Effects of α-tocopherol on bone marrow mesenchymal cells derived from type II diabetes mellitus rats

Noguchi M, Yamawaki I, Takahashi S, Taguchi Y, Umeda M

J Oral Sci. 2018;60(4):579-587. doi: 10.2334/josnusd.17-0422.

Abstract

It is widely accepted that vitamin E (VE) acts as an antioxidant and is involved in various metabolic systems including the regulation of gene expression and inhibition of cell proliferation. The most predominant isoform of VE in the living body is α-tocopherol. However, the influence of α-tocopherol on bone marrow mesenchymal cells (BMMCs) in a background of type II diabetes mellitus (DM) has not been investigated. The focus of the present study was to clarify the effect of α-tocopherol on BMMCs derived from rats with type II DM and the underlying mechanisms involved. BMMCs were isolated from rats with type II DM. The BMMCs were either untreated or exposed to α-tocopherol at concentrations of 1.0, 10, and 100 μM, and the resulting effects of α-tocopherol on cell proliferation, H2O2 activity, and antioxidant and inflammatory cytokine production were examined. At 100 μM, α-tocopherol had no effect on cell proliferation, but H2O2 activity was significantly increased. At 10 μM, α-tocopherol increased the gene expression of IL-1β, and markedly promoted that of TNF-α. Expression of catalase in the presence of 100 μM α-tocopherol was lower than for the other concentrations. At a low concentration, α-tocopherol exerted good antioxidant and anti-inflammatory effects on BMMCs. The study suggests that maintaining α-tocopherol at a low concentration might promote the recovery of BMMCs from oxidative stress.

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Exercise augments the modulatory effects of vitamin E on pre-diabetes-induced aortopathy: a potential role of adiponectin

Dallak MA, Al-Ani B, El Karib AO, Abd Ellatif M, Eid RA, Al-Ani R, Mahmoud HM, Haidara MA

Arch Physiol Biochem. 2018 Nov 22:1-7. doi: 10.1080/13813455.2018.1538250. [Epub ahead of print]

Abstract

BACKGROUND:

We tested the hypothesis that vitamin E may protect against pre-diabetes-induced aortic injury (aortopathy), and exercise can augment the action of vitamin E.

MATERIAL AND METHODS:

Rats were either fed with a high fat and fructose diet (HFD) (model group) or a standard laboratory chow (control group) for 15 weeks before being sacrificed. The three protective groups were treated with vitamin E (HFD + Vit E), swimming exercises (HFD + Ex), and vitamin E plus swimming exercises (HFD + VitE + Ex), respectively.

RESULTS:

Aortopathy was developed in the model group as demonstrated by substantial tissue ultrastructural alterations, which were partially protected by vitamin E and effectively protected with vitamin E plus swim exercise. Also, swimming exercises significantly (p < .05) increased the modulatory effects of vitamin E on dyslipidemia, insulin resistance, blood pressure, oxidative stress, inflammation, leptin, and adiponectin, except coagulation and thrombosis.

CONCLUSIONS:

Swim exercise augments the protective effects of vitamin E in a pre-diabetic animal model.

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Tocotrienol-Rich Vitamin E from Palm Oil (Tocovid) and Its Effects in Diabetes and Diabetic Nephropathy: A Pilot Phase II Clinical Trial.

Tan SMQ, Chiew Y, Ahmad B, Kadir KA

Nutrients. 2018 Sep 17;10(9). pii: E1315. doi: 10.3390/nu10091315.

Abstract

Tocotrienol-rich vitamin E from palm oil (Tocovid) has been shown to ameliorate diabetes through its superior antioxidant, antihyperglycemic, and anti-inflammatory properties in diabetic rats. This study aimed to investigate the effects of Tocovid on diabetic nephropathy in patients with type 2 diabetes. Baseline parameters of potential subjects such as HbA1c, blood pressure, Advanced Glycation Endproduct (AGE), soluble receptor for AGE (sRAGE), Nε-Carboxymethyllysine (Nε-CML), and Cystatin C were assessed for possible correlation with diabetic nephropathy. Only subjects with diabetic nephropathy or urine microalbuminuria-positive defined as Urine Albumin to Creatinine Ratio (UACR) >10 mg/mmol were recruited into a prospective, randomized, double-blinded, placebo-controlled trial. The intervention group (n = 22) received Tocovid 200 mg twice a day while the control group (n = 23) received placebo twice a day for 8 weeks. Changes in Hemoglobin A1c (HbA1c), blood pressure, serum biomarkers and renal parameters such as UACR, serum creatinine, and estimated Glomerular Filtration Rate (eGFR) were compared between the two groups. It was found that serum Nε-CML significantly correlated to the severity of microalbuminuria. For every 1 ng/mL increase in serum Nε-CML, the odds of diabetic nephropathy increased by 1.476 times. Tocovid, compared to placebo, significantly reduced serum creatinine but not eGFR, UACR, HbA1c, blood pressure, and serum biomarkers. In conclusion, serum Nε-CML is a potential biomarker for diabetic nephropathy. Treatment with Tocovid significantly reduced serum creatinine; therefore Tocovid may be a useful addition to the current treatment for diabetic nephropathy.

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Identifying Potential Therapeutics for Osteoporosis by Exploiting the Relationship between Mevalonate Pathway and Bone Metabolism

Wan Hasan WN, Chin KY, Jolly JJ, Abd Ghafar N, Soelaiman IN.

Endocr Metab Immune Disord Drug Targets. 2018 Apr 23. doi: 10.2174/1871530318666180423122409. [Epub ahead of print]

Abstract

BACKGROUND:

Osteoporosis is a silent skeletal disease characterized by low bone mass and destruction of skeletal microarchitecture, leading to an increased fracture risk. This occurs due to an imbalance in bone remodelling, whereby the rate of bone resorption is greater than bone formation. Mevalonate pathway, previously known to involve in cholesterol synthesis, is an important regulatory pathway for bone remodelling.

OBJECTIVE:

This review aimed to provide an overview of the relationship between mevalonate pathway and bone metabolism, as well as agents which act through this pathway to achieve their therapeutic potential.

DISCUSSION:

Mevalonate pathway produces farnesyl pyrophosphate and geranylgeranyl pyrophosphate essential in protein prenylation. An increase in protein prenylation favours bone resorption over bone formation. Non-nitrogen containing bisphosphonates inhibit farnesyl diphosphate synthase which produces farnesyl pyrophosphate. They are used as the first line therapy for osteoporosis. Statins, a well-known class of cholesterol-lowering agents, inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme in the mevalonate pathway. It was shown to increase bone mineral density and prevent fracture in humans. Tocotrienol is a group of vitamin E commonly found in palm oil, rice bran and annatto bean. It causes degradation of HMG-CoA reductase. Many studies demonstrated that tocotrienol prevented bone loss in animal studies but its efficacy has not been tested in humans.

CONCLUSION:

mevalonate pathway can be exploited to develop effective antiosteoporosis agents.

KEYWORDS:

bone; bone metabolism; mevalonate pathway; tocotrienol; vitamin E.

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Tocotrienol-rich fraction supplementation reduces hyperglycemia-induced skeletal muscle damage through regulation of insulin signaling and oxidative stress in type 2 diabetic mice

Lee H, Lim Y.

J Nutr Biochem. 2018 Mar 21;57:77-85. doi: 10.1016/j.jnutbio.2018.03.016. [Epub ahead of print]

Abstract

Chronic hyperglycemia induces impairment of muscle growth and development of diabetes mellitus (DM). Since skeletal muscle is the major site for disposal of ingested glucose, impaired glucose metabolism causes imbalance between protein synthesis and degradation which adversely affects physical mobility. In this study, we investigated the effect of tocotrienol-rich fraction (TRF) supplementation on skeletal muscle damage in diabetic mice. Diabetes was induced by a high-fat diet with streptozotocin (STZ) injection (100 mg/kg) in male C57BL/6J mice. After diabetes was induced (fasting blood glucose levels≥250 mg/dl), normal control (CON) and diabetic control (DMC) groups were administrated with olive oil, while TRF treatment groups were administrated with TRF (dissolved in olive oil) at low dose (100 mg/kg BW, LT) or high dose (300 mg/kg BW, HT) by oral gavage for 12 weeks. TRF supplementation ameliorated muscle atrophy, plasma insulin concentration and homeostatic model assessment estimated insulin resistance in diabetic mice. Moreover, TRF treatment up-regulated IRS-1 and Akt levels accompanied by increased translocation of GLUT4. Furthermore, TRF increased mitochondrial biogenesis by activating SIRT1, SIRT3 and AMPK in diabetic skeletal muscle. These changes were in part mechanistically explained by reduced levels of skeletal muscle proteins related to oxidative stress (4-hydroxynonenal, protein carbonyls, Nrf2 and HO-1), inflammation (NFkB, MCP-1, IL-6 and TNF-α), and apoptosis (Bax, Bcl₂ and caspase-3) in diabetic mice. Taken together, these results suggest that TRF might be useful as a beneficial nutraceutical to prevent skeletal muscle atrophy associated with diabetes by regulating insulin signaling via AMPK/SIRT1/PGC1α pathways in type 2 diabetic mice.

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Effect of Vitamin E and omega 3 fatty acids in type 2 diabetes mellitus patients.

Dass AS, Narayana S, Venkatarathnamma PN

J Adv Pharm Technol Res. 2018 Jan-Mar;9(1):32-36. doi: 10.4103/japtr.JAPTR_309_17.

Abstract

Diabetes mellitus (DM) and its complications have been implicated in hyperglycemia-induced oxidative stress. Antioxidants can improve glycemic control, lipid profile, and cognitive functions. We assessed the effect of Vitamin E and omega 3 fatty acids (OFA) on the above parameters. One hundred patients with type 2 DM receiving metformin 500 mg and glimepiride 1 mg were randomized to receive add-on therapy of Vitamin E 400 mg or OFA once daily for 12 weeks and the third group served as control. Fasting blood sugar (FBS), postprandial blood sugar (PPBS), glycated hemoglobin (HbA1c), body mass index (BMI), waist-hip ratio (WHR), lipid profile, and mini-mental state examination were done at baseline and 12 weeks. Eighty-seven patients completed the study. A significant reduction in FBS, PPBS, and HbA1c was observed in all the three groups at 12 weeks. There was significant reduction in total cholesterol and triglycerides (TG) in patients receiving either of the antioxidants and also significant reduction in low-density lipoprotein in patients receiving OFA at 12 weeks compared to baseline. BMI and WHR were significantly increased in control group. Intergroup analysis showed that in patients receiving Vitamin E and OFA, the reduction of FBS, PPBS, and HbA1c were similar. The patients receiving OFA had significant reduction in TG compared to control. There was no significant effect on cognitive function. Vitamin E and OFA had beneficial effects on lipid profile and anthropometric measurements; however, the glycemic control was similar to the patients in control group.

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Amelioration of diabetic nephropathy by oral administration of d-α-tocopherol and its mechanisms

Hayashi D, Ueda S, Yamanoue M, Ashida H, Shirai Y

Biosci Biotechnol Biochem. 2018 Jan;82(1):65-73. doi: 10.1080/09168451.2017.1411184. Epub 2018 Jan 3.

Abstract

Diabetic nephropathy (DN) is a diabetic vascular complication, and abnormal protein kinase C (PKC) activation from increased diacylglycerol (DG) production in diabetic hyperglycemia is one of the causes of DN. Diacylglycerol kinase (DGK) converts DG into phosphatidic acid. In other words, DGK can attenuate PKC activity by reducing the amount of DG. Recently, we reported that intraperitoneally administered d-α-tocopherol (vitamin E, αToc) induces an amelioration of DN in vivo through the activation of DGKα and the prevention of podocyte loss. However, the effect of the oral administration of αToc on DN in mice remains unknown. Here, we evaluated the effect of oral administration of αToc on DN and its molecular mechanism using streptozocin-induced diabetic mice. Consequently, the oral administration of αToc significantly ameliorated the symptoms of DN by preventing the loss of podocytes, and it was revealed that the inhibition of PKCactivity was involved in this amelioration.

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Anti-oxidative treatment with vitamin E improves peripheral vascular function in patients with diabetes mellitus and Haptoglobin 2-2 genotype: A double-blinded cross-over study.

Alshiek JA, Dayan L, Asleh R, Blum S, Levy AP, Jacob G

Diabetes Res Clin Pract. 2017 Sep;131:200-207. doi: 10.1016/j.diabres.2017.06.026. Epub 2017 Jul 13.

Abstract

Vascular dysfunction in both conduit arteries and small vessels is a major contributor to the development of cardiovascular disease (CVD) in diabetes mellitus (DM). In diabetes there is a process of systemic chronic inflammation accompanied by high oxidative stress causing a subsequent decrease in vascular reactivity and negatively affect the metabolic processes responsible for functioning of the microvasculature. Vitamin E is classified as an antioxidant due to its ability to scavenge lipid radicals and terminate oxidative chain reactions. We conducted a double-blinded cross-over study with vitamin E versus placebo in individuals with type 2DM and the Hp2-2 genotype and assessed different aspects of peripheral vascular function in these patients. Twenty patients completed the study with 10 individuals in each study cohort. We were able to show significant improvement of indirect indices of vascular function following 8weeks of treatment with vitamin E. This improvement was consistent for weeks even after stopping the vitamin E treatment. We concluded that a pharmacogenomic rationale utilizing the Hp genotype might potentially provide cardiovascular benefit with vitamin E.

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Tocotrienols Stimulate Insulin Secretion of Rat Pancreatic Isolated Islets in a Dynamic Culture.

Chia LL, Jantan I, Chua KH

Curr Pharm Biotechnol. 2017 Aug 8. doi: 10.2174/1389201018666170808144703. [Epub ahead of print]

Abstract

BACKGROUND:

Tocotrienols (T3) are the natural occurring vitamin E derivatives that possess antioxidant properties and therapeutic potential in diabetic complications. The bioactivities of the derivatives are determined by the number and arrangement of methyl substitution on the structure.

OBJECTIVE:

The objective of this study was to determine the effects of T3 derivatives, δ-T3, γ-T3 and α-T3 on insulin secretion of rat pancreatic islets in a dynamic culture.

METHOD:

Pancreatic islets isolated from male Wistar rats were treated with T3 for 1 h at 37 oC in a microfluidic system with continuous operation that provided a stable cell culture environment. Glucose (2.8 mM and 16.7 mM, as basal and stimulant, respectively) and potassium chloride (KCl) (30 mM) were added to the treatment in calcium free medium. The supernatant were collected for insulin measurements.

RESULTS:

Short-term exposure (1 h) of δ-T3 to β cells in the stimulant glucose condition significantly potentiated insulin secretion in a dose-dependent manner. γ-T3 and α-T3 also displayed dose-dependent effect but less effective in the activation of insulin secretion. Essentially, KCl, a pancreatic β cell membrane depolarizing agent, added into the treatment further enhanced the insulin secretion of δ-T3, γ-T3 and α-T3 with ED50 values of 504, 511 and 588 µM, respectively.

CONCLUSION:

The findings suggest the potential of δ-T3 in regulating glucose-stimulated insulin secretion (GSIS) in response to the intracellular calcium especially in the presence of KCl.

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Interaction Between the Haptoglobin Genotype and Vitamin E on Cardiovascular Disease in Diabetes

Hochberg I, Berinstein EM, Milman U, Shapira C, Levy AP

Curr Diab Rep. 2017 Jun;17(6):42. doi: 10.1007/s11892-017-0868-1.

Abstract

PURPOSE OF REVIEW:

Despite compelling evidence regarding the importance of oxidant stress in the development of vascular complications and observational studies suggesting that vitamin E may be protective from these complications, multiple clinical trials have failed to show benefit from vitamin E supplementation in the prevention of vascular complications in diabetes. One possible explanation for this failure of vitamin E may have been inappropriate patient selection. This review seeks to provide the clinical evidence and mechanistic basis for why a subset of individuals defined by their haptoglobin (Hp) genotype may derive cardiovascular protection by vitamin E supplementation.

RECENT FINDINGS:

Clinical trial data from the HOPE, ICARE, and WHS studies is presented showing a pharmacogenomic interaction between the Hp genotype and vitamin E on the development of CVD. Specifically, in individuals with diabetes and the Hp2-2 genotype, vitamin E has been shown to be associated with an approximately 35% reduction in CVD. Cardioprotection by vitamin E in individuals with the Hp2-2 genotype appears to be mediated in part by an improvement in HDL functionality as demonstrated in three independent trials in both type 1 diabetes and type 2 diabetes. Vitamin E may provide benefit in reducing CVD in Hp2-2 individuals with diabetes. However, in order for this pharmacogenomic algorithm to be accepted as a standard of care and used clinically, an additional large prospective study will need to be performed.

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