@article{28f8ef382f854011842672e6c09c991c,
title = "Palmitoylation couples insulin hypersecretion with β cell failure in diabetes",
abstract = "Hyperinsulinemia often precedes type 2 diabetes. Palmitoylation, implicated in exocytosis, is reversed by acyl-protein thioesterase 1 (APT1). APT1 biology was altered in pancreatic islets from humans with type 2 diabetes, and APT1 knockdown in nondiabetic islets caused insulin hypersecretion. APT1 knockout mice had islet autonomous increased glucose-stimulated insulin secretion that was associated with prolonged insulin granule fusion. Using palmitoylation proteomics, we identified Scamp1 as an APT1 substrate that localized to insulin secretory granules. Scamp1 knockdown caused insulin hypersecretion. Expression of a mutated Scamp1 incapable of being palmitoylated in APT1-deficient cells rescued insulin hypersecretion and nutrient-induced apoptosis. High-fat-fed islet-specific APT1-knockout mice and global APT1-deficient db/db mice showed increased β cell failure. These findings suggest that APT1 is regulated in human islets and that APT1 deficiency causes insulin hypersecretion leading to β cell failure, modeling the evolution of some forms of human type 2 diabetes.",
keywords = "S-acylation, acyl-protein thioesterases, beta cell failure, lipotoxicity, type 2 diabetes",
author = "Guifang Dong and Sangeeta Adak and George Spyropoulos and Qiang Zhang and Chu Feng and Li Yin and Speck, {Sarah L.} and Zeenat Shyr and Shuntaro Morikawa and Kitamura, {Rie Asada} and Kathayat, {Rahul S.} and Dickinson, {Bryan C.} and Ng, {Xue Wen} and Piston, {David W.} and Fumihiko Urano and Remedi, {Maria S.} and Xiaochao Wei and Semenkovich, {Clay F.}",
note = "Funding Information: This work was supported by the Washington University Centene Personalized Medicine Initiative ( P19-00559 ), the Washington University Diabetes Research Center ( DK020579 ), and the following NIH grants: DK101392 , DK056341 , DK115972 , DK123301 , DK112921, GM119840 , T32 HL125241 , F30 DK131830 , and HL157154 . G.D. is supported by China Scholarship Council (CSC) grant 201608420067 . S.M. is supported by Manpei Suzuki Diabetes Foundation and JSPS Overseas Research Fellowships . We thank Jeff Millman, Leonardo Velaszco-Cruz, Kristina Maxwell, Punn Augsornworawat, Cris Brown (all at Washington University), and Richard O{\textquoteright}Brien (Vanderbilt University) for advice. Funding Information: This work was supported by the Washington University Centene Personalized Medicine Initiative (P19-00559), the Washington University Diabetes Research Center (DK020579), and the following NIH grants: DK101392, DK056341, DK115972, DK123301, DK112921, GM119840, T32 HL125241, F30 DK131830, and HL157154. G.D. is supported by China Scholarship Council (CSC) grant 201608420067. S.M. is supported by Manpei Suzuki Diabetes Foundation and JSPS Overseas Research Fellowships. We thank Jeff Millman, Leonardo Velaszco-Cruz, Kristina Maxwell, Punn Augsornworawat, Cris Brown (all at Washington University), and Richard O'Brien (Vanderbilt University) for advice. G.D. planned and performed experiments, interpreted data, and wrote a draft of the manuscript. S.A. G.S. C.F. L.Y. S.L.S. Z.S. S.M. R.A.K. and X.W.N. planned and performed experiments. Q.Z. performed proteomics experiments and interpreted data. R.S.K. and B.C.D. provided reagents and interpreted results of experiments utilizing depalmitoylation probes. D.W.P. F.U. and M.S.R. planned experiments and interpreted data. X.W. designed and performed experiments, interpreted data, and edited the manuscript. C.F.S. designed experiments, obtained approvals, interpreted data, and wrote the manuscript. All authors provided input into the text of the manuscript. C.F.S. is a member of the Cell Metabolism advisory board. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2022 Elsevier Inc.",
year = "2023",
month = feb,
day = "7",
doi = "10.1016/j.cmet.2022.12.012",
language = "English",
volume = "35",
pages = "332--344.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
number = "2",
}