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.
Highlights
Rates of diabetes are expected to increase due to rampant obesity and will become a worldwide health crisis in the future [1].The manifestations include hypertension, hyperlipidemia, hyperglucocorticoidemia and type 2 diabetes
Treatment with PB28 did not affect Insulin Receptor β (IRβ) protein levels in adipocytes derived from high BMI donors, but increased IRβ in adipocytes derived from pooled BMI donors (Figure 1A and B, p=0.027, t-test)
insulin receptor (IR) signaling is key in the progression of metabolic disease, and we have shown that IR levels are elevated in adipocytes treated with two different ligands for the progesterone receptor membrane component 1 (PGRMC1) protein
Summary
Rates of diabetes are expected to increase due to rampant obesity and will become a worldwide health crisis in the future [1].The manifestations include hypertension, hyperlipidemia, hyperglucocorticoidemia and type 2 diabetes. AG205 significantly increased IRβ protein levels in adipocytes derived from pooled BMI (body-mass index, median 26.8, range of [25.3-28.6]) donors (Figure 1A and B, p=0.004, t-test) and the high BMI donor (BMI 38, p=0.013, t-test). Total basal IRβ protein levels were lower in adipocytes derived from pooled BMI donors and the high BMI donor (Figure 1A and B, p=0.001 and 0.006, respectively, t-test), indicative of reduced insulin sensitivity. The same lysates were precipitated with a control antibody that matched the antibodies for IRβ and PGRMC1 (Figure 2C-D, lanes 1) These results suggest a direct interaction of PGRMC1 with IR in adipocytes
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