<b>Regulatory roles of IGF2R in insulin secretion and adaptive β-cell proliferation</b>

<p dir="ltr">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 <i>in vitro</i> knockdown and <i>in vivo</i> 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.</p>