Dr. Ron’s Research Review – December 4, 2019

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This week’s research review focuses on Vitamin E and insulin resistance

Vitamin E induces regular structure and stability of human insulin, more intense than vitamin D3. Far- and near-UV circular dichroism studies showed that vitamin E can significantly change the secondary and tertiary structures of human insulin via an increase in the content of α-helix structure. Both vitamins D3 and E stabilize the structure of human insulin. Molecular dynamic simulation results indicated that vitamin D3 decreases the helical and strand structural contents of human insulin, but vitamin E stabilizes more regular secondary structures such as helical and strand structural contents. (Soleymani et al., 2016)

Vitamins D3 and E have good affinity to bind to the insulin and vitamin E has higher binding energy by engaging more residues in binding site. Distance and angle calculation results illustrated that vitamin E changes the B-chain conformation and it causes the formation of wide-open/active form of insulin. Vitamin D3, however, cannot change B-chain conformation. Thus our MD simulations propose a model for insulin activation through vitamin E interaction for therapeutic approaches. (Soleymani et al., 2019)

A study examined the effect of vitamin E to decrease markers of oxidative stress and plasma ALT levels and improve insulin sensitivity in overweight individuals. Eighty overweight individuals (BMI >27 kg/m(2)) were randomly allocated to receive either 800 IU vitamin E per day or a matching placebo for 3 months. The dose of vitamin E was increased to 1,200 IU per day for a further 3 months. Plasma peroxides decreased by 27% at 3 months and by 29% at 6 months in the group that received vitamin E and were positively correlated with plasma vitamin E concentrations at the 6-month time point. At 3 months, fasting plasma glucose and insulin concentrations were significantly reduced and homeostasis model assessment increased. These changes were not apparent at 6 months. Plasma ALT concentrations declined significantly throughout the study period. In conclusion, these findings indicate that vitamin E improves oxidative stress and hepatocellular function. Although insulin resistance also improves, this effect appears transient. (Manning et al., 2004)

A study evaluated the association of vitamin E with incidence of type 2 diabetes. The Insulin Resistance Atherosclerosis Study (IRAS) included 895 non-diabetic adults at baseline (including 303 with impaired glucose tolerance [IGT]), 148 of whom developed type 2 diabetes according to World Health Organization (WHO) criteria during the 5-year follow-up. At baseline, dietary vitamin E was estimated by a validated food frequency interview, usual supplement use was confirmed by supplement label, and plasma alpha-tocopherol was measured. Analyses were conducted separately for individuals who did (n = 318) and did not (n = 577) use vitamin E supplements. Among supplement nonusers, reported mean intake of vitamin E (mg alpha-tocopherol equivalents [alpha-TE]) did not differ between those who remained nondiabetic (n = 490) and those who developed diabetes (n = 87) (10.5 +/- 5.5 vs. 9.5 +/- 4.8 [means +/- SD], respectively, NS). After adjustment for demographic variables, obesity, physical activity, and other nutrients, the association remained nonsignificant (odds ratio [OR] 0.80, 95% CI 0.13-5.06) for the highest level of intake (> or =20 mg alpha-TE) compared with the lowest level (1-4 alpha-TE). However, results for plasma concentration of alpha-tocopherol showed a significant protective effect both before and after adjustment for potential confounders (adjusted OR 0.12, 95% CI 0.02-0.68, for the highest quintile vs. the lowest quintile; overall test for trend, P < 0.01). Among individuals who reported habitual use of vitamin E supplements (at least once per month in the year before baseline; 259 remained nondiabetic and 59 developed diabetes), no protective effect was observed for either reported intake of vitamin E or plasma concentration of alpha-tocopherol A protective effect of vitamin E may exist within the range of intake available from food. This effect may go undetected within studies of high-dose supplement use, which appears to hold no additional protective benefit. (Mayer-Davis et al., 2002)

 

Dr. Ron

 


Articles

 

Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects.
            (Manning et al., 2004) Download
OBJECTIVE:  Markers of oxidative stress and plasma alanine transferase (ALT) levels are increased and circulating antioxidant concentrations are reduced in individuals with insulin resistance. Vitamin E improves glycemic control in people with diabetes. We tested the hypothesis that vitamin E would decrease markers of oxidative stress and plasma ALT levels and improve insulin sensitivity in overweight individuals. RESEARCH DESIGN AND METHODS:  Eighty overweight individuals (BMI >27 kg/m(2)) were randomly allocated to receive either 800 IU vitamin E per day or a matching placebo for 3 months. The dose of vitamin E was increased to 1,200 IU per day for a further 3 months. RESULTS:  Plasma peroxides decreased by 27% at 3 months and by 29% at 6 months in the group that received vitamin E and were positively correlated with plasma vitamin E concentrations at the 6-month time point. At 3 months, fasting plasma glucose and insulin concentrations were significantly reduced and homeostasis model assessment increased. These changes were not apparent at 6 months. Plasma ALT concentrations declined significantly throughout the study period. CONCLUSIONS:  In conclusion, these findings indicate that vitamin E improves oxidative stress and hepatocellular function. Although insulin resistance also improves, this effect appears transient.

Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS).
            (Mayer-Davis et al., 2002) Download
OBJECTIVE:  To evaluate the association of vitamin E with incidence of type 2 diabetes and to do so separately among individuals who did and those who did not report regular use of vitamin supplementation. RESEARCH DESIGN AND METHODS:  The Insulin Resistance Atherosclerosis Study (IRAS) included 895 nondiabetic adults at baseline (including 303 with impaired glucose tolerance [IGT]), 148 of whom developed type 2 diabetes according to World Health Organization (WHO) criteria during the 5-year follow-up. At baseline, dietary vitamin E was estimated by a validated food frequency interview, usual supplement use was confirmed by supplement label, and plasma alpha-tocopherol was measured. Analyses were conducted separately for individuals who did (n = 318) and did not (n = 577) use vitamin E supplements. RESULTS:  Among supplement nonusers, reported mean intake of vitamin E (mg alpha-tocopherol equivalents [alpha-TE]) did not differ between those who remained nondiabetic (n = 490) and those who developed diabetes (n = 87) (10.5 +/- 5.5 vs. 9.5 +/- 4.8 [means +/- SD], respectively, NS). After adjustment for demographic variables, obesity, physical activity, and other nutrients, the association remained nonsignificant (odds ratio [OR] 0.80, 95% CI 0.13-5.06) for the highest level of intake (> or =20 mg alpha-TE) compared with the lowest level (1-4 alpha-TE). However, results for plasma concentration of alpha-tocopherol showed a significant protective effect both before and after adjustment for potential confounders (adjusted OR 0.12, 95% CI 0.02-0.68, for the highest quintile vs. the lowest quintile; overall test for trend, P < 0.01). Among individuals who reported habitual use of vitamin E supplements (at least once per month in the year before baseline; 259 remained nondiabetic and 59 developed diabetes), no protective effect was observed for either reported intake of vitamin E or plasma concentration of alpha-tocopherol CONCLUSIONS:  A protective effect of vitamin E may exist within the range of intake available from food. This effect may go undetected within studies of high-dose supplement use, which appears to hold no additional protective benefit.

Vitamin E induces regular structure and stability of human insulin, more intense than vitamin D
            (Soleymani et al., 2016) Download
Changes in human environment and lifestyle over the last century have caused a dramatic increase in the occurrence of diabetes. Research of past decades illustrated that vitamin D and E have a key role in the improvement of diabetes by reducing oxidative stress, protein glycosylation, insulin resistance and also improving beta cell function. Binding properties and conformational changes of human insulin upon interaction with vitamins D3 and E (α-tocopherol) were investigated by spectroscopy, differential scanning calorimetry (DSC) and molecular dynamic simulation. Tyrosine fluorescence quenching studies indicates changes in the human insulin conformation in the presence of vitamins. Binding constants of vitamins D3 and E for human insulin were determined to be 2.7 and 1.5 (×10-5M-1) and the corresponding average numbers of binding sites were determined to be 1.3 and 1.2, respectively. Far- and near-UV circular dichroism studies showed that vitamin E can significantly change the secondary and tertiary structures of human insulin via an increase in the content of α-helix structure. Results of DSC showed that both vitamins D3 and E stabilize the structure of human insulin. Molecular dynamic simulation results indicated that vitamin D3 decreases the helical and strand structural contents of human insulin, but vitamin E stabilizes more regular secondary structures such as helical and strand structural contents as shown by experimental results.

Activation of human insulin by vitamin E: A molecular dynamics simulation study.
            (Soleymani et al., 2019)  Download
Lack of perfect insulin signaling can lead to the insulin resistance, which is the hallmark of diabetes mellitus. Activation of insulin and its binding to the receptor for signaling process initiates via B-chain C-terminal hinge conformational change through an open structure to "wide-open" conformation. Observational studies and basic scientific evidence suggest that vitamin D and E directly and/or indirectly prevent diabetes through improving glucose secretion and tolerance, activating calcium dependent endopeptidases and thus improving insulin exocytosis, antioxidant effect and reducing insulin resistance. On the contrary, clinical trials have yielded inconsistent results about the efficacy of vitamin D supplementations for the control of glucose hemostasis. In this work, best binding modes of vitamin D3 and E on insulin obtained from AutoDock Vina were selected for Molecular Dynamic, MD, study. The binding energy obtained from Molecular Mechanics- Poisson Boltzman Surface Area, MM-PBSA method, revealed that Vitamins D3 and E have good affinity to bind to the insulin and vitamin E has higher binding energy (-46 kj/mol) by engaging more residues in binding site. Distance and angle calculation results illustrated that vitamin E changes the B-chain conformation and it causes the formation of wide-open/active form of insulin. Vitamin E increases the ValB12-TyrB26 distance to ∼15 Å and changes the hinge angle to ∼65°. Consequently, essential hydrophobic residues for binding to insulin receptor exposed to surface in the presence of vitamin E. However, our data illustrated that vitamin D3 cannot change B-chain conformation. Thus our MD simulations propose a model for insulin activation through vitamin E interaction for therapeutic approaches.

 

References

Manning, PJ, et al. (2004), ‘Effect of high-dose vitamin E on insulin resistance and associated parameters in overweight subjects.’, Diabetes Care, 27 (9), 2166-71. PubMed: 15333479
Mayer-Davis, EJ, et al. (2002), ‘Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS).’, Diabetes Care, 25 (12), 2172-77. PubMed: 12453956
Soleymani, H, et al. (2016), ‘Vitamin E induces regular structure and stability of human insulin, more intense than vitamin D’, Int J Biol Macromol, 93 (Pt A), 868-78. PubMed: 27642128
Soleymani, H, et al. (2019), ‘Activation of human insulin by vitamin E: A molecular dynamics simulation study.’, J Mol Graph Model, 91 194-203. PubMed: 31265936