Jun Shirakawa1,2,3,*, Dario F. De Jesus3, Takahiro Tsuno1, Giorgio Basile3, Ryota Inoue1, Tomozumi Takatani3, Akira Nishiyama4, Erin R. Okawa3, Tomohiko Tamura4, Yasuo Terauchi2, Rohit N. Kulkarni3,* (1. Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR), Gunma University, Japan; 2. Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan; 3. Joslin Diabetes Center, Harvard Medical School, Boston, USA; 4. Department of Immunology, Graduate School of Medicine, Yokohama City University, Yokohama, Japan; *Corresponding Author)
About
Insulin-like growth factor -2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor (CI-MPR), is localized in cytosolic vesicles and is unique in its ability to transport enzymes to the lysosome and to clear IGF2 from the cell surface by acting as a scavenger receptor. To evaluate the direct role of IGF2R in β-cell biology we undertook complementary in vitro knockdown and in vivo knockout approaches. A β-cell line with a stable knockdown of IGF2R (IGF2RKD), exhibited decreased glucose-induced insulin secretion, and enhanced cell proliferation. Tamoxifen-inducible β-cell-specific IGF2R knockout mice exhibited impaired glucose tolerance and blunted insulin secretion after high-fat diet-loading that was likely secondary to reduced β-cell mass due to attenuated proliferation. β-cells with IGF2RKD exhibited decreased autophagosomes following starvation, which was accompanied by a reduced expression of p62, LC3B, and ULK1. Aged mice also showed impaired autophagy in βIGF2R-deficient β-cells. Reduced IGF2R function and m6A methylation were observed in islets from both mouse and human type 2 diabetes. Taken together, these data point to IGF2R as an important regulator of insulin secretion, cell proliferation and autophagy in mammalian β-cells.
Paper information
Regulatory roles of IGF2R in insulin secretion and adaptive β-cell proliferation
Jun Shirakawa, Dario F. De Jesus, Takahiro Tsuno, Giorgio Basile, Ryota Inoue, Tomozumi Takatani, Akira Nishiyama, Erin R. Okawa, Tomohiko Tamura, Yasuo Terauchi, Rohit N. Kulkarni.
Diabetes. db250215, 2025. PMID: 41042627, doi: 10.2337/db25-0215
Online URL
https://pubmed.ncbi.nlm.nih.gov/41042627/
