Regulation of Insulin Receptor Trafficking by Bardet Biedl Syndrome Proteins.

Rachel D Starks,Qihong Zhang,Deng Fu Guo,Andreas M Beyer,Val C Sheffield,Lauren Boland,Kamal Rahmouni

doi:10.1371/journal.pgen.1005311

Abstract

Insulin and its receptor are critical for the regulation of metabolic functions, but the mechanisms underlying insulin receptor (IR) trafficking to the plasma membrane are not well understood. Here, we show that Bardet Biedl Syndrome (BBS) proteins are necessary for IR localization to the cell surface. We demonstrate that the IR interacts physically with BBS proteins, and reducing the expression of BBS proteins perturbs IR expression in the cell surface. We show the consequence of disrupting BBS proteins for whole body insulin action and glucose metabolism using mice lacking different BBS genes. These findings demonstrate the importance of BBS proteins in underlying IR cell surface expression. Our data identify defects in trafficking and localization of the IR as a novel mechanism accounting for the insulin resistance commonly associated with human BBS. This is supported by the reduced surface expression of the IR in fibroblasts derived from patients bearing the M390R mutation in the BBS1 gene.

Highlights

Insulin is critically involved in the regulation of glucose and lipid metabolism in various tissues ensuring the coordinated uptake and storage of the products of digestion
We show the consequence of disrupting Bardet Biedl Syndrome (BBS) proteins for whole body insulin action and glucose metabolism using mice lacking different BBS genes
Insulin resistance which reflects the inability of insulin to properly regulate glucose metabolism is common in people with obesity and/or type 2 diabetes

Summary

Introduction

Insulin is critically involved in the regulation of glucose and lipid metabolism in various tissues ensuring the coordinated uptake and storage of the products of digestion. Insulin binding to its receptor initiates a myriad of intracellular events resulting in downstream activation of glucose uptake as well as glycogen, fatty acid, and DNA synthesis [1]. In its mature form, the IR resides in the plasma membrane as tetrameric proteins consisting of two extracellular, α-subunits, and two transmembrane, β-subunits. BBS is associated with increased susceptibility to other disorders including insulin resistance and type 2 diabetes. Diabetes mellitus and the associated impairments in glucose metabolism and insulin sensitivity are common among BBS patients and often manifest during childhood [4,6,7,8,9]. Even when matched for pubertal stage and body composition, individuals with BBS were found to exhibit significantly elevated insulin levels than controls [9,10]

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