Establishing the mechanism underlying the genetic association of a glucose transporter to metformin response to improve its use in the clinic
Description: Metformin is prescribed to >100 million people, yet it is not effective in around 1 in 3 people with diabetes. Our recent studies in >10,000 patients identified a single nucleotide polymorphism (SNP) with a strong association with metformin response. This lies in the SLC2A2 gene that encodes the glucose transporter GLUT2, and this association was extended through eQTL analysis of multiple tissues in 100’s of patients. These data imply that SLC2A2 gene sequence modifies how metformin works in diabetes. Interestingly, the pharmacogenetic impact was even stronger in obese individuals. We propose that understanding how GLUT2 modulates metformin action could provide opportunities to help patients that currently don’t respond to metformin. The preliminary data associates a reduction of GLUT2 mRNA to lower metformin efficacy. To establish a mechanistic link we will compare the development of diet-induced type 2 diabetes, and subsequent molecular, physiological and clinical responses to metformin, in mice with reduced GLUT2 to that of controls. Importantly we will establish whether the association relates to reduced metformin sensitivity or maximal response, and perform a pilot to investigate whether the SLC2A2 gene sequence/GLUT2 protein levels could be used to inform the metformin starting dose for Type 2 diabetes in the clinic.
Funder: Diabetes UK
Amount: £282,500
Funding type: research
Funder scheme: Project Grant
Start date: 2017-06-01
End date: 2020-05-30
Investigators: Calum Sutherland, Calum Sutherland
Institution: University of Dundee
Funded outputs count: 2
Funder award ID: 16/0005487
OpenAlex ID: G934635470