lignans and Diabetes-Mellitus--Type-2

This systematic review aimed to appraise and recapitulate all research investigations to elucidate the effects of Sesamum indicum preparations on managing the cardiometabolic syndrome of Diabetes mellitus (DM) and metabolic syndrome (MetS).. A systematic review was carried out in a Cochrane fashion and in compliance with the PRISMA checklist using the published academic works in PubMed/MEDLINE, WOS, SCOPUS, and EMBASE databases that were searched up to June 2021. Abstracts that met PICO criteria for qualitative studies were duplicate reviewed for data extraction to assess the quality and details of the study.. Sesamum indicum preparations and its bioactive lignans, such as sesamin, sesamol, and pinoresinol, were found to possess anti-hyperglycemic, anti-hyperlipidemia, anti-inflammatory, antioxidative, anti-hypertensive, cardioprotective, and hepatoprotective effects both in patients with T2DM as well as in experimental animal models with T1DM and MetS. The incorporation of sesame oil as a natural adjuvant can be effective in improving vascular reactivity and aortic permeability, reproductive parameters, and diabetic nephropathy, as well as modification of anthropometry indices. Therefore, sesame oil and bioactive lignans as combination therapy with drugs can exhibit synergistic effects and provide a favorable preference in clinical settings.. Sesame oil and lignans present in it act in a dose-dependent manner. The best dosage to improve risk biomarkers of patients with T2DM and MetS is 30-35 ml daily of sesame oil or inclusion of sesame oil in daily dietary patterns up to 30% of total energy for 8-12 weeks and/or 200 mg daily of sesamin supplementation for eight weeks.

Topics: Animals; Diabetes Mellitus, Type 2; Humans; Lignans; Metabolic Syndrome; Seeds; Sesame Oil; Sesamum

We conducted a meta-analysis of 12 prospective cohort studies to further illuminate the associations of lignan intake with risk of cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Compared with the lowest intake, the highest intake of lignans was correlated with a decreased incidence of CVD (relative risk [RR]: 0.85, 95% confidence interval [CI]: 0.80-0.90) and T2DM (RR: 0.82, 95% CI: 0.68-0.99). The benefits of lignan intake in CVD prevention were consistent across subgroups. In dose-response analysis, the RR for every 500-μg/d increment in lignan intake was 0.83 (95% CI: 0.74-0.92) for CVD and 0.96 (95% CI: 0.95-0.98) for T2DM. Moreover, a curvilinear dose-response pattern was observed for both CVD (

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Lignans; Prospective Studies; Risk; Risk Factors

Diabetes mellitus is a chronic metabolic disease characterized by disturbances in carbohydrate, protein, and lipid metabolism, often accompanied by oxidative stress. Diabetes treatment is a complicated process in which, in addition to the standard pharmacological action, it is necessary to append a comprehensive approach. Introducing the aspect of non-pharmacological treatment of diabetes allows one to alleviate its many adverse complications. Therefore, it seems important to look for substances that, when included in the daily diet, can improve diabetic parameters. Magnolol, a polyphenolic compound found in magnolia bark, is known for its health-promoting activities and multidirectional beneficial effects on the body. Accordingly, the goal of this review is to systematize the available scientific literature on its beneficial effects on type 2 diabetes and its complications. Taking the above into consideration, the article collects data on the favorable effects of magnolol on parameters related to glycemia, lipid metabolism, or oxidative stress in the course of diabetes. After careful analysis of many scientific articles, it can be concluded that this lignan is a promising agent supporting the conventional therapies with antidiabetic drugs in order to manage diabetes and diabetes-related diseases.

Topics: Animals; Biphenyl Compounds; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eye Diseases; Homeostasis; Humans; Hypoglycemic Agents; Inflammation; Lignans; Lipid Metabolism; Magnolia; Mice; Oxidative Stress; Plant Bark; Polyphenols; Treatment Outcome

Functional foods describe the importance of foods in promoting health and preventing diseases aside their primary role of providing the body with the required amount of essential nutrients such as proteins, carbohydrates, vitamins, fats, and oils needed for its healthy survival. This review explains the interaction of functional food bioactive compounds including polyphenols (phenolic acids [hydroxybenzoic acids and hydroxycinnamic acids], flavonoids [flavonols, flavones, flavanols, flavanones, isoflavones, proanthocyanidins], stilbenes, and lignans), terpenoids, carotenoids, alkaloids, omega-3 and polyunsaturated fatty acids, among others with critical enzymes (α- amylase, α- glucosidase, angiotensin-I converting enzyme [ACE], acetylcholinesterase [AChE], and arginase) linked to some degenerative diseases (type-2 diabetes, cardiovascular diseases [hypertension], neurodegenerative diseases [Alzheimer's disease] and erectile dysfunction). Different functional food bioactive compounds may synergistically/additively confer an overwhelming protection against these degenerative diseases by modulating/altering the activities of these critical enzymes of physiological importance.

Topics: Alkaloids; Cardiovascular Diseases; Carotenoids; Chronic Disease; Diabetes Mellitus, Type 2; Dietary Supplements; Erectile Dysfunction; Flavonoids; Functional Food; Health Promotion; Humans; Lignans; Male; Neurodegenerative Diseases; Nutritional Requirements; Phenols; Polyphenols; Stilbenes

Flaxseed contains 32% to 45% of its mass as oil of which 51% to 55% is α-linolenic acid. Flax lignan complex and secoisolariciresinol diglucoside (SDG) have been isolated from flaxseed. Flaxseed and its components have antioxidant, hypolipidemic and hypoglycemic effects. These are mostly due to the SDG content. Oxidative stress has been implicated in both type 1 and type 2 diabetes. Flaxseed, flaxseed oil and flax lignan complex have not been investigated as to whether they reduce the incidence of diabetes and/or delay the development of diabetes. However, their effects on serum glucose have been studied. Flaxseed and flax lignan complex improve glycemic control. Animal models of type I diabetes involving streptozotocin administration or utilizing Bio-Breed diabetic (BBdp) prone rats are associated with oxidative stress. SDG treatment reduced the incidence of diabetes using serum glucose levels by 75% in the streptozotocin model of diabetes and by 72% in the BBdp rat model of diabetes. These reductions in development of diabetes were associated with decreases in oxidative stress measured by serum and pancreatic malondialdehyde (MDA). SDG delays the development of diabetes in Zucker diabetic fatty (ZDF) rat model of type 2 diabetes and this effect was associated with a reduction in serum MDA and glycated haemoglobin A1C. The data suggest that SDG may have a great potential for reducing the incidence of type 1 diabetes and delaying the development of type 2 diabetes in humans.

Topics: Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Flax; Lignans; Phytotherapy; Plant Oils; Rats; Seeds

The clinical impact of the fibrate and thiazolidinedione drugs on dyslipidemia and diabetes is driven mainly through activation of two transcription factors, peroxisome proliferator-activated receptors (PPAR)-α and PPAR-γ. However, substantial differences exist in the therapeutic and side-effect profiles of specific drugs. This has been attributed primarily to the complexity of drug-target complexes that involve many coregulatory proteins in the context of specific target gene promoters. Recent data have revealed that some PPAR ligands interact with other non-PPAR targets. Here we review concepts used to develop new agents that preferentially modulate transcriptional complex assembly, target more than one PPAR receptor simultaneously, or act as partial agonists. We highlight newly described on-target mechanisms of PPAR regulation including phosphorylation and nongenomic regulation. We briefly describe the recently discovered non-PPAR protein targets of thiazolidinediones, mitoNEET, and mTOT. Finally, we summarize the contributions of on- and off-target actions to select therapeutic and side effects of PPAR ligands including insulin sensitivity, cardiovascular actions, inflammation, and carcinogenicity.

Topics: Animals; Diabetes Mellitus, Type 2; Dyslipidemias; Humans; Hypoglycemic Agents; Lignans; Peroxisome Proliferator-Activated Receptors; Thiazolidinediones

Coffee consumption has been associated with improved glucose tolerance and a lower risk of type 2 diabetes in diverse populations in the U.S., Europe, and Japan. This review discusses the strength of the evidence, relevant mechanisms, possible implications, and directions for further research. The finding that higher consumption of decaffeinated coffee was associated with a lower risk of type 2 diabetes suggests that coffee constituents other than caffeine play a role. Coffee is a source of several compounds that improved glucose metabolism in animal studies, including the chlorogenic acids and lignans. Further research on phytochemicals in coffee may lead to the identification of novel mechanisms for effects of diet on the development of type 2 diabetes. In addition, knowledge on effects of coffee components may aid in the development or selection of types of coffee with improved health effects. Longer-term randomized intervention studies that test the effects of coffee consumption on glucose tolerance are warranted. Physical activity and weight management should be the mainstay of public health strategies to prevent type 2 diabetes. For individual choices regarding coffee consumption, potential effects of coffee on various health outcomes should be considered.

Topics: Adult; Aged; Aged, 80 and over; Caffeine; Chlorogenic Acid; Coffee; Diabetes Mellitus, Type 2; Female; Glucose Intolerance; Humans; Lignans; Male; Middle Aged; Risk Factors

Rye bran contains a high content not only of dietary fibre, but also of plant lignans and other bioactive compounds in the so-called dietary fibre complex. Blood concentrations of lignans such as enterolactone have been used as biomarkers of intake of lignan-rich plant food. At present,evidence from studies in human subjects does not warrant the conclusion that rye, whole grains orphyto-oestrogens protect against cancer. Some studies, however, have pointed in that direction,especially in relation to cancers of the upper digestive tract. A number of prospective epidemiological studies have clearly shown a protective effect of wholegrain cereals against myocardial infarctions. A corresponding protective effect against diabetes and ischaemic stroke(brain infarct) has also been demonstrated. It seems reasonable to assume that these protective effects are associated with one or more factors in the dietary fibre complex.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Dietary Fiber; Food, Organic; Humans; Lignans; Neoplasms; Secale

Elevated C-reactive protein (CRP), IL-6 and retinol-binding protein 4 (RBP4) levels are associated with insulin resistance and diabetes mellitus. Phytoestrogens (including lignans and isoflavones) may enhance the management of diabetes and are hypothesized to act through inflammation pathways. The present study explored the effects of flaxseed-derived lignan on inflammatory factors and RBP4 concentrations in type 2 diabetics, who have higher levels of these biomarkers. Seventy community-dwelling diabetic patients (twenty-six men and forty-four post-menopausal women) with mild hypercholesterolaemia completed a randomized, double-blind, placebo-controlled, cross-over trial of supplementation with flaxseed-derived lignan capsules (360 mg/d) or placebo for 12 weeks, separated by an 8-week wash-out period. The participants maintained their habitual diets and levels of physical activity. Baseline to follow-up concentrations of CRP increased significantly within the placebo group (1.42 (sem 0.19) v. 1.96 (sem 0.22) mg/l, P < 0.001), but were comparatively unchanged in the lignan-supplemented group (1.67 (sem 0.19) v. 1.90 (sem 0.26) mg/l, P = 0.94); a significant difference was observed between treatments ( - 0.45 (95 % CI - 0.76, - 0.08) mg/l, P = 0.021). This effect was confined to women (P = 0.016), but not observed in men (P = 0.49). No between-treatment differences were found with regard to IL-6 or RBP4; though IL-6 concentrations increased significantly from baseline to follow-up in both groups (P = 0.004 and P < 0.001 following lignan and placebo treatments, respectively). The study suggests that lignan might modulate CRP levels in type 2 diabetics. These results need to be confirmed by further large clinical trials of longer duration.

Topics: Aged; Biomarkers; C-Reactive Protein; Cross-Over Studies; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Flax; Humans; Inflammation Mediators; Interleukin-6; Lignans; Male; Middle Aged; Retinol-Binding Proteins, Plasma; Seeds; Treatment Outcome

Flaxseed consumption has been shown to improve blood lipids in humans and flaxseed-derived lignan has been shown to enhance glycemic control in animals. The study aimed to investigate the effect of a flaxseed-derived lignan supplement on glycemic control, lipid profiles and insulin sensitivity in type 2 diabetic patients.. This was a randomized, double-blind, placebo-controlled, cross-over trial and it was conducted between April and December 2006 in Shanghai, China. Seventy-three type 2 diabetic patients with mild hypercholesterolemia were enrolled into the study. Patients were randomized to supplementation with flaxseed-derived lignan capsules (360 mg lignan per day) or placebo for 12 weeks, separated by an 8-week wash-out period. HbA1c, lipid profiles, insulin resistance index and inflammatory factors were measured. Sixty-eight completed the study and were included in the analyses. The lignan supplement significantly improved glycemic control as measured by HbA(1c) (-0.10+/-0.65 % vs. 0.09+/-0.52 %, P = 0.001) compared to placebo; however, no significant changes were observed in fasting glucose and insulin concentrations, insulin resistance and blood lipid profiles. Urinary excretion of lignan metabolites (enterodiol and enterolactone) was significantly higher after the lignan supplement intervention compared to baseline (14.2+/-18.1 vs. 1.2+/-2.4 microg/mL, P<0.001). Data also suggested minimal competition between lignan and isoflavones for bioavailability when measured by the excretion concentrations.. Daily lignan supplementation resulted in modest, yet statistically significant improvements in glycemic control in type 2 diabetic patients without apparently affecting fasting glucose, lipid profiles and insulin sensitivity. Further studies are needed to validate these findings and explore the efficacy of lignans on type 2 diabetes.. ClinicalTrials.gov NCT00363233.

Topics: Aged; Cross-Over Studies; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Flax; Humans; Lignans; Male; Middle Aged; Placebos; Treatment Outcome

Diabetes is a chronic metabolic disease characterized by improperly regulating proteins, carbohydrates, and lipids due to insulin deficiency or resistance. The increasing prevalence of diabetes poses a tremendous socioeconomic burden worldwide, resulting in the rise of many studies on Chinese herbal medicines to discover the most effective cure for diabetes. Sesame seeds are among these Chinese herbal medicines that were found to contain various pharmacological activities, including antioxidant and anti-inflammatory properties, lowering cholesterol, improving liver function, blood pressure and sugar lowering, regulating lipid synthesis, and anticancer activities. These medicinal benefits are attributed to sesamin, which is the main lignan found in sesame seeds and oil. In this study, Wistar rat models were induced with type 2 diabetes using streptozotocin (STZ) and nicotinamide, and the effect of sesamin on the changes in body weight, blood sugar level, glycosylated hemoglobin (HbA1c), insulin levels, and the states of the pancreas and liver of the rats were evaluated. The results indicate a reduced blood glucose level, HbA1c, TG, and ALT and AST enzymes after sesamin treatment, while increased insulin level, SOD, CAT, and GPx activities were also observed. These findings prove sesamin's efficacy in ameliorating the symptoms of diabetes through its potent pharmacological activities.

Topics: Animals; Diabetes Mellitus, Type 2; Dioxoles; Glycated Hemoglobin; Insulin; Lignans; Plant Extracts; Rats; Rats, Wistar

Type 2 diabetes mellitus (T2DM) is a metabolic risk factor associated with non-alcoholic liver disease (NAFLD). Schisandrin B (Sch B) is a promising agent for NAFLD. However, the actions of Sch B on diabetes-associated NAFLD and the underlying mechanisms are not characterized. This study aimed to assess whether Sch B has beneficial effects on T2DM-associated NAFLD. Sch B (50 mg/kg, gavage) was administrated to C57BL/KSJ db/db mice for 2 weeks. Body weight, liver weight, blood glucose, and insulin resistance were measured. Serum lipid level and liver function were detected using the biochemistry analyzer. Quantitative Real-Time PCR assay was used to evaluate mRNA levers of lipid metabolism genes. Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining was performed to measure apoptosis in the liver. Pathological analysis and immunohistochemistry assessment were used to analyze hepatic steatosis and inflammatory infiltration. Sch B supplementation significantly decrease body weight, related liver weight, blood glucose, and serum insulin, and improved insulin resistance in db/db mice. Sch B obviously corrected NAFLD phenotypes including lipid deposition, steatohepatitis, and high levels of hepatic enzymes and serum lipid. In addition, mRNA levels of Sterol response element-bind protein 1c (SREBP-1c), fatty acid synthetase (Fasn), and acetyl-CoA carboxylase (ACC) were markedly downregulated by Sch B treatment. TUNEL-positive cells were also decreased by Sch B. Furthermore, Sch B inhibited the Kupffer cells, IL-1β, and TNF-α infiltration to the liver. Sch B ameliorated insulin resistance and lipid accumulation under high glucose conditions, which was partly associated with its inhibition of apoptosis and anti-inflammatory actions.

Topics: Animals; Anti-Inflammatory Agents; Blood Glucose; Body Weight; Cyclooctanes; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Insulin Resistance; Lignans; Lipid Metabolism; Lipids; Liver; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Polycyclic Compounds; RNA, Messenger; Sterol Regulatory Element Binding Protein 1

We aimed to examine the effect of Honokiol (HKL) on endothelial dysfunction in type 2 diabetic rats and its possible mechanism. A high-fat diet and streptozotocin (STZ) were used to establish the type 2 diabetic model in rats. Part of these rats were intraperitoneally injected with HKL 10 mg/kg daily. Then the expression of Ser1177 phosphorylation of endothelial nitric oxide synthase (p-eNOS), eNOS, and CD31, vasodilation function, insulin signaling, indicators of oxidative stress and relative signaling pathway were measured. Human umbilical vein endothelial cells (HUVECs) were used to explore the underlying mechanism of the effect of HKL on high glucose-related endothelial injury in vitro. The data showed that HKL could reverse the decline of the expression of p-eNOS and CD31, endothelium-related vasodilation dysfunction, insulin resistance and activation of oxidative stress induced by type 2 diabetes in vivo. The similar results were obtained in vitro. In summary, our study demonstrates that HKL improves endothelial function and diminishes insulin resistance and oxidative stress, suggesting that HKL could be used as a treatment option for diabetes in the future.

Topics: Animals; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Endothelium, Vascular; Human Umbilical Vein Endothelial Cells; Humans; Insulin Resistance; Lignans; Nitric Oxide; Nitric Oxide Synthase Type III; Oxidative Stress; Rats; Vascular Diseases; Vasodilation

Nutmeg is the seed of

Topics: Animals; Diabetes Mellitus, Type 2; Glucose; Lignans; Mice; Mice, Inbred ICR; Muscle Fibers, Skeletal; Myristica

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes lacking efficient treatment. Magnolol (MG), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, is a natural product derived from Magnolia officinalis and widely used to treat a variety of diseases as a traditional Chinese medicine and Japanese Kampo medicine.. Here, we aimed to investigate the potential of MG in ameliorating DPN-like pathology in mice and decipher the mechanism of MG in treating DPN.. MG promoted DRG neuronal neurite outgrowth and effectively ameliorated neurological dysfunctions in both T1DM and T2DM diabetic mice, including improvement of paw withdrawal threshold, thermal response latency and MNCV. Additionally, MG promoted neurite outgrowth of DRG neurons, protected sciatic nerve myelin sheath structure, and ameliorated foot skin intraepidermal nerve fiber (IENF) density in DPN mice by targeting PPARγ. Mechanism research results indicated that MG improved mitochondrial dysfunction involving PPARγ/MKP-7/JNK/SIRT1/LKB1/AMPK/PGC-1α pathway in DRG neurons, repressed inflammation via PPARγ/NF-κB signaling and inhibited apoptosis through regulation of PPARγ-mediated Bcl-2 family proteins in DRG neurons and sciatic nerves.. Our work has detailed the mechanism underlying the amelioration of PPARγ agonist on DPN-like pathology in mice with MG as a probe, and highlighted the potential of MG in the treatment of DPN.

Topics: AMP-Activated Protein Kinases; Animals; Biological Products; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Hypoglycemic Agents; Lignans; Male; Mice; NF-kappa B; PPAR gamma; Proto-Oncogene Proteins c-bcl-2; Sciatic Nerve; Sirtuin 1

Type 2 diabetes mellitus is strongly associated with cardiac mitochondrial dysfunction, which is one of the main reasons for cardiovascular diseases. Among the mitochondrial metabolic changes, fatty acid metabolism is of great importance as cardiac tissues depend primarily on fatty acids. Honokiol, a constituent of Magnolia tree bark extract, is reported to strongly influence cardiac mitochondrial functions, via various mechanisms. The current study showed that honokiol decreased fatty acid-mediated complex I respiration and increased carbohydrate-mediated complex I and II respiration in diabetic C57BL/6 mice cardiac mitochondria. It was also found that honokiol treatment decreased expression of Cluster of Differentiation 36, AMP-activated kinases and nuclear transcription factors like, Peroxisome proliferator-activated receptor γ co-activator 1α/β and Peroxisome proliferator-activated receptor α, surrogating the evidence of decreased fatty acid-mediated complex I respiration. Honokiol treatment also reduced the levels of mitochondrial acetylated proteins, suggesting the possible action of honokiol via acetylation/deacetylation mechanism of regulation of protein functions in diabetic mitochondria. The antioxidant effect of honokiol is evidenced by the augmented expression of Manganese super oxide dismutase. In conclusion, honokiol imparts beneficial effect on diabetic cardiac mitochondria by decreasing the oxidant burden via regulating mitochondrial fatty acid respiration and expression of oxidant response factors.

Topics: Acetylation; AMP-Activated Protein Kinases; Animals; Antioxidants; Biphenyl Compounds; CD36 Antigens; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Energy Metabolism; Fatty Acids; Lignans; Male; Mice, Inbred C57BL; Mitochondria, Heart; Myocytes, Cardiac; NF-E2-Related Factor 2; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR alpha; Streptozocin; Superoxide Dismutase

Type 2 diabetes, a global health concern has been considered as major risk factor for cardiovascular diseases. Hinokinin, an emerging bioactive lignin, is reported to show wide range of pharmacological activities. However, the protective role and mechanisms of Hinokinin against type 2 diabetes-mediated cardiotoxicity are still remains unknown. An experimental type 2 diabetic mice model was created by treating animals with high fat diet for four weeks and intraperitoneal injection of streptozotocin (35 mg/kg body weight). Post-type 2 diabetic induction, animals orally treated with Hinokinin (20 or 40 mg/kg body weight) for six weeks. The type 2 diabetic mice exhibited a rise in blood glucose level as well as glycated hemoglobin (HbA1c %), decrease in weekly body weights, decrease in food intake, reduction in absolute heart weight, fall in serum insulin level with altered lipid profile and cardiac functional damage. Diabetic mice treated with Hinokinin attenuated hyperglycemia, dyslipidemia and cardiac dysfunction. In addition, Hinokinin ameliorated histological alterations, fibrosis and glycated proteins in HFD/STZ-induced mice. Type 2 diabetic condition in mice exacerbated oxidative stress, inflammatory status and apoptosis. Hinokinin treatment significantly assuaged oxidative stress, inflammation and apoptosis and elevated antioxidant defenses in diabetic heart. The underlying mechanisms for such mitigation involved the modulation of Nrf2/Keap1/ARE pathway, MAPKs (JNK, p38 and ERK 1/2) and TLR4/MyD88/NF-κB mediated inflammatory pathways and mitochondrial-dependent (intrinsic) apoptosis pathway. In conclusion, the results of this study provided clear evidence that Hinokinin protects against HFD/STZ (type 2 diabetes)-induced cardiac injury by alleviating oxidative stress, inflammation and apoptosis.

Topics: 4-Butyrolactone; Animals; Anti-Inflammatory Agents; Antioxidants; Apoptosis; Benzodioxoles; Blood Glucose; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diet, High-Fat; Dyslipidemias; Hyperglycemia; Lignans; Mice; Oxidative Stress; Signal Transduction; Streptozocin

The current study aimed to evaluate the in vivo hypoglycemic potential of Myristica fragrans seed extract co-administered with glimepiride in Swiss albino mice. Computational tools were used to further verify the in vivo findings and to help compare this combination to the glimepiride-pioglitazone combination in terms of the binding affinity of the ligands to their respective target protein receptors and the relative stability of the drug-protein complexes. The effect of the combined therapy was observed both in alloxan- and glucose-induced hyperglycemic Swiss albino mice. The mean fasting blood glucose level of the test groups was measured and statistically evaluated using Student's t test. The combined therapy significantly reduced the blood glucose level in a time-dependent manner compared to glimepiride alone. The binding affinity of glimepiride was found to be -7.6 kcal/mol with sulfonylurea receptor 1 in molecular docking. Conversely, macelignan-peroxisome proliferator-activated receptor (PPAR) α and macelignan-PPAR γ complexes were stabilized with -9.2 and -8.3 kcal/mol, respectively. Molecular dynamic simulation revealed that macelignan-PPAR α and γ complexes were more stable than pioglitazone complexes. The combination shows promise in animal and computer models and requires further trials to provide evidence of its activity in humans.

Topics: Alloxan; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Drug Therapy, Combination; Female; Glucose; Humans; Hypoglycemic Agents; Lignans; Male; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; Myristica; Pioglitazone; Plant Extracts; PPAR alpha; PPAR gamma; Sulfonylurea Compounds; Time Factors

More effective treatments for diabetic nephropathy remain a major unmet clinical need. Increased oxidative stress is one of the most important pathological mechanisms that lead to kidney damage and functional impairment induced by diabetes. Sirtuin 3 (SIRT3) is the main mitochondrial deacetylase and critically regulates cellular reactive oxygen species (ROS) production and detoxification. Honokiol is a natural biphenolic compound that, by activating mitochondrial SIRT3, can carry out anti-oxidant, anti-inflammatory and anti-fibrotic activities. Here, we sought to investigate the renoprotective effects of honokiol in BTBR ob/ob mice with type 2 diabetes. Diabetic mice were treated with vehicle or honokiol between the ages of 8 and 14 weeks. Wild-type mice served as controls. Renal Sirt3 expression was significantly reduced in BTBR ob/ob mice, and this was associated with a reduction in its activity and increased ROS levels. Selective activation of SIRT3 through honokiol administration translated into the attenuation of albuminuria, amelioration of glomerular damage, and a reduction in podocyte injury. SIRT3 activation preserved mitochondrial wellness through the activation of SOD2 and the restoration of PGC-1α expression in glomerular cells. Additionally, the protective role of SIRT3 in glomerular changes was associated with enhanced tubular Sirt3 expression and upregulated renal Nampt levels, indicating a possible tubule-glomerulus retrograde interplay, which resulted in improved glomerular SIRT3 activity. Our results demonstrate the hitherto unknown renoprotective effect of SIRT3 against diabetic glomerular disease and suggest that the pharmacological modulation of SIRT3 activity is a possible novel approach to treating diabetic nephropathy.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents; Antioxidants; Biphenyl Compounds; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Kidney Glomerulus; Lignans; Male; Mice; Mice, Obese; Mitochondria; Nicotinamide Phosphoribosyltransferase; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Podocytes; Reactive Oxygen Species; Sirtuin 3; Superoxide Dismutase

Cardiac energetic dysfunction has been reported in patients with type 2 diabetes (T2D) and is an independent predictor of mortality. Identification of the mechanisms driving mitochondrial dysfunction, and therapeutic strategies to rescue these modifications, will improve myocardial energetics in T2D. We demonstrate using 31P-magnetic resonance spectroscopy (31P-MRS) that decreased cardiac ATP and phosphocreatine (PCr) concentrations occurred before contractile dysfunction or a reduction in PCr/ATP ratio in T2D. Real-time mitochondrial ATP synthesis rates and state 3 respiration rates were similarly depressed in T2D, implicating dysfunctional mitochondrial energy production. Driving this energetic dysfunction in T2D was an increase in mitochondrial protein acetylation, and increased ex vivo acetylation was shown to proportionally decrease mitochondrial respiration rates. Treating T2D rats in vivo with the mitochondrial deacetylase SIRT3 activator honokiol reversed the hyperacetylation of mitochondrial proteins and restored mitochondrial respiration rates to control levels. Using 13C-hyperpolarized MRS, respiration with different substrates, and enzyme assays, we localized this improvement to increased glutamate dehydrogenase activity. Finally, honokiol treatment increased ATP and PCr concentrations and increased total ATP synthesis flux in the T2D heart. In conclusion, hyperacetylation drives energetic dysfunction in T2D, and reversing acetylation with the SIRT3 activator honokiol rescued myocardial and mitochondrial energetics in T2D.

Topics: Acetylation; Adenosine Triphosphate; Animals; Anti-Arrhythmia Agents; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Metabolism; Heart Diseases; Lignans; Male; Mitochondria, Heart; Myocardium; Phosphocreatine; Rats; Rats, Wistar

In medicinal chemistry, the discovery of small organic molecules that can be optimized and lead to a future drug capable of effectively modulating the biological activity of a therapeutic target remains a major challenge. Because of the harmful secondary effects of synthesized therapeutic molecules, the development of research has been oriented towards phytomedicines. Phenolic compounds from medicinal plants are constantly explored for new therapeutic use.. In this paper, we studied interactions between main enzymes responsible for causing type 2 diabetes mellitus (T2DM) and phenolic compounds from nettle (Urtica dioica L.) using molecular Docking with Molecular Operating Environment Software (MOE).. Docking results show a common molecule (secoisolariciresinol), which may form stable complexes with depeptidyl peptidase 4 (DPP-4), alpha-amylase and beta-glucosidase with binding energy of -7.04732084 kcal/mol, -3.82946181 kcal/mol and -4.16077089 kcal/mol respectively. Besides secoisolariciresinol, other phenolic compounds give better docking score than the original co-crystallized ligand for alpha-amylase (PDB ID 5U3A) and beta-glucosidase (PDB ID 1OGS).. The obtained results are promising for the discovery of new alpha-amylase and betaglucosidase inhibitors. This study also confirms the folk use of nettle as antidiabetic agent.

Topics: alpha-Amylases; beta-Glucosidase; Blood Glucose; Butylene Glycols; Crystallography, X-Ray; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Drug Discovery; Humans; Hypoglycemic Agents; Insulin; Lignans; Molecular Docking Simulation; Plant Extracts; Urtica dioica

Type 2 Diabetes (T2D) cases continue to rise dramatically despite efforts to get people to exercise and eat with a view to health and combatting the cluster of 7 issues (central obesity (elevated waist circumference), hyperglycaemia, hypertension, dyslipidemia, pro-thrombotic state, increased oxidation (including Low-density Lipoprotein (LDL)) and the pro-inflammatory state associated with pre- and post-onset T2D.. There are numerous medications available to deal with these seven major issues. However, each medication currently available manages a maximum of two cluster members at a time. Consequently, polypharmacy is frequently required to manage the cluster of seven. Polypharmacy brings with it high financial costs for numerous medications, the risk of poor compliance (particularly so in older patients), side effects and drug interactions. Thus, there is a search for new agents that reduce the high costs and risks of polypharmacy while at the same time combatting three or more of the cluster of seven. There is very limited evidence to suggest that one or more lignans may efficaciously and safely, in the short and long term, manage at least three of the cluster of seven, pre- and post-T2D onset, thus reducing polypharmacy. However, multi-centre, large clinical trials are required before any definitive conclusions about these lignans can be reached regarding their safe and efficacious polypharmacy reduction potential, both long and short-term, in pre and post-onset T2D management.. It is concluded that some lignans appear to have the potential to manage at least three members of the cluster of seven in pre- or post-T2D onset and hence reduce polypharmacy but much more investigation is required to confirm if such is the case. At the moment, there is not enough evidence that any of the lignans will, in the long or short term, safely and efficaciously manage the cluster of seven via polypharmacy reduction.

Topics: Aged; Diabetes Mellitus, Type 2; Humans; Lignans; Obesity; Polypharmacy

Diabetic nephropathy (DN) is one of the most serious long-term complications of type 2 diabetes (T2D). 4-O-methylhonokiol (MH) is one of the biologically active ingredients extracted from the Magnolia stem bark. In this study, we aim to elucidate whether treatment with MH can ameliorate or slow-down progression of DN in a T2D murine model and, if so, whether the protective response of MH correlates with AMPK-associated anti-oxidant and anti-inflammatory effects. To induce T2D, mice were fed normal diet (ND) or high fat diet (HFD) for 3 months to induce insulin resistance, followed by an intraperitoneal injection of STZ to induce hyperglycemia. Both T2D and control mice received gavage containing vehicle or MH once diabetes onset for 3 months. Once completing 3-month MH treatment, five mice from each group were sacrificed as 3 month time-point. The rest mice in each group were sacrificed 3 months later as 6 month time-point. In T2D mice, the typical DN symptoms were induced as expected, reflected by increased proteinuria, renal lipid accumulation and lipotoxic effects inducing oxidative stress, and inflammatory reactions, and final fibrosis. However, these typical DN changes were significantly prevented by MH treatment for 3 months and even at 3 months post-MH withdrawal. Mechanistically, MH renal-protection from DN may be related to lipid metabolic improvement and oxidative stress attenuation along with increases in AMPK/PGC-1α/CPT1B-mediated fatty acid oxidation and Nrf2/SOD2-mediated anti-oxidative stress. Results showed the preventive effect of MH on the renal oxidative stress and inflammation in DN.

Topics: AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Antioxidants; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diet, High-Fat; Enzyme Activation; Fatty Acids; Insulin Resistance; Kidney; Lignans; Male; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Oxidation-Reduction; Oxidative Stress; Phytotherapy

The phytoestrogen enterolactone is a gut microbiota-derived metabolite of plant lignans with suggested beneficial properties for health. In the current study, we investigated the association between pre-diagnostic plasma enterolactone concentrations and mortality among individuals diagnosed with type 2 diabetes.. In a population of people diagnosed with diabetes, nested within the Danish Diet, Cancer and Health cohort, we conducted a case-cohort study including a random sample of n = 450 cases (deceased) and a randomly selected subcohort of n = 850 (in total n = 617 deaths). Information on diagnosis, vital status and cause of death was obtained from Danish registers. Cox proportional hazard models with special weighting were applied to assess all-cause and cause-specific mortality.. The median enterolactone concentration of the current population was low, 10.9 nmol/l (5th percentile to 95th percentile: 1.3-59.6), compared with previously reported concentrations from the Diet, Cancer and Health cohort. Pre-diagnostic enterolactone concentrations were associated with lower all-cause mortality when assessed linearly per doubling in concentration (log. Based on this large cohort of people with diabetes with detailed and complete baseline and follow-up information, pre-diagnostic enterolactone concentrations were inversely associated with mortality. To our knowledge, this is the first study on enterolactone and type 2 diabetes mortality. Our findings call for further exploration of enterolactone in type 2 diabetes management.

Topics: 4-Butyrolactone; Aged; Case-Control Studies; Cohort Studies; Diabetes Mellitus, Type 2; Female; Humans; Lignans; Male; Middle Aged; Neoplasms; Prognosis; Random Allocation

Diabetic cardiomyopathy (DCM) is characterized by increased left ventricular mass and wall thickness, decreased systolic function, reduced ejection fraction (EF) and ultimately heart failure. The 4-O-methylhonokiol (MH) has been isolated mainly from the bark of the root and stem of Magnolia species. In this study, we aimed to elucidate whether MH can effectively prevent DCM in type 2 diabetic (T2D) mice and, if so, whether the protective response of MH is associated with its activation of AMPK-mediated inhibition of lipid accumulation and inflammation. A total number of 40 mice were divided into four groups: Ctrl, Ctrl + MH, T2D, T2D + MH. Five mice from each group were sacrificed after 3-month MH treatment. The remaining animals in each group were kept for additional 3 months without further MH treatment. In T2D mice, the typical DCM symptoms were induced as expected, reflected by decreased ejection fraction and lipotoxic effects inducing lipid accumulation, oxidative stress, inflammatory reactions, and final fibrosis. However, these typical DCM changes were significantly prevented by the MH treatment immediately or 3 months after the 3-month MH treatment, suggesting MH-induced cardiac protection from T2D had a memory effect. Mechanistically, MH cardiac protection from DCM may be associated with its lipid metabolism improvement by the activation of AMPK/CPT1-mediated fatty acid oxidation. In addition, the MH treatment of DCM mice significantly improved their insulin resistance levels by activation of GSK-3β. These results indicate that the treatment of T2D with MH effectively prevents DCM probably via AMPK-dependent improvement of the lipid metabolism.

Topics: AMP-Activated Protein Kinases; Animals; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Fibrosis; Inflammation; Lignans; Lipid Metabolism; Male; Mice, Inbred C57BL; Models, Biological; Oxidative Stress

Obstructive sleep apnea hypopnea syndrome (OSAHS) is associated with glucose intolerance, insulin resistance and type 2 diabetes mellitus (T2DM). Although several studies have revealed that intermittent hypoxia (IH) in OSAHS may further aggravate pancreatic β cell damage and promote the evolution of type 2 diabetes (T2DM) by increasing oxidative stress, the underlying mechanisms are unclear. Honokiol, a potent radical scavenger, has been demonstrated to ameliorate oxidative stress in many cases. The present study aimed to explore the potential mechanism of IH and diabetes synergistically damage and destruct the pancreatic β cell, examine the effects of honokiol on ameliorating pancreatic β cell injury in this context and explore the mechanism of such effects. High glucose (HG) cultured INS-1 cells were exposed to 50 μM of honokiol for 24, 48 and 72 h with or without IH intervention. T2DM rats were treated with honokiol and exposed to 80 s of IH followed by 160 s of normoxia for 8 weeks. The cell proliferation, apoptosis and oxidative stress were measured. Blood glucose, insulin, glucagon and HOMA-IR (Homeostasis model assessment -insulin resistence) were also detected, and the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were detected by immunofluorescence staining and western blotting. Honokiol can reduce oxidative stress, cytotoxicity and apoptosis in the INS-1 cells of rats receiving HG treatment or both HG and IH treatment. IH can further aggravate pancreas dysfunction, cause a marked elevation in fasting blood glucose, glucagon, HOMA-IR and oxidative stress levels in DM rats. In addition, honokiol can effectively activate the Nrf2/ARE pathway and reverse this pancreatic dysfunction in vivo and in vitro. These findings indicate that honokiol acts as a potent ROS scavenger via Nrf2/ARE pathway and effectively attenuates oxidative stress and improves pancreatic β cell function of DM rats under IH treatment.

Topics: Animals; Apoptosis; Biphenyl Compounds; Blood Glucose; Cell Proliferation; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Free Radical Scavengers; Glucagon; Hypoxia; Insulin; Insulin Resistance; Insulin-Secreting Cells; Lignans; NF-E2-Related Factor 2; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Sleep Apnea, Obstructive

This study was aimed to clarify the effect of honokiol (Hon) on the activity of Cytochrome P450 (CYP450) enzymes, and the level of mRNA expression of liver and kidney transporters in type 2 diabetic rats induced by high-fat diet and strepotozotocin. Rats were randomly divided into normal control (NC) group, diabetic control (DC) group and Hon groups (

Topics: Animals; Anion Transport Proteins; Biphenyl Compounds; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Gastrointestinal Agents; Kidney; Lignans; Liver; Male; Rats; Rats, Sprague-Dawley; RNA, Messenger

Nine new neolignan glycosides (1-9), viburfordosides A-I, two new neolignans, fordianes A and B (10, 11), and seven known analogues (12-18) have been isolated and identified from the fruits of Viburnum fordiae Hance. The structures and absolute configurations of undescribed neolignan constituents were identified by chemical methods and spectroscopic analyses. The α-glucosidase inhibitory, ABTS

Topics: alpha-Glucosidases; Animals; Anti-Inflammatory Agents; Diabetes Mellitus, Type 2; Fruit; Glycoside Hydrolase Inhibitors; Humans; Lignans; Macrophages; Mice; Molecular Structure; Plant Extracts; RAW 264.7 Cells; Viburnum

We evaluated the relationship between urine concentrations of phyto-oestrogens (isoflavones and lignans) and risk of incident type 2 diabetes in middle-aged and elderly Chinese residing in Singapore. Urine metabolites of isoflavones and lignans were assayed by HPLC among 564 diabetes cases and 564 matched controls in a case-control study nested within the Singapore Chinese Health Study cohort. Participants were free of diagnosed diabetes, CVD and cancer at morning urine collections during 1999-2004. Cases were participants who reported to have physician-diagnosed diabetes at follow-up visits during 2006-2010, whereas controls were randomly selected among those who remained free of diabetes and were matched to the index cases by age, sex, dialect group and date of urine collection. Conditional logistic regression models were used to calculate OR and 95 % CI with adjustment for potential confounders. The mean age of the participants at the time of urine collection was 59·8 years, and the average interval between urine collection and diabetes diagnosis was 4·0 years. The multivariate-adjusted OR for diabetes were 1·00 (reference), 0·76 (95 % CI 0·52, 1·11), 0·78 (95 % CI 0·53, 1·14) and 0·79 (95 % CI 0·54, 1·15) across quartiles of urine isoflavones (P for trend=0·54), and were 1·00 (reference), 0·87 (95 % CI 0·60, 1·27), 1·10 (95 % CI 0·77, 1·56) and 0·93 (95 % CI 0·63, 1·37) for lignans (P for trend=0·93). The results were similar in men and women, as well as for individual metabolites of isoflavones (genistein, daidzein, glycitin and equol) or lignans (enterodiol and enterolactone). The present study did not find a significant association between urine phyto-oestrogen metabolites and risk of type 2 diabetes in Chinese adults.

Topics: Asian People; Case-Control Studies; Diabetes Mellitus, Type 2; Equol; Female; Genistein; Humans; Isoflavones; Lignans; Logistic Models; Male; Middle Aged; Odds Ratio; Phytoestrogens; Risk Factors; Singapore

To study the protective effect of Arctigenin in goto-kakizaki (GK) rats combined with hypertension macroangiopathy. Six-week-old GK rats were divided randomly according to blood glucose level into four groups: the model group and low, middle and high dose arctigenin groups (12.5, 25, 50 mg x kg(-1)), with Wistar rats as the normal group. All of GK rats were given high-glucose and high-fat diet. After 16 weeks, GK rats were orally administrated with 10 mg x kg(-1) x d(-1) N-Ω-nitro-L-arginine methyl ester for eight weeks. During the modeling, all of arctigenin groups were orally administrated with different dose of arctigenin twice a day; The model group and the normal group were given solvents. At the beginning, mid-term and end of the experiment, blood glucose was measured. At the end of the experiment, efforts were made to detect blood pressure, collect abdominal aortic blood after anesthesia, fix thoracic aorta after bloodletting to make paraffin sections, observe morphological characteristics and detect the expression of VEGF by immunohistochemistry. According to the results, the blood glucose rose in all GK rats, with no significant difference between the drug group and the model group. At the end of the experiment, the blood pressure significantly increased in GK rats, indicating that Arctigenin could notably reduce the blood pressure in GK rats in a dose-dependent manner. The blood routine test showed increases in both the total white blood cell count and differential blood count, MPV and PDW, abnormal blood platelet parameters and decrease in PLT in GK rats, suggesting that Arctigenin could remarkably reduce the total white blood cell count and differential blood count, MPV and PDW. The thoracic aortic morphological observation revealed obvious endangium lesions in GK rats, demonstrating that Arctigenin could ameliorate the lesion extent. VEGF immumohistochemical staining showed a higher VEGF expression in the model group but lower expression in Arctigenin groups. In conclusion, Arctigenin had a protective effect on aorta in GK rats. Its mechanism may be related to blood pressure lowering, anti-inflammation, improvement in blood platelet function and reduction of VEGF expression.

Topics: Animals; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Drugs, Chinese Herbal; Furans; Humans; Hypertension; Lignans; Male; Rats; Rats, Wistar

Results from animal studies have consistently suggested that lignans play a role in the regulation of in body weight, but evidence from human studies has been limited. We examined the associations between urinary excretion of enterolactone and enterodiol, the major intestinal microbial metabolites of dietary lignans, and 10-year prospective weight change using data from 2 well-characterized cohort studies of US women: the Nurses' Health Study (2000-2010) and Nurses' Health Study II (1997-2007). Urinary excretion levels of enterolactone and enterodiol were measured at baseline. Associations with prospective weight change were analyzed using a multivariable-adjusted linear mixed-effects model. We observed that women in the highest quartile of urinary excretion of total lignans had significantly lower baseline body mass indices (weight in kilograms divided by height in meters squared) (mean, 24.6, 95% confidence interval (CI): 23.9, 25.2) than did those in the lowest quartile (mean, 27.7, 95% CI: 27.0, 28.4; P for trend < 0.01). Compared with women in the lowest quartile of enterodiol excretion, those in the highest quartile gained 0.27 kg/year less weight (95% CI: 0.12, 0.41; P for trend < 0.01) during the 10-year follow-up. The association was borderline significant for enterolactone (for the fourth vs. first quartile, least square mean of weight change rate = -0.14 kg/year, 95% CI: -0.29, 0.00). Our data suggest that higher urinary excretion of lignan metabolites, especially enterodiol, is associated with modestly slower weight gain.

Topics: 4-Butyrolactone; Adult; Aged; Body Weight; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Humans; Incidence; Lignans; Middle Aged; Prospective Studies; United States; Urinalysis

Diet and exercise intervention can delay or prevent development of type-2-diabetes (T2D), and high habitual coffee consumption is associated with reduced risk of developing T2D. This study aimed to test whether selected bioactive substances in coffee acutely and/or chronically increase insulin secretion from β-cells and improve insulin sensitivity in skeletal muscle cells. Insulin secretion from INS-1E rat insulinoma cells was measured after acute (1-h) and long-term (72-h) incubation with bioactive substances from coffee. Additionally, we measured uptake of radioactive glucose in human skeletal muscle cells (SkMC) after incubation with cafestol. Cafestol at 10(-8) and 10(-6) M acutely increased insulin secretion by 12% (p < 0.05) and 16% (p < 0.001), respectively. Long-term exposure to 10(-10) and 10(-8) M cafestol increased insulin secretion by 34% (p < 0.001) and 68% (p < 0.001), respectively. Caffeic acid also increased insulin secretion acutely and chronically. Chlorogenic acid, trigonelline, oxokahweol, and secoisolariciresinol did not significantly alter insulin secretion acutely. Glucose uptake in SkMC was significantly enhanced by 8% (p < 0.001) in the presence of 10(-8) M cafestol. This newly demonstrated dual action of cafestol suggests that cafestol may contribute to the preventive effects on T2D in coffee drinkers and be of therapeutic interest.

Topics: Alkaloids; Animals; Butylene Glycols; Caffeic Acids; Chlorogenic Acid; Coffee; Diabetes Mellitus, Type 2; Diterpenes; Glucose; Guinea Pigs; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Lignans; Muscle, Skeletal

Honokiol is one of the main bioactive constituents of the traditional Chinese herbal drug Magnolia bark (Cortex Magnoliae officinalis, Hou Po). The aim of this study was to probe its anti-type 2 diabetes mellitus effects and the underlying mechanism.. Type 2 diabetic mouse model was established by intraperitoneally injecting with streptozotocin. Fasting blood glucose, body weight, and lipid profile were measured. The subcutaneous adipose tissue, skeletal muscle, and liver were isolated as well as homogenized. The phospho-insulin receptor β-subunit (IRβ), IRβ, phospho-AKT, AKT, phospho-ERK1/2, ERK1/2, phosphotyrosine, and actin were examined by Western blot assay. Cell viability or cytotoxicity was analyzed by using MTT method. The inhibitory potencies of honokiol on the protein tyrosine phosphatase 1B (PTP1B) activity were performed in reaction buffer. Molecular docking and dynamic simulation were also analyzed.. In in vivo studies, oral treatment with 200 mg/kg honokiol for 8 weeks significantly decreases the fasting blood glucose in type 2 diabetes mellitus mice. The phosphorylations of the IRβ and the downstream insulin signaling factors including AKT and ERK1/2 significantly increase in adipose, skeletal muscle, and liver tissue of the honokiol-treated mice. Moreover, honokiol enhanced the insulin-stimulated phosphorylations of IRβ, AKT, and ERK1/2 in a dose-dependent manner in C2C12 myotube cells. Meanwhile, honokiol enhanced insulin-stimulated GLUT4 translocation. Importantly, honokiol exhibited reversible competitive inhibitory activity against PTP1B with good selectivity in vitro and in vivo. Furthermore, using molecular docking and dynamic simulation approaches, we determined the potential binding mode of honokiol to PTP1B at an atomic level.. These findings indicated the hypoglycemic effects of honokiol and its mechanism that honokiol improved the insulin sensitivity by targeting PTP1B. Therefore, our study may highlight honokiol as a promising insulin sensitizer for the therapy of type 2 diabetes.

Topics: Administration, Oral; Animals; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Hypoglycemic Agents; Injections, Intraperitoneal; Lignans; Mice; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Streptozocin; Structure-Activity Relationship

To examine urinary levels of enterolactone and enterodiol, intestinal microbial metabolites of dietary lignans, in relation to type 2 diabetes (T2D) risk.. Urinary concentrations of the lignan metabolites were assayed by liquid chromatography-mass spectrometry among 1,107 T2D and 1,107 control subjects in a nested case-control study conducted in participants from the Nurses' Health Study (NHS) and NHSII. Subjects were free of diabetes, cardiovascular disease, and cancer at urine sample collection in 1995-2001. Incident self-reported T2D cases identified through 2008 were confirmed with a validated questionnaire.. In both cohorts, T2D subjects had significantly lower concentrations of both enterolactone and enterodiol than control subjects. After multivariate adjustment for lifestyle and dietary risk factors of T2D, urinary concentrations of enterolactone were significantly associated with a lower risk of T2D (pooled odds ratio [OR] comparing the extreme quartiles 0.62 [95% CI 0.44, 0.88], P for trend = 0.003). Higher urinary concentrations of enterodiol were also marginally significantly associated with a lower T2D risk (pooled OR comparing extreme quartiles 0.67 [95% CI 0.48, 0.96], P for trend = 0.08). When concentrations of both metabolites were combined to reflect total lignan intake, the OR was 0.70 (95% CI 0.53, 0.92) for each SD increment of total lignan metabolites.. These results indicate that lignan metabolites, especially enterolactone, are associated with a lower risk of T2D in U.S. women. Further studies are needed to replicate these findings and to explore potential mechanisms underlying the observed association.

Topics: 4-Butyrolactone; Adult; Case-Control Studies; Diabetes Mellitus, Type 2; Diet; Female; Humans; Lignans; Microbiota; Middle Aged; Prospective Studies; Risk Factors

To study the association between dietary flavonoid and lignan intakes, and the risk of development of type 2 diabetes among European populations.. The European Prospective Investigation into Cancer and Nutrition-InterAct case-cohort study included 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 participants from among 340,234 participants with 3.99 million person-years of follow-up in eight European countries. At baseline, country-specific validated dietary questionnaires were used. A flavonoid and lignan food composition database was developed from the Phenol-Explorer, the U.K. Food Standards Agency, and the U.S. Department of Agriculture databases. Hazard ratios (HRs) from country-specific Prentice-weighted Cox regression models were pooled using random-effects meta-analysis.. In multivariable models, a trend for an inverse association between total flavonoid intake and type 2 diabetes was observed (HR for the highest vs. the lowest quintile, 0.90 [95% CI 0.77-1.04]; P value trend = 0.040), but not with lignans (HR 0.88 [95% CI 0.72-1.07]; P value trend = 0.119). Among flavonoid subclasses, flavonols (HR 0.81 [95% CI 0.69-0.95]; P value trend = 0.020) and flavanols (HR 0.82 [95% CI 0.68-0.99]; P value trend = 0.012), including flavan-3-ol monomers (HR 0.73 [95% CI 0.57-0.93]; P value trend = 0.029), were associated with a significantly reduced hazard of diabetes.. Prospective findings in this large European cohort demonstrate inverse associations between flavonoids, particularly flavanols and flavonols, and incident type 2 diabetes. This suggests a potential protective role of eating a diet rich in flavonoids, a dietary pattern based on plant-based foods, in the prevention of type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Europe; Feeding Behavior; Female; Flavonoids; Follow-Up Studies; Humans; Incidence; Lignans; Male; Middle Aged; Nutritional Status; Population Surveillance; Prospective Studies

The ability of sesamin from sesame meal to ameliorate insulin resistance in KK-Ay mice (an animal model of type 2 diabetes) was evaluated.. Treatment with sesamin (100 or 50 mg kg(-1)) significantly decreased the level of fasting plasma glucose, glycosylated serum protein, serum insulin, triglycerides, cholesterol, free fatty acid and malondialdehyde content of livers. Treatment with sesamin significantly increased the content of hepatic glycogen, reduced glutathione and the activity of superoxide dismutase and glutathione peroxidase. Moreover, the insulin-binding capacity to liver crude plasma membranes increased and histopathological changes of the pancreas were ameliorated in the treatment group.. Sesamin has hypoglycaemic, hypolipidaemic and the ability to ameliorate insulin resistance in KK-Ay mice, which might be related to its effect on insulin receptors, and thus increases insulin sensitivity.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dioxoles; Female; Glutathione; Glutathione Peroxidase; Hypoglycemic Agents; Insulin Resistance; Lignans; Lipids; Mice; Mice, Inbred C57BL; Sesamum; Superoxide Dismutase

The inhibition of protein tyrosine phosphatase 1B (PTP1B) is considered a valid strategy to combat insulin resistance and type II diabetes. We show here that a dichloromethane extract of Ratanhiae radix ( RR_EX) dose-dependently inhibits human recombinant PTP1B in vitro and enhances insulin-stimulated glucose uptake in murine myocytes. By determination of the PTP1B inhibiting potential of 11 recently isolated lignan derivatives from RR_EX, the observed activity of the extract could be partly assigned to ratanhiaphenol III. This compound inhibited PTP1B in vitro with an IC (50) of 20.2 µM and dose-dependently increased insulin receptor phosphorylation as well as insulin-stimulated glucose uptake in cultured myotubes. This is the first report to reveal an antidiabetic potential for a constituent of rhatany root, traditionally used against inflammatory disorders, by showing its capability of inhibiting PTP1B.

Topics: Animals; Benzofurans; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Krameriaceae; Lignans; Metabolic Syndrome; Mice; Muscle Cells; Muscle Fibers, Skeletal; Phytotherapy; Plant Preparations; Plant Roots; Protein Tyrosine Phosphatase, Non-Receptor Type 1

Defatted sesame seeds have been reported for hypoglycemic effect in mice and T2DM women. An attempted to identify active components responsible for this effect was conducted using α-glucosidase-guided fractionation, resulting in the isolation of various lignans. Of compounds isolated, only (+)-pinoresinol showed inhibitory activity against rat intestinal maltase with an IC(50) value of 34.3 μM. The kinetic study indicated that enzymatic hydrolysis of maltose is inhibited by (+)-pinoresinol through competitive and noncompetitive manners. However, a lower dissociation constant (k(i) 288 M) of EI complex suggested that competitive inhibition is predominant over noncompetitive mode (k'(i) 1342 M).

Topics: alpha-Glucosidases; Animals; Diabetes Mellitus, Type 2; Enzyme Inhibitors; Female; Furans; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Intestines; Kinetics; Lignans; Mice; Rats; Seeds; Sesamum; Stereoisomerism

Peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual agonists have the potential to be used as therapeutic agents for the treatment of type 2 diabetes. This study evaluated the function of macelignan, a natural compound isolated from Myristica fragrans, as a dual agonist for PPARalpha/gamma and investigated its antidiabetes effects in animal models.. GAL4/PPAR chimera transactivation was performed and the expression of PPARalpha/gamma target genes was monitored to examine the ability of macelignan to activate PPARalpha/gamma. Additionally, macelignan was administrated to obese diabetic (db/db) mice to investigate antidiabetes effects and elucidate its molecular mechanisms.. Macelignan reduced serum glucose, insulin, triglycerides, free fatty acid levels, and triglycerides levels in the skeletal muscle and liver of db/db mice. Furthermore, macelignan significantly improved glucose and insulin tolerance in these mice, and without altering food intake, their body weights were slightly reduced while weights of troglitazone-treated mice increased. Macelignan increased adiponectin expression in adipose tissue and serum, whereas the expression and serum levels of tumor necrosis factor-alpha and interleukin-6 decreased. Macelignan downregulated inflammatory gene expression in the liver and increased AMP-activated protein kinase activation in the skeletal muscle of db/db mice. Strikingly, macelignan reduced endoplasmic reticulum (ER) stress and c-Jun NH(2)-terminal kinase activation in the liver and adipose tissue of db/db mice and subsequently increased insulin signaling.. Macelignan enhanced insulin sensitivity and improved lipid metabolic disorders by activating PPARalpha/gamma and attenuating ER stress, suggesting that it has potential as an antidiabetes agent for the treatment of type 2 diabetes.

Topics: Adaptor Proteins, Signal Transducing; Adipose Tissue, White; Animals; Cell Line; Diabetes Mellitus, Type 2; Endoplasmic Reticulum; Insulin Receptor Substrate Proteins; Lignans; Liver; Mice; Mice, Obese; Molecular Structure; Myristica; PPAR alpha; PPAR gamma; Stress, Physiological; Thapsigargin

We investigated the effect of magnolol (5,5'-diallyl-2,2'-dihydroxybiphenyl), a marker compound isolated from the cortex of Magnolia officinalis, in non-obese type 2 diabetic Goto-Kakizaki (GK) rats. The rats were treated orally with magnolol (100 mg/kg body weight) once a day for 13 weeks. In magnolol-treated GK rats, fasting blood glucose and plasma insulin were significantly decreased, and the pancreatic islets also showed strong insulin antigen positivity. Urinary protein and creatinine clearance (Ccr) were significantly decreased. Pathological examination revealed the prevention of the glomeruli enlargement in magnolol-treated GK rats. The overproduction of renal sorbitol, advanced glycation endproducts (AGEs), type IV collagen, and TGF-beta1 mRNA were significantly reduced in magnolol-treated GK rats. Thus based on our findings, the use of magnolol could result in good blood glucose control and prevent or retard development of diabetic complications such as diabetic nephropathy.

Topics: Animals; Biphenyl Compounds; Blood Glucose; Collagen Type IV; Creatinine; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Glycation End Products, Advanced; Hypoglycemic Agents; Immunohistochemistry; Insulin; Islets of Langerhans; Kidney Cortex; Lignans; Magnolia; Male; Plant Bark; Plant Roots; Proteinuria; Rats; Rats, Inbred Strains; Sorbitol; Transforming Growth Factor beta1