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Sea Buckthorn Fruit Oil Extract Alleviates Insulin Resistance through the PI3K/Akt Signaling Pathway in Type 2 Diabetes Mellitus Cells and Rats
Abstract
Sea buckthorn fruit oil is rich in palmitoleic acid (POA), which has been reported to play roles in many metabolic processes. In this study, a sea buckthorn fruit oil (SBFO) extract was evaluated through in vitro experiments (the does were 50, 100, 200 and 400 μM) and in vivo experiments (the does were 100, 200 and 300 mg/kg·day) to explore its mechanism of action in the treatment of type 2 diabetes mellitus (T2DM). The results revealed that the SBFO extract effectively increased the glucose uptake from 12.23 ± 1.09 to 14.90 ± 1.48 mmol/l in IR HepG2 cells, lowered blood glucose (the reductions rates of blood glucose in groups treated with SBFO extract at 200 and 300 mg/kg·day were 10.47% and 13.79%, respectively) and improved insulin indices from -6.11 ± 0.10 to -5.45 ± 0.31 after 4 weeks treatment with SBFO extract at 300 mg/kg·day in T2DM SD rats. RT-PCR and western blotting analyses suggested that the SBFO extract could promote the expression of phosphatidylinositol-3-kinase (PI3K) and glycogen synthesis (GS) while inhibiting the expression of glycogen synthesis kinase-3β (GSK-3β). Thus, the SBFO extract played a positive role in alleviating T2DM through the PI3K/Akt signaling pathway inHepG2 cells and diabetic rats and could be used for the future development of functional food and dietary supplements.
... PI3K, Grab-2, SHP-2, Fyn, c-Crk, CrkII, and Nck are major regulators for Akt/mTOR pathway. It mainly begins with the IR receptor activation in mammals [32]. Drosophila and C. elegans have receptor proteins similar to the IR, namely, INR and Daf 2 [33]. ...
... IRS is a primary mediator of glucose metabolism and expresses in various types of cancer [23]. Phosphorylation of IRS1 in the Ser/Thr amino acid sequence may suppress the activation of PI3K [32]. ...
... In most cases, mortality in T1DM depends on acute complications (children and young adults), while T2DM is related to chronic complications and relies on comorbidities [95]. Around 90% of the patients with DM suffer from T2DM, particularly youngsters [32,96]. Around half (45.8%) of adult DM cases worldwide are not reported and are left untreated, leading to severe comorbidity conditions [97]. ...
Insulin resistance is common in type 2 diabetes mellitus (T2DM), neurodegenerative diseases, cardiovascular diseases, kidney diseases, and polycystic ovary syndrome. Impairment in insulin signaling pathways, such as the PI3K/Akt/mTOR pathway, would lead to insulin resistance. It might induce the synthesis and deposition of advanced glycation end products (AGEs), reactive oxygen species, and reactive nitrogen species, resulting in stress, protein misfolding, protein accumulation, mitochondrial dysfunction, reticulum function, and metabolic syndrome dysregulation, inflammation, and apoptosis. It plays a huge role in various neurodegenerative diseases like Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Amyloid lateral sclerosis. In this review, we intend to focus on the possible effect of insulin resistance in the progression of neurodegeneration via the impaired P13K/Akt/mTOR signaling pathway, AGEs, and receptors for AGEs.
... 3,4 For simple perforations without other middle ear disorders (e.g., cholesteatoma), an alternative to rupture closure that is less invasive and expensive is preferable to surgical intervention. [5][6][7] Hippophae fructus oil (HFO), a traditional Chinese herb extracted from Hippophae fructus, [8][9][10] is composed of vitamin C, amino acids, and essential trace elements (e.g., zinc), which can enhance the proliferation of TM epithelial stem cells, promote their migration to lesions and induce blood vessel dilatation. 9,10 During the past few decades, HFO has been applied for the clinical treatment of TM perforation with satisfactory outcomes. ...
... [5][6][7] Hippophae fructus oil (HFO), a traditional Chinese herb extracted from Hippophae fructus, [8][9][10] is composed of vitamin C, amino acids, and essential trace elements (e.g., zinc), which can enhance the proliferation of TM epithelial stem cells, promote their migration to lesions and induce blood vessel dilatation. 9,10 During the past few decades, HFO has been applied for the clinical treatment of TM perforation with satisfactory outcomes. 8 However, the biological mechanism of HFO therapy for TM regeneration remains unclear, and the main compounds of HFO that promote TM healing require further exploration. ...
... 45,46 According to our analysis, 21 HFO displays a variety of advantages in addition to healing benefits and is less invasive. [8][9][10]31,32 As an extract from berries and seeds of traditional medicinal plants, HFO is extensively available from many sources. In addition, HFO is easily prepared and does not require cold storage, which may significantly reduce the associated costs. ...
Objective
This study aimed to explore the mechanisms of Hippophae fructus oil (HFO) in the treatment of tympanic membrane (TM) perforation through network pharmacology-based identification.
Methods
The compounds and related targets of HFO were extracted from the TCMSP database, and disease information was obtained from the OMIM, GeneCards, PharmGkb, TTD, and DrugBank databases. A Venn diagram was generated to show the common targets of HFO and TM, and GO and KEGG analyses were performed to explore the potential biological processes and signaling pathways. The PPI network and core gene subnetwork were constructed using the STRING database and Cytoscape software. A molecular docking analysis was also conducted to simulate the combination of compounds and gene proteins.
Results
A total of 33 compounds and their related targets were obtained from the TCMSP database. After screening the 393 TM-related targets, 21 compounds and 22 gene proteins were selected to establish the network diagram. GO and KEGG enrichment analyses revealed that HFO may promote TM healing by influencing cellular oxidative stress and related signaling pathways. A critical subnetwork was obtained by analyzing the PPI network with nine core genes: CASP3, MMP2, IL1B, TP53, EGFR, CXCL8, ESR1, PTGS2, and IL6. In addition, a molecular docking analysis revealed that quercetin strongly binds the core proteins.
Conclusion
According to the analysis, HFO can be utilized to repair perforations by influencing cellular oxidative stress. Quercetin is one of the active compounds that potentially plays an important role in TM regeneration by influencing 17 gene proteins.
... At present, increasing attention on the possible positive effects of SB berries for glycemic control was also noted. Several animal studies have shown positive effects of SB protein/fruit oil extract on reducing blood glucose, as well as alleviating insulin resistance [13][14][15]. In human trials, for example, compared with strawberry, SB decreased and delayed insulin response and improved glycemic profile following a sucrose-containing berry meal [16]. ...
... Administration of flavonoids from sea buckthorn pomace (SBP) for four weeks also resulted in significantly hypoglycemic effects in ICR mice with alloxan-induced diabetes, even in the low dose group (3.0 mg/kg/day) [37]. In the study by Gao et al., it was suggested that a middle or high dose of sea buckthorn fruit oil (SBFO, 200 or 300 mg/kg/day) could lower the FPG at a rate of 10.47% and 13.79% in T2DM SD rats, respectively [13]. In addition, the continuous intervention of methanolic extract from Hippophae salicifolia D.Don (a species of SB) leaves at 200 or 400 mg/kg for 45 days both exhibited significant reduction (22% and 39%, respectively) in FPG compared to the diabetic control rats [38]. ...
... When it comes to PPG, the results of previous studies were not completely consistent. The study by Gao et al. showed that four weeks' treatment of SBFO extracts improved the oral glucose tolerance test (OGTT) in T2DM SD rats in a dose-dependent manner [13]. A study based on ten healthy volunteers consuming one control meal and three experimental meals with dried and crushed whole SB berries, supercritical fluid (SF)-carbon dioxide (CO2)-extracted oil-free berries, and ethanol-extracted SF-CO2-extraction residue, respectively, suggested that meal with dried and crushed whole berries stabilize postprandial hyperglycemia [17]. ...
Sea buckthorn (SB) has been indicated to have hypoglycemic potential, but its effects on glucose in people with impaired glucose regulation (IGR) are still unclear. This work presents a randomized, double-blinded, two-way crossover study. A total of 38 subjects with IGR completed the intervention of consuming sea buckthorn fruit puree (SBFP, 90 mL/day, five weeks), washing out (four weeks), and then consuming placebo (90 mL/day, five weeks) or in reverse order. In our methodology, a unified questionnaire was used to gather information on physical activity and dietary intakes, and physical examinations were performed to measure blood pressure, height, and weight. Fasting blood samples were collected to detect the fasting plasma glucose (FPG) and glycated serum protein (GSP). To calculate the area under the curve of 2 h postprandial plasma glucose (2 h PG-AUC), blood samples at t = 30, 60, and 120 min were also collected and analyzed. Effects of the intervention were evaluated by paired-sample Wilcoxon test and mixed model analyses. Our results show that the FPG in subjects with IGR decreased by a median reduction of 0.14 mmol/L after five weeks’ consumption of SBFP, but increased by a median of 0.07 mmol/L after placebo intervention, and the comparison of these two interventions was statistically significant (p = 0.045). During the wash-out period, a similar difference was observed as the FPG decreased in the group that received SBFP intervention first, but increased in another group (p = 0.043). Both SBFP and placebo significantly raised GSP during the intervention period, but lowered it in the wash-out period (p < 0.05), while no significant difference was found between the two interventions. The 2 h PG-AUC remained relatively stable throughout the study. Our results indicated that consumption of SBFP for five weeks showed a slight downward trend on FPG in subjects with IGR.
... Administration of a concentration of 100 µg/mL, for 18 h, of palmitate-treated HuS-E/2 cells showed increased levels of p-AMPK, p-ACC, CPT1, PPARα and PPARδ, and suppressed SREBP-1c and PPARγ activity. Gao et al. demonstrated that Sea Buckthorn fruit oil extract showed promising effects on the PI3K/Akt pathway dependent insulin resistance, which originated from Hippophae rhamnoides L., traditionally used for sputum, coughs, skin diseases, and dyspepsia [35]. Insulin-resistant HepG2 cells were treated with 400 µM for 24 h and showed a significant rise in glucose uptake, GS, PI3K, and p-Akt, as well as a reduction in GSK-3β expression. ...
... Histological examinations showed increased number, size, and mass of β-cells, as well as a decrease in β-cell apoptosis. Gao et al. demonstrated that Sea Buckthorn fruit oil extract originating from Hippophae rhamnoides L. showed promising effects on PI3K/Akt pathway-dependent insulin resistance [35]. High-fat diet-induced type 2-diabetic male SD rats were administered with oral doses of 100, 200 or 300 mg/kg/day for 4 weeks, and this resulted in a decrease in insulin, blood glucose levels and ALT and AST, which was further explained by the increase in hepatic glycogen. ...
Type 2 diabetes mellitus (T2DM) is one of the largest public health problems worldwide. Insulin resistance-related metabolic dysfunction and chronic hyperglycemia result in devastating complications and poor prognosis. Even though there are many conventional drugs such as metformin (MET), Thiazolidinediones (TZDs), sulfonylureas (SUF), dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon like peptide 1 (GLP-1) and sodium-glucose cotransporter-2 (SGLT-2) inhibitors, side effects still exist. As numerous plant extracts with antidiabetic effects have been widely reported, they have the potential to be a great therapeutic agent for type 2 diabetes with less side effects. In this study, sixty-five recent studies regarding plant extracts that alleviate type 2 diabetes were reviewed. Plant extracts regulated blood glucose through the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway. The anti-inflammatory and antioxidant properties of plant extracts suppressed c-Jun amino terminal kinase (JNK) and nuclear factor kappa B (NF-κB) pathways, which induce insulin resistance. Lipogenesis and fatty acid oxidation, which are also associated with insulin resistance, are regulated by AMP-activated protein kinase (AMPK) activation. This review focuses on discovering plant extracts that alleviate type 2 diabetes and exploring its therapeutic mechanisms.
... Dwivedi et al. (2006) indicate that sea buckthorn berry oil is high in omega-3 fats. Pre-clinical research using sea buckthorn has discovered uses in oxidation protection (Luntraru et al., 2022), cancer prevention (Shah et al., 2021), cardiovascular protection (Kumari and Sharma, 2011;Guo et al., 2017), and diabetes prevention (Gao et al., 2017). Sea buckthorn berries are high in antioxidants, organic acids, vitamins B, E, and K, as well as carotene and flavonoids (Dong et al., 2021). ...
Sea buckthorn (Hippophae rhamnoides), also known as Chharma as well as a member of the Elaeagnaceae family, naturally occurs in Himachal Pradesh's high-altitude highlands amid harsh weather circumstances. This current research detailed the processing of sea buckthorn fruit juice into a ready-to-drink (RTD) drink, as well as variations throughout the beverage's condition improves after preservation about three months. During the September quarter, when the fruits were fully mature, sea buckthorn berries were picked from the Lahaul valley. The pulp was removed from the berries using a fruit pulper. Variable quantities of pulp and sugar were used in the beverage compositions to create ready-to-drink beverages. The ascorbic acid level rose considerably with increasing pulp percentage and declined with increasing curing time. In contrast, a growing tendency in decreasing sugars were found with increasing pulp and sugar concentration as well as storage time. A beverage composition combining 10%, 12% and 15% pulp with total soluble solids (TSS) 11°, 15° and 15°Bx respectively of zero-day prepared drink were voted the most acceptable by a panel of judges on a nine-point hedonic scale. It was determined that adding value to sea buckthorn can help to establish a commercial sector for such a natural berry, that has been ignored and underused in Himachal Pradesh.
... Lipophilic fractions of the soft parts and seeds also contain fatty acids especially palmitoleic acid, the oil extracted from the fruits is used for the treatment of digestive problems [16] and skin problems [17]. In many studies it has been observed that sea buckthorn berries oil extract evaluated through many in-vitro and in-vivo experiments in order to explore its mechanism of action for the treatment of type 2 diabetes mellitus [18] and also used in cancer therapy [19]. That plant is locally available and its cultivation can be increased by providing the friendly climate. ...
Obtaining edible oil from animals and plant sources is an ancient practice of the people in the tropical regions of the globe. Industrialization of oil and fats began with the creation of a cotton seed mill, due to higher demand several different plants have been studied to get good and healthy oil and fats. In this research the fixed oil from the berries of Sea Buckthorn was characterized and studied for its fatty acid composition by biochemical tests and Gas Chromatography Mass Spectroscopy (GCMS). The chemical characteristics of oil from seeds showed the saponification value 248.36, iodine value 80.49 and free fatty acid value 11.28%. While the identified fatty acids were palmitic acid (C16, 0) 24.98%, oleic acid (C18, 1) 20.97%, linoleic acid (C18:2) 11.51%, linolenic acid 4.31(C18:3) %, and stearic acid (C18, 0) 0.29%. The fatty acid profile and physico chemical value of the oil showed that oil has health promoting chemistry and good source of energy. These findings provide essential data explaining that the oil obtained from the berries is nothing less than any other good quality of edible oil.
... Several animal studies have shown the positive effects of SB protein/fruit oil extract on reducing blood glucose, as well as alleviating insulin resistance. (Gao et al., 2017;Yuan et. al., 2016;Zhang et al., 2010). ...
The cultivation of medicinal plants is a current topic of growing importance. In Europe, but also the world, the demand for high-quality food is constantly growing. Sea buckthorn can be considered a functional food, which is an intermediate step between classic foods and medicines. Sea buckthorn contains a high content of vitamin C, which makes it an ideal helper in the treatment of flu or angina; thanks to the high content of vitamin B, it heals burns, has antiseptic effects, consumption of products from this medicinal plant ensures prevention in the treatment of cardiovascular diseases and cancer, supports digestion, detoxifies the body, purifies and supports the activity of the kidneys and urinary system, reduces high cholesterol, improves memory, has anti-inflammatory effects. In the contribution, we focus on the economic assessment of the cultivation and processing of this superfood in an intensive cultivation method. We modeled two alternatives: “Alternative A” – frozen fruits, “Alternative B” – 100% sea buckthorn juice. Based on the performed analysis, the second alternative is more economically efficient, given that the payback period is before the seventh vegetation year, the internal rate of return is at the level of 35.67% and the net present value reaches the level of 1,379,316 €. In the contribution, we also evaluated the intensity of production based on the resulting indicators (revenues, costs, management result per hectare, average profitability of revenues and costs) with conventional crops grown in the corn production area (wheat, barley, corn). We found that the values of all indicators were more favorable for sea buckthorn.
... In order to further investigate the mechanisms of how the flavonoids relieve the diabetic symptoms of IR-HepG2 cells, the expression levels of IRS-1, IRS-2, PI3K, Akt and its phosphorylated form p-Akt, which are of great concern in maintaining the systematic glucose homeostasis, were determined by western blotting, while GADPH was used as internal standard [33,34]. In IR-HepG2 cells, the expression levels of IRS-1 and IRS-2 were significantly inhibited by high-glucose and DXMS stimulation. ...
Dietary flavonoids are abundant in natural plants and possess multiple pharmacological and nutritional activities. In this study, apigenin, luteolin, and baicalein were chosen to evaluate their anti-diabetic effect in high-glucose and dexamethasone induced insulin-resistant (IR) HepG2 cells. All flavonoids improves the glucose consumption and glycogen synthesis abilities in IR-HepG2 cells via activating glucose transporter protein 4 (GLUT4) and phosphor-glycogen synthase kinase (GSK-3β). These fl avonoids signifi cantly inhibited the production of reactive oxygen species (ROS) and advanced glycation end-products (AGEs), which were closely related to the suppression of the phosphorylation form of NF-κB and P65. The expression levels of insulin receptor substrate-1 (IRS-1), insulin receptor substrate-2 (IRS-2) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in IR-HepG2 cells were all partially activated by the fl avonoids, with variable effects. Furthermore, the intracellular metabolic conditions of the fl avonoids were also evaluated.
... Furthermore, it signifi-cantly reduces the blood glucose and insulin indices of T2 DM SD rats by regulating the phosphatidylinositol-3-kinase (PI3K)/Akt signaling pathway. Western blot and qRT-PCR analyses showed that sea buckthorn extracts promote PI3K and glycogen synthesis (GS) expression, but inhibit GSK-3β expression [85]. ...
Sea buckthorn (Hippophae rhamnoides L. or Elaeagnus rhamnoides L.) is a plant that has long been used as a Chinese herbal medicine. This species is known to contain numerous bioactive components, including polyphenols, fatty acids, vitamins, and phytosterols, which may be responsible for its medicinal value. In experiments both in vitro and in vivo (ranging from cell lines to animal models and human patients), sea buckthorn has shown positive effects on symptoms of metabolic syndrome; evidence suggests that sea buckthorn treatment can decrease blood lipid content, blood pressure, and blood sugar levels, and regulate key metabolites. This article reviews the main bioactive compounds present in sea buckthorn and discusses their efficacy in treating metabolic syndrome. Specifically, we highlight bioactive compounds isolated from distinct sea buckthorn tissues; their effects on abdominal obesity, hypertension, hyperglycemia, and dyslipidemia; and their potential mechanisms of action in clinical applications. This review provides key insight into the benefits of sea buckthorn, promoting future research of this species and expansion of sea buckthorn-based therapies for metabolic syndrome.
... During T2DM, liver tissue damage is represented by alteration in its two main enzymes SGPT and SGOT levels along with lipid profiles such as triglycerides, cholesterol, HDL and LDL levels [38]. The results showed that serum SGOT and SGPT levels became elevated in STZ induced diabetic rats compared to the control, but TTBF intervention prominently lowered the levels compared to the diabetic group. ...
Type 2 Diabetes Mellitus (T2DM) is characterized by hepatic insulin resistance, which results in increased glucose production and reduced glycogen storage in the liver. There is no previous study in the literature that has explored the role of Xanthosine in hepatic insulin resistance. Moreover, mechanistic explanation for the beneficial effects of Xanthosine in lowering glucose production in diabetes is yet to be determined. This study for the first time investigated the beneficial effects of Tribulus terrestris (TT) and its active constituent, Xanthosine on gluconeogenesis and glycogenesis in Free Fatty Acid (FFA)-induced CC1 hepatocytes and streptozotocin (STZ)-induced Wistar rats. Xanthosine enhanced glucose uptake and decreased glucose production through phosphorylation of AMP-activated protein kinase (AMPK) and forkhead box transcription factor O1 (FoxO1), and downregulation of two rate limiting enzymes of gluconeogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) expression in FFA-induced CC1 cells. Xanthosine also prevented FFA-induced decreases in the phosphorylation of AKT/Protein kinase B, glycogen synthase kinase-3β (GSK3β), and increased glycogen synthase (GS) phosphorylation to increase the glycogen content in the hepatocytes. Moreover, in STZ-induced diabetic rats, oral administration of TT n-butanol fraction (TTBF) enriched with compound Xanthosine (10, 50 & 100 mg/kg body weight) improved insulin sensitivity, reduced fasting blood glucose levels, improved glucose homeostasis by reducing gluconeogenesis via AMPK/FoxO1-mediated PEPCK and G6Pase down-regulation and increasing glycogenesis via AKT/GSK3β-mediated GS activation. Overall, Xanthosine may be developed further for treating insulin resistance and hyperglycemia in T2DM.
... Folic acid is an important nutrient that participates in the metabolism of genetic materials and proteins, affecting animal reproductive performance and secretion of bile in the pancreas (Savini et al., 2019;Sato, 2020). Mandenol is a fatty acid that regulates blood glucose and protects the retina (Bouras et al., 2017;Gao et al., 2017). Ent-epicatechin is a polyphenol with antioxidant properties that protect the liver (Maheshwari et al., 2011;Guo et al., 2017). ...
Background: Sea buckthorn (SBT) is a traditional Chinese medicine (TCM), rich in calcium, phosphorus, and vitamins, which can potentially prevent and treat osteoporosis. However, no research has been conducted to confirm these hypotheses. QiangGuYin (QGY) is a TCM compound used to treat osteoporosis. There is a need to investigate whether SBT enhances QGY efficacy.
Objectives: The aim of this study was to explore whether SBT enhances QGY efficacy by inhibiting CKIP-1 and Notum expression through the Wnt/β-catenin pathway. The study also aimed to explore the active components of SBT.
Methods: Experimental animals were divided into control, model, QGY, SBT, SBT + Eucommia ulmoides (EU), and SBT + QGY groups. After treatment, bone morphometric parameters, such as estrogen, PINP, and S-CTX levels, and Notum, CKIP-1, and β-catenin expression were examined. Screening of SBT active components was conducted by molecular docking to obtain small molecules that bind Notum and CKIP-1.
Results: The results showed that all the drug groups could elevate the estrogen, PINP, and S-CTX levels, improve femoral bone morphometric parameters, inhibit Notum and CKIP-1 expression, and promote β-catenin expression. The effect of SBT + EU and SBT + QGY was superior to the others. Molecular docking identified that SBT contains seven small molecules (folic acid, rhein, quercetin, kaempferol, mandenol, isorhamnetin, and ent-epicatechin) with potential effects on CKIP-1 and Notum.
Conclusion: SBT improves bone morphometric performance in PMOP rats by inhibiting CKIP-1 and Notum expression, increasing estrogen levels, and activating the Wnt/β-catenin signaling pathway. Furthermore, SBT enhances the properties of QGY. Folic acid, rhein, quercetin, kaempferol, mandenol, isorhamnetin, and ent-epicatechin are the most likely active ingredients of SBT. These results provide insight into the pharmacological mechanisms of SBT in treating osteoporosis.
... Both the GTT and ITT results confirmed that the HFD induced insulin resistance in mice, whereas dietary seabuckthorn freeze-dried powder effectively accelerated the rates of blood glucose clearance, indicating that certain bioactive compounds in seabuckthorn could be used as an insulin sensitizer, which may be at least partially attributed to the high concentration of omega-3 fatty acids [25]. Similarly, seabuckthorn fruit oil extract has been proved to attenuate insulin resistance via the activation of the PI3K/Akt pathway [26]. ...
Seabuckthorn possesses various bioactive compounds and exhibits several positive pharmacological activities. The present trial aims to determine the effect of seabuckthorn powder intake on high-fat diet (HFD)-induced obesity prevention in mice. The results suggest that seabuckthorn powder intake decreased body weight, fat mass, and circulating lipid levels, and improved insulin sensitivity in HFD-fed mice. Moreover, dietary seabuckthorn powder alleviated hepatic steatosis and hepatic lipid accumulation induced by the HFD. Furthermore, seabuckthorn exhibited obvious anti-inflammatory capacity in white adipose tissue (WAT) by regulating the abundance of inflammation-related cytokines, such as interleukins 4, 6, and 10; tumor necrosis factor α; and interferon-γ. More importantly, dietary seabuckthorn powder promoted a thermogenic program in BAT and induced beige adipocyte formation in iWAT in HFD-fed mice. Interestingly, we found that seabuckthorn powder effectively restored AMPK and SIRT1 activities in both BAT and iWAT in HFD-fed mice. Collectively, these results potentiate the application of seabuckthorn powder as a nutritional intervention strategy to prevent obesity and related metabolic diseases by promoting thermogenesis in BAT and improving beige adipocyte formation in WAT.
... Additionally, numerous natural products have been confirmed to exert their hypoglycemic effects through the PI3K/AKT signaling pathway. Gao et al. (47) found that sea buckthorn fruit oil (SBFO) extract could promote the expression of PI3K while inhibiting the expression of glycogen synthesis kinase-3β (GSK-3β) which revealed that it could alleviate T2DM through the PI3K/AKT signaling pathway. And the anti-diabetic effect of citrus pectin (48), Dendrobium officinale polysaccharide (49), corn silk (Maydis stigma) polysaccharide (50), and tea polysaccharides (51) also had been proved associated with the activation of PI3K/AKT signaling pathway, respectively. ...
Bee pollen is known as a natural nutrient storehouse and plays a key role in many biological processes. Based on the preliminary separation, identification, and characterization of the main active components of Fagopyrum esculentum Moench. bee pollen (FBP), the protective effects of F. esculentum bee pollen extract (FBPE) on high-fat-diet (HFD) and streptozocin (STZ) induced type II diabetes mellitus (T2DM) was evaluated in this study. The results revealed that FBPE contains 10 active compounds mainly including luteolin (9.46 g/kg), resveratrol (5.25 g/kg), kaemferol (3.67 g/kg), etc. The animal experiment results showed that FBPE could improve HFD-STZ induced T2DM mice. Moreover, the underlying mechanism of the above results could be: (i) FBPE could reduce the inflammation related to phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway, and (ii) the gut microbiota remodeling. The results of correlation analysis showed Candidatus Arthromitus and SMB53 indicated positive correlations to tumor necrosis factor-α (TNF-α); Coprococcus, Ruminocossus, and Odoribacteraceae reported negative correlations to transforming growth factor-β (TGF-β). That FBPE has an outstanding ability to improve T2DM and could be used as a kind of potential functional food for the prevention of T2DM.
... Furthermore, the glucose tolerance and insulin sensitivity of db/db mice were significantly improved after treatment with DPHC, and the serum insulin of db/db mice was significantly reduced. HOMA-IR and ISI were analyzed by homeostasis assessment methods, which represented the efficiency of insulin utilization in the body and the health of pancreatic β-cells (Gao et al., 2017), respectively. Our experimental results displayed that DPHC could ameliorate glucose tolerance and IR, thereby accelerated glucose metabolism and reduced FBG level in db/db mice. ...
(R)-5-hydroxy-1,7-diphenyl-3-heptanone (DPHC) from the natural plant Alpinia officinarum has been reported to have antioxidation and antidiabetic effects. In this study, the therapeutic effect and molecular mechanism of DPHC on type 2 diabetes mellitus (T2DM) were investigated based on the regulation of oxidative stress and insulin resistance (IR) in vivo and in vitro . In vivo , the fasting blood glucose (FBG) level of db/db mice was significantly reduced with improved glucose tolerance and insulin sensitivity after 8 weeks of treatment with DPHC. In vitro , DPHC ameliorated IR because of its increasing glucose consumption and glucose uptake of IR-HepG2 cells induced by high glucose. In addition, in vitro and in vivo experiments showed that DPHC could regulate the antioxidant enzyme levels including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px), thereby reducing the occurrence of oxidative stress and improving insulin resistance. Western blotting and polymerase chain reaction results showed that DPHC could promote the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), the heme oxygenase-1 (HO-1), protein kinase B (AKT), and glucose transporter type 4 (GLUT4), and reduced the phosphorylation levels of c-Jun N-terminal kinase (JNK) and insulin receptor substrate-1 (IRS-1) on Ser307 both in vivo and in vitro . These findings verified that DPHC has the potential to relieve oxidative stress and IR to cure T2DM by activating Nrf2/ARE signaling pathway in db/db mice and IR-HepG2 cells.
... Seabuckthorn fruit oil is a rich source in omega fatty acids (Dwivedi et al., 2006). Preclinical studies on seabuckthorn have found applications in protection from oxidation (Geetha et al., 2003), cancer (Padmavathi et al., 2005), cardiovascular (Malik et al., 2011;Guo et al., 2017) and diabetes (Gao et al., 2017). Seabuckthorn berries are rich source of vitamin C, organic acids, vitamin E, K, B, P, carotenoids and flavonoids etc. (Beveridge et al., 1999). ...
... They also found that D-chiro-inositol played a positive role in regulating insulin-mediated glucose uptake through the PI3K/Akt signaling pathway in T2D rats 27 . There is evidence 28 genes from A. The red-colored genes were upregulated and the blue-colored genes were downregulated. C: PCA for the m6A methylome between T2D and control. ...
N6-methyladenosine (m6A) methylation has been reported to play a role in type 2 diabetes (T2D). However, the key component of m6A methylation has not been well explored in T2D. This study investigates the biological role and underlying mechanism of m6A methylation genes in T2D. The Gene Expression Omnibus (GEO) database combined with the m6A methylation and transcriptome data of T2D patients were used to identify m6A methylation differentially expressed genes (mMDEGs). Ingenuity Pathway Analysis was used to predict T2D-related differentially expressed genes (DEGs). Gene Ontology (GO) term enrichment and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to determine the biological functions of mMDEGs. Gene Set Enrichment Analysis (GSEA) was performed to further confirm the functional enrichment of mMDEGs and determine candidate hub genes. The Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis was carried out to screen for the best predictors of T2D, and real-time polymerase chain reaction and western blot were used to verify the expression of the predictors. A total of 194 overlapping mMDEGs were detected. GO, KEGG, and GSEA analysis showed that mMDEGs were enriched in T2D and insulin signaling pathways, where the insulin gene (INS), the type 2 membranal glycoprotein gene MAFA, and hexokinase 2 (HK2) gene were found. The LASSO regression analysis of candidate hub genes showed the INS gene could be invoked as a predictive hub gene for T2D. INS, MAFA, and HK2 genes participate in the T2D disease process, but INS can better predict the occurrence of T2D.
... RT-PCR and Western blotting analyses suggested that the SBPO extract could promote the expression of phosphatidylinositol-3-kinase and glycogen synthesis while inhibiting the expression of glycogen synthesis kinase-3b. Thus, the SBPO extract played a positive role in alleviating T2DM through the PI3K/Akt signaling pathway in HepG2 cells, and diabetic rats and could be used for the future development of functional food and dietary supplements ( Gao et al., 2017). ...
Sea buckthorn (Hippophae rhamnoides L.), which has been categorized as a “medicine food homology” fruit by China’s National Health Commission for both nutritional and medicinal purposes, has nearly 200 kinds of nutritive and bioactive compounds such as polyunsaturated fatty acids, carotenoids, sugar alcohols, superoxide dismutase and phytosterols. Significant bioactivity, including cardiovascular improvement, antidiabetic and anti-obesity activity, have highlighted the application of sea buckthorn. This review compiled a database of the phytochemical compounds in sea buckthorn, which contains the contents of 106 nutrients and 74 bioactive compounds. The health benefits of sea buckthorn and its extracts were summarized and the mechanism of anti-oxidation and anti-inflammation were introduced in detail. Seventeen common marketed products of sea buckthorn from 8 countries were collected. A future scope is really needed to explore the mechanism of sea buckthorn bioactive compounds along with the incorporation cost-effective functional food products.
... Similar results were also showed in db/db and HFD mice [17,80]. Besides FoxO, GSK3-β is also a key inhibition target of P-AKT and it then inhibits the synthesis of glycogen through phosphorylating glycogen synthase [87]. Overexpression or abnormal activation of GSK3-β was associated with type 2 diabetes mellitus [88,89]. ...
The forkhead box O (FoxO) subfamily is a member of the forkhead transcription factor family. It has regulation functions in glucose metabolism in mammals and fish. In the present study, a gene of the foxo homolog in abalone Haliotis discus hannai was cloned. A conservative forkhead (FH) domain and a transactivation (FoxO-TAD) domain were identified. Abalone foxo-specific siRNA (small interfering RNA) was injected to investigate the functions of foxo on glucose metabolism. Knockdown of foxo inhibited expression of phosphoenolpyruvate carboxykinase (pepck) and significantly increased expressions of hexokinase (hk) and pyruvate kinase (pk), but it failed to inhibit the relative mRNA level of glucose-6-phosphatase (g6pase). Then, a 100-day feeding trial was conducted to investigate the response of foxo and glucose metabolism in abalone fed with 1.57% (LFD, low-fat diet), 3.82% (MFD, middle-fat diet) and 6.72% (HFD, high-fat diet) of dietary lipid, respectively. The insulin-signaling pathway (AKT) was depressed and FoxO was activated by the HFD, but it did not inhibit glycolysis (hk) or improved gluconeogenesis significantly (pepck and g6pase). At the same time, impaired hepatopancreas glycogen storage raised hemolymph glucose levels. In conclusion, abalone foxo can be regulated by dietary lipid and can regulate gluconeogenesis or glycolysis in response to changes of dietary lipid levels, in which glycogen metabolism plays an important role.
... Clinical trials suggested that sea buckthorn juice reduced the risk of cardiovascular disease via preventing low-density lipoprotein cholesterol (LDL-c) oxidation and increasing high-density lipoprotein cholesterol (HDL-c) levels in blood (Eccleston et al., 2002). Sea buckthorn fruit oil alleviated insulin resistance through activating the PI3K/Akt signaling pathway in type 2 diabetes mellitus cells and rats (Gao et al., 2017). Narayanan et al. reported that sea buckthorn had cytoprotective activity against hypoxia-induced oxidative injury via reducing reactive oxygen species (ROS) levels, restoring mitochondrial integrity and preventing DNA damage in glial cells (Narayanan et al., 2005). ...
Ethnopharmacological relevance:
Sea buckthorn is popularly used as a herbal medicine and food additive in the world. Sea buckthorn flavonoids (SF) is reported to have an ameliorative effect on obesity and hyperlipidemia (HLP).
Aim:
To identify the major bioactive compounds and the lipid-lowering mechanism of SF.
Methods:
We used network pharmacology analysis and in vitro experiments to identify the major bioactive compounds and the lipid-lowering mechanism of SF.
Results:
A total of 12 bioactive compounds, 60 targets related to SF and HLP were identified, and a component-target-disease network was constructed. The KEGG analysis revealed that SF regulated cholesterol metabolism, fat digestion and absorption, and PPAR signaling pathways in HLP. The experimental validation indicated that sea buckthorn flavonoids extract (SFE) and 4 bioactive compounds reduced lipid droplet accumulation, up-regulated the mRNA expression of PPAR-γ, PPAR-α, ABCA1 and CPT1A, etc, down-regulated SREBP-2 and its target gene LDLR, which are closely related to cholesterol conversion into bile acids, de novo synthesis and fatty acids oxidation. The major bioactive flavonoid isorhamnetin (ISOR) also increased the protein expression of PPAR-γ, LXRα and CYP7A1.
Conclusion:
SF might promote cholesterol transformation into bile acids and cholesterol efflux, inhibit cholesterol de novo synthesis and accelerate fatty acids oxidation for ameliorating HLP.
... Further, RT-PCR and western blotting based study revealed that the enhanced expression of phosphatidylinositol-3-kinase and glycogen synthesis and suppressed expression of glycogen synthesis kinase-3β (GSK-3β) by fruit oil. Therefore, the fruit oil extract had a positive effect through PI3K/Akt signaling pathway in HepG2 cells, and diabetic mice(Gao, Guo, Qin, Shang, & Zhang, 2017). 6.14 | Prevention of insulin resistance and oxidative stress Polyphenols enriched extract of Rosa rugosa in varying extract doses (37.5 to 150 mg/kg) alone or in combination with STZ was fed with high fat diet displayed in vitro α-glucosidase inhibitory activity, decreased the fasting blood glucose, increased insulin susceptibility (HOMA-IR), OGTT, insulin tolerance test and blood lipid profile. ...
Diabetes is a disease of serious concern faced by the health care industry today.
Primary diabetes mellitus and its complications are still costly to manage with modern
drugs. Extensive research on the screening of anti-diabetic agents in past decades
established natural products as one of the major potential sources of drug discovery.
However, only a few drugs of plant origin have been scientifically validated. Therefore,
the development of new anti-diabetic drugs is of great demand. Hence, natural
products could be explored as potential anti-diabetic drugs. Natural plants derived
extracts and molecules like berberine, ginsenosides, curcumin, stevioside, gingerols,
capsaicin, catechins, simple phenolic compounds, anthocyanins, resveratrol, genistein
and hesperidin obtained from different species are used for curing diabetes and
found to possess different action mechanisms. In this review, the importance of
medicinal plants and their active constituents for anti-diabetic agents are described.
The present study also emphasized the importance of diabetes control, reduction in
its complications and use of the anti-diabetic agents. The detailed action mechanism
of these extracts/compounds for their activities are also described. However, the
anti-diabetic drugs from plant origin require scientific validation through animal and
clinical studies to exploit in terms of modern commercial medicines.
... indicating the successful establishment of our T2DM rats model (Ashcroft & Rorsman, 2012). These results may result from not only the damaged energy metabolism and insufficient energy supply by long-term hyperglycemia, but also the impaired blood glycose metabolism which causes excessive protein and muscle consumption to thus lead to the weight reduction and FBG elevation (Gao, Guo, Qin, Shang, & Zhang, 2017). However, metformin and ZA treatment could significantly resist the body weight reduction as well as decrease the FBG compared to the DM group. ...
To investigate the effect of Zanthoxylum alkylamides (ZA) on amino acid metabolism of type 2 diabetes mellitus (T2DM), the present study was performed with T2DM rats model induced with high fat and sugar fodder combined with low‐dose of streptozotocin. ZA were fed to rats at three different doses of 2, 4, and 8 mg/kg for 28 days and metformin was fed to rats at 135 mg/kg as positive control. The results showed that compared with the normal control, the amino acid levels and the expression of related carrier genes were disordered in T2DM rats. Compared with the model, different doses of ZA could significantly resist (p < .05) the decrease in body weight of T2DM rats and improve hyperglycemia, with the best result observed with the high dose (8 mg/kg). Different doses of ZA could ameliorate the levels of 19 kinds of amino acid in the plasma, jejunum, liver, and skeletal muscle of T2DM rats by regulating the expression of related amino acid transporters including LAT1, SNAT2, CAT1, et al. to thereby ameliorating amino acid metabolism disorder in T2DM rats.
Practical applications
Previous studies showed that Zanthoxylum alkylamides (ZA) could promote the amino acid metabolism in the jejunum of healthy SD rats, improve protein metabolism disorder of type 1 diabetic rats, and also reduce the risk of metabolic syndrome in fat rats model. Herein, we investigated the effect of ZA on amino acid metabolism in type 2 diabetes mellitus (T2DM) rats. The results indicated that ZA could remarkably improve the abnormal expression of amino acid carriers in the jejunum, liver, and skeletal muscle, thereby ameliorating the disorder of amino acid metabolism in the plasma, jejunum, liver, and skeletal muscle of T2DM rats. Therefore, ZA are potential antidiabetic food/medicine product for the T2DM treatment.
... Research has shown that palmitoleic acid may have a role in glucose homeostasis as well as in the metabolism of fatty acids. Gao et al. (2017) investigated the effect of sea buckthorn fruit oil in vitro and in vivo and found that SB oil intake could significantly improve glucose homeostasis, insulin sensitivity, and liver injury in HepG2 cells and SD male rats. The oil is partly present in SB juice and therefore SB juice may have also an effect on improving insulin sensitivity and postprandial glycaemia. ...
Food industries seek to incorporate nutritious ingredients as they could bring added value to the final food products. One of the most interesting options is that sea buckthorn contains high concentrations of vitamin C, carotenoids, tocopherols, and other bioactive compounds, in addition to the unique lipid profile in the berry pulp, seed, and peel. This review summarizes the state-of-the-art of potential applications of sea buckthorn within the food and feed industry based on previously described applications. Products such as cheese, yoghurt or beverages already benefit from its application. Moreover, using sea buckthorn in feed products also derives into higher quality final products (e.g. meat quality, egg quality). Poultry, pig, and fish farming have been studied for that purpose. Despite all the accumulated articles depicted in the present review, the use of this fruit in food product formulation is nowadays scarce. New options for food product development with sea buckthorn are herein discussed.
Graphical abstract
... Sea buckthorn pulp oil (SBPO), a nutritive oil product obtained from the pulp of the SB berry, has been received attention in recent years for its healthy properties (Gao et al., 2017). SBPO is characterized by an abundant composition of fatty acids, chemically includes palmitoleic acid (C16:1, 19.4%~38.5%), ...
Food protein-stabilized with nanoemulsions were prepared by ultra-high pressure homogenization under appropriate homogenization condition, so as to improve the poor water solubility and instability of sea buckthorn pulp oil (SBPO). SBPO nanoemulsions stabilized by sodium caseinate (SC) and whey protein isolates (WPI) suggested good microstructures and rheological properties. SC-stabilized SBPO nanoemulsions system showed smaller mean particle size (<260 nm), lower Ke value (6.3–20.4%) and higher absolute value of zeta potential (55.70–67.20 mV) over various pH (3–9), salinity (0–200 mM), temperature (20–80 °C). The SC-stabilized SBPO nanoemulsions showed no significantly increase in droplet size over 30 days at 4 °C and 25 °C, which proved it has good stability. The antioxidant activity of SC-stabilized SBPO nanoemulsions was evaluated by employing cellular antioxidant activity (CAA) model and the results showed good antioxidant activity. This study implied that protein-stabilized nanoemulsions are a promising carrier for extending the applications of SBPO as nutraceutical or functional dairy beverage.
... Lipophilic fractions of the soft parts and seeds also contain fatty acids especially palmitoleic acid, the oil extracted from the fruits is used for the treatment of digestive problems [16] and skin problems [17]. In many studies it has been observed that sea buckthorn berries oil extract evaluated through many in-vitro and in-vivo experiments in order to explore its mechanism of action for the treatment of type 2 diabetes mellitus [18] and also used in cancer therapy [19]. That plant is locally available and its cultivation can be increased by providing the friendly climate. ...
... Therefore, the study of SBFO extract will substantiate our understanding of its health-promoting benefits and lay a foundation for future development of SBFO functional food. Besides, our previous experiments have confirmed the SBFO extract played a positive role in alleviating T2DM through the PI3K/Akt signaling pathway (Gao, Guo, Qin, Shang, & Zhang, 2017). As is well-known that glucose metabolism is interrelated lipid metabolism as an integral whole (Gaidhu & Ceddia, 2009;Imai, Inukai, Ikegami, Awata, & Katayama, 2006). ...
In this study, golden syrian hamsters were regarded as modeling objects, a series of sea buckthorn fruit oil (SBFO) extract, which is rich in palmitoleic acid (POA), was evaluated through in vivo experiments to explore its mechanism of action in anti-hyperlipidemia. The results revealed that SBFO extract could control body weight and adipose tissue mass, relieve fat accumulation, together with improving total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) level in dose-dependent manner. The extract could also alleviate oxidative stress and liver impairment caused by hyperlipemia through regulating antioxidant enzyme. RQ-PCR and western blotting analyses suggested that SBFO extract could affect the expression of key genes in AMPK and Akt pathway and promote the phosphorylation of AMPK and Akt proteins. As a conclusion, SBFO extract had antilipemic function on hyperlipidemia hamsters and could be used for future development of functional food and dietary supplements.
... The miR159, miR395, miR396 family and novel-1, 4, 8, 23, 28 miRNAs were predicted to target GSK-3β, which phosphorylates and inactivates glycogen synthase (GS) [33]. Therefore, the downstream activated gene encoding GS regulate glucose metabolism through affecting glucose transport and the synthesis of glycogen [17]. Those miRNAs may play a key role in glucose regulation network, and reduce the level of blood glucose. ...
Abstract Neolamarckia cadamba (Roxb.) Bosser (Rubiaceae) is a widespread plant with medicine value and has been used for treating various diseases, such as coughs, fevers, anemia, blood disorders and stomach pains. It had been reported that plant miRNAs might enter mammalian intestines and exert a special ingredient across the different species. However, the knowledge about miRNAs in N.cadamba is scarce. In this study, we first applied high-throughput sequencing to identify miRNAs in N.cadamba. Sequencing revealed a total of 11,285,965 raw reads in the small RNA library of N.cadamba leaves. By bioinformatics analysis, we identified a total of 192 miRNAs, including 167 conserved miRNAs and 25 novel miRNAs, which were distributed among 30 families. Next, we used miRanda to predict the targets of those miRNAs in human, 4030 target genes were predicted. Furthermore, Gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that the identified miRNAs majored in binding, vibrio cholerae infection and insulin signaling, which were likely to provide valuable references for further understanding of medical functions of N. cadamba.
... Type 2 diabetes is characterized by insulin resistance and progressive β cell failure with associated insulin deficiency ( Cinti et al., 2016). Irregularly increasing glucose leads to many chronic diseases (Wu, Shi, Gao, Guo, Qin, Shang, & Zhang, 2017). Thus, the control of blood glucose level is a critical method to prevent the progression of type 2 diabetes and its complications (Martinez, Lockhart, Davies, Lindsay, & Dempster, 2018). ...
Agaricus blazei Murrill (ABM) is an edible fungus. This study investigated the protective role of ABM fruiting body against streptozotocin (STZ)‐induced diabetic rats. After 4 weeks of ABM supplement, glucose homeostasis was improved in diabetic rats. Quantitative real‐time and Western blot analyses suggested that ABM could promote the gene and protein expression level of insulin receptor, pyruvate dehydrogenase kinase, phospho‐kinase B, kinase B, phosphatidylinositol 3‐kinase, insulin receptor substrate 1, glucose transporter‐4, and glutamine synthetase, while inhibiting the expression of glycogen synthase kinase 3β and c‐jun N‐terminal kinase 1 and 2. According to multivariate and univariate statistical analysis, liver metabolite profiles of the normal and diabetic rats fed basal and experimental diet were clearly separated. The differential liver metabolites from diabetic rats fed basal and ABM diet‐related pathways including the glycolysis pathway, pentose phosphate pathway, tricarboxylic acid cycle, and oxidative phosphorylation were analyzed. A total of 18 potential biomarker metabolites were identified as differential biomarkers associated with ABM supplement diet. Intake of Agaricus blazei Murrill (ABM) modulated characteristics of diabetic rats. ABM reduced elevated blood glucose and improved hepatic function. ABM plays an important role in ameliorating glucose homeostasis.
... Some studies indicate that abnormality in the PI3K/Akt signaling pathway is the most fundamental cause of diabetes, and it has been proposed that development of diabetes drugs should focus on this pathway [31][32][33]. The monomer composition of many traditional Chinese medicines is able to regulate diabetes metabolism through the PI3K/Akt signaling pathway, including seabuckthorn oil extracts [34], phytol [35], and Chinese catalpa [36]. ...
This study was performed to elucidate the potential influence of He Qi San (HQS) on glucose and lipid metabolism in type 2 diabetes mellitus (T2DM) patients with phlegm-blood stasis syndrome (PBSS), and to determine DNA methylation changes. Sixty T2DM patients with PBSS were randomly divided into control and HQS groups. The control group received conventional treatments, and the HQS group received conventional treatments plus HQS. Glucose metabolism (FPG, 2hPG, FINS, and HbA1c) and lipid metabolism indexes (TG, TC and LDL-C) were determined. Genes with differential DNA methylation were subjected to GO and KEGG analyses. Glucose and lipid metabolism indexes in both groups were reduced, but were much more pronounced in the HQS group. Differential promoter CpG methylation regions were identified in 682 genes, including 426 genes with high-CpG promoters, 150 genes with intermediate CpG promoters, and 106 genes with low CpG promoters. Genes with differential DNA methylation were mainly enriched in the AMPK and insulin signaling pathways, terpenoid backbone biosynthesis, and renin secretion. We concluded that HQS remarkably improved indexes of glucose and lipid metabolism in T2DM patients with PBSS through regulating the DNA methylation of genes in the AMPK and insulin signaling pathways and terpenoid backbone biosynthesis.
... Type 2 diabetes is characterized as insulin resistance, namely the body's sensitivity to reduced insulin levels, resulting in excessive accumulation of insulin in the plasma. Irregularly increasing glucose levels could lead to many chronic diseases (Gao, Guo, Qin, Shang, & Zhang, 2017;Wu, Shi, Wang, & Wang, 2016). Thus, the control of blood glucose level is a critical method to prevent the progression of type 2 diabetes and its complications (Martinez, Lockhart, Davies, Lindsay, & Dempster, 2018). ...
Agaricus blazei Murill (ABM), a medicinal mushroom, has beneficial effects on various human metabolic diseases. The objective of this research was to evaluate the antioxidant and antidiabetic properties of ABM extracts (ethanol extract and ethyl acetate extract). The antioxidant activities of ABM ethanol extract (EE) and ethyl acetate extract (EA) were analyzed using 1,1‐diphenyl‐2‐picrylhydrazyl (DPPH), 2,2′‐azino‐bis (3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS), and hydroxyl radical scavenging assays and the reducing power using K3Fe(CN)6 in vitro. Moreover, the effects of EE and EA on α‐glucosidase inhibitory activity and improving glucose uptake by HepG2 cells were investigated in vitro. The EA showed stronger antioxidant activity, as well as inhibition of α‐glucosidase, compared to EE. The analysis of glucose uptake by HepG2 cells showed that EA had significant glucose‐lowering activity and exhibited no difference compared to metformin. The results suggest that ABM extracts could improve the glucose uptake by HepG2 cells and thereby alleviate postprandial hyperglycemia. This investigation provides a strong rationale for further studies on the application of ABM to control type 2 diabetes. Agaricus blazei Murril extracts showed high antioxidant activity. Agaricus blazei Murril extracts demonstrated potential anti‐diabetic activity.
... The fruit oil of SBT was used to protect people from nuclear radiation from explosion at a nuclear plant at Chernobyl, Ukraine in 1986 [9]. SBT fruit extracts, fruit oil, seed oil, and leaf extracts have been reported for several pharmacological activities, such as anti-oxidant [10,11], immunomodulatory [12,13], anti-inflammatory [14,15], anti-cancer [16,17], anti-diabetic [18,19], anti-ulcer [20,21], antihyperlipidemic [22], and radioprotective [23,24]. Different parts of SBT are a good source of biologically active proteins and essential amino acids, sugars (mainly glucose and fructose), mineral elements, fatty acids (palmitoleic, oleic, linoleic, linolenic acid), phytosterols, terpenoids, vitamins (A, C, E, and K), flavonoids (isorhamnetin, quercetin, kaempferol and their glycosides), organic acids mainly malic, quinic, oxalic, citric, and tartaric acids [25][26][27][28]. ...
Introduction: Seabuckthorn (SBT) has received worldwide attention for therapeutic, nutraceutical and cosmetic purposes. It is used for the treatment of a number of diseases. Hundreds of commercial products containing seabuckthorn are available in the market.
Areas covered: This review article covers patents on the therapeutic potential of seabuckthorn and its chemical constituents. The therapeutic areas covered in this review include cancer, cardiovascular, diabetes, inflammation, anti-oxidant, and anti-microbial. The patents were searched through Sci-finder, Espacenet, Google Patent, and US Patent.
Expert opinion: Plant based drugs have played an important role in the modern drug industry. Since ancient times, seabuckthorn has been used to cure several ailments. SBT has emerged as an important plant which has been investigated for numerous pharmacological properties and shown to be beneficial in a number of therapeutic areas. Several clinical trials have demonstrated the therapeutic potential of seabuckthorn for the treatment of many diseases including cardiovascular, inflammation, diabetes, platelet inhibition etc. There is huge potential for developing standardized herbal products from different parts of SBT.
... The binding of insulin to its receptor causes phosphorylation and activation of IRS1, which further phosphorylates PI3K and Akt, leading to Glut4 translocation [29]. Here, 16% dietary SBP supplementation increased phosphorylation of both IRS1 and Akt, in line with a recent study showing that palmitoleic acid extracted from sea buckthorn alleviates insulin resistance through the Akt signaling pathway [30]. ...
The sea buckthorn contains substantial amounts of bioactive compounds. The objective of this study was to investigate the effects of dietary sea buckthorn pomace (SBP) on sheep beige adipocyte formation. A total of thirty lambs were equally divided into three groups and fed with diets containing different levels of SBP: 0% SBP (Control), 7.8% SBP (7.8SBP), and 16.0% SBP (16SBP). The results showed that dietary SBP affected inguinal adipocytes’ size distribution, and increased both UCP1 protein content (p < 0.05) and mitochondrial numbers (p < 0.05). mRNA expression of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A were increased when animals were subjected to 16% SBP (p < 0.05). Supplementation with 16% SBP increased CCAAT/enhancer-binding protein β content (p < 0.05) and PR domain containing 16 mRNA abundance (p < 0.05). Consistently, inguinal white adipose tissue (iWAT) from the 16SBP group exhibited increased insulin sensitivity, which was associated with elevated glucose transporter 4 abundance (p < 0.05). Importantly, AMP-activated protein kinase (AMPK) was activated in the 16SBP group (p < 0.05). Collectively, these results suggest that dietary SBP promotes iWAT browning in lambs, which might be through the activation of the AMPK–PGC-1α–UCP1 signaling pathway.
VLATSGPG (VLA) was a DPP-IV inhibitory peptide isolated from salmon (Salmo Salar) skin. Here, we demonstrated that VLA inhibited the activation of PERK through the AKT signaling pathway. Furthermore, we investigated the effect of VLA on free fatty acid (FFA)-induced lipid accumulation disorder and inflammation in HepG2 cells, elucidating the potential regulatory mechanism in this nonalcoholic fatty liver disease cell model. VLA reduced the mRNA expression of adipogenic factors FAS, ACC, and SCD-1 through the PERK/eIF2α pathway and the level of apolipoprotein B-100 secretion. These may contribute to the reducing FFA-induced lipid accumulation in cells and reducing intracellular lipid levels. In addition, VLA increased IκBα mRNA expression via the PERK/IκBα pathway, inhibited the NF-κB p65 activation, and thus inhibited cell inflammation.
In the era of global health consciousness, the demand for non-saccharides or zero-calorie natural sweeteners has consequently increased day by day. Siraitia grosvenorii, luohan guo, or monk fruit is well known for its zero caloric natural sweetener cucurbitane triterpene glycosides compounds. The mogroside V (300 times sweeter than sucrose) is the major specialized metabolite and comprises more than 30% of the total sweetener compounds in its fruit pulp. Moreover, S. grosvenorii is also approved as a medicine food homology (MFH) plant because of its both nutritional and medicinal properties. In recent years, cutting-edge progress in plant biology, biotechnology, transcriptomics, nutraceuticals, and pharmaceutics has allowed unprecedented insights into biosynthesis and regulation mechanisms of health-promoting compounds of S. grosvenorii. This review includes comprehensive information about the biosynthetic pathway, plant cell/tissue culture, molecular mechanism, phytochemistry, nutraceutical and pharmaceutical properties of specialized metabolites of S. grosvenorii. Also, biotechnological interventions to produce alternative specialized metabolites and development strategies for the future of S. grosvenorii have also been discussed.
Sea buckthorn (Hippophae rhamnoides L.) is described by various beneficial effects as it contains several bioactive substances characterized by antioxidant effects. These effects are closely related to the reduction of oxidative stress that is involved in the development of the disease. One such diseases is Diabetes mellitus, the prevalence of which is growing and is associated primarily with diet, lack of exercise and/or genetics. This study intends to examine the effects of sea buckthorn and metformin on body weight, water and feed intake, glycaemia, insulinemia, sorbitol accumulation and cataract development in Zucker diabetic fatty rats, which represent an animal model of type 2 Diabetes mellitus, as well as to characterize the individual content of bioactive substances and the antioxidant activity of sea buckthorn. Particular concentrations were applied (500 and 1000 mg.kg⁻¹ body weight of sea buckthorn, and combinations with 150 mg.kg⁻¹ body weight of metformin) by gastric gavage. The total antioxidant capacity and bioactive compounds were determined by spectrophotometric analysis. The best results of the study showed suppression of hyperglycaemia, water intake, decreased sorbitol levels in the lens of the eyes after sea buckthorn treatment. Determination of bioactive compounds showed significantly higher values in dry berries when compared to fresh berries of sea buckthorn and high total antioxidant capacity. Our results represent an interest in sea buckthorn and its potential use in the treatment of Diabetes mellitus as well as other experimental studies.
Scope:
Sea buckthorn (Hippophaes rhamnoides) is capable of ameliorating disturbed glucose metabolism in animal models and human subjects. Here, the effect of sea buckthorn oil as well as of extracts of fruits, leaves, and press cake on postprandial glucose metabolism is systematically investigated.
Methods and results:
Sea buckthorn did neither exert decisive effects in an in vitro model of intestinal glucose absorption nor did it alter insulin secretion. However, sea buckthorn stimulates GLUT4 translocation to the plasma membrane comparable to insulin, indicative of increased glucose clearance from the circulation. Isorhamnetin is identified in all sea buckthorn samples investigated and is biologically active in triggering GLUT4 cell surface localization. Consistently, sea buckthorn products lower circulating glucose by ≈10% in a chick embryo model. Moreover, sea buckthorn products fully revert hyperglycemia in the nematode Caenorhabditis elegans while they are ineffective in Drosophila melanogaster under euglycemic conditions.
Conclusion:
These data indicate that edible sea buckthorn products as well as by-products are promising resources for hypoglycemic nutrient supplements that increase cellular glucose clearance into target tissues.
It is important to maintain the normal function of the pancreas in the prevention and intervention of type 2 diabetes mellitus (T2DM). This study was undertaken to explore the protective effects of fucoidan on the pancreas in T2DM rats induced by using a high fat diet (HFD) and low dose of streptozotocin (STZ) injection. The results showed fucoidan remarkably decreased the levels of fasting blood glucose, serum insulin and glycated serum protein, and increased the level of glucagon-like peptide-1 in T2DM rats. Also, fucoidan improved insulin sensitivity and reduced the postprandial blood glucose level. Meanwhile, fucoidan alleviated pancreas damage and improved the islet β cell function in T2DM rats. Additionally, fucoidan activated the PI3K/AKT signaling pathway and regulated glucose homeostasis, which seemed to be related to the protection of the pancreas from damage by inhibiting inflammation and endoplasmic reticulum stress in T2DM rats. Collectively, these results indicated that fucoidan had a potential protective effect on the pancreas, which enriched ideas for the use of fucoidan as a nutritional agent in the cure of T2DM.
EGCG and quercetin are flavonoids which usually co-exist in edible plants and they exhibit anti-diabetes effects. This study aimed to explore the mechanisms by which quercetin and EGCG synergistically protected pancreatic β-cells from streptozotocin-induced apoptosis. EGCG, quercetin, and their combinations (both 15 μM) all reversed STZ-induced cells damage and enhanced glucose-stimulated insulin secretion, with the combination being more effective than a single compound. At the molecular level, the EGCG-quercetin combination upregulated BCL-2 expression and caused a greater reduction in miR-16-5p level than EGCG alone or quercetin alone. Overexpression of miR-16-5p could offset the down-regulated apoptotic genes caused by the synergistic action of the combination. These findings suggest that EGCG and quercetin exert synergistic anti-diabetes effect, possibly via decreasing the expression of miR-16-5p that targets directly BCL-2. This is the first report on a miRNA-based mechanism underlying the synergistic protective effect of EGCG and quercetin against pancreatic cell damage.
This study was designed to investigate the effects of ultrafine grinding on the physicochemical properties of pea dietary fiber (PDF) and the hypoglycemic effect of ultrafine grinding dietary fiber on diabetes mellitus (DM). So, the PDF was treated by ultrafine grinding technology, and its microstructure and physicochemical properties were determined. Then, the DM model was established, and the 4‐week ultrafine grinded pea dietary fiber (UGPDF) diet intervention was conducted by using gavage and feeding. During this period, the blood glucose and body weight of the mice were measured, and an oral glucose tolerance test was measured on the last day. The biochemical blood indexes of the mice were determined, and the pancreas was stained with HE after dissecting. The results showed that after ultrafine grinding, the structure fragmentation, specific surface area increased, and UGPDF showed higher swelling ability as well as water and oil holding capacities. Simultaneously, UGPDF had a significant effect on reducing blood glucose and glycosylated hemoglobin in DM mice, improving the wasting state of mice and increasing the tolerance to glucose. Further, the results of the HE section showed that the pancreatic islet cells gradually returned to normal regular morphology. In biochemical blood indicators, UGPDF reduced TC and TG levels in the blood. This study provided a specific data basis for the following research on the hypoglycemic mechanism, and broadens the application field of PDF.
Practical Application
The physicochemical properties of pea dietary fiber were improved by ultrafine grinding technology. Because of this, the application of pea dietary fiber in the field of hypoglycemic had a better effect, laying a foundation for the next research on hypoglycemic mechanism.
Dihydromyricetin (DHM), as a bioactive flavanonol compound, is mainly found in “Tengcha” (Ampelopsis grossedentata) cultivated in south of China. This study aimed to investigate the anti-hyperglycemic and anti-dyslipidemic activities of DHM using type 2 diabetes mellitus (T2D) rats, which was induced by feeding with high fat and fructose diet for 42 days and intraperitoneal administration of streptozocin. Forty-eight freshly-weaned rats were randomly assigned into the negative control (Blank), low dose (100 mg/kg), medium dose (200 mg/kg), high dose (400 mg/kg), and positive (40 mg/kg, met) groups. Fasting blood glucose and body weight were measured at weekly interval. Oral glucose tolerance tests were performed on days 42. The results revealed that DHM possessed significant antihyperglycaemic and antihyperinsulinemic effects. Moreover, after the DHM treatment, p-Akt and p-AMPK expression was upregulated, and glycogen synthase kinase-3β (GSK-3β) expression was downregulated, indicating that the potential anti-diabetic mechanism of DHM might be due to the regulation of the AMPK/Akt/GSK-3β signaling pathway.
Ethnopharmacological relevance
Inonotus obliquus (Fr.) Pilat is a mushroom belonging to the family Hymenochaetaceae. It is popularly called the Chaga mushroom in Russian folk medicine and has been used as a traditional medicine to treat diabetes mellitus in Eastern European and Asian countries. However, its effects on glycolipid metabolism disorders and underlying molecular mechanism of action remain unclear.
Aim of the study: I. obliquus contains abundant functional components, which provide potential medicinal value. The purpose of this study was to investigate compositions of I. obliquus extract with a high-pressure water extraction method, and investigate the anti-type 2 diabetic effects of I. obliquus extract and the possible underlying mechanisms involved.
Materials and methods
The I. obliquus was extracted by a high-pressure water extraction method, and tested its main components by special assay kit and instrumental analysis. Type 2 diabetic C57BL/6 mice were induced by high-fat diet with low-dose STZ injection, and were daily gavaged with different doses of I. obliquus extract for 8 weeks. Glycemic, blood lipid profile, and histopathology of liver and pancreas were assessed. Underlying mechanisms related to glycemic control in liver were further performed.
Results
The I. obliquus extract main compounds were β-Glucans, triterpenoids and polyphenol by determination. Oral administration of 250 mg/kg and 500 mg/kg I. obliquus extract significantly alleviated blood glucose and insulin resistance. Moreover, 250 mg/kg and 500 mg/kg of I. obliquus extract increased liver glycogen content and high-density lipoprotein cholesterol (HDL-C) levels while decreased total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels. Furthermore, the protein expression levels of phosphatidylinositol-3 kinase (PI3K), p-protein kinase B (Akt), p-adenosine monophosphate activated protein kinase (AMPK), and p-acetyl-CoA carboxylase (ACC) were upregulated, whereas sterol regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) were downregulated after supplement with 250 mg/kg and 500 mg/kg of I. obliquus extract. Interestingly, I. obliquus extract was a dose-effect relationship within a certain range. 250 mg/kg had obvious anti-diabetes effect, and the effect of 500 mg/kg dose was the same as that of metformin.
Conclusion
I. obliquus extract ameliorated insulin resistance and lipid metabolism disorders in diabetic mice. The hypoglycemic and hypolipidemic properties of I. obliquus extract were supposedly exerted via the regulation of the PI3K/Akt and AMPK/ACC signaling pathways.
The aim of this study is to investigate the hypoglycemic mechanism of ginsenoside Rh4 (G-Rh4) in vivo and in vitro models. Our results showed that G-Rh4 markedly improved the symptoms of diabetes, normalized glucose metabolism, and promoted insulin secretion which contributed to attenuate symptoms of hyperglycemia in high-fat diet/streptozocin induced type 2 diabetes mellitus mice. This positive effect was associated with increased expression of Nrf2 by G-Rh4. Further results demonstrated that G-Rh4 promoted Nrf2 nucleus translocation as well as up-regulated the expression of HO-1, NQO1 and GCLC. Furthermore, we also found that G-Rh4 increased insulin secretion by activating the signal pathway of PDX-1, GLUT2 and GCK. More importantly, the protective effects of G-Rh4 on alloxan-induced upregulation of Nrf2 target gene and insulin secretion were abolished by Nrf2 knockdown. Finally, we explored the mechanism of G-Rh4 associated with Nrf2 activation and found that the Akt deficiency inhibited G-Rh4-mediated Nrf2 nuclear translocation. Altogether, we present evidence that G-Rh4 increased expression of Nrf2 and results in increased antioxidant gene, as well as a rise in insulin secretion in vivo and in vitro. Exploiting the Nrf2 pathway may show great potential as a therapeutic strategy to improve pancreatic β-cells dysfunction in the diabetic population.
Eurocristatine (ECT) is an alkaloid isolated from Eurotium cristatum, and it has been used in multiple applications. However, its use as a treatment for type 2 diabetes mellitus (T2DM) has not yet been reported. In this study, we investigated the anti-T2DM effect of ECT and explored its potential molecular mechanism. In vivo, after treatment with ECT (20, 40 mg/kg) for 6 weeks, fasting blood glucose (FBG) was remarkably reduced in db/db mice. Moreover, glucose tolerance, insulin sensitivity and hyperinsulinemia were ameliorated treatment with ECT. The values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) also showed that ECT could alleviate liver toxicity caused by diabetes in db/db mice. In vitro, ECT (15 and 30 μM) alleviated insulin resistance by increasing glucose consumption, glucose uptake and glycogen content in high glucose-induced HepG2 cells. The Western blotting (WB) results showed that ECT could upregulate the expression of phosphatidylinositol 3-kinase (PI3K), increase the phosphorylation of insulin receptor substrate 1 (IRS1) and protein kinase B (AKT) in vivo and in vitro. Besides, ECT improved the glycogen content by inhibiting the expression of glycogen synthase kinase3β (GSK3β) and promoting that of glycogen synthase (GS). Furthermore, administration of the PI3K/AKT signaling pathway inhibitor LY294002 abolished the beneficial effects of ECT. These findings are the first to verify that ECT has the potential to improve glucose metabolism and alleviate insulin resistance by activating the PI3K/AKT signaling pathway in db/db mice.
The objective of this study is to investigate the effects of sea buckthorn oil (SBO) on proliferation, adipogenic differentiation and insulin sensitivity of 3T3-L1 cells. Results showed that SBO increased cell proliferation ability, accompanied by up-regulated proliferating cell nuclear antigen content (p < 0.05) and p38 activity (p < 0.05). SBO also promoted adipogenesis and enhanced adipogenic transcriptional factors expression. Mitochondrial biogenesis related gene expressions were elevated in SBO treated cells (p < 0.05). Of note, SBO also increased glucose uptake and glucose transporter 4 abundance (p < 0.05). Cells treated with SBO exhibited greater phosphorylated insulin receptor substrate 1 (p < 0.05), phosphorylated-Akt (p < 0.05) and phosphorylated AMP-activated protein kinase (p < 0.01) contents. When taken together, these results suggest that SBO promotes 3T3-L1 cells proliferation, adipogenesis and insulin sensitivity.
The aim of the present trial was to evaluate the effects of dietary sea buckthorn pomace (SBP) supplementation on muscle mass, meat nutritional value and quality of lambs. The results showed that dietary 16% SBP supplementation increased muscle mass and altered muscle fiber size distribution. Both nutritional compositions, including crude protein, moisture and ash, and lamb meat quality, including pH, color and cooking loss were not affected by SBP supplementation. Importantly, crude fat content was elevated, and shear force was decreased in Longissimus thoracis (LT) when lambs were fed the SBP containing diet. Moreover, the total antioxidative capacity in LT and the HDL content in serum were elevated in SBP feed lambs. Dietary SBP supplementation increased the Akt/mTOR signaling activity, and downregulated myostatin expression. Taken together, these data suggested that SBP could be used as a feed ingredient for lamb meat production by increasing muscle mass and improving tenderness, water holding capacity and antioxidative capacity of resulting meat.
Mogroside, a triterpenoid of Siraitia grosvenorii, has been reported to play an important role in glycometabolism processes. In this study, the mechanism of mogroside was evaluated through in vitro experiments using Mogroside III (MO3), IV (MO4), V (MO5), Siamenoside I (SO1) at 1, 5, 10 μM, and in vivo experiments using MO5 at 30, 75, 150 mg/(kg·bw·day). In cell experiments, mogrosides at 5 μM significantly restored glucose metabolism and insulin resistance (IR), and MO5 had the most obvious hypoglycemic effect. In rat experiments, fasting blood glucose, liver damage, and insulin sensitivity were improved by MO5 treatment. Moreover, the Real-Time Polymerase Chain Reaction and Western bolt analysis indicated that MO5 up-regulated the expression of phosphatidylinositol-3-kinase (PI3K), glucose transporter type 2 (GLUT2), glycogen synthesis (GS). It also down-regulated phosphorylated insulin receptor substrate-1 (p-IRS-1(ser)) and glycogen synthesis kinase-3β (p-GSK-3β). Overall, MO5 alleviated IR and increased glycogen synthesis through the PI3K/Akt pathway.
Gymnemic acid (GA) isolated from gymnema sylvestre (Retz.) Schult has been shown to display anti-diabetic activity, however the molecular mechanisms governing these effects are unclear. In this study, GA (40, 80 mg/kg/day) was evaluated by type 2 diabetes mellitus (T2DM) rats to explore its hypoglycemic activity and underlying mechanisms of action. The results indicated that GA decreased fasting blood glucose (FBG) concentrations by 26.7 %, and lowered insulin concentrations by 16.1 % after oral administration of GA at a dose of 80 mg/kg/day for 6 weeks in T2DM rats. Our data showed that RT-PCR and Western blot analysis indicated that GA up-regulated the expression of phosphatidylinositol-3-kinase (PI3K) and glycogen synthesis (GS), promoted the phosphorylation of protein kinase B (Akt), while down-regulated the expression of glycogen synthesis kinase-3β (GSK-3β) in T2DM rats. In addition, key proteins involved in AMPK-mediated gluconeogenesis (such as phosphoenolpyruvate carboxy kinase (PEPCK) and glucose-6-phosphatase (G6Pase)) were down-regulated in GA-treated T2DM rats. In summary, the hypoglycemic mechanisms of GA may be related to promoting insulin signal transduction and activating PI3K/Akt and AMPK-mediated signaling pathway in T2DM rats.
Insulin resistance is a condition in which insulin sensitivity is reduced and the insulin signaling pathway is impaired. Although often expressed as an increase in insulin concentration, the disease is characterized by a decrease in insulin action. This increased workload of the pancreas and the consequent decompensation are not only the main mechanisms for the development of type 2 diabetes (T2D), but also exacerbate the damage of metabolic diseases, including obesity, nonalcoholic fatty liver disease, polycystic ovary syndrome, metabolic syndrome, and others. Many clinical trials have suggested the potential role of herbs in the treatment of insulin resistance, although most of the clinical trials included in this review have certain flaws and bias risks in their methodological design, including the generation of randomization, the concealment of allocation, blinding, and inadequate reporting of sample size estimates. These studies involve not only the single-flavored herbs, but also herbal formulas, extracts, and active ingredients. Numerous of in vitro and in vivo studies have pointed out that the role of herbal medicine in improving insulin resistance is related to interventions in various aspects of the insulin signaling pathway. The targets involved in these studies include insulin receptor substrate, phosphatidylinositol 3-kinase, glucose transporter, AMP-activated protein kinase, glycogen synthase kinase 3, mitogen-activated protein kinases, c-Jun-N-terminal kinase, nuclear factor-kappaB, protein tyrosine phosphatase 1B, nuclear factor-E2-related factor 2, and peroxisome proliferator-activated receptors. Improved insulin sensitivity upon treatment with herbal medicine provides considerable prospects for treating insulin resistance. This article reviews studies of the target mechanisms of herbal treatments for insulin resistance.
Cancer management is a worldwide challenge. In addition to effective cancer therapies like chemotherapy, radiotherapy and surgery, treatment based on traditional Chinese medicine (TCM) and combined TCM with western medicine has gradually gained attention in Oriental countries. One potential TCM approach using extracted fatty oils, containing fatty acids which are important active ingredients with a variety of pharmacological activities, makes significant contributions to cancer treatment. The strategies of treating cancer with the fatty oils of TCM were classified into “Fuzheng”, which usually associates with improving immunity, represented by coix seed oil. The other classification is “Quxie”, which relates to inducing apoptosis of cancer cells, and is represented by Brucea javanica oil. Compared with other active substances, the literature about anticancer fatty oils is relatively limited, and most of them focus on the composition and other biological activities without a systematic review. Therefore, based on the theories of “Fuzheng” and “Quxie” in TCM, in this paper, the anticancer effects of fatty oils have been reviewed. The chemical composition, anticancer mechanism, listed drugs, studying dosage form and clinical application of fatty oils have also been discussed. In summary, since there are different types and abundance of fatty oils among botanicals, anticancer effects of fatty oils can be achieved through two TCM theory-based strategies. We hoped that this review paper can reveal the anticancer potential of fatty oils and provide a reference for future related studies.
Gymnemic acid (GA) is a naturally occurring herbal ingredient that is improves glucose metabolism in patients with diabetes mellitus. In this study, we evaluated the ameliorative effects of GA on insulin resistance (IR) and identified the mechanisms in a rat model of type 2 diabetes mellitus (T2DM) and IR HepG2 cells. GA effectively increased glucose uptake in IR HepG2 cells from 11.9 ± 1.09 to 14.7 ± 1.38 mmol/l, lowered fasting blood glucose (blood glucose levels in groups treated with GA at 40 and 80 mg/kg/day were reduced by 15.2 % and 26.7 %, respectively) and oral glucose tolerance. Both in vivo and in vitro, GA downregulated the expression of endoplasmic reticulum (ER) stress indicator proteins such as ORP150, p-c-Jun, p-PERK, and p-eIF2α. In addition, the improvement of ER stress regulated the insulin signal transduction proteins, reducing p-IRS-1(ser) levels and increasing p-IRS-1(tyr) in GA-treated T2DM rats and IR HepG2 cells. In summary, the mechanism underlying the hypoglycemic effects of GA may be related to attenuation of ER stress and improvement of insulin signal transduction in T2DM rats and IR HepG2 cells.
Marine bioactive lipids have been utilized to overcome insulin resistance. However, oil from swimming crab has never been studied. Here, we analyzed the constituents of egg oil from Portunus trituberculatus (Pt-egg oil) and investigated its protective effects against insulin resistance in mice on a high-fat diet. The results showed that Pt-egg oil contained 52.05% phospholipids, 8.61% free fatty acids (especially eicosapentaenoic acid and docosahexaenoic acid), 32.38% triglyceride, 4.79% total cholesterol, and ditissimus astaxanthin. Animal experiments showed that Pt-egg oil significantly mitigated insulin resistance and was associated with reductions in blood glucose, insulin, glucose tolerance, insulin tolerance, serum lipids, and hepatic glycogen. Pt-egg oil activated the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (Akt)/glucose transporter 4 pathway in skeletal muscle both at the transcriptional level and at the translational level. Pt-egg oil also promoted hepatic glycogen synthesis through activation of the PI3K/Akt/glycogen synthase kinase-3 beta pathway. These indicate that Pt-egg oil can be used as an alternative to marine bioactive lipids to improve insulin resistance.
Previous studies have indicated that 4‑hydroxyisoleucine (4‑HIL) improves insulin resistance, however, the underlying mechanisms remain to be elucidated. In the present study, the molecular mechanisms underlying how 4‑HIL improves insulin resistance in hepatocytes were examined. HepG2 cells were co‑cultured with insulin and a high glucose concentration to obtain insulin‑resistant (IR) HepG2 cells. Insulin sensitivity was determined by measuring the glucose uptake rate. The IR HepG2 cells were treated with different concentrations of 4‑HIL to determine its effect on IR Hep2 cells. The levels of tumor necrosis factor‑α (TNF‑α) were measured by an enzyme‑linked immunosorbent assay and protein levels of TNF‑α converting enzyme (TACE)/tissue inhibitor of metalloproteinase 3 (TIMP3), insulin receptor substrate (IRS)‑1, IRS‑2, phosphorylated (p)‑IRS‑1 (Ser307) and glucose transporter type 4 (GLUT4) were measured by western blot analysis. The results of the present study demonstrated that insulin‑induced glucose uptake was reduced in IR HepG2 cells; however, this reduction was reversed by 4‑HIL in a dose‑dependent manner. 4‑HIL achieved this effect by downregulating the expression of TNF‑α and TACE, and upregulating the expression of TIMP3 in IR HepG2 cells. In addition, 4‑HIL increased the expression of the insulin transduction regulators IRS‑1 and GLUT4, and decreased the expression of p‑IRS‑1 (Ser307), without affecting the expression of IRS‑2. The present study suggests that 4‑HIL improved insulin resistance in HepG2 cells by the following mechanisms: 4‑HIL reduced TNF‑α levels by affecting the protein expression of the TACE/TIMP3 system and 4‑HIL stimulated the expression of IRS‑1 and GLUT4, but inhibited the expression of p‑IRS‑1 (Ser307).
Objective
The objectives were to (i) describe the characteristics of a large ethnically/racially and geographically diverse population of adolescents with recent-onset type 2 diabetes (T2D), and (ii) assess the effects of short-term diabetes education and treatment with metformin on clinical and biochemical parameters in this cohort.Research design and methodsDescriptive characteristics were determined for subjects screened for Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) who met criteria for diagnosis of T2D (n = 1092). Changes in clinical and biochemical parameters were determined for those who completed at least 8 wk of the run-in phase of the trial, which included standardized diabetes education and treatment with metformin. Further analysis determined whether these changes differed according to the treatment at screening.Main outcome measuresDemographic, biochemical measurements, and anthropometrics at screening and changes over 8 wk of run-in were the outcome measures.ResultsSubjects screened for TODAY had a median age of 14 yr and median hemoglobin A1c (HbA1c) of 6.9% (52 mM/M), 2/3 were female, and ethnic/racial minorities were overrepresented. Dyslipidemia and hypertension were common comorbidities. During run-in, HbA1c, body mass index, low-density lipoprotein cholesterol, triglycerides, and blood pressure significantly improved. Nearly all participants on insulin therapy at screening were able to attain target HbA1c following insulin discontinuation.Conclusions
Treatment with metformin and diabetes education provided short-term improvements in glycemic control and cardiometabolic risk factors in a large adolescent T2D cohort. Nearly all insulin-treated youth could be successfully weaned off insulin with continued improvement in glycemic control.
Palmitoleic acid was previously shown to improve glucose homeostasis by reducing hepatic glucose production and by enhancing insulin-stimulated glucose uptake in skeletal muscle. Herein we tested the hypothesis that palmitoleic acid positively modulates glucose uptake and metabolism in adipocytes.
For this, both differentiated 3 T3-L1 cells treated with either palmitoleic acid (16:1n7, 200 muM) or palmitic acid (16:0, 200 muM) for 24 h and primary adipocytes from mice treated with 16:1n7 (300 mg/kg/day) or oleic acid (18:1n9, 300 mg/kg/day) by gavage for 10 days were evaluated for glucose uptake, oxidation, conversion to lactate and incorporation into fatty acids and glycerol components of TAG along with the activity and expression of lipogenic enzymes.
Treatment of adipocytes with palmitoleic, but not oleic (in vivo) or palmitic (in vitro) acids, increased basal and insulin-stimulated glucose uptake and GLUT4 mRNA levels and protein content. Along with uptake, palmitoleic acid enhanced glucose oxidation (aerobic glycolysis), conversion to lactate (anaerobic glycolysis) and incorporation into glycerol-TAG, but reduced de novo fatty acid synthesis from glucose and acetate and the activity of lipogenic enzymes glucose 6-phosphate dehydrogenase and ATP-citrate lyase. Importantly, palmitoleic acid induction of adipocyte glucose uptake and metabolism were associated with AMPK activation as evidenced by the increased protein content of phospho(p)Thr172AMPKalpha, but no changes in pSer473Akt and pThr308Akt. Importantly, such increase in GLUT4 content induced by 16:1n7, was prevented by pharmacological inhibition of AMPK with compound C.
In conclusion, palmitoleic acid increases glucose uptake and the GLUT4 content in association with AMPK activation.
Obesity and saturated fatty acid (SFA) treatment are both associated with skeletal muscle insulin resistance (IR) and increased macrophage infiltration. However, the relative effects of SFA and unsaturated fatty acid (UFA)-activated macrophages on muscle are unknown. Here, macrophages were treated with palmitic acid, palmitoleic acid or both and the effects of the conditioned medium (CM) on C2C12 myotubes investigated. CM from palmitic acid-treated J774s (palm-mac-CM) impaired insulin signalling and insulin-stimulated glycogen synthesis, reduced Inhibitor κBα and increased phosphorylation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase in myotubes. p38 MAPK inhibition or siRNA partially ameliorated these defects, as did addition of tumour necrosis factor-α blocking antibody to the CM. Macrophages incubated with both FAs generated CM that did not induce IR, while palmitoleic acid-mac-CM alone was insulin sensitising. Thus UFAs may improve muscle insulin sensitivity and counteract SFA-mediated IR through an effect on macrophage activation.
Palmitoleic acid has been shown to regulate adipokine expression and systemic metabolic homeostasis in animal studies. However, its association with human metabolic diseases remains controversial.
We aimed to investigate associations of erythrocyte palmitoleic acid with adipokines, inflammatory markers, and metabolic syndrome (MetS) in a Chinese population.
Erythrocyte fatty acids were measured in a population-based sample of 3107 men and women aged 50-70 y, for whom plasma glucose, insulin, lipid profile, adiponectin, retinol binding protein 4 (RBP-4), plasminogen activator inhibitor type 1, and high-sensitivity C-reactive protein (hsCRP) were measured. MetS was defined according to the updated National Cholesterol Education Program Adult Treatment Panel III criteria for Asian Americans.
The mean (±SD) erythrocyte palmitoleic acid value was 0.41 ± 0.20% of total fatty acids. Palmitoleic acid was positively correlated with RBP-4 (r = 0.14, P < 0.001) and inversely correlated with adiponectin (r = -0.15, P < 0.001). After multivariable adjustment, palmitoleic acid was strongly associated with MetS and its components. ORs (95% CIs) for comparisons of extreme quartiles of palmitoleic acid were 3.50 (2.66, 4.59) for MetS, 7.88 (5.90, 10.52) for hypertriglyceridemia, 2.13 (1.66, 2.72) for reduced HDL cholesterol, 1.99 (1.60, 2.48) for central obesity, and 1.86 (1.41, 2.44) for elevated blood pressure (all P < 0.001). Further control for adipokines and hsCRP abolished the association of palmitoleic acid with central obesity but not with other MetS components.
Erythrocyte palmitoleic acid is associated with an adverse profile of adipokines and inflammatory markers and an increased risk of MetS in this Chinese population.
Studies have demonstrated the beneficial effect of palmitoleic acid (C16:1 n-7) on reducing muscle insulin resistance and preventing beta-cell apoptosis. However, the effect of palmitoleic acid on diabetes remains to be elucidated. The aim of this study was to examine the antidiabetic effect of palmitoleic acid in KK-Ay mice, a spontaneous model for studies of obese type 2 diabetes with low insulin sensitivity.
KK-Ay mice were orally administered vehicle, 300 mg/kg of palmitoleic acid, or 300 mg/kg of palmitic acid (C16:0) on a daily basis for 4 weeks.
Palmitoleic acid reduced body weight increase, ameliorated the development of hyperglycemia and hypertriglyceridemia, and improved insulin sensitivity. In addition, hepatic characteristics were significantly affected, as weight of the liver and hepatic triglyceride levels were lower in the palmitoleic acid group when compared to the control (vehicle and palmitic acid groups). Oil red O staining clearly indicated reduced hepatic lipid accumulation in response to palmitoleic acid. Furthermore, palmitoleic acid down-regulated mRNA expressions of proinflammatory adipocytokine genes (TNFα and resistin) in white adipose tissue and lipogenic genes (SREBP-1, FAS, and SCD-1) in liver.
These results suggest that palmitoleic acid improves hyperglycemia and hypertriglyceridemia by increasing insulin sensitivity, in part owing to suppressing proinflammatory gene expressions and improving hepatic lipid metabolism in diabetic mice.
We investigated whether palmitoleate, which prevents insulin resistance in mice, predicts insulin sensitivity in humans.
The fasting fatty acid pattern in the plasma free fatty acid (FFA) fraction was determined in 100 subjects at increased risk for type 2 diabetes. Insulin sensitivity was estimated during an oral glucose tolerance test (OGTT) at baseline and after 9 months of lifestyle intervention and measured during the euglycemic-hyperinsulinemic clamp (n = 79).
Circulating palmitoleate (OGTT:F ratio = 8.2, P = 0.005; clamp:F ratio = 7.8, P = 0.007) but not total FFAs (OGTT:F ratio = 0.6, P = 0.42; clamp:F ratio = 0.7, P = 0.40) correlated positively with insulin sensitivity, independently of age, sex, and adiposity. High baseline palmitoleate predicted a larger increase in insulin sensitivity. For 1-SD increase in palmitoleate, the odds ratio for being in the highest versus the lowest tertile of adjusted change in insulin sensitivity was 2.35 (95% CI 1.16-5.35).
Circulating palmitoleate strongly and independently predicts insulin sensitivity, suggesting that it plays an important role in the pathophysiology of insulin resistance in humans.
Factors secreted by macrophages contribute to whole body insulin resistance, acting in part on adipose tissue. Muscle is the major tissue for glucose disposal, but how macrophage-derived factors impact skeletal muscle glucose uptake is unknown, or whether the macrophage environment influences this response. We hypothesized that conditioned medium from macrophages pretreated with palmitate or LPS would directly affect insulin action and glucose uptake in muscle cells. L6-GLUT4myc myoblasts were exposed to conditioned medium from RAW 264.7 macrophages pretreated with palmitate or LPS. Conditioned medium from palmitate-treated RAW 264.7 macrophages inhibited myoblast insulin-stimulated glucose uptake, GLUT4 translocation, and Akt phosphorylation while activating JNK p38 MAPK, decreasing IkappaBalpha, and elevating inflammation markers. Surprisingly, and opposite to its effects on adipose cells, conditioned medium from LPS-treated macrophages stimulated myoblast insulin-stimulated glucose uptake, GLUT4 translocation, and Akt phosphorylation without affecting stress kinases or inflammation indexes. This medium had markedly elevated IL-10 levels, and IL-10, alone, potentiated insulin action in myoblasts and partly reversed the insulin resistance imparted by medium from palmitate-treated macrophages. IL-10 neutralizing antibodies blunted the positive influence of LPS macrophage-conditioned medium. We conclude that myoblasts and adipocytes respond differently to cytokines. Furthermore, depending on their environment, macrophages negatively or positively influence muscle cells. Macrophages exposed to palmitate produce a mixture of proinflammatory cytokines that reduce insulin action in muscle cells; conversely, LPS-activated macrophages increase insulin action, likely via IL-10. Macrophages may be an integral element in glucose homeostasis in vivo, relaying effects of circulating factors to skeletal muscle.
L6 myoblasts stably transfected with a GLUT4 cDNA harboring an exofacial myc epitope tag (L6-GLUT4myc myoblasts) were used to study the role of protein kinase B alpha (PKBalpha)/Akt1 in the insulin-induced translocation of GLUT4 to the cell surface. Surface GLUT4myc was detected by immunofluorescent labeling of the myc epitope in nonpermeabilized cells. Insulin induced a marked translocation of GLUT4myc to the plasma membrane within 20 min. This was prevented by transient transfection of a dominant inhibitory construct of phosphatidylinositol (PI) 3-kinase (Deltap85alpha). Transiently transfected cells were identified by cotransfection of green fluorescent protein. A constitutively active PKBalpha, created by fusion of a viral Gag protein at its N terminus (GagPKB), increased the cell surface density of GLUT4myc compared to that of neighboring nontransfected cells. A kinase-inactive, phosphorylation-deficient PKBalpha/Akt1 construct with the mutations K179A (substitution of alanine for the lysine at position 179), T308A, and S473A (AAA-PKB) behaved as a dominant-negative inhibitor of insulin-dependent activation of cotransfected wild-type hemagglutinin (HA)-tagged PKB. Furthermore, AAA-PKB markedly inhibited the insulin-induced phosphorylation of cotransfected BAD, demonstrating inhibition of the endogenous PKB/Akt. Under the same conditions, AAA-PKB almost entirely blocked the insulin-dependent increase in surface GLUT4myc. PKBalpha with alanine substitutions T308A and S473A (AA-PKB) or K179A (A-PKB) alone was a less potent inhibitor of insulin-dependent activation of wild-type HA-PKB or GLUT4myc translocation than was AAA-PKB. Cotransfection of AAA-PKB with a fourfold DNA excess of HA-PKB rescued insulin-stimulated GLUT4myc translocation. AAA-PKB did not prevent actin bundling (membrane ruffling), though this response was PI 3-kinase dependent. Therefore, it is unlikely that AAA-PKB acted by inhibiting PI 3-kinase signaling. These results outline an important role for PKBalpha/Akt1 in the stimulation of glucose transport by insulin in muscle cells in culture.
To conduct a systematic review of the published literature on the efficacy and safety of herbal therapies and vitamin/mineral supplements for glucose control in patients with diabetes.
We conducted an electronic literature search of MEDLINE, OLDMEDLINE, Cochrane Library Database, and HealthSTAR, from database inception to May 2002, in addition to performing hand searches and consulting with experts in the field. Available clinical studies published in the English language that used human participants and examined glycemic control were included. Data were extracted in a standardized manner, and two independent investigators assessed methodological quality of randomized controlled trials using the Jadad scale.
A total of 108 trials examining 36 herbs (single or in combination) and 9 vitamin/mineral supplements, involving 4,565 patients with diabetes or impaired glucose tolerance, met the inclusion criteria and were analyzed. There were 58 controlled clinical trials involving individuals with diabetes or impaired glucose tolerance (42 randomized and 16 nonrandomized trials). Most studies involved patients with type 2 diabetes. Heterogeneity and the small number of studies per supplement precluded formal meta-analyses. Of these 58 trials, the direction of the evidence for improved glucose control was positive in 76% (44 of 58). Very few adverse effects were reported.
There is still insufficient evidence to draw definitive conclusions about the efficacy of individual herbs and supplements for diabetes; however, they appear to be generally safe. The available data suggest that several supplements may warrant further study. The best evidence for efficacy from adequately designed randomized controlled trials (RCTs) is available for Coccinia indica and American ginseng. Chromium has been the most widely studied supplement. Other supplements with positive preliminary results include Gymnema sylvestre, Aloe vera, vanadium, Momordica charantia, and nopal.
ID-1101 (4-hydroxyisoleucine), an amino acid extracted from fenugreek seeds, exhibits an interesting glucose-dependent insulin-stimulating activity. The present study was undertaken to investigate a possible extrapancreatic effect of ID-1101 on insulin signaling and action besides its previously described insulinotropic action. Insulin-sensitizing effects of ID-1101 were investigated in rat in vivo by three different approaches: 1) using euglycemic hyperinsulinemic clamps in two different rat models of insulin resistance, i.e., Zucker fa/fa rats and rats fed a sucrose-lipid diet; 2) measuring liver and muscle phosphatidylinositol (PI) 3-kinase activity after an acute injection of ID-1101 in normal and insulin-resistant diabetic rats; and 3) after chronic treatment in two rat models of insulin resistance. Euglycemic hyperinsulinemic clamp experiments revealed that ID-1101 can improve insulin resistance through an increase of peripheral glucose utilization rate in sucrose-lipid-fed rats and by decreasing hepatic glucose production in Zucker fa/fa rats. Moreover, we demonstrated that a single injection of ID-1101 activates the PI 3-kinase activity in liver and muscle from normal rats but also in muscle from diabetic rats. Finally, chronic ID-1101 treatment significantly reduced insulinemia in type 2 diabetic rats and reduced the progression of hyperinsulinemia in insulin-resistant obese Zucker fa/fa rats. These findings clearly demonstrate that ID-1101 can reduce insulin resistance through activation of the early steps of insulin signaling in peripheral tissues and in liver. In summary, ID-1101, besides its insulinotropic effect, directly improves insulin sensitivity, making it a potentially very valuable therapeutic agent for diabetes treatment.
To investigate the effect of a sustained (7-day) decrease in plasma free fatty acid (FFA) concentrations on insulin action and intramyocellular long-chain fatty acyl-CoAs (LCFA-CoAs), we studied the effect of acipimox, a potent inhibitor of lipolysis, in seven type 2 diabetic patients (age 53 +/- 3 years, BMI 30.2 +/- 2.0 kg/m2, fasting plasma glucose 8.5 +/- 0.8 mmol/l, HbA 1c 7.5 +/- 0.4%). Subjects received an oral glucose tolerance test (OGTT) and 120-min euglycemic insulin (80 mU/m2 per min) clamp with 3-[3H]glucose/vastus lateralis muscle biopsies to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and intramyocellular LCFA-CoAs before and after acipimox (250 mg every 6 h for 7 days). Acipimox significantly reduced fasting plasma FFAs (from 563 +/- 74 to 230 +/- 33 micromol/l; P < 0.01) and mean plasma FFAs during the OGTT (from 409 +/- 44 to 184 +/- 22 micromol/l; P < 0.01). After acipimox, decreases were seen in fasting plasma insulin (from 78 +/- 18 to 42 +/- 6 pmol/l; P < 0.05), fasting plasma glucose (from 8.5 +/- 0.8 to 7.0 +/- 0.5 mmol/l; P < 0.02), and mean plasma glucose during the OGTT (from 14.5 +/- 0.8 to 13.0 +/- 0.8 mmol/l; P < 0.05). After acipimox, insulin-stimulated Rd increased from 3.3 +/- 0.4 to 4.4 +/- 0.4 mg x kg(-1) x min(-1) (P < 0.03), whereas suppression of endogenous glucose production (EGP) was similar and virtually complete during both insulin clamp studies (0.16 +/- 0.10 vs. 0.14 +/- 0.10 mg x kg(-1) x min(-1); P > 0.05). Basal EGP did not change after acipimox (1.9 +/- 0.2 vs. 1.9 +/- 0.2 mg x kg(-1) x min(-1)). Total muscle LCFA-CoA content decreased after acipimox treatment (from 7.26 +/- 0.58 to 5.64 +/- 0.79 nmol/g; P < 0.05). Decreases were also seen in muscle palmityl CoA (16:0; from 1.06 +/- 0.10 to 0.75 +/- 0.11 nmol/g; P < 0.05), palmitoleate CoA (16:1; from 0.48 +/- 0.05 to 0.33 +/- 0.05 nmol/g; P = 0.07), oleate CoA (18:1; from 2.60 +/- 0.11 to 1.95 +/- 0.31 nmol/g; P < 0.05), linoleate CoA (18:2; from 1.81 +/- 0.26 to 1.38 +/- 0.18 nmol/g; P = 0.13), and linolenate CoA (18:3; from 0.27 +/- 0.03 to 0.19 +/- 0.02 nmol/g; P < 0.03) levels after acipimox treatment. Muscle stearate CoA (18:0) did not decrease after acipimox treatment. The increase in R(d) correlated strongly with the decrease in muscle palmityl CoA (r = 0.75, P < 0.05), oleate CoA (r = 0.76, P < 0.05), and total muscle LCFA-CoA (r = 0.74, P < 0.05) levels. Plasma adiponectin did not change significantly after acipimox treatment (7.9 +/- 1.8 vs. 7.5 +/- 1.5 microg/ml). These data demonstrate that the reduction in intramuscular LCFA-CoA content is closely associated with enhanced insulin sensitivity in muscle after a chronic reduction in plasma FFA concentrations in type 2 diabetic patients despite the lack of an effect on plasma adiponectin concentration.
An increase in circulating levels of specific NEFAs (non-esterified fatty acids) has been implicated in the pathogenesis of insulin resistance and impaired glucose disposal in skeletal muscle. In particular, elevation of SFAs (saturated fatty acids), such as palmitate, has been correlated with reduced insulin sensitivity, whereas an increase in certain MUFAs and PUFAs (mono- and poly-unsaturated fatty acids respectively) has been suggested to improve glycaemic control, although the underlying mechanisms remain unclear. In the present study, we compare the effects of palmitoleate (a MUFA) and palmitate (a SFA) on insulin action and glucose utilization in rat L6 skeletal muscle cells. Basal glucose uptake was enhanced approx. 2-fold following treatment of cells with palmitoleate. The MUFA-induced increase in glucose transport led to an associated rise in glucose oxidation and glycogen synthesis, which could not be attributed to activation of signalling proteins normally modulated by stimuli such as insulin, nutrients or cell stress. Moreover, although the MUFA-induced increase in glucose uptake was slow in onset, it was not dependent upon protein synthesis, but did, nevertheless, involve an increase in the plasma membrane abundance of GLUT1 and GLUT4. In contrast, palmitate caused a substantial reduction in insulin signalling and insulin-stimulated glucose transport, but was unable to antagonize the increase in transport elicited by palmitoleate. Our findings indicate that SFAs and MUFAs exert distinct effects upon insulin signalling and glucose uptake in L6 muscle cells and suggest that a diet enriched with MUFAs may facilitate uptake and utilization of glucose in normal and insulin-resistant skeletal muscle.
Ethnopharmacological relevance:
Liuwei Dihaung decoction(LWDHT) is a well-known classic traditional Chinese medicine formula, consists of six herbs including Rehmannia glutinosa Libosch.(family: Scrophulariaceae), Cornus officinalis Sieb.(family: Cornaceae), Dioscorea opposite Thunb.(family:Dioscoreaceae), Alisma orientale(G.Samuelsson) Juz (family: Alismataceae),Poria cocos (Schw.) Wolf (family: Polyporaceae) and Paeonia suffruticosa Andrews (family: Paeoniaceae). It has been used in the treatment of many types of diseases with signs of deficiency of Yin in the kidneys in China clinically. This study is aimed at investigating the effect of Liuwei dihuang decoction on PI3K/Akt signaling pathway in liver of T2DM rats with insulin resistance.
Materials and methods:
T2DM model was induced by high sugar and high fat diet in combination with small dose of streptozocin (STZ) injection in male Sprague-Dawley (SD) rats.The successful T2DM rats were randomly divided into three group--vehicle group，positive control group and Liuwei Dihuang decoction group. After 12 weeks of treatment with distilled water, rosiglitazone and LWDH by intragastric administration respectively, the rats were put to death in batch. The changes of fasting blood glucose (FBG), fasting insulin (FINS) in serum were determined, the pathological changes of each rats' liver were observed by hematoxylin-eosin (HE) staining, the expression of insulin receptor substrate 2(IRS2), phosphatidylinositol 3-kinase (PI3K) and protein kinas B (Akt) involving the canonical PI3K/Akt signaling pathway were detected by Real-time fluorescent quantitative PCR (RT-PCR), and the expression level of IRS2, PI3K, Akt protein and phosphorylated IRS2, PI3K, Akt protein were detected by Western Blot. All the data were analyzed by SPSS 17.0.
Results:
Four weeks of treatment with LWDHT could significantly decrease the level of FBG and FINS in serum, improve the cellular morphology of liver, kidney, pancreas tissue, and the expression of IRS2, PI3K, Akt mRNA and phosphorylated IRS2, PI3K, Akt protein involved in the canonical PI3K/Akt signaling pathway of T2DM rats in liver were significantly up-regulated, while the total IRS2, PI3K, and Akt protein had no obvious changes.
Conclusions:
Our results suggest that Liuwei Dihuang decoction could intervene insulin resistance of T2DM, in part, through regulation of canonical PI3K/Akt signaling pathway of T2DM rats in liver.
Atorvastatin is a cholesterol-lowering statin that has been shown to exert several pleiotropic effects in the nervous system as a neuroprotective and antidepressant-like agent. Antidepressant-like effect of atorvastatin in mice is mediated by glutamatergic and serotoninergic receptors, although the precise intracellular signaling pathways involved are unknown. PI3K/Akt/GSK-3β/mTOR signaling pathway has been associated to neurobiology of depression and seems to be modulated by some pharmacological antidepressant strategies. The present study investigated the participation of the PI3K/Akt/GSK-3β/mTOR signaling pathway in the antidepressant-like effect of an acute atorvastatin treatment in mice. Atorvastatin sub-effective (0.01 mg/kg) or effective (0.1 mg/kg) doses in the tail suspension test (TST) was administered orally alone or in combination with PI3K, GSK-3β or mTOR inhibitors. The administration of PI3K inhibitor, LY294002 (10 nmol/site, i.c.v) completely prevented the antidepressant-like effect of atorvastatin (0.1 mg/kg, p.o.). The participation of GSK-3β in the antidepressant-like effect of atorvastatin was demonstrated by co-administration of a sub-effective dose of atorvastatin (0.01 mg/kg, p.o.) with AR-A014418 (0.01 μg/site, i.c.v., a selective GSK-3β inhibitor) or with lithium chloride (10 mg/kg, p.o., a non-selective GSK-3β inhibitor). The mTOR inhibitor, rapamycin (0.2 nmol/site, i.c.v.) was also able to prevent atorvastatin (0.1 mg/kg, p.o.) antidepressant-like effect. These behavioral findings were supported by neurochemical observations, as atorvastatin treatment increased the immunocontent of the phosphorylated isoforms of Akt, GSK-3β and mTOR in the hippocampus of mice. Taken together, our results suggest an involvement of the PI3K/Akt/GSK-3β/mTOR signaling pathway in the antidepressant-like effect of atorvastatin in mice.
Type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD) and the cardiovascular effect of antidiabetic drugs are today critical medical issues, with the prevalence of T2DM in particular showing a steep increase worldwide, mainly due to unhealthy lifestyle habits. T2DM in association with obesity and other cardiovascular risk factors, results in the development of CVD, the leading cause of morbidity and mortality in patients with T2DM. Thus, treatment of T2DM is an individualized and complex challenge in which targeting cardiovascular risk factors is an important component in the decision making. Given the cardiovascular adverse events associated with rosiglitazone, both the Food and Drug Administration and the European Medicines Agency currently require the demonstration of cardiovascular safety of new antidiabetic drugs. Consequently, clinical trials to guarantee their cardiovascular safety are now obligatory. This review aims to summarize the available evidence on the cardiovascular effects and safety of the major drugs used in T2DM treatment and also to provide an overview of upcoming and ongoing clinical trials in this field. Our belief is that this review will be of substantial assistance to all medical doctors who are treating diabetic patients, namely primary care physicians, internal medicine doctors, endocrinologists, diabetologists and less well experienced personnel such as young doctors in training.
This study was performed to investigate the anti-diabetic effect of citrus pectin in type 2 diabetic rats and its potential mechanism of action. The results showed that fasting blood glucose levels were significantly decreased after 4 weeks of citrus pectin administration. Citrus pectin improved glucose tolerance, hepatic glycogen content and blood lipid levels (TG, TC, LDL-c and HDL-c) in diabetic rats. Citrus pectin also significantly reduced insulin resistance, which played an important role in the resulting anti-diabetic effect. Moreover, after the pectin treatment, phosphorylated Akt expression was upregulated and GSK3β expression was downregulated, indicating that the potential anti-diabetic mechanism of citrus pectin might occur through regulation of the PI3K/Akt signaling pathway. Together, these results suggested that citrus pectin could ameliorate type 2 diabetes and potentially be used as an adjuvant treatment.
Aim:
To evaluate glycemic control among women with gestational diabetes mellitus (GDM) under insulin versus metformin (with or without insulin supplementation), and to identify metformin poor responders requiring supplemental insulin.
Methods:
In Ain Shams University Hospital, mothers with 26-32-week GDM pregnancies, failing diet control, were randomized to receive metformin (n = 47) or insulin (n = 48). The primary outcome was glycemic control. Secondary outcomes included maternal weight, parameters predicting successful metformin monotherapy, neonatal hypoglycemia, and birthweight.
Results:
Women using metformin (23.4% needing supplemental insulin) gained less weight (P < 0.001), and had lower fasting glucose during the first and last 2 weeks of treatment (P = 0.014 and 0.008, respectively) when compared with insulin monotherapy. Insulin supplementation in the metformin group was related to initial body mass index, HbA1c, oral glucose tolerance test (GTT), and first week mean glucose level. The 1-h glucose level during initial GTT (Hr1-GTT) and the mean fasting glucose level during the first week of therapy (Wk1-mFG) were the two independent parameters associated with requiring supplemental insulin. Women with Hr1-GTT >212 mg/dL and Wk1-mFG >95 mg/dL had a risk ratio of 58.6 (95%CI: 3.68-933.35, P = 0.004) and 11.5 (95%CI: 2.77-47.34,= 0.0008), respectively for needing supplemental insulin during the course of the study compared with women without.
Conclusion:
Metformin is an effective and safe alternative to insulin in GDM. Women using metformin (± supplemental insulin) had similar glycemic control, less weight gain, and similar rates of side-effects as those on insulin monotherapy. Insulin supplementation to metformin therapy was more likely with elevated Hr1-GTT and Wk1-mFG.
Chenpi is the dry peel of the plant Citrus reticulata Blanco after aging processing. It has been used as an anti-digestive and anti-inflammatory traditional medicine, as well as culinary seasoning and dietary supplements in China. But its efficacy and underlying scientific mechanism have not been sufficiently investigated. Chenpi is uniquely enriched with high content of 5-demethylated polymethoxflavones (5-OH PMFs). The effect of chenpi extract on improving metabolic features was examined using high fat diet (HFD) induced obesity/diabetes mouse model. Oral administration of 0.25% and 0.5% chenpi extract in food over 15 weeks markedly prevented HFD-induced obesity, hepatic steatosis, and diabetic symptoms. The beneficial effect is associated with AMPK activation in adipose tissue. Our results indicate that 5-OH PMFs enriched chenpi extract is effective in preventing obesity and type 2 diabetes and its effect might be related to improvement in lipid metabolism associated with activation of AMPK pathway.
D-pinitol, a compound isolated from pinaceae and leguminosae plants, has been reported to possess insulin-like properties. Although hypoglycemic activity of D-pinitol was recognized in recent years, the molecule mechanism of D-pinitol in the treatment of diabetes mellitus remains unclear. In this investigation, a model of type 2 diabetes mellitus (T2DM) with insulin resistance was established by feeding a high-fat diet (HFD) and injecting streptozocin (STZ) to the Sprague Dawley (SD) rats, targeting to explore more details of mechanism in the therapy of T2DM. D-pinitol was administrated to the diabetic rats as two doses [30, 60 mg/ (kg•bodyweight•d)]. The level of fasting blood glucose (FBG) was decreased 12.63% in high-dosage group. And the ability of oral glucose tolerance was improved in D-pinitol treated groups. The biochemical indexes revealed that D-pinitol had a positive effect on hypoglycemic activity. Western boltting suggested that D-pinitol could promote the expression of the phosphatidylinositol-3-kinase (PI3K) p85, PI3Kp110 as well as the downstream target protein kinase B/Akt (at Ser473). Besides, D-pinitol inhibited the expression of glycogen synthesis kinase-3β (GSK-3β) protein and regulated the expression of glycogen synthesis (GS) protein and then accelerated the glycogen synthesis. From above all, D-pinitol played a positive role in regulating insulin mediated glucose uptake in liver through translocation and activation of PI3K/Akt signaling pathway in T2DM rats.
Palmitoleate (cis-Δ9-16:1) shows numerous health benefits such as increased cell membrane fluidity, reduced inflammation, protection of the cardiovascular system, and inhibition of oncogenesis. Plant oils containing this unusual fatty acid can also be sustainable feedstocks for producing industrially important and high-demand 1-octene. Vegetable oils rich in palmitoleate are the ideal candidates for biodiesel production. Several wild plants are known that can synthesize high levels of palmitoleate in seeds. However, low yields and poor agronomic characteristics of these plants limit their commercialization. Metabolic engineering has been developed to create oilseed crops that accumulate high levels of palmitoleate or other unusual fatty acids, and significant advances have been made recently in this field, particularly using the model plant Arabidopsis as the host. The engineered targets for enhancing palmitoleate synthesis include overexpression of Δ9 desaturase from mammals, yeast, fungi, and plants, down-regulating KASII, coexpression of an ACP-Δ9 desaturase in plastids and CoA-Δ9 desaturase in endoplasmic reticulum (ER), and optimizing the metabolic flux into triacylglycerols (TAGs). This review will mainly describe the recent progress towards producing palmitoleate in transgenic plants by metabolic engineering along with our current understanding of palmitoleate biosynthesis and its regulation, as well as highlighting the bottlenecks that require additional investigation by combining lipidomics, transgenics and other "-omics" tools. A brief review of reported health benefits and non-food uses of palmitoleate will also be covered.
ETHNOPHARMACOLOGICAL CONTEXT: This review explores the medicinal and therapeutic applications of Sea buckthorn (Hippophae rhamnoides L.) in curtailing different types of acute as well as chronic maladies. The plant is being used in different parts of the world for its nutritional and medicinal properties.
Sea buckthorn based preparations have been extensively exploited in folklore treatment of slow digestion, stomach malfunctioning, cardiovascular problems, liver injury, tendon and ligament injuries, skin diseases and ulcers. In the recent years, medicinal and pharmacological activities of Sea buckthorn have been well investigated using various in vitro and in vivo models as well as limited clinical trials.
Sea buckthorn has been scientifically analyzed and many of its traditional uses have been established using several biochemical and pharmacological studies. Various pharmacological activities such as cytoprotective, anti-stress, immunomodulatory, hepatoprotective, radioprotective, anti-atherogenic, anti-tumor, anti-microbial and tissue regeneration have been reported.
It is clear that Sea buckthorn is an important plant because of its immense medicinal and therapeutic potential. However, several knowledge gaps identified in this paper would give impetus to new academic and R&D activities especially for the development of Sea buckthorn based herbal medicine and nutraceuticals.
The global epidemic of type 2 diabetes demands the rapid evaluation of new and accessible interventions. This study investigated whether Aegle marmelos fruit aqueous extract (AMF; 250, 500 and 1000 mg/kg) improves insulin resistance, dyslipidemia and β-cell dysfunction in high fat diet fed-streptozotocin (HFD-STZ)-induced diabetic rats by modulating peroxisome proliferator-activated receptor-γ (PPARγ) expression. The serum levels of glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-B), lipid profile, TNF-α and IL-6 were evaluated. Further, the TBARS level and SOD activity in pancreatic tissue and PPARγ protein expression in liver were assessed. In addition, histopathological and ultrastructural studies were performed to validate the effect of AMF on β-cells. The HFD-STZ treated rats showed a significant increase in the serum levels of glucose, insulin, HOMA-IR, TNF-α, IL-6, dyslipidemia with a concomitant decrease in HOMA-B and PPARγ expression. Treatment with AMF for 21 days in diabetic rats positively modulated the altered parameters in a dose-dependent manner. Furthermore, AMF prevented inflammatory changes and β-cell damage along with a reduction in mitochondrial and endoplasmic reticulum swelling. These findings suggest that the protective effect of AMF in type 2 diabetic rats is due to the preservation of β-cell function and insulin-sensitivity through increased PPARγ expression.
Based on research findings this study is aimed to generate database on ethnobotanical aspects, sustainable utilization by value addition and awareness generation through outreach programme related to Hippophae salicifolia D. Don. (Elaeagnaceae) in the higher Himalayan zone of Uttarakhand in Central Himalaya, India.
An in-depth survey from June 2004 to July 2006 followed by 480 interviews with the help of semi-structured questionnaires was carried out in 24 Hippophae growing locations in 12 different valleys of Uttarakhand.
Plant has immense multipurpose properties and is traditionally utilized for food (20(Min)-90%(Max)), medicine (10(Min)-60%(Max)), veterinary (20(Min)-100%(Max)), fuel (10(Min)-80%(Max)), fencing (20(Min)-80%(Max)), agricultural tools (20(Min)-50%(Max)) and dye mordant (60%). Besides, awareness programmes and value added product demonstration resulted in economical upliftment of local inhabitants of Central Himalaya.
The present manuscript will certainly provide an ethnobotanical statistics' impact on the modern scientific societies regarding conservation, cultivation and popularization of this underutilized wild edible species at mass scale. Simultaneously, these findings have important connotations in light of upcoming organic food and nutraceutical industries in the country.
For experimental research on type 2 diabetes mellitus, a diet-induced obesity-dependent diabetes model developed using genetically normal animals is essential. However, attempts at feeding a high-fat diet (HFD) to major inbred strains of mice have not resulted in the establishment of an ideal model. Here, we show that BDF1 mice, the F(1) hybrids of C57BL/6 and DBA/2 normal strains, develop HFD-induced obesity-dependent diabetes. BDF1 mice fed a HFD gained weight rapidly and developed severe diabetes characterized by hyperglycemia, glucosuria, and elevation of hemoglobin A(1C) levels in 3 to 4 months. The glucose tolerance of the diabetic mice was significantly impaired, and the elevation of plasma insulin after a glucose load was significantly reduced. Isolated pancreatic islets of HFD-fed BDF1 mice showed decreased insulin content and a reduced insulin secretory response to higher concentrations of glucose. Immunohistochemical analysis of the pancreas showed reduced staining intensity to insulin and aberrant distribution of glucagon-positive cells in diabetic BDF1 mice. These observations suggest the cause of the diabetes in HFD-fed BDF1 mice to be dysfunction of the pancreatic beta-cells, which do not produce or secrete enough insulin to compensate for insulin resistance. BDF1 mice fed a HFD showing obesity-dependent diabetes are suggested to be an appropriate animal model of type 2 diabetes mellitus. This model would be useful for exploring the mechanism of obesity-dependent type 2 diabetes mellitus and evaluating antiobesity and antidiabetic drugs.
Dysregulation of lipid metabolism in individual tissues leads to systemic disruption of insulin action and glucose metabolism. Utilizing quantitative lipidomic analyses and mice deficient in adipose tissue lipid chaperones aP2 and mal1, we explored how metabolic alterations in adipose tissue are linked to whole-body metabolism through lipid signals. A robust increase in de novo lipogenesis rendered the adipose tissue of these mice resistant to the deleterious effects of dietary lipid exposure. Systemic lipid profiling also led to identification of C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses hepatosteatosis. Our data reveal a lipid-mediated endocrine network and demonstrate that adipose tissue uses lipokines such as C16:1n7-palmitoleate to communicate with distant organs and regulate systemic metabolic homeostasis.
Metformin has been used for over 40 years as an effective glucose-lowering agent in type 2 (noninsulin-dependent) diabetes mellitus. Typically it reduces basal and postprandial hyperglycaemia by about 25% in more than 90% of patients when either given alone or coadministered with other therapies including insulin during a programme of managed care.
Metformin counters insulin resistance and offers benefits against many features of the insulin resistance syndrome (Syndrome X) by preventing body weight gain, reducing hyperinsulinaemia and improving the lipid profile. In contrast to sulphonylureas, metformin does not increase insulin secretion or cause serious hypoglycaemia. Treatment of type 2 diabetes mellitus with metformin from diagnosis also offers greater protection against the chronic vascular complications of type 2 diabetes mellitus.
The most serious complication associated with metformin is lactic acidosis which has an incidence of about 0.03 cases per 1000 patients years of treatment and a mortality risk of about 0.015 per 1000 patient-years. Most cases occur in patients who are wrongly prescribed the drug, particularly patients with impaired renal function (e.g. serum creatinine level >130μmol/Lor >1.5 g/L). Other major contraindications include congestive heart failure, hypoxic states and advanced liver disease. Serious adverse events with metformin are predictable rather than spontaneous and are potentially preventable if the prescribing guidelines are respected.
Gastrointestinal adverse effects, notably diarrhoea, occur in less than 20% of patients and remit when the dosage is reduced.
The life-threatening risks associated with metformin are rare and could mostly be avoided by strict adherence to the prescribing guidelines. Given the 4 decades of clinical experience with metformin, its antihyperglycaemic efficacy and benefits against Syndrome X, metformin offers a very favourable risk-benefit assessment when compared with the chronic morbidity and premature mortality among patients with type 2 diabetes mellitus.
Type 2 diabetes is a chronic metabolic derangement that results from defects in both insulin action and secretion. New thiazolidinedione insulin sensitizers have been recently launched. New approaches with mechanisms different from current therapies are being explored, including novel ligands of peroxisome proliferator-activated receptor, glucagon receptor antagonists, dipeptidyl peptidase IV inhibitors, and insulin receptor activators.
Hyperglycemia results from an imbalance between endocrine pancreatic function and hepatic and extrahepatic insulin sensitivity. We studied 57 well-matched Swedish men with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), or mild diabetes. Oral glucose tolerance and insulin release were assessed during an oral glucose tolerance test (OGTT). Insulin sensitivity and glucose turnover were determined during a two-step euglycemic insulin clamp (infusion 0.25 and 1.0 mU. kg(-1). min(-1)). High-performance liquid chromatography-purified [6-(3)H]glucose was used as a tracer. During low-insulin infusion, the rate of endogenous glucose production (EGP) decreased more in subjects with NGT than in subjects with IGT or diabetes (delta rate of appearance [R(a)] 1.25 +/- 0.10 vs. 0.75 +/- 0.14 vs. 0.58 +/- 0.09 mg. kg(-1). min(-1), P < 0.001). The corresponding rates of glucose infusion during the high-dose insulin infusion (M values) were 8.3 +/- 0.6 vs. 5.4 +/- 0.9 vs. 4.7 +/- 0.4 mg. kg(-1). min(-1) (P < 0.001). A total of 56% of the variation in glucose area under the curve (AUC) during OGTT (glucose AUC) was mainly explained by delta R(a) (increase in multiple R(2) 0.42) but also by delta R(d) (rate of disappearance) (increase in multiple R(2) 0.05), and the early insulin response during OGTT contributed significantly (increase in multiple R(2) 0.07). When M value was included in the model, reflecting extrahepatic insulin sensitivity, it contributed to 20% of the variation in glucose AUC, and together with the incremental insulin response (increase in multiple R(2) 0.21), it explained 45% of the variation. In conclusion, insulin sensitivity of suppression of EGP plays the most important role in the determination of blood glucose response during OGTT.