Increased glucagon-like peptide-1 secretion may be involved in antidiabetic effects of ginsenosides

Panax ginseng is one of the most popular herbal remedies. Ginsenosides, major bioactive constituents in P. ginseng, have shown good antidiabetic action, but the precise mechanism was not fully understood. Glucagon-like peptide-1 (GLP1) is considered to be an important incretin that can regulate glucose homeostasis in the gastrointestinal tract after meals. The aim of this study was to investigate whether ginseng total saponins (GTS) exerts its antidiabetic effects via modulating GLP1 release. Ginsenoside Rb1 (Rb1), the most abundant constituent in GTS, was selected to further explore the underlying mechanisms in cultured NCI-H716 cells. Diabetic rats were developed by a combination of high-fat diet and low-dose streptozotocin injection. The diabetic rats orally received GTS (150 or 300 mg/kg) daily for 4 weeks. It was found that GTS treatment significantly ameliorated hyperglycemia and dyslipidemia, accompanied by a significant increase in glucose-induced GLP1 secretion and upregulation of proglucagon gene expression. Data from NCI-H716 cells showed that both GTS and Rb1 promoted GLP1 secretion. It was observed that Rb1 increased the ratio of intracellular ATP to ADP concentration and intracellular Ca2+ concentration. The metabolic inhibitor azide (3 mM), the KATP channel opener diazoxide (340 μM), and the Ca2+ channel blocker nifedipine (20 μM) significantly reversed Rb1-mediated GLP1 secretion. All these results drew a conclusion that ginsenosides stimulated GLP1 secretion both in vivo and in vitro. The antidiabetic effects of ginsenosides may be a result of enhanced GLP1 secretion.

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Glucagon-like peptide-1(7-36)-amide confers glucose sensitivity to previously glucose-incompetent beta-cells in diabetic rats: in vivo and in vitro studies

Journal of Endocrinology ◽

10.1677/joe.0.1550369 ◽

1997 ◽

Vol 155 (2) ◽

pp. 369-376 ◽

Cited By ~ 28

Author(s):

N Dachicourt ◽

P Serradas ◽

D Bailbe ◽

M Kergoat ◽

L Doare ◽

...

Keyword(s):

Glucose Tolerance ◽

Beta Cells ◽

Insulin Release ◽

Insulin Response ◽

Diabetic Rats ◽

Insulin Response To Glucose ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

The effects of glucagon-like peptide-1(7-36)-amide (GLP-1) on cAMP content and insulin release were studied in islets isolated from diabetic rats (n0-STZ model) which exhibited impaired glucose-induced insulin release. We first examined the possibility of re-activating the insulin response to glucose in the beta-cells of the diabetic rats using GLP-1 in vitro. In static incubation experiments, GLP-1 amplified cAMP accumulation (by 170%) and glucose-induced insulin release (by 140%) in the diabetic islets to the same extent as in control islets. Using a perifusion procedure, GLP-1 amplified the insulin response to 16.7 mM glucose by diabetic islets and generated a clear biphasic pattern of insulin release. The incremental insulin response to glucose in the presence of GLP-1, although lower than corresponding control values (1.56 +/- 0.37 and 4.53 +/- 0.60 pg/min per ng islet DNA in diabetic and control islets respectively), became similar to that of control islets exposed to 16.7 mM glucose alone (1.09 +/- 0.15 pg/min per ng islet DNA). Since in vitro GLP-1 was found to exert positive effects on the glucose competence of the residual beta-cells in the n0-STZ model. we investigated the therapeutic effect of in vivo GLP-1 administration on glucose tolerance and glucose-induced insulin release by n0-STZ rats. An infusion of GLP-1 (10 ng/min per kg; i.v.) in n0-STZ rats enhanced significantly (P < 0.01) basal plasma insulin levels, and, when combined with an i.v. glucose tolerance and insulin secretion test, it was found to improve (P < 0.05) glucose tolerance and the insulinogenic index, as compared with the respective values of these parameters before GLP-1 treatment.

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A synthetic glucagon-like peptide-1 analog with improved plasma stability

Journal of Endocrinology ◽

10.1677/joe.0.1590093 ◽

1998 ◽

Vol 159 (1) ◽

pp. 93-102 ◽

Cited By ~ 44

Author(s):

U Ritzel ◽

U Leonhardt ◽

M Ottleben ◽

A Ruhmann ◽

K Eckart ◽

...

Keyword(s):

Amino Acid ◽

Plasma Insulin ◽

Rat Plasma ◽

Plasma Stability ◽

Terminal Amino Acid ◽

Terminal Amino ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) is the most potent endogenous insulin-stimulating hormone. In the present study the plasma stability and biological activity of a GLP-1 analog, [Ser]GLP-1(7-36)amide, in which the second N-terminal amino acid alanine was replaced by serine, was evaluated in vitro and in vivo. Incubation of GLP-1 with human or rat plasma resulted in degradation of native GLP-1(7-36)amide to GLP-1(9-36)amide, while [Ser]GLP-1(7-36)amide was not significantly degraded by plasma enzymes. Using glucose-responsive HIT-T15 cells, [Ser]GLP-1(7-36)amide showed strong insulinotropic activity, which was inhibited by the specific GLP-1 receptor antagonist exendin-4(9-39)amide. Simultaneous i.v. injection of [Ser]GLP-1(7-36)amide and glucose in rats induced a twofold higher increase in plasma insulin levels than unmodified GLP-1(7-36)amide with glucose and a fivefold higher increase than glucose alone. [Ser]GLP-1(7-36)amide induced a 1.5-fold higher increase in plasma insulin than GLP-1(7-36)amide when given 1 h before i.v. application of glucose. The insulinotropic effect of [Ser]GLP-1(7-36)amide was suppressed by i.v. application of exendin-4(9-39)amide. The present data demonstrate that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide. The insulinotropic action in vitro and in vivo was not impaired significantly by this modification.

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Flavonoid constituents of Amomum tsao-ko Crevost et Lemarie and its antioxidant, antidiabetic effects in diabetic rats–in vitro and in vivo studies

Food & Function ◽

10.1039/d1fo02974f ◽

2021 ◽

Author(s):

Xiaofeng Zhang ◽

Yujun Tang ◽

Xiaoxian Guan ◽

Xin Lu ◽

Jiao Li ◽

...

Keyword(s):

Chinese Medicine ◽

Traditional Chinese Medicine ◽

Diabetic Rats ◽

In Vivo Studies ◽

Antidiabetic Effects

Amomum tsao-ko Crevost et Lemarie (A. tsao-ko) is a well-known dietary spice and traditional Chinese medicine. This study aimed to identify the flavonoids in A. tsao-ko and evaluate its antioxidant...

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Glucagon-like Peptide 1 Receptor Agonists, Diabetic Retinopathy and Angiogenesis: The AngioSafe Type 2 Diabetes Study

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz069 ◽

2019 ◽

Vol 105 (4) ◽

pp. e1549-e1560 ◽

Cited By ~ 7

Author(s):

Bénédicte Gaborit ◽

Jean-Baptiste Julla ◽

Samaher Besbes ◽

Matthieu Proust ◽

Clara Vincentelli ◽

...

Keyword(s):

Type 2 Diabetes ◽

Diabetic Retinopathy ◽

Fundus Photography ◽

Endothelial Cell Proliferation ◽

Receptor Agonists ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Abstract Aims Recent trials provide conflicting results on the association between glucagon-like peptide 1 receptor agonists (GLP-1RA) and diabetic retinopathy (DR). The aim of the AngioSafe type 2 diabetes (T2D) study was to determine the role of GLP-1RA in angiogenesis using clinical and preclinical models. Methods We performed two studies in humans. In study 1, we investigated the effect of GLP-1RA exposure from T2D diagnosis on the severity of DR, as diagnosed with retinal imaging (fundus photography). In study 2, a randomized 4-week trial, we assessed the effect of liraglutide on circulating hematopoietic progenitor cells (HPCs), and angio-miRNAs. We then studied the experimental effect of Exendin-4, on key steps of angiogenesis: in vitro on human endothelial cell proliferation, survival and three-dimensional vascular morphogenesis; and in vivo on ischemia-induced neovascularization of the retina in mice. Results In the cohort of 3154 T2D patients, 10% displayed severe DR. In multivariate analysis, sex, disease duration, glycated hemoglobin (HbA1c), micro- and macroangiopathy, insulin therapy and hypertension remained strongly associated with severe DR, while no association was found with GLP-1RA exposure (o 1.139 [0.800–1.622], P = .47). We further showed no effect of liraglutide on HPCs, and angio-miRNAs. In vitro, we demonstrated that exendin-4 had no effect on proliferation and survival of human endothelial cells, no effect on total length and number of capillaries. Finally, in vivo, we showed that exendin-4 did not exert any negative effect on retinal neovascularization. Conclusions The AngioSafe T2D studies provide experimental and clinical data confirming no effect of GLP-1RA on angiogenesis and no association between GLP-1 exposure and severe DR.

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Oral intake of slowly digestible α-glucan, isomaltodextrin, stimulates glucagon-like peptide-1 secretion in the small intestine of rats

British Journal Of Nutrition ◽

10.1017/s0007114519003210 ◽

2019 ◽

Vol 123 (6) ◽

pp. 619-626

Author(s):

Yoshihiko Komuro ◽

Takashi Kondo ◽

Shingo Hino ◽

Tatsuya Morita ◽

Naomichi Nishimura

Keyword(s):

Small Intestine ◽

Oral Delivery ◽

Oral Intake ◽

Membrane Vesicles ◽

Rat Small Intestine ◽

Maize Starch ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

AbstractTo investigate whether oral intake of highly branched α-glucan isomaltodextrin (IMD) could stimulate ileal glucagon-like peptide-1 (GLP-1) secretion, we examined (1) the digestibility of IMD, (2) the digestion and absorption rates of IMD, in rat small intestine and (3) portal GLP-1 concentration in rats given IMD. In Expt 1, ileorectostomised rats were given a 3 % IMD diet for 10 d. Separately, a 16-h in vitro digestion of IMD, using porcine pancreatic α-amylase and brush-border membrane vesicles from rat small intestine, was conducted. In Expt 2, upon 24-h fasting, rats were given any of glucose, IMD and high-amylose maize starch (HAMS) (1 g/kg of body weight). In Expt 3, caecectomised rats were given 0·2 % neomycin sulphate and a 5 % IMD diet for 10 d. The in vivo and in vitro digestibility of IMD was 70–80 %. The fraction of IMD digested in vitro for the first 120 min was 67 % of that in maize starch. The AUC for 0–120 min of plasma glucose concentration was significantly lower in HAMS group and tended to be lower in IMD group than in the glucose group. Finally, we also observed that, when compared with control rats, glucose of IMD significantly stimulated and improved the concentration of portal active GLP-1 in antibiotic-administered, caecectomised rats. We concluded that IMD was slowly digested and the resulting glucose stimulated GLP-1 secretion in rat small intestine. Oral delivery of slowly released IMD glucose to the small intestine probably exerts important, yet unknown, physiological effects on the recipient.

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α-Glucosidase Inhibitory, Anti-Oxidant, and Anti-Hyperglycemic Effects of Euphorbia nivulia–Ham. in STZ-Induced Diabetic Rats

Dose-Response ◽

10.1177/1559325820939429 ◽

2020 ◽

Vol 18 (3) ◽

pp. 155932582093942

Author(s):

Muhammad Younus ◽

Muhammad Mohtasheem ul Hasan ◽

Khalil Ahmad ◽

Ali Sharif ◽

Hafiz Muhammad Asif ◽

...

Keyword(s):

High Performance ◽

Wistar Rat ◽

Inhibitory Effect ◽

Diabetic Rats ◽

In Vivo Studies ◽

Control Group ◽

Control Drug ◽

Antidiabetic Effects

In this study, we aimed to investigate the antidiabetic effects of Euphorbia nivulia (En), native to Cholistan Desert area of Bahawalpur, Pakistan. First, we performed high-performance liquid chromatography analysis and found that this plant contains ferulic acid, gallic acid, quercetin, benzoic acid, polyphenols, and flavonoids. Then, we performed in vitro and in vivo studies to assess its effects on diabetic Wistar rat model. The experiments were performed and compared with control drug glibenclamide. The 70% hydroalcoholic extract of En exhibited 97.8% in vitro α-glucosidase inhibitory effect at a dose of 1.0 mg/mL. We orally administered the extract of En and control drug to the streptozotocin (STZ)-induced diabetic rats and analyzed its antidiabetic effects. We found that the extract of En with a dose of 500 mg/kg/body weight exhibited significant effect to reduce blood glucose in STZ-induced rats as compared with the control group ( P < .001). Our histological data also showed that the extract significantly improved the histopathology of pancreas. Collectively, both in vitro and in vivo studies revealed that En possesses α-glucosidase inhibitory, antioxidant, and anti-hyperglycemic effect in STZ-induced diabetic rats.

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Ginsenoside Rg1 Alleviates Podocyte Injury Induced by Hyperlipidemia via Targeting the mTOR/NF-κB/NLRP3 Axis

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/2735714 ◽

2020 ◽

Vol 2020 ◽

pp. 1-14

Author(s):

Tao Wang ◽

Yanbin Gao ◽

Rongchuan Yue ◽

Xiaolei Wang ◽

Yimin Shi ◽

...

Keyword(s):

Mammalian Target Of Rapamycin ◽

Diabetic Rats ◽

Therapeutic Effects ◽

Ginsenoside Rg1 ◽

Podocyte Injury ◽

Therapeutic Function ◽

Polymerase Chain ◽

Underlying Mechanisms

Background. Podocyte injury plays an important role in diabetic nephropathy (DN). The aim of this study was to determine the potential therapeutic effects of the ginsenoside Rg1 on hyperlipidemia-stressed podocytes and elucidate the underlying mechanisms. Methods. In vitro and in vivo models of DN were established as previously described, and the expression levels of relevant markers were analyzed by Western blotting, real-time Polymerase Chain Reaction (PCR), immunofluorescence, and immunohistochemistry. Results. Ginsenoside Rg1 alleviated pyroptosis in podocytes cultured under hyperlipidemic conditions, as well as in the renal tissues of diabetic rats, and downregulated the mammalian target of rapamycin (mTOR)/NF-κB pathway. In addition, Rg1 also inhibited hyperlipidemia-induced NLRP3 inflammasome in the podocytes, which was abrogated by the mTOR activator L-leucine (LEU). The antipyroptotic effects of Rg1 manifested as improved renal function in the DN rats. Conclusion. Ginsenoside Rg1 protects podocytes from hyperlipidemia-induced damage by inhibiting pyroptosis through the mTOR/NF-κB/NLRP3 axis, indicating a potential therapeutic function in DN.

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Activation of glucagon-like peptide-1 receptor inhibits growth and promotes apoptosis of human pancreatic cancer cells in a cAMP-dependent manner

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00017.2014 ◽

2014 ◽

Vol 306 (12) ◽

pp. E1431-E1441 ◽

Cited By ~ 19

Author(s):

Hejun Zhao ◽

Rui Wei ◽

Liang Wang ◽

Qing Tian ◽

Ming Tao ◽

...

Keyword(s):

Pancreatic Cancer ◽

Cancer Cells ◽

Human Pancreatic Cancer ◽

Dependent Manner ◽

Pancreatic Cancer Cells ◽

Tumor Tissues ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) promotes pancreatic β-cell regeneration through GLP-1 receptor (GLP-1R) activation. However, whether it promotes exocrine pancreas growth and thereby increases the risk of pancreatic cancer has been a topic of debate in recent years. Clinical data and animal studies published so far have been controversial. In the present study, we report that GLP-1R activation with liraglutide inhibited growth and promoted apoptosis in human pancreatic cancer cell lines in vitro and attenuated pancreatic tumor growth in a mouse xenograft model in vivo. These effects of liraglutide were mediated through activation of cAMP production and consequent inhibition of Akt and ERK1/2 signaling pathways in a GLP-1R-dependent manner. Moreover, we examined GLP-1R expression in human pancreatic cancer tissues and found that 43.3% of tumor tissues were GLP-1R-null. In the GLP-1R-positive tumor tissues (56.7%), the level of GLP-1R was lower compared with that in tumor-adjacent normal pancreatic tissues. Furthermore, the GLP-1R-positive tumors were significantly smaller than the GLP-1R-null tumors. Our study shows for the first time that GLP-1R activation has a cytoreductive effect on human pancreatic cancer cells in vitro and in vivo, which may help address safety concerns of GLP-1-based therapies in the context of human pancreatic cancer.

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