GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent

PLoS One. 2017 Oct 20;12(10):e0186033. doi: 10.1371/journal.pone.0186033. eCollection 2017.

Abstract

GPR40 agonists are effective antidiabetic agents believed to lower glucose through direct effects on the beta cell to increase glucose stimulated insulin secretion. However, not all GPR40 agonists are the same. Partial agonists lower glucose through direct effects on the pancreas, whereas GPR40 AgoPAMs may incorporate additional therapeutic effects through increases in insulinotrophic incretins secreted by the gut. Here we describe how GPR40 AgoPAMs stimulate both insulin and incretin secretion in vivo over time in diabetic GK rats. We also describe effects of AgoPAMs in vivo to lower glucose and body weight beyond what is seen with partial GPR40 agonists in both the acute and chronic setting. Further comparisons of the glucose lowering profile of AgoPAMs suggest these compounds may possess greater glucose control even in the presence of elevated glucagon secretion, an unexpected feature observed with both acute and chronic treatment with AgoPAMs. Together these studies highlight the complexity of GPR40 pharmacology and the potential additional benefits AgoPAMs may possess above partial agonists for the diabetic patient.

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line
  • Cricetulus
  • Glucagon / metabolism
  • Glucose / metabolism*
  • Glucose Tolerance Test
  • Humans
  • Incretins / metabolism*
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Rats
  • Receptors, G-Protein-Coupled / agonists*

Substances

  • FFAR1 protein, human
  • Incretins
  • Insulin
  • Receptors, G-Protein-Coupled
  • Glucagon
  • Glucose

Grants and funding

The funder Merck and Co Inc. provided support in the form of salaries for all authors, study design, data collection and analysis, decision to publish, and preparation of the manuscript. The specific roles of these authors are articulated in the 'author contributions' section.