Novel G-Protein Coupled Receptor Therapeutic Target and Related Agonists for Treatment of Type 2 Diabetes (U452)

Tuesday, 25 October 2016

Ulster University researchers from the Biomedical Sciences Research Institute have identified a G-Protein Coupled Receptor (GPCR) codified as GPRa1 in the pancreas and have demonstrated a key role of GPRa1 in islet function. The research has uncovered a novel therapeutic target for use in treatment of metabolic disease.

Problem Being Solved

Diabetes is a major public health challenge, with at least 180 million reported cases of diabetes world- wide, a figure set to more than double by 2030 (WHO). This alarming increase in incidence coupled with the failure of established anti-diabetic drugs to manage or control diabetes demonstrates the market need for new innovations.

Technology

A new islet target, GPRa1 has been validated for improved diabetes treatment and care. These studies have identified the involvement of GPRa1 in regulating hormone secretion and β-cell mass; and determined the role of GPRa1 in the regulation of insulin secretion using small molecule agonists in in vitro and in vivo studies using diabetic animal models.

Results to date have demonstrated the following:

  • GPRa1 agonists exhibit enhanced potency in insulin secretion studies using a clonal pancreatic cell line, BRIN-BD11 and isolated mouse islets. GPRa1 agonists exhibited no cytotoxicity.
  • Agonists to GPRa1 exhibited anti-hyperglycaemic activity and substantially enhanced insulin-releasing action in acute studies in high fat fed (HFF) mice.
  • GPRa1 has an effect on the β- cell stimulus secretion coupling pathway in pancreatic islets. The mechanism of action of GPRa1 agonist-induced insulin release, predominately works through the Ca2+ activated pathway and the cAMP dependent pathway.

Following long term administration in HFF mice, GPRa1 agonists reduced body weight after 15 days, significantly decreased plasma glucose and enhanced insulin secretion in oral glucose tolerance tests, increased GLP-1 secretion by 61% and decreased body fat in HFF mice.

Benefits/Applications

 GPR1a agonists have been identified exhibit superior anti-hyperglycaemic activity and are potent insulin secretagogues in animal models of diabetes.

 This exciting preliminary data package  paves the way for lead candidate optimisation and in vivo demonstration of activity and efficacy, examining the pharmacokinetic and pharmacodynamic profile as well as the longer-term, chronic benefits of repeated daily treatment with lead GPCR agonists in a range of diabetic animal models.

Publications

Moran, BM, Abdel-Wahab, Yasser, Flatt, Peter and Mckillop, Aine (2014) Evaluation of the insulin-releasing and glucose-lowering effects of GPR120 activation in pancreatic β-cells.. Diabetes Obesity and Metabolism, 16 (11). pp. 1128-1139.

 

Mckillop, Aine, Moran, BM, Abdel-Wahab, Yasser and Flatt, Peter (2013) Evaluation of the insulin releasing and antihyperglycaemic activities of GPR55 lipid agonists using clonal beta-cells, isolated pancreatic islets and mice.. British Journal of Pharmacology, 170 (5). pp. 978-990.

Opportunity/Partnership Sought

Further long term studies using GPR1a agonists and combination therapies in diabetic models are ongoing to assess the scientific basis, therapeutic usefulness and extra-pancreatic actions of this promising class of anti-diabetic agents.

 Ulster University is looking for a potential partner or collaborator to progress this technology. An exclusive licensing of Ulster’s U452 technology provides an opportunity to enhance a licensor’s existing intellectual property pipeline or competitive positioning of this emerging technology.

 In addition, inventors of this technology are able to provide valuable know-how in order to assist in its successful commercialization.

 For more information please contact:

 Dr Oonagh Lynch

Technology Commercialisation Executive

Research & Impact

Tel: +44 (0) 28 9036 6707

Mob: +44 (0) 77 6536 3191

Email:ot.lynch@ulster.ac.uk