Insulin Receptor Levels Regulated by the Receptor- Associated Protein Progesterone Receptor Membrane Component 1 (PGRMC1)

Abstract

As of 2014, 29.1 million Americans suffer from diabetes, creating a severe socioeconomic and medical burdenon society. Impaired insulin signaling is key to the development of type 2 diabetes, presenting a unique therapeutic challenge. Obese individuals demonstrate decreased insulin binding due to a reduction in IR levels, without an alteration in ligand-receptor binding affinity. The progesterone receptor membrane component 1 (PGRMC1) is an endosomal protein that promotes cellular signaling via altered receptor trafficking. A recent translational study determined that PGRMC1 was decreased in patients with insulin-resistant disease, suggesting a role in insulin signaling. In the present study, we hypothesized that PGRMC1 affects the levels of IR? (insulin receptor-? sub-unit) in adipocytes. Indeed, we show that treatment with PGRMC1 ligands significantly increase IR? protein levels in fully differentiated human subcutaneous adipocytes. Protein levels are likely affected through the direct interaction of PGRMC1 and IR?, as we demonstrate their co immunoprecipitation in differentiated 3T3-L1 cells. Notably, PGRMC1 ligand treatment significantly reduced IR? protein levels in two rodent model systems, indicating a pharmacological difference across species.