Regulatory Roles of IGF2R in Insulin Secretion and Adaptive β-Cell Proliferation

Insulin-like growth factor-2 receptor (IGF2R), also known as cation-independent mannose-6-phosphate receptor, 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 had fewer autophagosomes after starvation and reduced expression of p62, LC3B, and ULK1. Aged mice also had impaired autophagy in βIGF2R-deficient β-cells. Reduced IGF2R function and N6-methyladenosine (m6A) mRNA 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. ARTICLE HIGHLIGHTS: The significance of insulin-like growth factor-2 receptor (IGF2R) in β-cells remains unclear. To assess the physiological role of IGF2R in β-cells, the effects of IGF2R deficiency in vivo and in vitro were investigated. IGF2R modulates insulin secretion, cell proliferation, and autophagy in β-cells. IGF2R plays a role in the regulation of β-cell biology.