An INSR-BECN1-KIAA0825 complex prevents hepatocytic insulin receptor secretion via extracellular vesicles against monogenic diabetes.

Monogenic diabetes from insulin receptor (INSR) mutations is a rare genetic disorder causing early-onset, profound insulin resistance. However, the pathogenic mechanisms by which INSR mutations disrupt receptor trafficking, cell-surface stability, and signaling are unresolved, and consequently, current treatment remains largely symptomatic and prognosis is not optimal. Here we discover that INSR, the autophagy protein BECN1, and KIAA0825, encoded by a diabetic-risk gene of previously unknown function, form a complex to regulate INSR transport, membrane presentation, and functionality in hepatocytes. Loss of hepatic BECN1 or KIAA0825, or expression of monogenic diabetes-causing mutations in INSR, disrupts the INSR-BECN1-KIAA0825 complex and mis-routes INSR to extracellular vesicles for secretion from hepatocytes, leading to impaired hepatocytic INSR cell-surface presentation and defects in hepatic insulin sensitivity, glycogen storage and exercise capacity. These findings identify new regulators and mechanisms governing INSR sorting, trafficking and signaling, uncover a non-canonical, non-degradative role for BECN1, and reveal the cellular fate of pathogenic INSR mutants underlying monogenic diabetes.