Sandbox Reserved 1170: Difference between revisions

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One proposed pathway of insulin secretion by hGPR40 involves the activation of the [https://en.wikipedia.org/wiki/Gq_alpha_subunit Gaq/11] protein complex. This complex then activates [[phospholipase C]] (PLC) which in turn phosphorylates [https://en.wikipedia.org/wiki/Phosphatidylinositol_4,5-bisphosphate phosphatidylinositol 4,5-bisphosphate] to inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 can then mediate the [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560308/ influx of Ca2+] caused by the binding of free fatty acids to hGPR40 by moving into the cytoplasm, binding to the endoplasmic reticulum, and allowing for the release of Ca2+ into the cytosol.<ref name="Burant"/> This increase in [Ca2+] amplifies the similar increase in [Ca2+] that results from high concentrations of glucose. In this way, hGPR40 mimics glucose dependent insulin secretion.<ref name="Itoh">PMID:12629551</ref>

Another pathway through which hGPR40 may induce insulin expression is through phospholipase D1 (PLD1). When free fatty acids bind to hGPR40, it ~~is able to phosphorylate~~ and ~~therefore activate~~ PLD1. The PLD1 plays a role in controlling the organization of an actin network that plays in role in insulin secretion.<ref name="Burant"/>

Another pathway through which hGPR40 may induce insulin expression is through phospholipase D1 (PLD1). When free fatty acids bind to hGPR40, it phosphorylates and activates PLD1. The PLD1 plays a role in controlling the organization of an actin network that plays in role in insulin secretion.<ref name="Burant"/>

== Clinical Relevance ==

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=== TAK-875 ===

[[Image:Tak-875.png |300 px|right|thumb|Figure 4. Structure of TAK-875]] One example of an hGPR40 agonist is <scene name='72/721541/Tak875/2'>TAK-875</scene>. The carboxylate moiety of the agonist enters through ~~the it of~~ the auxiliary loop, interrupts the charge network, and binds with Arg 183, Arg 258, Tyr 91, and Tyr 240.<ref name="Srivastava"/> TAK-875 has shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes.<ref name="Burant"/> This drug was studied in stage III clinical trials ~~and was able to~~ significantly ~~reduce~~ [http://www.diabetes.co.uk/what-is-hba1c.html HbA1c] and fasting plasma glucose levels in Japanese patients with type 2 diabetes that was not controlled by diet and exercise. However, clinical trials were stopped shortly after this study because TAK-875 was suspected of causing liver damage.<ref name="Kaku">PMID:25787200</ref>

[[Image:Tak-875.png |300 px|right|thumb|Figure 4. Structure of TAK-875]] One example of an hGPR40 agonist is <scene name='72/721541/Tak875/2'>TAK-875</scene>. The carboxylate moiety of the agonist enters through the auxiliary loop of hGPR40, interrupts the charge network, and binds with Arg 183, Arg 258, Tyr 91, and Tyr 240.<ref name="Srivastava"/> TAK-875 has shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes.<ref name="Burant"/> This drug was studied in stage III clinical trials. It significantly reduced [http://www.diabetes.co.uk/what-is-hba1c.html HbA1c] and fasting plasma glucose levels in Japanese patients with type 2 diabetes that was not controlled by diet and exercise. However, clinical trials were stopped shortly after this study because TAK-875 was suspected of causing liver damage.<ref name="Kaku">PMID:25787200</ref>

Sandbox Reserved 1170: Difference between revisions

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@@ Line 25: / Line 25: @@
 One proposed pathway of insulin secretion by hGPR40 involves the activation of the [https://en.wikipedia.org/wiki/Gq_alpha_subunit G<sub>aq/11</sub>] protein complex. This complex then activates [[phospholipase C]] (PLC) which in turn phosphorylates [https://en.wikipedia.org/wiki/Phosphatidylinositol_4,5-bisphosphate phosphatidylinositol 4,5-bisphosphate] to inositol 1,4,5-triphosphate (IP<sub>3</sub>) and diacylglycerol (DAG). IP<sub>3</sub> can then mediate the [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3560308/ influx of Ca<sup>2+</sup>] caused by the binding of free fatty acids to hGPR40 by moving into the cytoplasm, binding to the endoplasmic reticulum, and allowing for the release of Ca<sup>2+</sup> into the cytosol.<ref name="Burant"/> This increase in [Ca<sup>2+</sup>] amplifies the similar increase in [Ca<sup>2+</sup>] that results from high concentrations of glucose. In this way, hGPR40 mimics glucose dependent insulin secretion.<ref name="Itoh">PMID:12629551</ref>
-Another pathway through which hGPR40 may induce insulin expression is through phospholipase D1 (PLD1). When free fatty acids bind to hGPR40, it is able to phosphorylate and therefore activate PLD1. The PLD1 plays a role in controlling the organization of an actin network that plays in role in insulin secretion.<ref name="Burant"/>
+Another pathway through which hGPR40 may induce insulin expression is through phospholipase D1 (PLD1). When free fatty acids bind to hGPR40, it phosphorylates and activates PLD1. The PLD1 plays a role in controlling the organization of an actin network that plays in role in insulin secretion.<ref name="Burant"/>
 == Clinical Relevance ==
@@ Line 31: / Line 31: @@
 === TAK-875 ===
-[[Image:Tak-875.png |300 px|right|thumb|Figure 4. Structure of TAK-875]] One example of an hGPR40 agonist is <scene name='72/721541/Tak875/2'>TAK-875</scene>. The carboxylate moiety of the agonist enters through the it of the auxiliary loop, interrupts the charge network, and binds with Arg 183, Arg 258, Tyr 91, and Tyr 240.<ref name="Srivastava"/> TAK-875 has shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes.<ref name="Burant"/> This drug was studied in stage III clinical trials and was able to significantly reduce [http://www.diabetes.co.uk/what-is-hba1c.html HbA1c] and fasting plasma glucose levels in Japanese patients with type 2 diabetes that was not controlled by diet and exercise. However, clinical trials were stopped shortly after this study because TAK-875 was suspected of causing liver damage.<ref name="Kaku">PMID:25787200</ref>
+[[Image:Tak-875.png |300 px|right|thumb|Figure 4. Structure of TAK-875]] One example of an hGPR40 agonist is <scene name='72/721541/Tak875/2'>TAK-875</scene>. The carboxylate moiety of the agonist enters through the auxiliary loop of hGPR40, interrupts the charge network, and binds with Arg 183, Arg 258, Tyr 91, and Tyr 240.<ref name="Srivastava"/> TAK-875 has shown efficacy in increasing insulin secretion and lowering blood glucose in rodent models of type 2 diabetes.<ref name="Burant"/> This drug was studied in stage III clinical trials. It significantly reduced [http://www.diabetes.co.uk/what-is-hba1c.html HbA1c] and fasting plasma glucose levels in Japanese patients with type 2 diabetes that was not controlled by diet and exercise. However, clinical trials were stopped shortly after this study because TAK-875 was suspected of causing liver damage.<ref name="Kaku">PMID:25787200</ref>