Characterization of Signaling Pathways Associated with Pancreatic β-cell Adaptive Flexibility in Compensation of Obesity-linked Diabetes in db/db Mice.

Autor:	Kang T; Protein research group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark; The Danish Diabetes Academy, Odense, Denmark., Boland BB; The Kovler Diabetes Center, Department of Medicine Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, Illinois 60637; Cardiovascular, Renal and Metabolic Disease, BioPharmaceuticals Research and Development, AstraZeneca Gaithersburg, Maryland 20878., Jensen P; Protein research group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark., Alarcon C; The Kovler Diabetes Center, Department of Medicine Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, Illinois 60637., Nawrocki A; Protein research group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark., Grimsby JS; Cardiovascular, Renal and Metabolic Disease, BioPharmaceuticals Research and Development, AstraZeneca Gaithersburg, Maryland 20878., Rhodes CJ; The Kovler Diabetes Center, Department of Medicine Section of Endocrinology, Diabetes & Metabolism, University of Chicago, Chicago, Illinois 60637; Cardiovascular, Renal and Metabolic Disease, BioPharmaceuticals Research and Development, AstraZeneca Gaithersburg, Maryland 20878., Larsen MR; Protein research group, Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark. Electronic address: mrl@bmb.sdu.dk.
Jazyk:	angličtina
Zdroj:	Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2020 Jun; Vol. 19 (6), pp. 971-993. Date of Electronic Publication: 2020 Apr 07.
DOI:	10.1074/mcp.RA119.001882
Abstrakt:	The onset of obesity-linked type 2 diabetes (T2D) is marked by an eventual failure in pancreatic β-cell function and mass that is no longer able to compensate for the inherent insulin resistance and increased metabolic load intrinsic to obesity. However, in a commonly used model of T2D, the db/db mouse, β-cells have an inbuilt adaptive flexibility enabling them to effectively adjust insulin production rates relative to the metabolic demand. Pancreatic β-cells from these animals have markedly reduced intracellular insulin stores, yet high rates of (pro)insulin secretion, together with a substantial increase in proinsulin biosynthesis highlighted by expanded rough endoplasmic reticulum and Golgi apparatus. However, when the metabolic overload and/or hyperglycemia is normalized, β-cells from db/db mice quickly restore their insulin stores and normalize secretory function. This demonstrates the β-cell's adaptive flexibility and indicates that therapeutic approaches applied to encourage β-cell rest are capable of restoring endogenous β-cell function. However, mechanisms that regulate β-cell adaptive flexibility are essentially unknown. To gain deeper mechanistic insight into the molecular events underlying β-cell adaptive flexibility in db/db β-cells, we conducted a combined proteomic and post-translational modification specific proteomic (PTMomics) approach on islets from db/db mice and wild-type controls (WT) with or without prior exposure to normal glucose levels. We identified differential modifications of proteins involved in redox homeostasis, protein refolding, K48-linked deubiquitination, mRNA/protein export, focal adhesion, ERK1/2 signaling, and renin-angiotensin-aldosterone signaling, as well as sialyltransferase activity, associated with β-cell adaptive flexibility. These proteins are all related to proinsulin biosynthesis and processing, maturation of insulin secretory granules, and vesicular trafficking-core pathways involved in the adaptation of insulin production to meet metabolic demand. Collectively, this study outlines a novel and comprehensive global PTMome signaling map that highlights important molecular mechanisms related to the adaptive flexibility of β-cell function, providing improved insight into disease pathogenesis of T2D. (© 2020 Kang et al.)
Databáze:	MEDLINE
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