iridoids and Insulin-Resistance

In the 1970s, Eucommia leaf tea, known as Tochu-cha in Japanese, was developed from roasted Eucommia leaves in Japan and is considered as a healthy tea. The antihypertensive, diuretic, anti-stress, insulin resistance improving, and anti-obesity effects of Eucommia leaf extract have been reported. However, the identification and properties of the active components as well as the underlying mechanism of action are largely unknown. In this review, we summarize studies involving the oral administration of geniposidic acid, a major iridoid component of Eucommia leaf extract which increases plasma atrial natriuretic peptide (ANP) on the atria of spontaneously hypertensive rats (SHR) by activating the glucagon-like peptide-1 receptor (GLP-1R). To achieve the antihypertensive effects of the Eucommia leaf extract through ANP secretion in humans, combining a potent cyclic adenosine monophosphate phosphodiesterase (cAMP-PDE) inhibitor, such as pinoresinol di-β-d-glucoside, with geniposidic acid may be necessary. Changes in the gut microbiota are an important aspect involved in the efficacy of asperuloside, another component of the Eucommia leaf extract, which improves obesity and related sequelae, such as insulin resistance and glucose intolerance. There are species differences of mechanisms associated with the antihypertensive and anti-obesity effects between rodents and humans, and not all animal test results are consistent with that of human studies. This review is focused on the mechanisms in antihypertensive and anti-obesity effects of the Eucommia leaf extract and summarizes the differences of mechanisms in their effects on rodents and humans based on our studies and those of others.

Topics: Animals; Antihypertensive Agents; Eucommiaceae; Humans; Insulin Resistance; Iridoids; Plant Extracts; Rats; Rats, Inbred SHR; Rodentia; Tea

Systemic insulin signal transduction is influenced by the inter-tissue crosstalk, which might be the potential therapeutic strategy for T2DM. Although anti-diabetic function of geniposide has been previously reported, the underlying mechanism was not completely clear in light of the complex pathogenesis of T2DM.. The present experiment is devoted to investigate the potential effects of geniposide on systemic insulin sensitivity mediated by hepatokine-RBP4 in high fat diet (HFD)-fed mice.. The HFD-fed wild type mice were administered with geniposide (25 or 50 mg/kg/d) by intraperitoneal injection, and the normal saline and Metformin were used as negative control group and positive control group, respectively. After administration for 4 weeks, the food intake, body weight, glucose tolerance tests, insulin tolerance tests and serum biochemical indices were examined, along with insulin signaling pathway-associated proteins and hepatic histomorphological analysis. The liver, gastrocnemius and mouse primary hepatocytes were also harvested for molecular mechanism study.. After geniposide treatment for 4 weeks, the blood glucose level was reduced in HFD-fed mice. Furthermore, geniposide treatment improved insulin sensitivity both in the liver and gastrocnemius (GAS). In terms of mechanism, geniposide disturbed circulating RBP4 level including its synthesis, secretion and homeostasis. Moreover, geniposide modified fuel selection and promoted glucose uptake in skeletal muscle and reduced glycogen storage, which were closely related to impaired circulating RBP4 homeostasis, leading to ameliorative systemic insulin sensitivity.. Our current study proposes a novel regulatory mechanism of geniposide for improving glucose homeostasis through regulating circulating RBP4 level, which also provides new strategies for the prevention and treatment of T2DM.

Topics: Adipose Tissue; Animals; Diet, High-Fat; Glucose; Homeostasis; Insulin; Insulin Resistance; Iridoids; Liver; Mice; Mice, Inbred C57BL; Retinol-Binding Proteins, Plasma

Loganin is an iridoid glycoside with antioxidant, anti-inflammatory, glucose-lowering activities which may address the pathological mechanisms of painful diabetic neuropathy (PDN) related to inflammation, oxidative stress, and hyperglycemia. This study investigated the underlying mechanisms of action of loganin on PDN. The in vivo model of PDN was established by streptozotocin-nicotinamide (STZ-NA) induction in Sprague Dawley (SD) rats. Subsequently, loganin (5 mg/kg) was administered by daily intraperitoneal injection. High-glucose stimulated human SH-SY5Y cells co-incubated with loganin were used to mimic the in vitro model of PDN. Loganin improved PDN rats' associated pain behaviors (allodynia and hyperalgesia), insulin resistance index (HOMA-IR), and serum levels of superoxide dismutase (SOD), catalase and glutathione. Loganin also reduced pain-associated channel protein Ca

Topics: Animals; Antioxidants; Behavior, Animal; Blood Glucose; Body Weight; Calcitonin Gene-Related Peptide; Calcium Channels, T-Type; Cell Line, Tumor; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Fasting; Humans; Hyperglycemia; Inflammation; Inflammation Mediators; Insulin; Insulin Resistance; Iridoids; Male; Neuralgia; Neuroglia; NF-kappa B; Niacinamide; Oxidative Stress; Rats, Sprague-Dawley; Signal Transduction; Spinal Cord Dorsal Horn; Streptozocin

Thioredoxin-interacting protein (Txnip) has emerged as a key regulator of insulin resistance. In this study, we investigated the roles of geniposide and Txnip in insulin resistance in differentiated 3T3-L1 adipocytes. Our results revealed that geniposide markedly enhanced glucose uptake, increased the protein levels of insulin receptor substrate (IRS)-1 and GLUT-1, and prevented the phosphorylation of IRS-1 and Akt Thr308 induced by insulin resistance in 3T3-L1 adipocytes. We also observed that geniposide accelerated protein degradation of Txnip through proteasome pathway, and knockdown of Txnip with small interfering RNA attenuated the effect of geniposide on insulin signaling molecules, implying that Txnip played a pivotal role in the regulation of insulin signaling molecules by geniposide in 3T3-L1 adipocytes. Furthermore, geniposide induced the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) in the presence of high glucose in differentiated 3T3-L1 adipocytes, while compound C, an inhibitor of AMPK, prevented the effect of geniposide on Txnip degradation and the regulation of glucose uptake and insulin signaling molecules including p-IRS-1, IRS-1, and GLUT-1 in differentiated 3T3-L1 adipocytes. Taken together, all these findings suggest that geniposide improves the insulin signaling defect possibly by AMPK-mediated Txnip degradation in 3T3-L1 adipocytes.

Topics: 3T3-L1 Cells; AMP-Activated Protein Kinases; Animals; Carrier Proteins; Enzyme Activation; Insulin Resistance; Iridoids; Mice; Proteolysis; Signal Transduction; Thioredoxins

Hyperlipidemia is a chronic disorder which plays an important role in the development of cardiovascular diseases, type 2 diabetes, atherosclerosis, hypertension, and nonalcoholic fatty liver disease. Genipin (GNP) is a metabolite from genipioside, which is an active component of the traditional Chinese medicine Gardenia jasminoides Ellis, and has been recognized as a beneficial compound against metabolic disorders. However, whether it can correct overnutrition-induced dyslipidemia is still unknown. In this study, the effects of GNP on attenuating hyperlipidemia and hepatic lipid accumulation were investigated using normal and obese mice induced with a high-fat diet (HFD) and primary hepatocytes treated with free fatty acids. We also sought to identify potential targets of GNP to mediate its effects in the liver. We found that obese mice treated with GNP showed a decrease in the body weight, serum lipid levels, as well as hepatic lipid accumulation. Besides, GNP regulated hepatic expression levels of lipid metabolic genes, which are important in maintaining systemic lipid homeostasis. At the molecular level, GNP increased the expression levels of miR-142a-5p, which bound to 3' untranslated region of Srebp-1c, an important regulator of lipogenesis, which thus led to the inhibition of lipogenesis. Collectively, our data demonstrated that GNP effectively antagonized HFD-induced hyperlipidemia and hepatic lipid accumulation in mice. Such effects were achieved by regulating miR-142a-5p/SREBP-1c axis.

Topics: Animals; Anti-Obesity Agents; Cells, Cultured; Computational Biology; Diet, High-Fat; Dose-Response Relationship, Drug; Fatty Acids, Nonesterified; Gene Expression Regulation; Genes, Reporter; Hyperlipidemias; Insulin Resistance; Iridoids; Lipid Metabolism; Lipotropic Agents; Liver; Male; Mice, Inbred C57BL; MicroRNAs; Non-alcoholic Fatty Liver Disease; Obesity; Random Allocation; Sterol Regulatory Element Binding Protein 1

Insulin resistance (IR) is known to be an important factor, which can lead to the onset of type 2 diabetes. Autophagy is a cellular process, which sequesters senescent or damaged proteins in autophagosomes for recycling of their products. Insulin and intracellular molecules, including mammalian target of rapamycin (mTOR), are well‑known inhibitors of autophagy. In patients with type 2 diabetes, the expression levels of glucose transporter 4 (GLUT‑4) in skeletal muscles are significantly decreased, indicating decreased glucose‑processing ability. Geniposide is an iridoid compound isolated from Gardenia jasminoides Ellis. Previously, it was reported that geniposide significantly promoted glucose uptake. In the present study, a HepG2 cell model of IR was constructed to determine whether geniposide can promote autophagy to inhibit insulin resistance in HepG2 cells via P62/nuclear factor (NF)‑κB/GLUT‑4. Cell proliferation was analyzed by performing an MTT assay, and the mRNA expression levels of NF‑κB and GLUT‑4 were assessed using semi‑quantitative polymerase chain reaction and immunohistochemical staining. In addition, the protein levels of GLUT‑4, P62 and phosphorylated‑P65 were assessed by western blotting. The expression of GLUT‑4 was initially increased following geniposide treatment, decreasing in time to its lowest level at 8 h. The expression levels of NF‑κB and GLUT‑4 in the IR cells treated with and without geniposide were significantly different, compared with those in the control group. Geniposide promoted autophagy in the IR HepG2 cells and significantly improved IR in the HepG2 cells, which may be associated with the dynamic regulation of the P62/NF‑κB/GLUT‑4 pathway.

Topics: Autophagy; Glucose Transporter Type 4; Hep G2 Cells; Humans; Insulin Resistance; Iridoids; Microscopy, Confocal; Microscopy, Electron, Transmission; Microtubule-Associated Proteins; Models, Biological; NF-kappa B; Sequestosome-1 Protein; Signal Transduction; Sirolimus

Oleuropein has been recognized as an important medicinal compound because of its various biological properties, including anti-cancer, antidiabetic and anti-atherosclerotic activities. Here, we evaluate the antioxidant activity as well as the mechanism of the hypoglycemic effects of oleuropein in C2C12 cells and we establish the mechanism underlying these effects.. To perform this study, C2C12 cells viability was analyzed via MTT assay and the antioxidant activity was investigated by ROS and TBARS assays. Also, the effect of oleuropein on AMPK and PI3 kinase signaling pathways was evaluated.. Treatment with oleuropein was able to protect cells against H2O2 induced stress in cells. On the other hand, the molecular bases of its actions have been scarcely understood. Oleuropein significantly enhanced glucose consumption and the phosphorylation of AMPK (AMP-activated protein kinase/ACC (acetyl-CoA carboxylase)) and MAPKs (mitogen-activated protein kinases), but not PI3 kinase (Phosphatidylinositol 3-kinase)/Akt. However, the co-treatment of oleuropein and insulin improved the insulin sensitivity via insulin-dependent (PI3 kinase/Akt) and insulin independent (AMPK/ACC) pathways. These results could be confirmed from the findings of GLUT4 translocation which was strongly enhanced in the case of oleuropein.. Our results provide important insights for the possible mechanism of action of oleuropein as a therapeutic agent in diabetic patients.

Topics: AMP-Activated Protein Kinases; Animals; Cell Line; Cell Survival; DNA-Binding Proteins; Drug Synergism; Enzyme Activation; Hydrogen Peroxide; Hypoglycemic Agents; Insulin; Insulin Resistance; Iridoid Glucosides; Iridoids; Mice; Mitogen-Activated Protein Kinases; Muscle, Skeletal; Oxidative Stress; Phosphatidylinositol 3-Kinase; Phosphorylation; Protective Agents; Reactive Oxygen Species; Signal Transduction; Thiobarbituric Acid Reactive Substances; Transcription Factors

Amarogentin is a bitter-tasting secoiridoid glycoside isolated from an herb. Inhibition of aldose reductase by amarogentin has been documented as an antidiabetic action. However, the mechanisms of action of amarogentin in diabetic disorders remain unknown. The present study employed streptozotocin-induced type 1 diabetic (T1DM) rats to investigate the antihyperglycemic action of amarogentin. Changes in the protein expression of glucose transporter 4 (GLUT4) and phosphoenolpyruvate carboxykinase (PEPCK) in skeletal muscle and liver, respectively, were also detected by Western blotting. Additionally, a type 2 diabetes (T2DM) animal model induced using a fructose-rich diet was also applied to assess the effect of amarogentin on insulin resistance according to the homeostasis model assessment-insulin resistance (HOMA-IR). Amarogentin dose-dependently attenuated hyperglycemia in the T1DM rats lacking insulin. The action of amarogentin was further supported in rats administered the oral glucose tolerance test. Western blotting showed that amarogentin reversed the decreased GLUT4 level in skeletal muscle and reduced the elevated PEPCK expression in livers isolated from the T1DM rats. Moreover, amarogentin decreased the HOMA-IR and increased insulin sensitivity in the T2DM rats. These data show that amarogentin may ameliorate glucose homeostasis in diabetic rats, indicating its potential for future development as an antidiabetic drug.

Topics: Animals; Biomarkers; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Dietary Carbohydrates; Dose-Response Relationship, Drug; Fructose; Glucose Tolerance Test; Glucose Transporter Type 4; Hypoglycemic Agents; Insulin; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Iridoids; Liver; Male; Muscle, Skeletal; Phosphoenolpyruvate Carboxykinase (GTP); Rats, Wistar; Streptozocin

Insulin resistance (IR) increases with age and plays a key role in the pathogenesis of type 2 diabetes mellitus. Oxidative stress and mitochondrial dysfunction are supposed to be major factors leading to age-related IR. Genipin, an extract from Gardenia jasminoides Ellis fruit, has been reported to stimulate insulin secretion in pancreatic islet cells by regulating mitochondrial function. In this study, we first investigated the effects of genipin on insulin sensitivity and the potential mitochondrial mechanisms in the liver of aging rats. The rats were randomly assigned to receive intraperitoneal injections of either 25mg/kg genipin or vehicle once daily for 12days. The aging rats showed hyperinsulinemia and hyperlipidemia, and insulin resistance as examined by the decreased glucose decay constant rate during insulin tolerance test (kITT). The hepatic tissues showed steatosis and reduced glycogen content. Hepatic malondialdehyde level and mitochondrial reactive oxygen species (ROS) were higher, and levels of mitochondrial membrane potential (MMP) and ATP were lower as compared with the normal control rats. Administration of genipin ameliorated systemic and hepatic insulin resistance, alleviated hyperinsulinemia, hyperglyceridemia and hepatic steatosis, relieved hepatic oxidative stress and mitochondrial dysfunction in aging rats. Furthermore, genipin not only improved insulin sensitivity by promoting insulin-stimulated glucose consumption and glycogen synthesis, inhibited cellular ROS overproduction and alleviated the reduction of levels of MMP and ATP, but also reversed oxidative stress-associated JNK hyperactivation and reduced Akt phosphorylation in palmitate-treated L02 hepatocytes. In conclusion, genipin ameliorates age-related insulin resistance through inhibiting hepatic oxidative stress and mitochondrial dysfunction.

Topics: Adenosine Triphosphate; Age Factors; Aging; Animals; Antioxidants; Cell Line; Dose-Response Relationship, Drug; Enzyme Activation; Fatty Liver; Hepatocytes; Hyperinsulinism; Hyperlipidemias; Hypoglycemic Agents; Insulin Resistance; Iridoids; JNK Mitogen-Activated Protein Kinases; Liver; Male; Malondialdehyde; Membrane Potential, Mitochondrial; Mitochondria, Liver; Oxidative Stress; Palmitic Acid; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species

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.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Diabetes Mellitus, Type 2; Drug Evaluation, Preclinical; Fatty Acids, Nonesterified; Fatty Liver; Gardenia; Glucose Intolerance; Hep G2 Cells; Humans; Hyperinsulinism; Hypoglycemic Agents; Insulin Resistance; Iridoids; Lipid Metabolism; Liver; Male; Metabolic Diseases; Metabolic Syndrome; Mice; Mice, Obese; Obesity; Phytotherapy; Plant Preparations

Uncoupling protein 2 (UCP2) was reported to be involved in insulin-glucose homeostasis, based on well established event that inhibition of UCP2 stimulates insulin secretion in pancreatic beta-cells. However, the role of UCP2 on insulin-stimulated glucose uptake in adipose tissue, which is an indispensable process in insulin-glucose homeostasis, remains unknown. In this study, UCP2 was inhibited by genipin in 3T3-L1 adipocytes, which increased mitochondrial membrane potential, intracellular ATP level and production of reactive oxygen species (ROS). Importantly, insulin-stimulated glucose uptake in 3T3-L1 adipocytes was largely impaired in the presence of genipin, and recovered by CCCP, a mitochondrial uncoupler. Furthermore, genipin leaded to suppression of insulin signal transduction through hyperactivation of c-Jun N-terminal kinase (JNK) and subsequent serine phosphorylation of insulin receptor substrate-1 (IRS-1). These results suggest that mitochondrial uncoupling in adipocytes positively regulates insulin-stimulated glucose uptake in adipocytes, and UCP2 may play an important role in insulin resistance.

Topics: 3T3-L1 Cells; Adenosine Triphosphate; Adipocytes; Animals; Anthracenes; Biological Transport, Active; Glucose; Insulin; Insulin Resistance; Ion Channels; Iridoid Glycosides; Iridoids; JNK Mitogen-Activated Protein Kinases; Membrane Potential, Mitochondrial; Mice; Mitochondrial Proteins; Models, Biological; Protein Kinase Inhibitors; Reactive Oxygen Species; Signal Transduction; Uncoupling Protein 2