Misfolded Proinsulin Affects Bystander Proinsulin in Neonatal Diabetes

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2009 Nov 3

PMID 19880509

Citations 51

Authors

Israel Hodish

Ming Liu

Gautam Rajpal

Dennis Larkin

Ronald W Holz

Aaron Adams

Leanza Liu

Peter Arvan

Affiliations

Soon will be listed here.

Abstract

It has previously been shown that misfolded mutant Akita proinsulin in the endoplasmic reticulum engages directly in protein complexes either with nonmutant proinsulin or with "hProCpepGFP" (human proinsulin bearing emerald-GFP within the C-peptide), impairing the trafficking of these "bystander" proinsulin molecules (Liu, M., Hodish, I., Rhodes, C. J., and Arvan, P. (2007) Proc. Natl. Acad. Sci. U.S.A. 104, 15841-15846). Herein, we generated transgenic mice, which, in addition to expressing endogenous proinsulin, exhibit beta-cell-specific expression of hProCpepGFP via the Ins1 promoter. In these mice, hProCpepGFP protein levels are physiologically regulated, and hProCpepGFP is packaged and processed to CpepGFP that is co-stored in beta-secretory granules. Visualization of CpepGFP fluorescence provides a quantifiable measure of pancreatic islet insulin content that can be followed in live animals in states of health and disease. We examined loss of pancreatic insulin in hProCpepGFP transgenic mice mated to Akita mice that develop neonatal diabetes because of the expression of misfolded proinsulin. Loss of bystander insulin in Akita animals is detected initially as a block in CpepGFP/insulin production with intracellular accumulation of the precursor, followed ultimately by loss of pancreatic beta-cells. The data support that misfolded proinsulin perturbs bystander proinsulin in the endoplasmic reticulum, leading to beta-cell failure.

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References

Jeffrey K, Alejandro E, Luciani D, Kalynyak T, Hu X, Li H . Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis. Proc Natl Acad Sci U S A. 2008; 105(24):8452-7. PMC: 2448857. DOI: 10.1073/pnas.0711232105. View

Leahy J . Pathogenesis of type 2 diabetes mellitus. Arch Med Res. 2005; 36(3):197-209. DOI: 10.1016/j.arcmed.2005.01.003. View

Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith R . Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006; 313(5790):1137-40. PMC: 4741373. DOI: 10.1126/science.1128294. View

Molven A, Ringdal M, Nordbo A, Raeder H, Stoy J, Lipkind G . Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes. 2008; 57(4):1131-5. DOI: 10.2337/db07-1467. View

Porte Jr D, Kahn S . beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes. 2001; 50 Suppl 1:S160-3. DOI: 10.2337/diabetes.50.2007.s160. View

Herbach N, Rathkolb B, Kemter E, Pichl L, Klaften M, de Angelis M . Dominant-negative effects of a novel mutated Ins2 allele causes early-onset diabetes and severe beta-cell loss in Munich Ins2C95S mutant mice. Diabetes. 2007; 56(5):1268-76. DOI: 10.2337/db06-0658. View

Liu M, Li Y, Cavener D, Arvan P . Proinsulin disulfide maturation and misfolding in the endoplasmic reticulum. J Biol Chem. 2005; 280(14):13209-12. PMC: 2527538. DOI: 10.1074/jbc.C400475200. View

Riggs A, Bernal-Mizrachi E, Ohsugi M, Wasson J, Fatrai S, Welling C . Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia. 2005; 48(11):2313-21. DOI: 10.1007/s00125-005-1947-4. View

Laybutt D, Preston A, Akerfeldt M, Kench J, BUSCH A, Biankin A . Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia. 2007; 50(4):752-63. DOI: 10.1007/s00125-006-0590-z. View

10.

Watkins S, Geng X, Li L, Papworth G, Robbins P, Drain P . Imaging secretory vesicles by fluorescent protein insertion in propeptide rather than mature secreted peptide. Traffic. 2002; 3(7):461-71. DOI: 10.1034/j.1600-0854.2002.30703.x. View

11.

Lin M, Lubag A, McGuire M, Seliounine S, Tsyganov E, Antich P . Advances in molecular imaging of pancreatic beta cells. Front Biosci. 2008; 13:4558-75. PMC: 2790725. DOI: 10.2741/3023. View

12.

Takeshita S, Moritani M, Kunika K, Inoue H, Itakura M . Diabetic modifier QTLs identified in F2 intercrosses between Akita and A/J mice. Mamm Genome. 2006; 17(9):927-40. DOI: 10.1007/s00335-005-0130-z. View

13.

Poitout V, Robertson R . Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev. 2007; 29(3):351-66. PMC: 2528858. DOI: 10.1210/er.2007-0023. View

14.

Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E . Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest. 2002; 109(4):525-32. PMC: 150879. DOI: 10.1172/JCI14550. View

15.

Ladiges W, Knoblaugh S, Morton J, Korth M, Sopher B, Baskin C . Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes. 2005; 54(4):1074-81. DOI: 10.2337/diabetes.54.4.1074. View

16.

Park S, Bell G . Noninvasive monitoring of changes in pancreatic beta-cell mass by bioluminescent imaging in MIP-luc transgenic mice. Horm Metab Res. 2008; 41(1):1-4. PMC: 2610407. DOI: 10.1055/s-0028-1087209. View

17.

Hara M, Wang X, Kawamura T, Bindokas V, Dizon R, Alcoser S . Transgenic mice with green fluorescent protein-labeled pancreatic beta -cells. Am J Physiol Endocrinol Metab. 2002; 284(1):E177-83. DOI: 10.1152/ajpendo.00321.2002. View

18.

Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U . The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia. 2007; 50(12):2486-94. DOI: 10.1007/s00125-007-0816-8. View

19.

Axelrod D . Total internal reflection fluorescence microscopy. Methods Cell Biol. 1989; 30:245-70. DOI: 10.1016/s0091-679x(08)60982-6. View

20.

Oyadomari S, Takeda K, Takiguchi M, Gotoh T, Matsumoto M, Wada I . Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proc Natl Acad Sci U S A. 2001; 98(19):10845-50. PMC: 58562. DOI: 10.1073/pnas.191207498. View