Defective insulin maturation in patients with type 2 diabetes

in European Journal of Endocrinology
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  • 1 Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
  • | 2 Tianjin Research Institute of Endocrinology, Tianjin, China
  • | 3 Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin, China
  • | 4 NHC Key Laboratory for Critical Care Medicine, Tianjin First Central Hospital, Tianjin, China

Correspondence should be addressed to S Wang or M Liu; Email: shusen@vip.163.com or mingliu@tmu.edu.cn

*(Y Huang, J Zhen and T Liu contributed equally to this work)

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Objective

Progressive beta-cell dysfunction is a hallmark of type 2 diabetes (T2D). Increasing evidence indicates that over-stimulating proinsulin synthesis causes proinsulin misfolding and impairs insulin maturation and storage in db/db mice. However, defective insulin maturation in patients with T2D remains unknown.

Methods

We examined intra-islet and intra-cellular distributions of proinsulin and insulin and proinsulin to insulin ratio in the islets of patients with T2D. The expression of transcription factor NKX6.1 and dedifferentiation marker ALDH1A3, as well as glucagon, were detected by immunofluorescence.

Results

We identified a novel subgroup of beta cells expressing only proinsulin but not insulin. Importantly, significantly increased proinsulin positive and insulin negative (PI+/INS) cells were evident in T2D, and this increase was strongly correlated with levels of hemoglobin A1C (HbA1c) in T2D and prediabetes. The percentages of beta cells expressing prohormone convertase 1/3 and carboxypeptidase E were not reduced. Indeed, while proinsulin displayed a higher degree of co-localization with the golgi markers GM130/TGN46 in control beta cells, it appeared to be more diffused within the cytoplasm and less co-localized with GM130/TGN46 in PI+/INS cells. Furthermore, the key functional transcription factor NKX6.1 markedly decreased in the islets of T2D, especially in the cells with PI+/INS. The decreased NKX6.1+/PI+/INS+ was strongly correlated with levels of HbA1c in T2D. Almost all PI+/INS cells showed absence of NKX6.1. Moreover, the percentages of PI+/INS cells expressing ALDH1A3 were elevated along with an increased acquisition of glucagon immunostaining.

Conclusion

Our data demonstrate defective insulin maturation in patients with T2D.

 

     European Society of Endocrinology

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  • 1

    Liu M, Huang Y, Xu X, Li X, Alam M, Arunagiri A, Haataja L, Ding L, Wang S & Itkin-Ansari P et al.Normal and defective pathways in biogenesis and maintenance of the insulin storage pool. Journal of Clinical Investigation 2021 131 e142240. (https://doi.org/10.1172/JCI142240)

    • Search Google Scholar
    • Export Citation
  • 2

    Sun J, Cui J, He Q, Chen Z, Arvan P, Liu M. Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes. Molecular Aspects of Medicine 2015 42 105118. (https://doi.org/10.1016/j.mam.2015.01.001)

    • Search Google Scholar
    • Export Citation
  • 3

    Schuit FC, In’t Veld PA, Pipeleers DG. Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells. PNAS 1988 85 38653869. (https://doi.org/10.1073/pnas.85.11.3865)

    • Search Google Scholar
    • Export Citation
  • 4

    Liu M, Weiss MA, Arunagiri A, Yong J, Rege N, Sun J, Haataja L, Kaufman RJ, Arvan P. Biosynthesis, structure, and folding of the insulin precursor protein. Diabetes, Obesity and Metabolism 2018 20 (Supplement 2) 2850. (https://doi.org/10.1111/dom.13378)

    • Search Google Scholar
    • Export Citation
  • 5

    Liu M, Li Y, Cavener D, Arvan P. Proinsulin disulfide maturation and misfolding in the endoplasmic reticulum. Journal of Biological Chemistry 2005 280 1320913212. (https://doi.org/10.1074/jbc.C400475200)

    • Search Google Scholar
    • Export Citation
  • 6

    Liu M, Hodish I, Rhodes CJ, Arvan P. Proinsulin maturation, misfolding, and proteotoxicity. PNAS 2007 104 1584115846. (https://doi.org/10.1073/pnas.0702697104)

    • Search Google Scholar
    • Export Citation
  • 7

    Zito E, Chin KT, Blais J, Harding HP, Ron D. ERO1-beta, a pancreas-specific disulfide oxidase, promotes insulin biogenesis and glucose homeostasis. Journal of Cell Biology 2010 188 821832. (https://doi.org/10.1083/jcb.200911086)

    • Search Google Scholar
    • Export Citation
  • 8

    Tsuchiya Y, Saito M, Kadokura H, Miyazaki JI, Tashiro F, Imagawa Y, Iwawaki T, Kohno K. IRE1-XBP1 pathway regulates oxidative proinsulin folding in pancreatic beta cells. Journal of Cell Biology 2018 217 12871301. (https://doi.org/10.1083/jcb.201707143)

    • Search Google Scholar
    • Export Citation
  • 9

    Arunagiri A, Haataja L, Pottekat A, Pamenan F, Kim S, Zeltser LM, Paton AW, Paton JC, Tsai B & Itkin-Ansari P et al.Proinsulin misfolding is an early event in the progression to type 2 diabetes. eLife 2019 8 e44532. (https://doi.org/10.7554/eLife.44532)

    • Search Google Scholar
    • Export Citation
  • 10

    Liu S, Li X, Yang J, Zhu R, Fan Z, Xu X, Feng W, Cui J, Sun J, Liu M. Misfolded proinsulin impairs processing of precursor of insulin receptor and insulin signaling in beta cells. FASEB Journal 2019 33 1133811348. (https://doi.org/10.1096/fj.201900442R)

    • Search Google Scholar
    • Export Citation
  • 11

    Zhu R, Li X, Xu J, Barrabi C, Kekulandara D, Woods J, Chen X, Liu M. Defective endoplasmic reticulum export causes proinsulin misfolding in pancreatic beta cells. Molecular and Cellular Endocrinology 2019 493 110470. (https://doi.org/10.1016/j.mce.2019.110470)

    • Search Google Scholar
    • Export Citation
  • 12

    Sun J, Xiong Y, Li X, Haataja L, Chen W, Mir SA, Lv L, Madley R, Larkin D & Anjum A et al.Role of proinsulin self-association in mutant INS Gene-induced diabetes of youth. Diabetes 2020 69 954964. (https://doi.org/10.2337/db19-1106)

    • Search Google Scholar
    • Export Citation
  • 13

    Liu M, Hodish I, Haataja L, Lara-Lemus R, Rajpal G, Wright J, Arvan P. Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth. Trends in Endocrinology and Metabolism 2010 21 652659. (https://doi.org/10.1016/j.tem.2010.07.001)

    • Search Google Scholar
    • Export Citation
  • 14

    Liu M, Sun J, Cui J, Chen W, Guo H, Barbetti F, Arvan P. INS-gene mutations: from genetics and beta cell biology to clinical disease. Molecular Aspects of Medicine 2015 42 318. (https://doi.org/10.1016/j.mam.2014.12.001)

    • Search Google Scholar
    • Export Citation
  • 15

    Wang H, Saint-Martin C, Xu J, Ding L, Wang R, Feng W, Liu M, Shu H, Fan Z & Haataja L et al.Biological behaviors of mutant proinsulin contribute to the phenotypic spectrum of diabetes associated with insulin gene mutations. Molecular and Cellular Endocrinology 2020 518 111025. (https://doi.org/10.1016/j.mce.2020.111025)

    • Search Google Scholar
    • Export Citation
  • 16

    Arunagiri A, Haataja L, Cunningham CN, Shrestha N, Tsai B, Qi L, Liu M, Arvan P. Misfolded proinsulin in the endoplasmic reticulum during development of beta cell failure in diabetes. Annals of the New York Academy of Sciences 2018 1418 519. (https://doi.org/10.1111/nyas.13531)

    • Search Google Scholar
    • Export Citation
  • 17

    Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E, Mori M. Targeted disruption of the chop gene delays endoplasmic reticulum stress-mediated diabetes. Journal of Clinical Investigation 2002 109 525532. (https://doi.org/10.1172/JCI14550)

    • Search Google Scholar
    • Export Citation
  • 18

    Colombo C, Porzio O, Liu M, Massa O, Vasta M, Salardi S, Beccaria L, Monciotti C, Toni S & Pedersen O et al.Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. Journal of Clinical Investigation 2008 118 21482156. (https://doi.org/10.1172/JCI33777)

    • Search Google Scholar
    • Export Citation
  • 19

    Huang CJ, Haataja L, Gurlo T, Butler AE, Wu X, Soeller WC, Butler PC. Induction of endoplasmic reticulum stress-induced beta-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide. American Journal of Physiology: Endocrinology and Metabolism 2007 293 E1656E 1662. (https://doi.org/10.1152/ajpendo.00318.2007)

    • Search Google Scholar
    • Export Citation
  • 20

    Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 2007 50 752763. (https://doi.org/10.1007/s00125-006-0590-z)

    • Search Google Scholar
    • Export Citation
  • 21

    Fonseca SG, Burcin M, Gromada J, Urano F. Endoplasmic reticulum stress in beta-cells and development of diabetes. Current Opinion in Pharmacology 2009 9 763770. (https://doi.org/10.1016/j.coph.2009.07.003)

    • Search Google Scholar
    • Export Citation
  • 22

    Costes S, Huang CJ, Gurlo T, Daval M, Matveyenko AV, Rizza RA, Butler AE, Butler PC. Beta-cell dysfunctional ERAD/ubiquitin/proteasome system in type 2 diabetes mediated by islet amyloid polypeptide-induced UCH-L1 deficiency. Diabetes 2011 60 227238. (https://doi.org/10.2337/db10-0522)

    • Search Google Scholar
    • Export Citation
  • 23

    Spijker HS, Song H, Ellenbroek JH, Roefs MM, Engelse MA, Bos E, Koster AJ, Rabelink TJ, Hansen BC & Clark A et al.Loss of beta-cell identity occurs in type 2 diabetes and Is associated with islet amyloid deposits. Diabetes 2015 64 29282938. (https://doi.org/10.2337/db14-1752)

    • Search Google Scholar
    • Export Citation
  • 24

    Jonas JC, Sharma A, Hasenkamp W, Ilkova H, Patane G, Laybutt R, Bonner-Weir S, Weir GC. Chronic hyperglycemia triggers loss of pancreatic beta cell differentiation in an animal model of diabetes. Journal of Biological Chemistry 1999 274 1411214121. (https://doi.org/10.1074/jbc.274.20.14112)

    • Search Google Scholar
    • Export Citation
  • 25

    Guo S, Dai C, Guo M, Taylor B, Harmon JS, Sander M, Robertson RP, Powers AC, Stein R. Inactivation of specific beta cell transcription factors in type 2 diabetes. Journal of Clinical Investigation 2013 123 33053316. (https://doi.org/10.1172/JCI65390)

    • Search Google Scholar
    • Export Citation
  • 26

    Ramzy A, Asadi A, Kieffer TJ. Revisiting proinsulin processing: evidence that human beta-cells process proinsulin with prohormone convertase (PC) 1/3 but not PC2. Diabetes 2020 69 14511462. (https://doi.org/10.2337/db19-0276)

    • Search Google Scholar
    • Export Citation
  • 27

    Aigha II, Abdelalim EM. NKX6.1 transcription factor: a crucial regulator of pancreatic beta cell development, identity, and proliferation. Stem Cell Research and Therapy 2020 11 459. (https://doi.org/10.1186/s13287-020-01977-0)

    • Search Google Scholar
    • Export Citation
  • 28

    Burke SJ, Batdorf HM, Burk DH, Noland RC, Eder AE, Boulos MS, Karlstad MD, Collier JJ. Db mice exhibit features of human type 2 diabetes that are not present in weight-matched C57BL/6J mice fed a western diet. Journal of Diabetes Research 2017 2017 8503754. (https://doi.org/10.1155/2017/8503754)

    • Search Google Scholar
    • Export Citation
  • 29

    Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, Marselli L, Suleiman M, Ratner LE & Marchetti P et al.Evidence of beta-cell dedifferentiation in human type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 2016 101 10441054. (https://doi.org/10.1210/jc.2015-2860)

    • Search Google Scholar
    • Export Citation
  • 30

    Talchai C, Xuan S, Lin HV, Sussel L, Accili D. Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 2012 150 12231234. (https://doi.org/10.1016/j.cell.2012.07.029)

    • Search Google Scholar
    • Export Citation
  • 31

    Tersey SA, Levasseur EM, Syed F, Farb TB, Orr KS, Nelson JB, Shaw JL, Bokvist K, Mather KJ, Mirmira RG. Episodic beta-cell death and dedifferentiation during diet-induced obesity and dysglycemia in male mice. FASEB Journal 2018 32 fj201800150RR. (https://doi.org/10.1096/fj.201800150RR)

    • Search Google Scholar
    • Export Citation
  • 32

    Sims EK, Chaudhry Z, Watkins R, Syed F, Blum J, Ouyang F, Perkins SM, Mirmira RG, Sosenko J & DiMeglio LA et al.Elevations in the fasting serum proinsulin-to-C-peptide ratio precede the onset of type 1 diabetes. Diabetes Care 2016 39 15191526. (https://doi.org/10.2337/dc15-2849)

    • Search Google Scholar
    • Export Citation
  • 33

    Pradhan AD, Manson JE, Meigs JB, Rifai N, Buring JE, Liu S, Ridker PM. Insulin, proinsulin, proinsulin:insulin ratio, and the risk of developing type 2 diabetes mellitus in women. American Journal of Medicine 2003 114 438444. (https://doi.org/10.1016/s0002-9343(0300061-5)

    • Search Google Scholar
    • Export Citation
  • 34

    Rodriguez-Calvo T, Zapardiel-Gonzalo J, Amirian N, Castillo E, Lajevardi Y, Krogvold L, Dahl-Jorgensen K, von Herrath MG. Increase in pancreatic proinsulin and preservation of beta-cell mass in autoantibody-positive donors prior to type 1 diabetes onset. Diabetes 2017 66 13341345. (https://doi.org/10.2337/db16-1343)

    • Search Google Scholar
    • Export Citation
  • 35

    Sims EK, Syed F, Nyalwidhe J, Bahnson HT, Haataja L, Speake C, Morris MA, Balamurugan AN, Mirmira RG & Nadler J et al.Abnormalities in proinsulin processing in islets from individuals with longstanding T1D. Translational Research 2019 213 9099. (https://doi.org/10.1016/j.trsl.2019.08.001)

    • Search Google Scholar
    • Export Citation
  • 36

    Leete P, Oram RA, McDonald TJ, Shields BM, Ziller CTIGI Study Team, Hattersley AT, Richardson SJ, Morgan NG. Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis. Diabetologia 2020 63 12581267. (https://doi.org/10.1007/s00125-020-05115-6)

    • Search Google Scholar
    • Export Citation
  • 37

    Teitelman G Heterogeneous expression of proinsulin processing enzymes in beta cells of non-diabetic and Type 2 diabetic humans. Journal of Histochemistry and Cytochemistry 2019 67 385400. (https://doi.org/10.1369/0022155419831641)

    • Search Google Scholar
    • Export Citation
  • 38

    Alarcon C, Boland BB, Uchizono Y, Moore PC, Peterson B, Rajan S, Rhodes OS, Noske AB, Haataja L & Arvan P et al.Pancreatic beta-cell adaptive plasticity in obesity increases insulin production but adversely affects secretory function. Diabetes 2016 65 438450. (https://doi.org/10.2337/db15-0792)

    • Search Google Scholar
    • Export Citation
  • 39

    Wright J, Birk J, Haataja L, Liu M, Ramming T, Weiss MA, Appenzeller-Herzog C, Arvan P. Endoplasmic reticulum oxidoreductin-1alpha (Ero1alpha) improves folding and secretion of mutant proinsulin and limits mutant proinsulin-induced endoplasmic reticulum stress. Journal of Biological Chemistry 2013 288 3101031018. (https://doi.org/10.1074/jbc.M113.510065)

    • Search Google Scholar
    • Export Citation
  • 40

    Cunningham CN, He K, Arunagiri A, Paton AW, Paton JC, Arvan P, Tsai B. Chaperone-driven degradation of a misfolded proinsulin mutant in parallel with restoration of wild-type insulin secretion. Diabetes 2017 66 741753. (https://doi.org/10.2337/db16-1338)

    • Search Google Scholar
    • Export Citation
  • 41

    Spracklen CN, Horikoshi M, Kim YJ, Lin K, Bragg F, Moon S, Suzuki K, Tam CHT, Tabara Y & Kwak SH et al.Identification of type 2 diabetes loci in 433,540 East Asian individuals. Nature 2020 582 240245. (https://doi.org/10.1038/s41586-020-2263-3)

    • Search Google Scholar
    • Export Citation
  • 42

    Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, Nanjo K, Mori H, Kasuga M & Hara K et al.Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. Diabetes 2006 55 23792386. (https://doi.org/10.2337/db05-1203)

    • Search Google Scholar
    • Export Citation
  • 43

    Taylor BL, Liu FF, Sander M. Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells. Cell Reports 2013 4 12621275. (https://doi.org/10.1016/j.celrep.2013.08.010)

    • Search Google Scholar
    • Export Citation
  • 44

    Kim-Muller JY, Fan J, Kim YJ, Lee SA, Ishida E, Blaner WS, Accili D. Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic beta cells in diabetic mice. Nature Communications 2016 7 12631. (https://doi.org/10.1038/ncomms12631)

    • Search Google Scholar
    • Export Citation