Glucose Uptake In Insulin-resistant Cells Research Articles

Effects of β-carotene on glucose metabolism dysfunction in humans and type 2 diabetic rats

Background Type 2 diabetes mellitus (T2DM) is a common chronic disease that is strongly associated with cardiovascular risk. Long-term high blood glucose levels may induce cardiomyocyte apoptosis, cardiac dysfunction and suppress fetal cardiomyocyte proliferation. Recent epidemiological studies have shown a link between antioxidant carotenoids and T2DM, but a comprehensive longitudinal study of this association has not yet been conducted. Methods We included participants with biological measurements for both serum cis-β-carotene and fasting glucose from NHANES (2001–2006). We divided the participants into quartiles according to serum cis-β-carotene levels and determined the association between these levels and glucose metabolism by using multivariable regression models adjusted for confounding factors. The mechanism through which β-carotene levels regulate plasma glucose levels was further investigated in vivo and in vitro. In addition, we performed a preliminary exploration of the effects of β-carotene on diabetic rats and primary cardiomyocytes. Results Higher cis-β-carotene (quartile 4) was associated with higher LDL-cholesterol levels but lower fasting blood glucose levels. However, T2DM rats subjected to β-carotene treatment showed diminished total triglycerides and LDL-cholesterol, and their β-carotene levels were associated with better cardiac function than that in the T2DM group (P<0.05). Moreover, β-carotene was found to be an important protective factor improving cardiac and mitochondrial function in diabetes. At non-cytotoxic doses, β-carotene clearly improved glucose uptake in insulin-resistant cells. Treatment with β-carotene increased GLUT4 and p-Akt expression, and attenuated the phosphorylation of IRS-1. Our data demonstrated that β-carotene improved cardiac mitochondria biogenesis in diabetes due to activation of PGC-1β. Conclusion Our results indicate that β-carotene can be used to treat metabolic disorders through inhibition of the insulin-resistance pathway in diabetes.

Fruits of Rosa laevigata and its bio-active principal sitostenone facilitate glucose uptake and insulin sensitivity in hepatic cells via AMPK/PPAR-γ activation

BackgroundFruits of Rosa laevigata Michx is commonly used in traditional Chinese medicine for treating of spleen deficiency, chronic diarrhea, and chronic urinary tract infection. Recently, fruits of R. laevigate have been shown to have renal protective effects in diabetic rats. However, up to now, no studies have been reported on the anti-hyperglycemic or anti-diabetic effect of R. laevigata or its derived compounds. PurposeTherefore, this study investigated the anti-diabetic effect of ethanol extract of R. laevigata (EtRL) fruits, its derivate sub-fractions, and pure compounds in terms of glucose-lowering effect on hyperglycemia-induced hepatic cells in vitro. MethodsWe investigated the anti-hyperglycemic effect of EtRL and its derivate sub-fractions (water, n-butanol, ethyl acetate, and n-hexane), and its major bioactive compound, sitostenone, in normal and high glucose-induced insulin-resistant hepatic HepG2 cells using in vitro DNS glucose uptake and Western blotting assays. ResultsTreatment with EtRL and its derivate sub-fractions significantly increased glucose uptake by hepatic cells. Besides, co-treatment with insulin further improved glucose uptake in insulin-resistant cells. Notably, compared with all soluble fractions, the n-hexane sub-fraction displayed the strongest activity in the context of glucose consumption. Furthermore, sitostenone, a primary bioactive compound was isolated from n-hexane sub-fraction by bioactivity-guided fractionation procedure. Sitostenone treatment significantly increased glucose uptake, whereas there was no further increase when co-treatment with insulin. Indeed, sitostenone significantly increased glucose uptake and promote insulin sensitivity in insulin-resistant cells. Further analysis revealed that sitostenone activates proteins involved in the insulin signal transduction pathway, including insulin receptor substrate-1 (IRS-1), AKT, and glycogen synthase kinase 3 β (GSK3β). It was also found that sitostenone provoked glucose uptake in insulin-resistant cells via peroxisome proliferator-activated receptor-γ (PPAR-γ) and AMP-activated protein kinase (AMPK) activation, which facilitates up-regulation of glucose transporters, GLUT2 and GLUT4 in the cell membrane and down-regulation of Forkhead box protein O1 (FOXO1) in the nucleus. ConclusionThis study demonstrating that sitostenone, a steroid-like compound from fruits of R. laevigata has a promising ability to promote glucose uptake and repairs insulin resistance in hepatic cells.

Механізми дії метформіну за діабету та пов’язаних із діабетом патологій

Метформін (МФ) — основний пероральний препарат, який використовується в клініці для лікування пацієнтів із цукровим діабетом 2-го типу (ЦД2) понад 60 років. Предіабет — метаболічний стан, що характеризується резистентністю до інсуліну та первинною або вторинною дисфункцією β-клітин, що збільшує ризик ЦД2. Отримані дані підтверджують роль МФ у запобіганні ЦД2 в людей із предіабетом. Його ефективність для затримки або запобігання виникненню діабету доведено у великих, добре обгрунтованих і спланованих ран- домізованих дослідженнях. За діабету МФ знижує гіперглікемію, пригнічуючи глюконеогенез у печінці через активацію шляху LKB/AMPK, а також підвищує чутливість до інсуліну — ефект, що підсилює опосередковану інсуліном супресію продукції глюкози в печінці й утилізацію глюкози в скелетних м’язах. Дію МФ пов’язано з руйнуванням мітохондріального комплексу I і зменшенням продукції АТР, посиленням автофагії та іншими механізмами. Отримані дані надійно свідчать про зв’язок ЦД із порушеннями когнітивних здібностей людини. За діабету відбуваються структурні та функціональні зміни в нервовій системі та її кровоносних судинах. ЦД прискорює розвиток хвороби Альцгеймера, стимулюючи утворення сенильних бляшок і нейрофібрилярних клубочків. Хворі на діабет, які приймають МФ, меншою мірою схильні до когнітивних розладів. МФ запобігає апоптозу в первинних нейронах, ефективно посилює споживання глюкози в інсулінорезистентних клітинах. Нейропротекторні ефекти МФ, мабуть, пов’язано з його цукрознижуючими, антиоксидантними й антиапоптотичними властивостями. Відомо, що хворі на ЦД характеризуються підвищеним ризиком канцерогенезу, а в разі захворювання на рак їхня здатність до виживання є нижчою, ніж у недіабетичних пацієнтів. Антидіабетична терапія гальмує клітинний ріст, проліферацію та метаболізм і, як наслідок, впливає на потенціал онкогенезу. Гіперінсулінемія та гіперглікемія є добре встановленими чинниками ризику канцерогенезу, тому зниження їх рівня є важливим моментом у запобіганні злоякісній трансформації клітин. МФ має протипухлиннівластивості та може пригнічувати онкогенез за допомогою системних і клітинних механізмів. Цей препарат справляє пряму, спрямовану на ракові клітини, та непряму дію, впливаючи на системну інсулінемію та глікемію.

Theaflavins Improve Insulin Sensitivity through Regulating Mitochondrial Biosynthesis in Palmitic Acid-Induced HepG2 Cells.

Theaflavins, the characteristic and bioactive polyphenols in black tea, possess the potential improving effects on insulin resistance-associated metabolic abnormalities, including obesity and type 2 diabetes mellitus. However, the related molecular mechanisms are still unclear. In this research, we investigated the protective effects of theaflavins against insulin resistance in HepG2 cells induced by palmitic acid. Theaflavins significantly increased glucose uptake of insulin-resistant cells at noncytotoxic doses. This activity was mediated by upregulating the total and membrane bound glucose transporter 4 protein expressions, increasing the phosphor-Akt (Ser473) level, and decreasing the phosphorylation of IRS-1 at Ser307. Moreover, theaflavins were found to enhance the mitochondrial DNA copy number, down-regulate the PGC-1β mRNA level and increase the PRC mRNA expression. Mdivi-1, a selective mitochondrial division inhibitor, could attenuate TFs-induced promotion of glucose uptake in insulin-resistant HepG2 cells. Taken together, these results suggested that theaflavins could improve hepatocellular insulin resistance induced by free fatty acids, at least partly through promoting mitochondrial biogenesis. Theaflavins are promising functional food ingredients and medicines for improving insulin resistance-related disorders.

γ-Oryzanol Enhances Adipocyte Differentiation and Glucose Uptake.

Recent studies show that brown rice improves glucose intolerance and potentially the risk of diabetes, although the underlying molecular mechanisms remain unclear. One of the phytochemicals found in high concentration in brown rice is γ-oryzanol (Orz), a group of ferulic acid esters of phytosterols and triterpene alcohols. Here, we found that Orz stimulated differentiation of 3T3-L1 preadipocytes and increased the protein expression of adipogenic marker genes such as peroxisome proliferator-activated receptor gamma (PPAR-γ) and CCAAT/enhanced binding protein alpha (C/EBPα). Moreover, Orz significantly increased the glucose uptake in insulin-resistant cells and translocation of glucose transporter type 4 (GLUT4) from the cytosol to the cell surface. To investigate the mechanism by which Orz stimulated cell differentiation, we examined its effects on cellular signaling of the mammalian target of rapamycin complex 1 (mTORC1), a central mediator of cellular growth and proliferation. The Orz treatment increased mTORC1 kinase activity based on phosphorylation of 70-kDa ribosomal S6 kinase 1 (S6K1). The effect of Orz on adipocyte differentiation was dependent on mTORC1 activity because rapamycin blocks cell differentiation in Orz-treated cells. Collectively, our results indicate that Orz stimulates adipocyte differentiation, enhances glucose uptake, and may be associated with cellular signaling mediated by PPAR-γ and mTORC1.

Bitter melon triterpenes work as insulin sensitizers and insulin substitutes in insulin-resistant cells

The triterpenes 3β,25-dihydroxy-7β-methoxycucurbita-5,23(E)-diene (DHM) and 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (THC) were previously isolated from Momordica charantia (bitter melon) and identified as hypoglycaemic principles. This study further investigated their hypoglycaemic mechanisms. FL83B cells were treated with tumour necrosis factor-α to result in insulin resistance, a feature of type 2 diabetes. DHM and THC increased the tyrosine phosphorylation of insulin receptor substrate isoform 1 and the phosphorylation of Akt only in the presence of insulin in insulin-resistant cells, suggesting that they are insulin sensitizers. However, they enhanced the phosphorylation of AS160 (Akt substrate of 160 kDa), the migration of glucose transporter-4 and the glucose uptake of insulin-resistant cells in the absence of insulin, suggesting that they can substitute for insulin to promote glucose clearance. The insulin substitution function was blocked by an AMP-activated protein kinase (AMPK) inhibitor, whereas the insulin-sensitizing function may involve the inhibition of protein-tyrosine phosphatase-1B (PTP-1B). The IC50 of DHM and THC to PTP-1B is 92.84 µM and 25.42 µM, respectively. In summary, DHM and THC have insulin-sensitizing and insulin-substitution functions, which are likely correlated with their effects on inhibiting PTP-1B and activating AMPK, respectively.

Berberine modulates insulin signaling transduction in insulin-resistant cells

Berberine has been shown to have insulin-sensitizing effect, but the molecular mechanism underlying remains elusive. In this work, we investigated the effect of berberine on insulin-induced signal transduction and glucose uptake in both insulin-sensitive and insulin-resistant rat skeletal muscle cells. Berberine increased the activity of AMPK and PKCζ and AS160 phosphorylation in normal cells, but had little effect on PKB activation. In insulin-resistant state, berberine exhibited synergistic effect on insulin-induced glucose uptake and GLUT4 translocation. Berberine improved insulin-induced tyrosine-phosphorylation of IRS-1 and the recruitment of p85 to IRS-1. These changes were accompanied by enhancement in insulin-induced PKCζ and PKB activity and actin remodeling. The ameliorated insulin signal transduction was related to the inhibition of mTOR by berberine, which attenuated serine-phosphorylation of IRS-1. These results suggest that berberine may overcome insulin resistance via modulating key molecules in insulin signaling pathway, leading to increased glucose uptake in insulin-resistant cells.

P2-103 SYM-KEM: an intervention program for prevention of lifestyle disorders in school children

Berberine has been shown to have insulin-sensitizing effect, but the molecular mechanism underlying remains elusive. In this work, we investigated the effect of berberine on insulin-induced signal transduction and glucose uptake in both insulin-sensitive and insulin-resistant rat skeletal muscle cells. Berberine increased the activity of AMPK and PKCζ and AS160 phosphorylation in normal cells, but had little effect on PKB activation. In insulin-resistant state, berberine exhibited synergistic effect on insulin-induced glucose uptake and GLUT4 translocation. Berberine improved insulin-induced tyrosine-phosphorylation of IRS-1 and the recruitment of p85 to IRS-1. These changes were accompanied by enhancement in insulin-induced PKCζ and PKB activity and actin remodeling. The ameliorated insulin signal transduction was related to the inhibition of mTOR by berberine, which attenuated serine-phosphorylation of IRS-1. These results suggest that berberine may overcome insulin resistance via modulating key molecules in insulin signaling pathway, leading to increased glucose uptake in insulin-resistant cells.