GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent.
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 AgoP...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2017-01-01
|
| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5650142?pdf=render |
| _version_ | 1819118423663181824 |
|---|---|
| author | Michele J Pachanski Melissa E Kirkland Daniel T Kosinski Joel Mane Boonlert Cheewatrakoolpong Jiyan Xue Daphne Szeto Gail Forrest Corin Miller Michelle Bunzel Christopher W Plummer Harry R Chobanian Michael W Miller Sarah Souza Brande S Thomas-Fowlkes Aimie M Ogawa Adam B Weinglass Jerry Di Salvo Xiaoyan Li Yue Feng Daniel A Tatosian Andrew D Howard Steven L Colletti Maria E Trujillo |
| author_facet | Michele J Pachanski Melissa E Kirkland Daniel T Kosinski Joel Mane Boonlert Cheewatrakoolpong Jiyan Xue Daphne Szeto Gail Forrest Corin Miller Michelle Bunzel Christopher W Plummer Harry R Chobanian Michael W Miller Sarah Souza Brande S Thomas-Fowlkes Aimie M Ogawa Adam B Weinglass Jerry Di Salvo Xiaoyan Li Yue Feng Daniel A Tatosian Andrew D Howard Steven L Colletti Maria E Trujillo |
| author_sort | Michele J Pachanski |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T05:48:39Z |
| format | Article |
| id | doaj.art-32189b3be78e4819b3311bc01c779ade |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T05:48:39Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-32189b3be78e4819b3311bc01c779ade2022-12-21T18:36:56ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-011210e018603310.1371/journal.pone.0186033GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent.Michele J PachanskiMelissa E KirklandDaniel T KosinskiJoel ManeBoonlert CheewatrakoolpongJiyan XueDaphne SzetoGail ForrestCorin MillerMichelle BunzelChristopher W PlummerHarry R ChobanianMichael W MillerSarah SouzaBrande S Thomas-FowlkesAimie M OgawaAdam B WeinglassJerry Di SalvoXiaoyan LiYue FengDaniel A TatosianAndrew D HowardSteven L CollettiMaria E TrujilloGPR40 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.http://europepmc.org/articles/PMC5650142?pdf=render |
| spellingShingle | Michele J Pachanski Melissa E Kirkland Daniel T Kosinski Joel Mane Boonlert Cheewatrakoolpong Jiyan Xue Daphne Szeto Gail Forrest Corin Miller Michelle Bunzel Christopher W Plummer Harry R Chobanian Michael W Miller Sarah Souza Brande S Thomas-Fowlkes Aimie M Ogawa Adam B Weinglass Jerry Di Salvo Xiaoyan Li Yue Feng Daniel A Tatosian Andrew D Howard Steven L Colletti Maria E Trujillo GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent. PLoS ONE |
| title | GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent. |
| title_full | GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent. |
| title_fullStr | GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent. |
| title_full_unstemmed | GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent. |
| title_short | GPR40 partial agonists and AgoPAMs: Differentiating effects on glucose and hormonal secretions in the rodent. |
| title_sort | gpr40 partial agonists and agopams differentiating effects on glucose and hormonal secretions in the rodent |
| url | http://europepmc.org/articles/PMC5650142?pdf=render |
| work_keys_str_mv | AT michelejpachanski gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT melissaekirkland gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT danieltkosinski gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT joelmane gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT boonlertcheewatrakoolpong gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT jiyanxue gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT daphneszeto gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT gailforrest gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT corinmiller gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT michellebunzel gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT christopherwplummer gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT harryrchobanian gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT michaelwmiller gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT sarahsouza gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT brandesthomasfowlkes gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT aimiemogawa gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT adambweinglass gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT jerrydisalvo gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT xiaoyanli gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT yuefeng gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT danielatatosian gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT andrewdhoward gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT stevenlcolletti gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent AT mariaetrujillo gpr40partialagonistsandagopamsdifferentiatingeffectsonglucoseandhormonalsecretionsintherodent |