Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Because AM had limited efficacy on rodent GPR

    2021-10-16

    Because (AM-3189) had limited efficacy on rodent GPR40, we used two rodent models expressing human GPR40 to demonstrate efficacy of (AM-3189). First, we used human islet transplanted nude mice. In this model, endogenous pancreatic β-cells were ablated using streptozotocin, and mice were rescued to euglycemia using human islets transplanted under the kidney capsule. In these mice, (AM-8139) dosed at 1 and 10mg/kg po prior to a glucose challenge lowered glucose AUC levels (A). The glucose lowering effect was comparable to that of a 100μg/kg dose of GLP-1 (A). The efficacy of was also examined in human GPR40 knock-in mice. Again, (30mg/kgpo) lowered glucose levels during an OGTT (B andC). In summary, further optimization of beta-substituted carboxylic acids as GPR40 agonists led to the discovery of (AM-3189), a potent GPR40 agonist that has good pre-clinical pharmacokinetic properties and low CNS penetration. (AM-3189) represents a valuable tool in the exploration of the role that the GPR40 receptor may play in type II diabetes. Acknowledgments
    Introduction
    Polyunsaturated fatty acids (PUFAs) and GPR40 (FFA1) receptor
    Physiological role of GPR40 receptor
    Role of GPR40 in neuropathological conditions
    Concluding remarks It is an established fact that (PUFAs) are expressed abundantly in the nervous system, play a vital role in Biotin-HPDP functioning, and serve as agonist for the GPR40 receptor. GPR40 currently appears to be a potential target in the management of several neuropathological conditions such as Alzheimer's disease, Parkinson's disease, neurogenesis, apoptosis, and inflammatory pain. Many studies have shown that PUFAs and GPR40 signaling contributes to the neurogensis, antinocieptive effects, anti-apoptotic effect, Ca2+ homeostasis in Alzheimer's disease and in the functioning of nigrostriatal pathways. However, there is a lack of clear data supporting its role in Alzheimer's disease and Parkinson's disease, therefore complementary studies are needed to fully clarify GPR40 functions and to determine in which condition(s) this receptor should be activated or blocked. Until now, no single study exists concerning the evaluation of the GPR40 role in the brain in genetically deficient mice. This emphasizes the need to evaluate its role in the brain by using KO mice models and to develop new pharmacological tools to ascertain the functional role of GPR40 in physiological and pathological conditions.
    Acknowledgements We gratefully acknowledge funding from National 12th Five-year Plan “Major Scientific and Technological Special Project for Significant New Drugs Creation” project of “Novel G protein-coupled receptor targeted drug screening system and key technology research” (NO. 2012ZX09504001-001) and Program for New Century Excellent Talents in University (No. NCET-10-0817), which have supported aspects of our research covered in this review.
    Introduction In addition to glucose, which is the foremost stimulator of insulin secretion in beta-cells, other nutrients such as free fatty acids (also called non-esterified fatty acids, NEFA) contribute to glucose-stimulated insulin secretion (GSIS). Glucose triggers the processes leading to insulin secretion by its metabolism within beta-cells [1], [2]. NEFA also act as fuels in beta-cells and they are able to modulate insulin secretion by influencing intracellular metabolism [3]. It was not until 2003, the discovery of the role of a previously orphaned receptor, the G-protein-coupled receptor 40 (GPR40), now called free fatty acid receptor 1 (FFAR1), that an additional important coupling mechanism between NEFA and insulin secretion was revealed [4]. The acute increase of insulin secretion after raising NEFA levels was shown to be ∼50% in healthy volunteers [5], [6], and the FFAR1-pathway is thought to be involved in at least 50% of NEFA-mediated insulin secretion [7]. FFAR1-agonists have been developed to enhance GSIS, some of which could be candidates for a new class of antidiabetic drugs [8]. We recently demonstrated that FFAR1-agonism may be protective against beta-cell apoptosis and provided evidence that common variation near the FFAR1 gene modulates insulin secretion dependent on free-fatty acid levels [9].