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Genipin & Type 2 Diabetes

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Genipin & Type 2 Diabetes

Product Abstract:

Genipin is an excellent natural biochemical crosslinker which is extracted from gardenia fruit.
Cas No. 6902-77-8 white powder.


Product Description

GENERAL INFORMATION

Genipin is an aglycone derived from geniposide, which is found in the fruit of Gardenia jasminoides Ellis.  Djerassi and his colleagues discovered the structure of Genipin in the 1960’s using NMR spectroscopic data and chemical degradation experiments.  It possesses the molecular formula C11H14Oand contains a dihydropyran ring.1  Genipin itself is colorless but it reacts spontaneously with amino acids to form blue pigments.2  The blue pigments are edible and are currently being used as a blue food colorant in East Asia.3  The structure of Genipin is shown in Figure 1 along with other characteristics. 

Molecular Formula: C11H14O51

Molecular Weight: 226.227 4

Melting Point: 120-121 °C 2

Systematic Name: Cyclopenta(c) pyran-4-carboxylic acid, 1,4a-alpha,5,7a-alpha-tetrahydro-1-hydroxy-7-(hydroxymethyl)-, methyl ester4

Registry Number: 6902-77-8

Application:  Genipin & Type 2 Diabetes

1?Wu X, Zhou Y, Yin F, Mao C, Li L, Cai B, Lu T. Quality control and producing areas differentiation of Gardeniae Fructus for eight bioactive constituents by HPLC-DAD-ESI/MS.Phytomedicine. 2013 Oct 31. pii: S0944-7113(13)00373-5. doi: 10.1016/j.phymed.2013.10.002. [Epub ahead of print]

Abstract

Gardeniae Fructus (G.Fructus), the fruit of Gardenia jasminoides Ellis (Rubiaceae), is a commonly used traditional Chinese medicine (TCM) that has been used for the treatment of hepatitis, jaundice, hypersonic, diabetes and hematuria. Numerous researches have demonstrated that the major active constituents in G.Fructus were responsible for the majority of medical effects of this fruit and their quantification were important for the quality control of G.Fructus. However, in the current quality control standard, only geniposide was used as characteristic marker of G.Fructus, which could not reflect the overall quality of this fruit. In order to identify more chemical makers for improving the quality control standard and evaluate producing areas differentiation of G.Fructus, in the present study, a novel and sensitive high-performance liquid chromatography-diode array detector coupled to an electrospray tandem mass spectrometer (HPLC-DAD-ESI/MS) was developed for the simultaneous determination of 8 major constituents, including geniposidic acid (1), chlorogenic acid (2), genipin-1-β-gentiobioside (3), geniposide (4), genipin (5), rutin (6), crocin-1 (7), crocin-2 (8) in G.Fructus. Moreover, chemometric analysis techniques with principal component constituent analysis (PCA) and cluster analysis (CA) involved were introduced in statistical analysis of 8 investigated constituents in the 34 batches samples to discriminate the samples from different producing areas. The results indicated that the contents of the 8 major bioactive constituents in G.Fructus varied significantly among different producing areas. From results of the loading plot from PCA analysis, genipin-1-β-gentiobioside may have more influence in discriminating the sample from different producing areas, and which was found to be the most abundant bioactive component besides geniposide in all the 34 batches samples, suggesting that it should be added as chemical marker for further investigation on the pharmacological actions and the quality control of G.Fructus.

Copyright © 2013 Elsevier GmbH. All rights reserved.

KEYWORDS: Bioactive constituents, Gardeniae Fructus, HPLC–DAD–ESI/MS, Producing areas differentiation, Quality control

PMID:24183952

 

2. Guan L, Feng H, Gong D, Zhao X, Cai L, Wu Q, Yuan B, Yang M, Zhao J, Zou Y. Genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction. Exp Gerontol. 2013 Dec;48(12):1387-94. doi: 10.1016/j.exger.2013.09.001. Epub 2013 Sep 14.

PMID:24041487

 

3. Allister EM, Robson-Doucette CA, Prentice KJ, Hardy AB, Sultan S, Gaisano HY, Kong D, Gilon P, Herrera PL, Lowell BB, Wheeler MB. UCP2 regulates the glucagon response to fasting and starvation. Diabetes. 2013 May;62(5):1623-33. doi: 10.2337/db12-0981. Epub 2013 Feb 22.

Abstract?Glucagon is important for maintaining euglycemia during fasting/starvation, and abnormal glucagon secretion is associated with type 1 and type 2 diabetes; however, the mechanisms of hypoglycemia-induced glucagon secretion are poorly understood. We previously demonstrated that global deletion of mitochondrial uncoupling protein 2 (UCP2(-/-)) in mice impaired glucagon secretion from isolated islets. Therefore, UCP2 may contribute to the regulation of hypoglycemia-induced glucagon secretion, which is supported by our current finding that UCP2 expression is increased in nutrient-deprived murine and human islets. Further to this, we created α-cell-specific UCP2 knockout (UCP2AKO) mice, which we used to demonstrate that blood glucose recovery in response to hypoglycemia is impaired owing to attenuated glucagon secretion. UCP2-deleted α-cells have higher levels of intracellular reactive oxygen species (ROS) due to enhanced mitochondrial coupling, which translated into defective stimulus/secretion coupling. The effects of UCP2 deletion were mimicked by the UCP2 inhibitor genipin on both murine and human islets and also by application of exogenous ROS, confirming that changes in oxidative status and electrical activity directly reduce glucagon secretion. Therefore, α-cell UCP2 deletion perturbs the fasting/hypoglycemic glucagon response and shows that UCP2 is necessary for normal α-cell glucose sensing and the maintenance of euglycemia?

 

4. Ma CJ, Nie AF, Zhang ZJ, Zhang ZG, Du L, Li XY, Ning G. Genipin stimulates glucose transport in C2C12 myotubes via an IRS-1 and calcium-dependent mechanism. J Endocrinol. 2013 Feb 25;216(3):353-62. doi: 10.1530/JOE-11-0473. Print 2013 Mar.

Abstract: Genipin, a compound derived from Gardenia jasminoides Ellis fruits, has been used over the years in traditional Chinese medicine to treat symptoms of type 2 diabetes. However, the molecular basis for its antidiabetic effect has not been fully revealed. In this study, we investigated the effects of genipin on glucose uptake and signaling pathways in C(2)C(12) myotubes. Our study demonstrates that genipin stimulated glucose uptake in a time- and dose-dependent manner. The maximal effect was achieved at 2 h with a concentration of 10 μM. In myotubes, genipin promoted glucose transporter 4 (GLUT4) translocation to the cell surface, which was observed by analyzing their distribution in subcellular membrane fraction, and increased the phosphorylation of insulin receptor substrate-1 (IRS-1), AKT, and GSK3β. Meanwhile, genipin increased ATP levels, closed K(ATP) channels, and then increased the concentration of calcium in the cytoplasm in C(2)C(12) myotubes. Genipin-stimulated glucose uptake could be blocked by both the PI3-K inhibitor wortmannin and calcium chelator EGTA. Moreover, genipin increases the level of reactive oxygen species and ATP in C(2)C(12) myotubes. These results suggest that genipin activates IRS-1, PI3-K, and downstream signaling pathway and increases concentrations of calcium, resulting in GLUT4 translocation and glucose uptake increase in C(2)C(12) myotubes.

 

5. Qiu W, Zhou Y, Jiang L, Fang L, Chen L, Su W, Tan R, Zhang CY, Han X, Yang J. Genipin inhibits mitochondrial uncoupling protein 2 expression and ameliorates podocyte injury in diabetic mice.

 PLoS One. 2012;7(7):e41391. doi: 10.1371/journal.pone.0041391. Epub 2012 Jul 19.

Abstract : Diabetic nephropathy (DN) is one of the most common causes of end stage renal disease (ESRD) in China, which requires renal replacement therapy. Recent investigations have suggested an essential role of podocyte injury in the initial stage of DN. This study investigated the potential therapeutic role of genipin, an active extract from a traditional Chinese medicine, on progression of DN in diabetic mice induced by intraperitoneally injection of streptozocin (STZ). In diabetic mice, orally administration of genipin postponed the progression of DN, as demonstrated by ameliorating body weight loss and urine albumin leakage, attenuating glomerular basement membrane thickness, restoring the podocyte expression of podocin and WT1 in diabetic mice. The protective role of genipin on DN is probably through suppressing the up-regulation of mitochondrial uncoupling protein 2 (UCP2) in diabetic kidneys. Meanwhile, through inhibiting the up-regulation of UCP2, genipin restores podocin and WT1 expression in cultured podocytes and attenuates glucose-induced albumin leakage through podocytes monolayer. Therefore, these results revealed that genipin inhibited UCP2 expression and ameliorated podocyte injury in DN mice.

PMID: 22848482

 6. Li F, Porterfield DM, Zheng XY, Wang WJ, Xu Y, Zhang ZM. normal mitochondrial function impairs calcium influx in diabetic mouse pancreatic beta cells.Chin Med J (Engl).2012 Feb;125(3):502-10.

Abstract:

BACKGROUND: Abnormal insulin secretion of pancreatic beta cells is now regarded as the more primary defect than the insulin function in the etiology of type 2 diabetes. Previous studies found impaired mitochondrial function and impaired Ca(2+) influx in beta cells in diabetic patients and animal models, suggesting a role for these processes in proper insulin secretion. The aim of this study was to investigate the detailed relationship of mitochondrial function, Ca(2+) influx, and defective insulin secretion.

METHODS: We investigated mitochondrial function and morphology in pancreatic beta cell of diabetic KK-Ay mice and C57BL/6J mice. Two types of Ca(2+) channel activities, L-type and store-operated Ca(2+) (SOC), were evaluated using whole-cell patch-clamp recording. The glucose induced Ca(2+) influx was measured by a non-invasive micro-test technique (NMT).

RESULTS: Mitochondria in KK-Ay mice pancreatic beta cells were swollen with disordered cristae, and mitochondrial function decreased compared with C57BL/6J mice. Ca(2+) channel activity was increased and glucose induced Ca(2+) influx was impaired, but could be recovered by genipin.

CONCLUSION: Defective mitochondrial function in diabetic mice pancreatic beta cells is a key cause of abnormal insulin secretion by altering Ca(2+) influx, but not via Ca(2+) channel activity.

PMID:22490411

 

7. Zhang H1, Li J, Liang X, Luo Y, Zen K, Zhang CY. Uncoupling protein 2 negatively regulates glucose-induced glucagon-like peptide 1 secretion. J Mol Endocrinol.2012 Feb 24;48(2):151-8. doi: 10.1530/JME-11-0114. Print 2012 Apr.

Abstract:

It is known that endogenous levels of the incretin hormone glucagon-like peptide 1 (GLP1) can be enhanced by various secretagogues, but the mechanism underlying GLP1 secretion is still not fully understood. We assessed the possible effect of uncoupling protein 2 (UCP2) on GLP1 secretion in mouse intestinal tract and NCI-H716 cells, a well-characterized human enteroendocrine L cell model. Localization of UCP2 and GLP1 in the gastrointestinal tract was assessed by immunofluorescence staining. Ucp2 mRNA levels in gut were analyzed by quantitative RT-PCR. Human NCI-H716 cells were transiently transfected with siRNAs targeting UCP2. The plasma and ileum tissue levels of GLP1 (7-36) amide were measured using an ELISA kit. UCP2 was primarily expressed in the mucosal layer and colocalized with GLP1 in gastrointestinal mucosa. L cells secreting GLP1 also expressed UCP2. After glucose administration, UCP2-deficient mice showed increased glucose-induced GLP1 secretion compared with wild-type littermates. GLP1 secretion increased after NCI-H716 cells were transfected with siRNAs targeting UCP2. UCP2 was markedly upregulated in ileum tissue from ob/ob mice, and GLP1 secretion decreased compared with normal mice. Furthermore, GLP1 secretion increased after administration of genipin by oral gavage. Taken together, these results reveal an inhibitory role of UCP2 in glucose-induced GLP1 secretion.

PMID: 22257551

 

8. Kojima K, Shimada T, Nagareda Y, Watanabe M, Ishizaki J, Sai Y, Miyamoto K, Aburada M. Preventive effect of geniposide on metabolic disease status in spontaneously obese type 2 diabetic mice and free fatty acid-treated HepG2 cells.Biol Pharm Bull.2011;34(10):1613-8.

Abstract: Accumulation of visceral fat induces various symptoms of metabolic syndrome such as insulin resistance and abnormal glucose/lipid metabolism and eventually leads to the onset of ischemic cerebrovascular diseases. Geniposide, which is iridoid glycoside from the fruit of Gardenia jasminoides ELLIS, is recognized as being useful against hyperlipidemia and fatty liver. In order to clarify the effect of geniposide on metabolic disease-based visceral fat accumulation and the relevant molecular mechanism, experiments were performed in spontaneously obese Type 2 diabetic TSOD mice and the free fatty acid-treated HepG2 cells. In the TSOD mice, geniposide showed suppression of body weight and visceral fat accumulation, alleviation of abnormal lipid metabolism and suppression of intrahepatic lipid accumulation. In addition, geniposide alleviated abnormal glucose tolerance and hyperinsulinemia, suggesting that geniposide has an insulin resistance-alleviating effect. Next, in order to investigate the direct effect of geniposide on the liver, the effect on the free fatty acid-treated HepG2 fatty liver model was investigated using genipin, which is the aglycone portion of geniposide. Genipin suppressed the intracellular lipid accumulation caused by the free fatty acid treatment and also significantly increased the intracellular expression of a fatty acid oxidation-related gene (peroxisomal proliferator-activated receptor: PPARα). From these results, it was confirmed that geniposide has an anti-obesity effect, an insulin resistance-alleviating effect and an abnormal lipid metabolism-alleviating effect, and the metabolite genipin shows a direct effect on the liver, inducing expression of a lipid metabolism-related gene as one of its molecular mechanisms.

PMID:21963504

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