Acknowledgement
This study was supported by a grant from the Korean Diabetes Association to J.L. (G.D.H., 2023F-1) and the Daegu Gyeongbuk Institute of Science and Technology R&D Program and Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT and Ministry of Education to J.L. (22-CoE-BT-04, NRF-2019R1A4A102972413, and NRF-2020M3A9D8038660), Y.-J.K (2019R1A4A102972413), and J.-H.L. (NRF-2019R1A6A3A01094138).
References
- Ahren, B. (8AD). Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes (Reprinted from Nature Reviews Drug Discovery, vol 8, pg 369-385, 2009). Nat. Rev. Drug Discovery, 8, 679 (2009).
- Arunagiri, A., Haataja, L., Pottekat, A., Pamenan, F., Kim, S., Zeltser, L.M., Paton, A.W., Paton, J.C., Tsai, B., Itkin-Ansari, P., et al. (2019). Proinsulin misfolding is an early event in the progression to type 2 diabetes. Elife, 8, Article e44532.
- Baggio, L.L., and Drucker, D.J. (2007). Biology of incretins: GLP-1 and GIP. Gastroenterology, 132, 2131-2157. https://doi.org/10.1053/j.gastro.2007.03.054
- Chen, L., Magliano, D.J., and Zimmet, P.Z. (2011). The worldwide epidemiology of type 2 diabetes mellitus-present and future perspectives. Nat. Rev. Endocrinol. 8, 228-236. https://doi.org/10.1038/nrendo.2011.183
- Cross, B.C., Bond, P.J., Sadowski, P.G., Jha, B.K., Zak, J., Goodman, J.M., Silverman, R.H., Neubert, T.A., Baxendale, I.R., Ron, D., et al. (2012). The molecular basis for selective inhibition of unconventional mRNA splicing by an IRE1-binding small molecule. Proc. Natl. Acad. Sci. U.S.A. 109, E869-E878. https://doi.org/10.1073/pnas.1115623109
- Engin, F., Yermalovich, A., Nguyen, T., Hummasti, S., Fu, W., Eizirik, D.L., Mathis, D., and Hotamisligil, G.S. (2013). Restoration of the unfolded protein response in pancreatic beta cells protects mice against type 1 diabetes. Sci. Transl. Med. 5 211ra156.
- Gallagher, C.M., and Walter, P. (2016). Ceapins inhibit ATF6alpha signaling by selectively preventing transport of ATF6alpha to the Golgi apparatus during ER stress. Elife, 5, Article e11880.
- Gao, Y., Kim, S., Lee, Y.I., and Lee, J. (2019). Cellular stress-modulating drugs can potentially be identified by in silico screening with connectivity map (CMap). Int. J. Mol. Sci. 20, 5601.
- Grandjean, J.M.D., Madhavan, A., Cech, L., Seguinot, B.O., Paxman, R.J., Smith, E., Scampavia, L., Powers, E.T., Cooley, C.B., Plate, L., et al. (2020). Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming. Nat. Chem. Biol. 16, 1052-1061. https://doi.org/10.1038/s41589-020-0584-z
- Holst, J.J., Gasbjerg, L.S., and Rosenkilde, M.M. (2021). The role of incretins on insulin function and glucose homeostasis. Endocrinology, 162, 1-10. https://doi.org/10.1210/endocr/bqab065
- Holst, J.J., and Gromada, J. (2004). Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am. J. Physiol.-Endocrinol. Metab. 287, E199-E206. https://doi.org/10.1152/ajpendo.00545.2003
- Holst, J.J., Gromada, J., and Nauck, M.A. (1997). The pathogenesis of NIDDM involves a defective expression of the GIP receptor. Diabetologia, 40, 984-986. https://doi.org/10.1007/s001250050779
- Hussain, M.A., Laimon-Thomson, E., Mustafa, S.M., Deck, A., and Song, B.Y. (2021). Detour ahead: Incretin hormone signaling alters its intracellular path as beta-cell failure progresses during diabetes. Front. Endocrinol. 12, Article 665345.
- Kim, M.K., Kim, H.S., Lee, I.K., and Park, K.G. (2012). Endoplasmic reticulum stress and insulin biosynthesis: A review. Exp. Diabetes Res. 2012, Article 509437.
- Kubota, T., Kubota, N., and Kadowaki, T. (2017). Imbalanced insulin actions in obesity and type 2 diabetes: Key mouse models of insulin signaling pathway. Cell Metab. 25, 797-810. https://doi.org/10.1016/j.cmet.2017.03.004
- Lee, A.H., Heidtman, K., Hotamisligil, G.S., and Glimcher, L.H. (2011). Dual and opposing roles of the unfolded protein response regulated by IRE1alpha and XBP1 in proinsulin processing and insulin secretion. Proc. Natl. Acad. Sci. U.S.A. 108, 8885-8890. https://doi.org/10.1073/pnas.1105564108
- Lee, J., and Ozcan, U. (2014). Unfolded protein response signaling and metabolic diseases. J. Biol. Chem. 289, 1203-1211. https://doi.org/10.1074/jbc.R113.534743
- Lee, J.H., and Lee, J. (2022). Endoplasmic reticulum (er) stress and its role in pancreatic beta-cell dysfunction and senescence in type 2 diabetes. Int. J. Mol. Sci. 23, 4843.
- Lee, J.H., Ryu, H., Lee, H., Yu, H.R., Gao, Y., Lee, K.M., Kim, Y.J., and Lee, J. (2023). Endoplasmic reticulum stress in pancreatic beta cells induces incretin desensitization and beta-cell dysfunction via ATF4-mediated PDE4D expression. Am. J. Physiol. Endocrinol. Metab. 325, E448-E465.
- Lee, J.W., Kim, W.H., Yeo, J., and Jung, M.H. (2010). ER stress is implicated in mitochondrial dysfunction-induced apoptosis of pancreatic beta cells. Mol. Cells, 30, 545-549. https://doi.org/10.1007/s10059-010-0161-5
- Lee, K., Chan, J.Y., Liang, C., Ip, C.K., Shi, Y.C., Herzog, H., Hughes, W.E., Bensellam, M., Delghingaro-Augusto, V., Koina, M.E., et al. (2022). XBP1 maintains beta cell identity, represses beta-to-alpha cell transdifferentiation and protects against diabetic beta cell failure during metabolic stress in mice. Diabetologia, 65, 984-996. https://doi.org/10.1007/s00125-022-05669-7
- Li, D.S., Yuan, Y.H., Tu, H.J., Liang, Q.L., and Dai, L.J. (2009). A protocol for islet isolation from mouse pancreas. Nat. Protoc. 4, 1649-1652. https://doi.org/10.1038/nprot.2009.150
- Liu, M., Weiss, M.A., Arunagiri, A., Yong, J., Rege, N., Sun, J.H., Haataja, L., Kaufman, R.J., and Arvan, P. (2018). Biosynthesis, structure, and folding of the insulin precursor protein. Diabetes Obes. Metab. 20, 28-50. https://doi.org/10.1111/dom.13378
- Madhavan, A., Kok, B.P., Rius, B., Grandjean, J.M.D., Alabi, A., Albert, V., Sukiasyan, A., Powers, E.T., Galmozzi, A., Saez, E., et al. (2022). Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity. Nat. Commun. 13, Article 608.
- Mazzone, T., Chait, A., and Plutzky, J. (2008). Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet, 371, 1800-1809. https://doi.org/10.1016/S0140-6736(08)60768-0
- Montane, J., de Pablo, S., Castano, C., Rodriguez-Comas, J., Cadavez, L., Obach, M., Visa, M., Alcarraz-Vizan, G., Sanchez-Martinez, M., Nonell-Canals, A., et al. (2017). Amyloid-induced beta-cell dysfunction and islet inflammation are ameliorated by 4-phenylbutyrate (PBA) treatment. FASEB J. 31, 5296-5306. https://doi.org/10.1096/fj.201700236R
- Nauck, M.A., and Meier, J.J. (2016). The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions. Lancet Diabetes Endocrinol. 4, 525-536. https://doi.org/10.1016/S2213-8587(15)00482-9
- Nichols, C.G., York, N.W., and Remedi, M.S. (2020). Preferential Gq signaling in diabetes: an electrical switch in incretin action and in diabetes progression? J. Clin. Invest. 130, 6235-6237. https://doi.org/10.1172/JCI143199
- Oduori, O.S., Murao, N., Shimomura, K., Takahashi, H., Zhang, Q., Dou, H., Sakai, S., Minami, K., Chanclon, B., Guida, C., et al. (2020). Gs/Gq signaling switch in beta cells defines incretin effectiveness in diabetes. J. Clin. Invest. 130, 6639-6655. https://doi.org/10.1172/JCI140046
- Ogurtsova, K., Fernandes, J.D.D.R., Huang, Y., Linnenkamp, U., Guariguata, L., Cho, N.H., Cavan, D., Shaw, J.E., and Makaroff, L.E. (2017). IDF diabetes atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pract. 128, 40-50. https://doi.org/10.1016/j.diabres.2017.03.024
- Ozcan, U., Yilmaz, E., Ozcan, L., Furuhashi, M., Vaillancourt, E., Smith, R.O., Gorgun, C.Z., and Hotamisligil, G.S. (2006). Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science, 313, 1137-1140. https://doi.org/10.1126/science.1128294
- Park, S.W., Zhou, Y., Lee, J., Lu, A., Sun, C., Chung, J., Ueki, K., and Ozcan, U. (2010). The regulatory subunits of PI3K, p85alpha and p85beta, interact with XBP-1 and increase its nuclear translocation. Nat. Med. 16, 429-437. https://doi.org/10.1038/nm.2099
- Paxman, R., Plate, L., Blackwood, E.A., Glembotski, C., Powers, E.T., Wiseman, R.L., and Kelly, J.W. (2018). Pharmacologic ATF6 activating compounds are metabolically activated to selectively modify endoplasmic reticulum proteins. Elife, 7, Article e37168.
- Plate, L., Cooley, C.B., Chen, J.J., Paxman, R.J., Gallagher, C.M., Madoux, F., Genereux, J.C., Dobbs, W., Garza, D., Spicer, T.P., et al. (2016). Small molecule proteostasis regulators that reprogram the ER to reduce extracellular protein aggregation. Elife, 5, 15550.
- Preitner, F., Ibberson, M., Franklin, I., Binnert, C., Pende, M., Gjinovci, A., Hansotia, T., Drucker, D.J., Wollheim, C., Burcelin, R., et al. (2004). Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors. J. Clin. Invest. 113, 635-645. https://doi.org/10.1172/JCI200420518
- Scheuner, D., Mierde, D.V., Song, B., Flamez, D., Creemers, J.W.M., Tsukamoto, K., Ribick, M., Schuit, F.C., and Kaufman, R.J. (2005). Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat. Med. 11, 757-764. https://doi.org/10.1038/nm1259
- Seino, S., and Shibasaki, T. (2005). PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol. Rev. 85, 1303-1342. https://doi.org/10.1152/physrev.00001.2005
- Sharma, R.B., O'Donnell, A.C., Stamateris, R.E., Ha, B., McCloskey, K.M., Reynolds, P.R., Arvan, P., and Alonso, L.C. (2015). Insulin demand regulates beta cell number via the unfolded protein response. J. Clin. Invest. 125, 3831-3846. https://doi.org/10.1172/JCI79264
- Shrestha, N., De Franco, E., Arvan, P., and Cnop, M. (2021). Pathological beta-cell endoplasmic reticulum stress in type 2 diabetes: Current evidence. Front. Endocrinol. 12, Article 650158.
- So, J.S. (2018). Roles of endoplasmic reticulum stress in immune responses. Mol. Cells, 41, 705-716.
- Tang, C., Koulajian, K., Schuiki, I., Zhang, L., Desai, T., Ivovic, A., Wang, P., Robson-Doucette, C., Wheeler, M.B., Minassian, B., et al. (2012). Glucose-induced beta cell dysfunction in vivo in rats: link between oxidative stress and endoplasmic reticulum stress. Diabetologia, 55, 1366-1379. https://doi.org/10.1007/s00125-012-2474-8
- Vilsboll, T., Krarup, T., Madsbad, S., and Holst, J.J. (2003). Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul. Peptides, 114, 115-121. https://doi.org/10.1016/S0167-0115(03)00111-3
- Walter, P., and Ron, D. (2011). The unfolded protein response: From stress pathway to homeostatic regulation. Science, 334, 1081-1086. https://doi.org/10.1126/science.1209038
- Wang, Y., Vera, L., Fischer, W.H., and Montminy, M. (2009). The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature, 460, 534-537. https://doi.org/10.1038/nature08111
- Yabe, D., and Seino, Y. (2011). Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and beta cell preservation. Prog. Biophys. Mol. Biol. 107, 248-256. https://doi.org/10.1016/j.pbiomolbio.2011.07.010
- Yamamoto, K., Yoshida, H., Kokame, K., Kaufman, R.J., and Mori, K. (2004). Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J. Biochem. 136, 343-350. https://doi.org/10.1093/jb/mvh122
- Yong, J., Johnson, J.D., Arvan, P., Han, J., and Kaufman, R.J. (2021). Therapeutic opportunities for pancreatic beta-cell ER stress in diabetes mellitus. Nat. Rev. Endocrinol. 17, 455-467. https://doi.org/10.1038/s41574-021-00510-4
- Zhu, Y.X., Zhou, Y.C., Zhang, Y., Sun, P., Chang, X.A., and Han, X. (2021). Protocol for in vivo and ex vivo assessments of glucose-stimulated insulin secretion in mouse islet beta cells. STAR Protoc. 2, Article 100728.