Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival

Abstract

Type 2 Diabetes (T2DM) affects more than 300 million people worldwide. One of the hallmarks of T2DM is peripheral insulin resistance, in part due to unproductive insulin signaling through the insulin receptor. The insulin receptor (INSR) exists as two isoforms, INSR-A and INSR-B, which results from skipping or inclusion of exon 11 respectively. What determines the relative abundance of the different insulin receptor splice variants is unknown. Moreover, it is not yet clear what the physiological roles of each of the isoforms are in normal and diseased beta cells. In this study, we show that insulin induces INSR exon 11 inclusion in pancreatic beta cells in both human and mouse. This occurs through activation of the Ras-MAPK/ERK signaling pathway and up-regulation of the splicing factor SRSF1. Induction of exon 11 skipping by a splice-site competitive antisense oligonucleotide inhibited the MAPK-ERK signaling pathway downstream of the insulin receptor, sensitizing the pancreatic β-cell line MIN6 to stress-induced apoptosis and lipotoxicity. These results assign to insulin a regulatory role in INSR alternative splicing through the Ras-MAPK/ERK signaling pathway. We suggest that in beta cells, INSR-B has a protective role, while INSR-A expression sensitizes beta cells to programmed cell death.

Differential Impacts of Alternative Splicing Networks on Apoptosis

“…The manipulated expression of SRSF1 is frequently observed during the organogenesis and carcinogenesis [115]. More than 500 potential candidates, including insulin receptor ( INSR ) were identified as the potential candidates of SRSF1 by using the RNA-seq approach [116]. INSR gene was demonstrated to generate two alternatively-spliced variants in a spatial-temporal manner [116].…”

“…More than 500 potential candidates, including insulin receptor ( INSR ) were identified as the potential candidates of SRSF1 by using the RNA-seq approach [116]. INSR gene was demonstrated to generate two alternatively-spliced variants in a spatial-temporal manner [116]. The exon 11-excluded INSR ( INSR-A ) transcripts were predominantly expressed in embryonic and cancerous cells [116], whereas the exon 11-included INSR ( INSR-B ) transcripts were widely noted in the pancreatic β-cells, skeletal muscle, and adipocytes [117].…”

“…INSR gene was demonstrated to generate two alternatively-spliced variants in a spatial-temporal manner [116]. The exon 11-excluded INSR ( INSR-A ) transcripts were predominantly expressed in embryonic and cancerous cells [116], whereas the exon 11-included INSR ( INSR-B ) transcripts were widely noted in the pancreatic β-cells, skeletal muscle, and adipocytes [117]. Overexpression of SRSF1 was demonstrated to constitute a molecular mechanism in enhancing the relative level of exon 11-included INSR–B , which subsequently lessened the sensitivity of pancreatic progenitors to stress-induced apoptosis [116].…”

“…The exon 11-excluded INSR ( INSR-A ) transcripts were predominantly expressed in embryonic and cancerous cells [116], whereas the exon 11-included INSR ( INSR-B ) transcripts were widely noted in the pancreatic β-cells, skeletal muscle, and adipocytes [117]. Overexpression of SRSF1 was demonstrated to constitute a molecular mechanism in enhancing the relative level of exon 11-included INSR–B , which subsequently lessened the sensitivity of pancreatic progenitors to stress-induced apoptosis [116]. In addition, the up-regulated SRSF1 expression with a concomitant increase in the relative level of exon-9-included cancer susceptibility candidate 4 ( CASC4 ) transcripts was revealed in breast cancer cells compared to the normal ductal cells [115].…”

S961, a biosynthetic insulin receptor antagonist, downregulates insulin receptor expression & suppresses the growth of breast cancer cells

“…IR-B is associated with stronger insulin binding, while isoform IR-A binds both insulin and IGF20. Studies found IR-A often aberrantly expressed in tumour cells, thus increasing its responsiveness to insulin and IGF and explaining the cancer-promoting effect of hyperinsulinaemia observed in type 2 diabetes patients.…”