel.2019.05.011. Epub 2019 Jun 5.PMID: 31176671
The Role of Thyroglobulin in Thyroid Hormonogenesis
Citterio CE, Targovnik HM, Arvan P. Nat Rev Endocrinol. 2019 Jun;15(6):323-338. doi: 10.1038/s41574-019-0184-8.PMID: 30886364 Review
In the News
- Dr. Peter Arvan - Unraveling the Manufacturing Process - Department of Internal Medicine News, January 2020
- How Proinsulin Misfolding Is a Prelude to Type 2 Diabetes - Michigan Medicine Health Lab, October 2019
- Is Type 2 Diabetes Reversible? - U.S. News & World Report, April 2019
- Researching Proinsulin Misfolding to Understand Diabetes - Michigan Medicine Health Lab, November 2016
- Weird Aches, Dry Skin, Horrible Fatigue, Puffy Face: I Had a Thyroid Problem - The Washington Post, May 2016
- Shining a Light on Pancreatic Insulin - Michigan Medicine Health Lab, March 2016
Contact Info. & Useful Links
University of Michigan Health System
Brehm Center for Diabetes Research
1000 Wall Street, 5th floor Brehm Tower
Ann Arbor, MI 48105
Campus Address: Suite 5100 Brehm Tower, SPC 5714
Peter Arvan, MD, PhD
Sheila Tarasow, Division Chief Assistant
phone: (734) 936-5505
fax: (734) 936-6684