Aberrant liver insulin receptor isoform a expression normalises with remission of type 2 diabetes after gastric bypass surgery.

Vinko Besic,Mark T Hayes,Richard S Stubbs,Hongjun Shi,Victor Sanchez-Margalet

doi:10.1371/journal.pone.0119270

Vinko Besic, Mark T Hayes + Show 3 more

Open Access

https://doi.org/10.1371/journal.pone.0119270

Copy DOI

Abstract

Type 2 diabetes mellitus (T2DM) results from a combination of progressive insulin resistance and loss of pancreatic beta cell function and/or mass. Insulin signalling occurs through the insulin receptor, (INSR) which is alternatively spliced into two isoforms: INSRA (-exon 11) and INSRB (+exon 11). Because the INSR isoforms have different functional characteristics, their relative expression ratio has been implicated in the pathogenesis of insulin resistance and T2DM. We studied levels of INSR isoform mRNA in liver samples taken from 46 individuals with or without T2DM at Roux-en-Y (RYGB) surgery, and on average 17 (± 5.6) months later in 16 of the same individuals (8 diabetic and non-diabetic patients). INSRA or INSRB was also overexpressed in HepG2 cells to ascertain their effect on AKT phosphorylation and PCK1 expression as markers of insulin-mediated metabolic signalling. We found the INSRB:A isoform ratio was reduced in individuals with T2DM in comparison to those with normal glucose tolerance and normalised with remission of diabetes. The INSRB:A ratio increased due to a reduction in the alternatively spliced INSRA isoform following remission of diabetes. Overexpressing INSRA isoform in HepG2 hepatoma cells reduced inhibition of PCK1 transcription and did not increase AKT phosphorylation in response to insulin load compared to the effect of overexpressing the B isoform. Data presented here revitalizes the role of the INSR isoforms in the pathogenesis of T2DM, and suggests that an abrogated INSRB:A ratio that favours the INSRA isoform may negatively impact insulin-mediated metabolic signalling.

Highlights

Type 2 diabetes mellitus (T2DM) results from progressive increases in insulin resistance—a hindered biological response to insulin—coupled with a progressive loss of beta cell function and/or mass
Current evidence on the functional properties of the two isoforms suggests that insulin signalling through INSRA is predominantly mitogenic while insulin signalling though the INSRB is metabolic
Plasma insulin concentrations and Homeostasis model assessment (HOMA)-IR values were significantly higher in the T2DM group in comparison to the NGT group (p

Summary

Introduction

Type 2 diabetes mellitus (T2DM) results from progressive increases in insulin resistance—a hindered biological response to insulin—coupled with a progressive loss of beta cell function and/or mass. Current evidence on the functional properties of the two isoforms suggests that insulin signalling through INSRA is predominantly mitogenic while insulin signalling though the INSRB is metabolic (for review see Belfiore et al [4]). In vitro experiments with dexamethasone-treated HepG2 cells showed that increasing INSRB expression improved insulin sensitivity for insulin-mediated glucose metabolism and gene expression [9,10]. These data are consistent with the tissue distribution of the two isoforms. INSRB is expressed in differentiated adult cells and is predominant in insulin sensitive tissues which regulate glucose homeostasis such as the liver [13,14]

Methods

Results

Conclusion