Kindlin-2 modulates MafA and β-catenin expression to regulate β-cell function and mass in mice

• Published in: Nature communications Vol. 11; no. 1; p. 484
• Main Authors: Zhu, Ke, Lai, Yumei, Cao, Huiling, Bai, Xiaochun, Liu, Chuanju, Yan, Qinnan, Ma, Liting, Chen, Di, Kanaporis, Giedrius, Wang, Junqi, Li, Luyuan, Cheng, Tao, Wang, Yong, Wu, Chuanyue, Xiao, Guozhi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 631/45; 631/80; Animals; beta Catenin - genetics; beta Catenin - metabolism; Beta cells; Calcium; Calcium ions; Cell Proliferation; Clonal deletion; Cytoskeletal Proteins - deficiency; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - metabolism; Diabetes; Diabetes mellitus; Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Female; Gene Expression; Gene Knockdown Techniques; Glucose; Humanities and Social Sciences; Humans; Insulin; Insulin - genetics; Insulin Resistance; Insulin secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - metabolism; Islets of Langerhans - growth & development; Islets of Langerhans - metabolism; Maf Transcription Factors, Large - metabolism; Male; Membrane Proteins - antagonists & inhibitors; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; multidisciplinary; Muscle Proteins - deficiency; Muscle Proteins - genetics; Muscle Proteins - metabolism; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Pancreas; Pathogenesis; Phenotype; Phenotypes; Protein Stability; Proteins; Reduction; Science; Science (multidisciplinary); Secretion; Therapeutic applications; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14186-y

β-Cell dysfunction and reduction in β-cell mass are hallmark events of diabetes mellitus. Here we show that β-cells express abundant Kindlin-2 and deleting its expression causes severe diabetes-like phenotypes without markedly causing peripheral insulin resistance. Kindlin-2, through its C-terminal region, binds to and stabilizes MafA, which activates insulin expression. Kindlin-2 loss impairs insulin secretion in primary human and mouse islets in vitro and in mice by reducing, at least in part, Ca 2+ release in β-cells. Kindlin-2 loss activates GSK-3β and downregulates β-catenin, leading to reduced β-cell proliferation and mass. Kindlin-2 loss reduces the percentage of β-cells and concomitantly increases that of α-cells during early pancreatic development. Genetic activation of β-catenin in β-cells restores the diabetes-like phenotypes induced by Kindlin-2 loss. Finally, the inducible deletion of β-cell Kindlin-2 causes diabetic phenotypes in adult mice. Collectively, our results establish an important function of Kindlin-2 and provide a potential therapeutic target for diabetes. Beta cell dysfunction and reduction in beta cell mass are hallmark events in the pathogenesis of diabetes mellitus. We identify focal adhesion protein Kindlin-2 as a key factor that controls insulin synthesis and secretion and beta cell mass by modulating MafA and beta-catenin proteins in pancreatic beta cells.