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

PLoS One. 2015 Mar 5;10(3):e0119270. doi: 10.1371/journal.pone.0119270. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alternative Splicing
  • Antigens, CD / genetics*
  • Antigens, CD / metabolism*
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Female
  • Gastric Bypass / methods
  • Hep G2 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Middle Aged
  • Obesity, Morbid / complications
  • Obesity, Morbid / genetics
  • Obesity, Morbid / surgery*
  • Phosphoenolpyruvate Carboxykinase (GTP) / genetics
  • Phosphorylation
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Receptor, Insulin / genetics*
  • Receptor, Insulin / metabolism*

Substances

  • Antigens, CD
  • Intracellular Signaling Peptides and Proteins
  • Protein Isoforms
  • INSR protein, human
  • Receptor, Insulin
  • Proto-Oncogene Proteins c-akt
  • PCK1 protein, human
  • Phosphoenolpyruvate Carboxykinase (GTP)

Grant support

This work was supported by the Wellington Medical Research Foundation, Wakefield Gastroenterology Research Trust and the Wakefield Clinic who provided contributions to salaries and consumables. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.