Obesity-induced upregulation of miR-483-5p impairs the function and identity of pancreatic β-cells.

Publisher: Wiley-Blackwell Country of Publication: England NLM ID: 100883645 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1463-1326 (Electronic) Linking ISSN: 14628902 NLM ISO Abbreviation: Diabetes Obes Metab Subsets: MEDLINE

Original Publication: Oxford : Wiley-Blackwell, c1999-

Insulin-Secreting Cells*/metabolism ; MicroRNAs*/genetics ; MicroRNAs*/metabolism ; Obesity*/genetics ; Obesity*/metabolism ; Up-Regulation*; Animals ; Humans ; Male ; Mice ; Cell Differentiation/genetics ; Diet, High-Fat/adverse effects ; Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; Insulin/metabolism ; Insulin Secretion ; Maf Transcription Factors, Large/genetics ; Maf Transcription Factors, Large/metabolism ; Mice, Inbred C57BL ; Trans-Activators/genetics ; Trans-Activators/metabolism

Aim: To assess the expression and function of miR-483-5p in diabetic β cells.
Methods: The expression of miR-483-5p was evaluated in the pancreatic islets of obesity mouse models by quantitative reverse transcription polymerase chain reaction. Dual-luciferase activity, and western blotting assays, were utilized for miR-483-5p target gene verification. Mice with β cell-specific miR-483-5p downregulation were studied under metabolic stress (i.e. a high-fat diet) condition. Lineage tracing was used to determine β-cell fate.
Results: miR-483-5p increased in the islets of obese mouse models. Expression levels of miR-483-5p were significantly upregulated with the treatment of high glucose and palmitate, in both MIN6 cells and mouse islets. Overexpression of miR-483-5p in β cells results in impaired insulin secretion and β-cell identity. Cell lineage-specific analyses revealed that miR-483-5p overexpression deactivated β-cell identity genes (insulin, Pdx1 and MafA) and derepressed β-cell dedifferentiation (Ngn3) genes. miR-483-5p downregulation in β cells of high-fat diet-fed mice alleviated diabetes and improved glucose intolerance by enhancing insulin secretory capacity. These detrimental effects of miR-483-5p relied on its seed sequence recognition and repressed expression of its target genes Pdx1 and MafA, two crucial markers of β-cell maturation.
Conclusions: These findings indicate that the miR-483-5p-mediated reduction of mRNAs specifies β-cell identity as a contributor to β-cell dysfunction via the loss of cellular differentiation.
(© 2024 John Wiley & Sons Ltd.)

Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14(2):88‐98.
Sun H, Saeedi P, Karuranga S, et al. IDF diabetes atlas: global, regional and country‐level diabetes prevalence estimates for 2021 and projections for 2045. Diabetes Res Clin Pract. 2022;183:109119.
Mathis D, Vence L, Benoist C. Beta‐cell death during progression to diabetes. Nature. 2001;414(6865):792‐798.
Butler AE, Janson J, Bonner‐Weir S, Ritzel R, Rizza RA, Butler PC. Beta‐cell deficit and increased beta‐cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102‐110.
Guo S, Dai C, Guo M, et al. Inactivation of specific beta cell transcription factors in type 2 diabetes. J Clin Invest. 2013;123(8):3305‐3316.
Cinti F, Bouchi R, Kim‐Muller JY, et al. Evidence of beta‐cell dedifferentiation in human type 2 diabetes. J Clin Endocrinol Metab. 2016;101(3):1044‐1054.
Sun T, Han X. Death versus dedifferentiation: the molecular bases of beta cell mass reduction in type 2 diabetes. Semin Cell Dev Biol. 2020;103:76‐82.
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(6):1223‐1234.
Lv Y, Huang Y, Xu M, et al. The miR‐193a‐3p‐MAP3k3 signaling Axis regulates substrate topography‐induced osteogenesis of bone marrow stem cells. Adv Sci (Weinh). 2020;7(1):1901412.
Eliasson L, Esguerra JLS. MicroRNA networks in pancreatic islet cells: Normal function and type 2 diabetes. Diabetes. 2020;69(5):804‐812.
Jordan SD, Kruger M, Willmes DM, et al. Obesity‐induced overexpression of miRNA‐143 inhibits insulin‐stimulated AKT activation and impairs glucose metabolism. Nat Cell Biol. 2011;13(4):434‐446.
Zhang F, Ma D, Zhao W, et al. Obesity‐induced overexpression of miR‐802 impairs insulin transcription and secretion. Nat Commun. 2020;11(1):1822.
Hu Q, Mu J, Liu Y, et al. Obesity‐induced miR‐455 upregulation promotes adaptive pancreatic beta‐cell proliferation through the CPEB1/CDKN1B pathway. Diabetes. 2022;71(3):394‐411.
Zhu Y, Sun Y, Zhou Y, et al. MicroRNA‐24 promotes pancreatic beta cells toward dedifferentiation to avoid endoplasmic reticulum stress‐induced apoptosis. J Mol Cell Biol. 2019;11(9):747‐760.
Ibrahim S, Johnson M, Stephens CH, et al. Beta‐cell pre‐mir‐21 induces dysfunction and loss of cellular identity by targeting transforming growth factor beta 2 (Tgfb2) and Smad family member 2 (Smad2) mRNAs. Mol Metab. 2021;53:101289.
Martinez‐Sanchez A, Rutter GA, Latreille M. MiRNAs in beta‐cell development, identity, and disease. Front Genet. 2016;7:226.
Mohan R, Mao Y, Zhang S, et al. Differentially expressed MicroRNA‐483 confers distinct functions in pancreatic beta‐ and alpha‐cells. J Biol Chem. 2015;290(32):19955‐19966.
Wu T, Shao Y, Li X, et al. NR3C1/glucocorticoid receptor activation promotes pancreatic beta‐cell autophagy overload in response to glucolipotoxicity. Autophagy. 2023;19(9):2538‐2557.
Brissova M, Fowler M, Wiebe P, et al. Intraislet endothelial cells contribute to revascularization of transplanted pancreatic islets. Diabetes. 2004;53(5):1318‐1325.
Ciregia F, Bugliani M, Ronci M, et al. Palmitate‐induced lipotoxicity alters acetylation of multiple proteins in clonal β cells and human pancreatic islets. Sci Rep. 2017;7(1):13445.
Wu T, Zhang S, Xu J, et al. HRD1, an important player in pancreatic beta‐cell failure and therapeutic target for type 2 diabetic mice. Diabetes. 2020;69(5):940‐953.
Mosser RE, Maulis MF, Moullé VS, et al. High‐fat diet‐induced β‐cell proliferation occurs prior to insulin resistance in C57Bl/6J male mice. Am J Physiol Endocrinol Metab. 2015;308(7):E573‐E582.
Butcher MJ, Trevino MB, Imai Y, Galkina EV. Characterization of islet leukocyte populations in human and murine islets by flow cytometry. Methods Mol Biol. 2020;2076:185‐197.
Sun Y, Zhou Y, Shi Y, et al. Expression of miRNA‐29 in pancreatic beta cells promotes inflammation and diabetes via TRAF3. Cell Rep. 2021;34(1):108576.
Nesca V, Guay C, Jacovetti C, et al. Identification of particular groups of microRNAs that positively or negatively impact on beta cell function in obese models of type 2 diabetes. Diabetologia. 2013;56(10):2203‐2212.
Li Y, Zhang T, Huang Q, et al. Inhibition of tumor suppressor p53 preserves glycation‐serum induced pancreatic beta‐cell demise. Endocrine. 2016;54(2):383‐395.
Rutter GA. Diabetes: controlling the identity of the adult pancreatic beta cell. Nat Rev Endocrinol. 2017;13(3):129‐130.
Nishimura W, Takahashi S, Yasuda K. MafA is critical for maintenance of the mature beta cell phenotype in mice. Diabetologia. 2015;58(3):566‐574.
Oshima M, Pechberty S, Bellini L, et al. Stearoyl CoA desaturase is a gatekeeper that protects human beta cells against lipotoxicity and maintains their identity. Diabetologia. 2020;63(2):395‐409.
Mandal P, De D, Im DU, Um SH, Kim KK. Exosome‐mediated differentiation of mouse embryonic fibroblasts and exocrine cells into beta‐like cells and the identification of key miRNAs for differentiation. Biomedicine. 2020;8(11):485.
Nathan G, Kredo‐Russo S, Geiger T, et al. MiR‐375 promotes redifferentiation of adult human beta cells expanded in vitro. PLoS One. 2015;10(4):e0122108.
Xu Y, Tang Z, Dai H, et al. MiR‐195 promotes pancreatic beta‐cell dedifferentiation by targeting Mfn2 and impairing Pi3k/Akt signaling in type 2 diabetes. Obesity (Silver Spring). 2022;30(2):447‐459.
Rosselot C, Kumar A, Lakshmipathi J, et al. Myc is required for adaptive beta‐cell replication in young mice but is not sufficient in one‐year‐old mice fed with a high‐fat diet. Diabetes. 2019;68(10):1934‐1949.
Wang Z, Mohan R, Chen X, et al. microRNA‐483 protects pancreatic beta‐cells by targeting ALDH1A3. Endocrinology. 2021;162(5):bqab031.
Kim‐Muller JY, Fan J, Kim YJ, et al. Aldehyde dehydrogenase 1a3 defines a subset of failing pancreatic beta cells in diabetic mice. Nat Commun. 2016;7:12631.
Nordmann TM, Dror E, Schulze F, et al. The role of inflammation in beta‐cell dedifferentiation. Sci Rep. 2017;7(1):6285.
Berchtold LA, Prause M, Storling J, Mandrup‐Poulsen T. Cytokines and pancreatic beta‐cell apoptosis. Adv Clin Chem. 2016;75:99‐158.
Hajmrle C, Smith N, Spigelman AF, et al. Interleukin‐1 signaling contributes to acute islet compensation. JCI Insight. 2016;1(4):e86055.

32171116 National Natural Science Foundation of China; 32371168 National Natural Science Foundation of China; 82370803 National Natural Science Foundation of China; 82170810 National Natural Science Foundation of China; TZKY20230310 Research Project of Taizhou Clinical Medical College of Nanjing Medical University

Keywords: miR‐483‐5p; obesity; type 2 diabetes; β‐cell function; β‐cell identity

0 (Homeodomain Proteins)
0 (Insulin)
0 (Maf Transcription Factors, Large)
0 (Mafa protein, mouse)
0 (MicroRNAs)
0 (Mirn483 microRNA, mouse)
0 (pancreatic and duodenal homeobox 1 protein)
0 (Trans-Activators)
0 (MIRN483 microRNA, human)

Date Created: 20240729 Date Completed: 20240918 Latest Revision: 20240925

20240925

10.1111/dom.15805

39072950