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The Role and Future of FFA1 as a Therapeutic Target

Julien Ghislain1,2, Vincent Poitout3,4,5,6

  • 1Montreal Diabetes Research Center, University of Montreal, Montreal, QC, Canada.

Handbook of Experimental Pharmacology
|November 4, 2016
PubMed

Insights

FFA1 agonists show promise for treating type 2 diabetes by enhancing glucose-dependent insulin secretion. Despite setbacks, ongoing research into FFA1 signaling diversity offers hope for safer, effective diabetes treatments.

Area of Science:

  • Endocrinology
  • Metabolic Diseases
  • Pharmacology

Background:

  • Type 2 diabetes affects 90% of 415 million global diabetes cases, characterized by hyperglycemia due to insulin resistance.
  • Current diabetes drugs aim to improve glucose disposal or stimulate insulin secretion, but many insulin secretagogues risk hypoglycemia.
  • FFA1 (Gpr40), a receptor on pancreatic beta cells, is activated by long-chain fatty acids and potentiates glucose-dependent insulin secretion.

Purpose of the Study:

  • To explore FFA1 agonism as a therapeutic strategy for type 2 diabetes.
  • To investigate the potential of targeting FFA1 for improved glucose homeostasis.
  • To address the limitations of existing insulin secretagogues and seek safer alternatives.

Main Methods:

  • Preclinical studies in rodent models of diabetes.
  • Clinical trials involving type 2 diabetes patients.
  • Analysis of FFA1 signaling pathways and biological outcomes.

Main Results:

  • Preclinical data demonstrated FFA1 agonism's efficacy in restoring glucose homeostasis in diabetic rodents.
  • Initial clinical trials showed promising results for type 2 diabetes patients.
  • The lead compound TAK-875/fasiglifam was withdrawn due to liver safety concerns.

Conclusions:

  • FFA1 agonism presents a potential therapeutic avenue for type 2 diabetes, targeting glucose-dependent insulin secretion.
  • Despite clinical setbacks, recent discoveries reveal complexities in FFA1 agonist action and signaling.
  • Further understanding of FFA1 mechanisms is crucial for developing safer and more effective second-generation therapies.
Keywords:
Allosteric agonistBiased agonismFFA1/Gpr40Functional selectivityInsulin secretionPancreatic isletType 2 diabetesβ cell

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