Vincamine as a GPR40 agonist improves glucose homeostasis in type 2 diabetic mice

Du, Tian; Yang, Liu; Xu, Xu; Shi, Xiaofan; Xu, Xin; Lu, Jian; Lv, Jiajia; Huang, Xi; Chen, Jing; Wang, He-Yao; Ye, Ji-Ming; Hu, Lihong; Shen, Xu

doi:10.1530/joe-18-0432

Cited by 16 publications

(7 citation statements)

References 58 publications

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“…As previously mentioned, VIN is a compound with multiple mechanism of actions. Several studies have shown that it is a PDE1 inhibitor, a GPR40 agonist, and a blocker of VGNC (Abdel-Salam et al, 2016; Du et al, 2019; Sheref et al, 2021). The effect of PDE inhibitors has been widely studied in several PD models.…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have indicated the potential role of nutraceuticals, such as VIN as well as its semi-synthetic derivative vinpocetine, to target the underlying neurodegenerative processes of PD (Lama et al, 2020).VIN exhibits antioxidant and anti-inflammatory activities, and may work through several mechanisms of action. It is a phosphodiesterase (PDE) I inhibitor, a blocker of voltage-gated Na + channels (VGNC), and a GPR40 agonist (Abdel-Salam et al, 2016;Du et al, 2019;Sheref et al, 2021). VIN is commercially available in the United States as a health care product with nootropic function, and exerts a beneficial effect in a number of brain disorders of elderly patients, such as memory disturbances, vertigo, transient ischemic deficits and headache (Fandy et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

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Disease-modifying effects of Vincamine supplementation inDrosophilaand human cell models of Parkinson’s disease

Sanz

Solana-Manrique

Paricio

2022

Preprint

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Parkinson's disease (PD) is an incurable neurodegenerative disorder caused by the selective loss of dopaminergic neurons in thesubstantia nigra pars compacta. Current therapies are only symptomatic, and are not able to stop or delay its progression. In order to search new and more effective therapies, our group carried out a high-throughput screening assay, identifying several candidate compounds able to suppress motor defects inDJ-1βmutant flies (aDrosophilamodel of familial PD) and to reduce oxidative stress (OS)-induced lethality inDJ-1-deficient SH-SY5Y human cells. One of them was vincamine (VIN), a natural alkaloid obtained from the leaves of Vinca minor. Our results showed that VIN is able to suppress PD-related phenotypes in bothDrosophilaand human cell PD models. Specifically, VIN reduced OS levels in PD model flies. Besides, VIN diminished OS-induced lethality by decreasing apoptosis, increased mitochondrial viability and reduced OS levels inDJ-1-deficient human cells. In addition, we have demonstrated that VIN is able to exert its beneficial role, at least partially, by the inhibition of voltage-gated Na+channels. Therefore, we propose that these channels might be a promising target in the search for new compounds to treat PD, and that VIN constitutes a potential therapeutic treatment for the disease.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Disease-modifying effects of Vincamine supplementation inDrosophilaand human cell models of Parkinson’s disease

Sanz

Solana-Manrique

Paricio

2022

Preprint

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“…This may have been caused by a decrease in glucotoxicity via the glucose-lowering activity of SCO-267. Furthermore, it has been reported that vincamine, a monoterpenoid indole alkaloid, which activates GPR40, protected STZ-treated INS-832/13 cells, a rat insulinoma cell line, through GPR40 activation (Du et al, 2019), and CNX-011-67, a GPR40 agonist, reduces inflammation-induced apoptosis of NIT1 cells, a mouse pancreatic β-cell line (Verma et al, 2014). Overall, SCO-267 may improve β-cell function via a direct GPR40-mediated effect.…”

Section: Discussionmentioning

confidence: 96%

Chronic Exposure to SCO-267, an Allosteric GPR40 Full Agonist, Is Effective in Improving Glycemic Control in Rats

Koyama¹,

Ookawara²,

Watanabe³

et al. 2021

Mol Pharmacol

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Full agonist-mediated activation of free fatty acid receptor 1 (FFAR1/GPR40) alleviates diabetes in rodents. Considering that diabetes is a chronic disease, assessment of treatment durability of chronic exposure to a GPR40 full agonist is pivotal for treating patients with diabetes. However, the physiological significance of chronic in vitro and in vivo exposure to GPR40 full agonists is largely unclear. Here, we evaluated the in vitro and in vivo effects of chronic treatment with SCO-267, a GPR40 full agonist, on signal transduction and glucose control. In vitro experiments showed that SCO-267 is an allosteric full agonist for GPR40, which activates the Gα q , Gα s , and Gα 12/13 pathways and β-arrestin recruitment. The calcium signal response was largely sustained in GPR40-overexpressing CHO cells even after prolonged incubation with SCO-267. To evaluate the in vivo relevance of chronic exposure to GPR40 full agonists, SCO-267 (1 and 10 mg/kg) was administered once daily to neonatally streptozotocin-induced diabetic rats for 15-33 days, and glucose control was evaluated. After 15 days of dosing followed by the drug wash-out period, SCO-267 improved glucose tolerance most likely by increasing insulin sensitivity in rats. After 33 days, repeated exposure to SCO-267 was highly effective in improving glucose tolerance in rats. Furthermore, chronic exposure to SCO-267 increased pancreatic insulin content. These results demonstrated that even after chronic exposure, SCO-267 effectively activates GPR40 in cells and rats, suggesting the clinical application of SCO-267 in treating chronic diseases This article has not been copyedited and formatted. The final version may differ from this version.

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“…NOTCH1 regulated the PI3K/Akt pathway through targeting FOXC2, thus regulating glucose and lipids metabolism in type 2 diabetes model cells A previous study showed that FOXC2 could regulate the PI3K/ Akt pathway in colorectal cancer 24 . The PI3K/Akt pathway was reported to play an important role in regulating glucose metabolism 25 . Here, we aimed to explore regulating relationships between NOTCH1, FOXC2 and the PI3K/Akt pathway in regulating glucose and lipids metabolism, so we both overexpressed NOTCH1 and knockdown FOXC2 in HG-treated HepG2 cells.…”

Section: Mir-363 Regulated Glucose and Lipids Metabolism In Type 2 Di...mentioning

confidence: 99%

Micro ribonucleic acid‐363 regulates the phosphatidylinositol 3‐kinase/threonine protein kinase axis by targeting NOTCH1 and forkhead box C2, leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes mellitus

Peng

Wang

et al. 2021

J of Diabetes Invest

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Aims/Introduction Glucose metabolic disorder is the main cause for type 2 diabetes progression. Exploring the molecular mechanisms of metabolic disorder are crucial for type 2 diabetes treatment. Materials and Methods Micro ribonucleic acid (miR)‐363, NOTCH1 and forkhead box C2 (FOXC2) expressions in high glucose (HG)‐treated HepG2 cells and the livers of type 2 diabetes mellitus rats were assessed using quantitative polymerase chain reaction. Protein levels of NOTCH1, FOXC2 and phosphatidylinositol 3‐kinase (PI3K)/serine/threonine protein kinase (Akt)‐related proteins were evaluated using western blot. Lipid accumulation was determined using Oil Red O staining. Then glucose consumption, blood glucose level and glycogen content were detected using kits. Finally, dual luciferase reporter assay was used to verify the binding relationship between miR‐363 and NOTCH1, and the binding relationship between miR‐363 and FOXC2. Results MiR‐363 was significantly upregulated in the livers of diabetic rats and HG‐induced HepG2 cells, whereas NOTCH1 and FOXC2 were downregulated. In HG‐induced HepG2 cells, miR‐363 inhibitor markedly increased glucose consumption and uptake, and reduced accumulation of lipid droplets. Then NOTCH1 and FOXC2 were identified as downstream targets of miR‐363. NOTCH1 overexpression or FOXC2 overexpression could ameliorate glucose and lipids metabolism disorder in type 2 diabetes model cells. In addition, we found that FOXC2 inhibition abolished the effect of NOTCH1 overexpression on HG‐induced HepG2 cells. Finally, we proved that the PI3K/Akt pathway was the downstream pathway of FOXC2. Conclusion MiR‐363 was considered as a key regulator of glucose and lipids metabolism in type 2 diabetes mellitus, which regulated PI3K/Akt axis by targeting NOTCH1 and FOXC2, thus leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes.

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Vincamine as a GPR40 agonist improves glucose homeostasis in type 2 diabetic mice

Cited by 16 publications

References 58 publications

Disease-modifying effects of Vincamine supplementation inDrosophilaand human cell models of Parkinson’s disease

Disease-modifying effects of Vincamine supplementation inDrosophilaand human cell models of Parkinson’s disease

Chronic Exposure to SCO-267, an Allosteric GPR40 Full Agonist, Is Effective in Improving Glycemic Control in Rats

Micro ribonucleic acid‐363 regulates the phosphatidylinositol 3‐kinase/threonine protein kinase axis by targeting NOTCH1 and forkhead box C2, leading to hepatic glucose and lipids metabolism disorder in type 2 diabetes mellitus

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