MIC Capsules

Overview of Methionine / Inositol / Choline Bitartrate Capsules

Dosage Strengths of Methionine / Inositol / Choline Bitartrate Capsules

Methionine / Inositol / Choline Bitartrate 150/300/300 mg

General Information

Methionine

Methionine is a sulfur-containing branched-chain amino acid. A precursor for cellular methylation reactions, methionine plays an important role in lipid metabolism, polyamine synthesis, immune function, heavy metal chelation, and maintenance of redox balance.1 Conversely, dietary methionine restriction in rodents increased energy expenditure, improved insulin resistance, and enhanced lipolysis and fatty acid oxidation in adipose tissue.2

The lipotropic effects of methionine may be attributed to its metabolite S-adenosyl methionine (SAM). SAM is synthesized from methionine via an energy-consuming reaction. SAM administered orally or by injection has been investigated as a treatment for liver diseases, osteoarthritis, and depression.3 The benefits bestowed by SAM may be due to its role as a methyl donor in biochemical processes governing lipid homeostasis, DNA stability, gene expression, and neurotransmitter release.456

 

Inositol

Inositol is a family of cyclic sugar alcohols consisting of nine stereoisomers of hexahydroxycyclohexane. The stereoisomers of the inositol family are myo-, scyllo-, muco-, neo-, allo-, epi-, cis-, and the enantiomers L- and D-chiro-inositol. Of these, myo-inositol and D-chiro-inositol are among the most abundant biologically active forms. The enzyme epimerase converts myo-inositol to the D-chiro-inositol isomer, maintaining organ-specific ratios of the two isomers. Physiologically, the concentration of myo-inositol is several times higher than D-chiro-inositol in most tissues.7

The myo-inositol derivative phosphatidylinositol is an important component of the lipid bilayer of cell membranes. Phosphatidylinositol and its phosphorylated forms act as second messengers that are involved in a host of cellular functions including membrane trafficking, autophagy, cell migration, and survival. Disruption of phosphoinositide lipid signaling is implicated in cancer, diabetes, and cardiovascular disorders.8

Inositol has shown clinical benefits in treating disorders associated with metabolic syndrome. Inositol supplementation has been effectively used to accelerate weight loss, reduce fat mass,9 improve serum lipid profiles and upregulate the expression of genes involved in lipid metabolism and insulin sensitivity10 in women with polycystic ovarian syndrome. Myo-inositol alone or in combination with D-chiro-inositol significantly reduced weight, BMI, and waist-hip circumference ratios in overweight/obese women with PCOS. Weight loss, reduction in fat mass and increase in lean mass were accelerated when inositol supplementation was accompanied by a low-calorie diet.11 In addition, inositol supplementation was associated with lower rate of gestational diabetes and preterm delivery in pregnant women.9 Currently, research is being performed to assess whether inositol may be used in treating various cancers.

Mechanism of Action

Methionine

An essential sulfur-containing amino acid, methionine undergoes transmethylation reactions to generate metabolic by-products including S-adenosyl methionine (SAM) and homocysteine. SAM is a universal methyl group donor that serves as a co-factor in numerous cellular and physiological processes including lipid homeostasis. By donating its methyl group, SAM is converted first to S-adenosyl homocysteine (SAH) and then to homocysteine. As a methyl donor, SAM contributes to the formation of phosphatidylethanolamine and subsequently to phosphatidylcholine. In the liver, phosphatidylcholine is packaged into very low-density lipoproteins (VLDL) and transported to other tissues. Inadequate levels of SAM in the liver disrupts VLDL assembly and leads to hepatic accumulation of triglycerides or fatty liver.12

By promoting DNA methylation SAM plays a crucial role in epigenetic regulation. Methylation near gene promoters is a well-known mechanism of transcriptional repression. Therefore, SAM may act as a sensor for cellular nutrient status and epigenetically alter the expression of genes influencing appetite, glucose metabolism, and lipogenesis.1314 SAM also functions as a methyl donor in the synthesis of creatine – a high-energy molecule known to improve exercise.15

 

Inositol

Structurally, all inositol stereoisomers are 6-carbon sugar alcohols with the same molecular formula as glucose (C6H12O6). Myo-inositol and D-chiro-inositol have insulin-mimetic effects. Inositol administration in diabetic rodents, rhesus monkeys, and humans lowers post-prandial blood glucose levels and improves insulin sensitivity.161718 These benefits may be attributed to the effects of inositol on the insulin signaling pathway. Stimulating the insulin receptor activates the phosphatidylinositol-3-kinase (PI3K) pathway. Phosphorylated forms of phosphatidylinositol act as second messengers that lead to downstream activation of Akt. Akt inactivates the enzyme glycogen synthase kinase-3, enhancing glycogen synthase activity. This increases translocation of the glucose transporter (GLUT4) to the surface of skeletal muscle cells, increasing glucose uptake and lowering blood glucose levels.19

Excess circulating glucose is often deposited as fat in the liver and around visceral organs. Dietary supplementation with inositol reduced weight gain and lipid accumulation in the liver of rats.202122 Inositol-mediated activation of PI3K/Akt signaling is believed to play a role in hepatic lipid metabolism and gluconeogenesis. Inositol also affects transcription of SREBP-1 and PPAR-α – genes involved in fatty acid synthesis, oxidation, and lipid transport.

Pharmacokinetics

Methionine

Methionine is primarily metabolized in the liver. It is transported into hepatocytes via facilitative transport.23 Methionine metabolism consists of three parts: the methionine cycle, the transsulfuration pathway, and the salvage cycle.24 In the first step of the methionine cycle, the enzyme methyl adenosyltransferase catalyzes the conversion of methionine to S-adenosyl methionine (SAM). SAM donates its methyl group, generating S-adenosyl homocysteine, which is then hydrolyzed to adenosine and homocysteine. Homocysteine may be remethylated to regenerate methionine. Alternatively, it can be converted to cysteine via the transsulfuration pathway. In the salvage pathway, SAM is decarboxylated and used as an aminopropyl donor for polyamine biosynthesis. In healthy human subjects, 9-15% of methionine was excreted through urine following oral ingestion of 1-1.5 g of methionine. Decrease in urinary excretion occurred when the subjects were on a high-fat diet.25

 

Inositol

Myo-inositol and inositol phosphate derivatives are primarily absorbed in the gut. Cellular uptake of inositol occurs via sodium ion-coupled transporters as well as sodium-glucose co-transporters. Because they compete for the same transporters for uptake into cells, high glucose levels can significantly inhibit the uptake of inositol.19 Kidneys are the main sites for breakdown of inositol. Renal cortical tubules express the enzyme myo-inositol oxygenase. This enzyme metabolizes myo-inositol via the glucuronate-xylulose pathway, converting it into the monosaccharides xylulose and ribulose. Inositol that is unmetabolized or not re-absorbed at the renal tubular level is excreted unchanged through urine.2627 Although most studies have evaluated the pharmacokinetics of inositol following oral administration, one study assessed the pharmacokinetics of myo-inositol following intravenous (IV) administration in preterm infants.28 In this study, the serum half-life of inositol following a single IV dose was 5.22 hours and after multiple IV dosing was 7.9 hours.

Contraindications/Precautions

 

Pregnancy

Methionine

Excess methionine in the maternal diet may be detrimental to fetal development. This is because additional glycine and serine may be required to catabolize the excess methionine, inadvertently resulting in the deficiency of these amino acids. Excess methionine may also be metabolized to homocysteine. Elevated plasma homocysteine levels are associated with preeclampsia, spontaneous abortion, placental rupture, and miscarriage.29

 

Inositol

Given its use in the treatment of polycystic ovarian syndrome and gestational diabetes, myo-inositol may be considered relatively safe during pregnancy. In a meta-analysis of randomized controlled trials, 2 g of myo-inositol administered orally twice daily was reported to be safe during pregnancy.30 However, high concentrations of D-chiro-inositol negatively affect the quality of oocytes.31 Therefore, D-chiro-inositol may not be used by women seeking to get pregnant. Effects of other inositol isomers are not well characterized.

Breast-feeding

Methionine

Excess methionine in the maternal diet may be detrimental to fetal development. This is because additional glycine and serine may be required to catabolize the excess methionine, inadvertently resulting in the deficiency of these amino acids. Excess methionine may also be metabolized to homocysteine. Elevated plasma homocysteine levels are associated with preeclampsia, spontaneous abortion, placental rupture, and miscarriage.29

 

Inositol

Given its use in the treatment of polycystic ovarian syndrome and gestational diabetes, myo-inositol may be considered relatively safe during pregnancy. In a meta-analysis of randomized controlled trials, 2 g of myo-inositol administered orally twice daily was reported to be safe during pregnancy.30 However, high concentrations of D-chiro-inositol negatively affect the quality of oocytes.31 Therefore, D-chiro-inositol may not be used by women seeking to get pregnant. Effects of other inositol isomers are not well characterized.

Interactions

 

Adverse Reactions/Side Effects

 

Storage

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond-use date. Do not flush unused medications or pour down a sink or drain.

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  • 2. Zhou, X. et al. Methionine restriction on lipid metabolism and its possible mechanisms. Amino Acids vol. 48 1533–1540 (2016).
  • 3. S-Adenosyl-L-Methionine (SAMe): In Depth | NCCIH. https://www.nccih.nih.gov/health/sadenosyllmethionine-same-in-depth.
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  • 10. Shokrpour, M. et al. Comparison of myo-inositol and metformin on glycemic control, lipid profiles, and gene expression related to insulin and lipid metabolism in women with polycystic ovary syndrome: a randomized controlled clinical trial. Gynecol. Endocrinol. 35, 406–411 (2019).
  • 11. Effects of three treatment modalities (diet, myoinositol or myoinositol associated with D-chiro-inositol) on clinical and body composition outcomes in women with polycystic ovary syndrome.
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  • 13. Elshorbagy, A. K. et al. S-Adenosylmethionine Is Associated with Fat Mass and Truncal Adiposity in Older Adults. J. Nutr. 143, 1982–1988 (2013).
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  • 16. Ortmeyer, H. K. Dietary myoinositol results in lower urine glucose and in lower postprandial plasma glucose in obese insulin resistant rhesus monkeys. Obes. Res. 4, 569–575 (1996).
  • 17. Pintaudi, B., Di Vieste, G. & Bonomo, M. The Effectiveness of Myo-Inositol and D-Chiro Inositol Treatment in Type 2 Diabetes. Int. J. Endocrinol. 2016, (2016).
  • 18. Fan, C. et al. Effects of D-Chiro-Inositol on Glucose Metabolism in db/db Mice and the Associated Underlying Mechanisms. Front. Pharmacol. 11, 354 (2020).
  • 19. a. b. Bevilacqua, A. & Bizzarri, M. Inositols in insulin signaling and glucose metabolism. International Journal of Endocrinology vol. 2018 (2018).
  • 20. Kenney, J. L. & Carlberg, K. A. The effect of choline and myo-inositol on liver and carcass fat levels in aerobically trained rats. Int. J. Sports Med. 16, 114–116 (1995).
  • 21. Andersen, D. B. & Holub, B. J. The relative response of hepatic lipids in the rat to graded levels of dietary myo-inositol and other lipotropes. J. Nutr. 110, 496–504 (1980).
  • 22. Shimada, M., Hibino, M. & Takeshita, A. Dietary supplementation with myo-inositol reduces hepatic triglyceride accumulation and expression of both fructolytic and lipogenic genes in rats fed a high-fructose diet. Nutr. Res. 47, 21–27 (2017).
  • 23. Kuang, Y., Wang, F., Corn, D. J., Tian, H. & Lee, Z. In vitro characterization of uptake mechanism of L-[methyl- 3H]-methionine in hepatocellular carcinoma. Mol. Imaging Biol. 16, 459–468 (2014).
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  • 26. Dinicola, S. et al. Nutritional and acquired deficiencies in inositol bioavailability. Correlations with metabolic disorders. International Journal of Molecular Sciences vol. 18 (2017).
  • 27. DAUGHADAY, W. H. & LARNER, J. The renal excretion of inositol in normal and diabetic human beings. J. Clin. Invest. 33, 326–332 (1954).
  • 28. Phelps, D. L. et al. Safety and pharmacokinetics of multiple dose myo-inositol in preterm infants. Pediatr. Res. 80, 209–217 (2016).
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  • 30. a. b. Vitagliano, A. et al. Inositol for the prevention of gestational diabetes: a systematic review and meta-analysis of randomized controlled trials. Archives of Gynecology and Obstetrics vol. 299 55–68 (2019).
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