COMPOSITIONS AND METHODS FOR INCREASING INTRACELLULAR GLUCOSE UPTAKE

Abstract

A method for increasing intracellular glucose uptake by administering a composition comprising at least one Glut-4 expression inducement agent in combination with an antioxidant, an amino acid, and a vasodilator.

Claims

1. A method for increasing glucose uptake in muscle cell to boost energy comprising administering an effect amount of a composition comprising: an effective amount of at least one GLUT-4 expression inducement agent in combination with an effective amount of antioxidant in combination with at least one amino acid and an effective amount vasodilator, wherein said composition contains said at least one GLUT-4 expression inducement agent in combination with said antioxidant in combination with said at least one amino acid and said vasodilator in an amount and at a ratio therapeutically effective for at least one time per day dosage.

2. The method of claim 1, said at least one GLUT-4 expression inducement agent is erythritol in about a dosage of 10 g to 50 g, preferably 10 g to 20 g, preferably 20 g to 30 g, preferably 30 g to 40 g, preferably 40 g to 50 g.

3. The method of claim 1, wherein said antioxidant is selected from the group consisting of chromium ionic, alpha pinene, caffeine, and any combination thereof.

4. The method of claim 3, wherein said chromium ionic is selected from the group consisting of chromium picolinate, chromium nicotinate, chromium glycinate, or other chromium comprising chromium content of between about 100 micrograms to 1,500 micrograms.

5. The method of claim 1, wherein the concentration of antioxidant metabolite, derivative, or analogue thereof is from 0.01% (w/w) to 1% (w/w).

6. The method of claim 4, wherein said chromium ionic is combined with niacin or niacinamide for increasing absorption rate.

7. The method of claim 1, wherein said amino acid comprises L-arginine in combination with L-citrulline.

8. The method of claim 1, wherein said vasodilator is selected from the group consisting of magnesium glycinate, magnesium stearate, magnesium citrate, magnesium chloride, magnesium oxide, magnesium lactate, magnesium L-threonate, magnesium malate, magnesium orotate, and any combination thereof.

9. The method of claim 1, wherein the concentration of vasodilator and/or vasodilator metabolite, derivative, or analogue thereof is from 1% (w/w) to 15% (w/w).

10. The composition of claim 1 further comprises tocopherol (vitamin E), cholecalciferol (vitamin D3), and frankincense extract.

11. The method of claim 1, wherein in an aqueous environment of said chromium ionic is released into solution rapidly.

12. The method of claim 1 further comprises a pharmaceutically acceptable carrier, adjuvant, excipientor diluent.

13. The method of claim 11, wherein said pharmaceutically acceptable carrier is selected from the group consisting of a pill, capsule, lozenge, caplet, syrup, emulsion, suspensional liquid, powder, spray, cream or lotion.

14. The method of claim 1, wherein said composition is administered orally, nasally, sublingually, intramuscularly, subcutaneously, transdermally, and any combination thereof.

Description

EXAMPLES

[0054] The following examples are presented to illustrate presently preferred practice thereof. As illustrations they are not intended to limit the scope of the invention. All quantities are in weight %.

Example 1

[0055] The CrCl3.6H2O (1 mmol, 0.267 g) in 10 mL methanol was mixed with 30 mL methanol of (1.0 mmol, 0.122 g) niacinamide. The mixture was refluxed with stirring at 50° C. for 45 min. The solid chromium (III) complex was isolated after left to be precipitated within one day. This complex was washed with (C2H5)2O ether and then dried over anhydrous CaCl.sub.2).

[0056] The effect of chromium compounds on membrane fluidity was assayed with homogeneous liposomes prepared as described by Barenholz et al. (1977). The liposome preparations contained 0.5 mM phosphatidylcholinedioleoyly and 5.0 μM metal complex (chromium picolinate, chromium nicotinate, or zinc picolinate) in 3.0 ml of 50 mM KCl. A preparation that contained 5.0 μM chromium chloride and a control that contained no metal compound (3 ml of 50 mM KCl only) were also prepared. The liposomes were tagged with 1,3-diphenyl-1,3,5-hexatriene (DPH) in tetrahydrofuran. Fluorescence depolarization was determined as a function of temperature with a Jansco spectrofluorometer adapted by connecting the cuvette holder to a circulating water bath.

[0057] Also, two polarizers were added to the spectrofluorometer, one in the excitation beam and one in the emission beam. Urine sample assayed using an excitation wavelength of 382 nm and an emission wavelength of 430 nm after an equilibration period of 10 min at each temperature. Emission values were measured with the polarizers both parallel and perpendicular. Corrections for light scattering were made by use of liposomes prepare without DPH. Anisotropy ®, the measure of the bilayer fluidity was calculated by the method of Surkusk et al (1976) as modified by Shinitzky et al (1971).

[0058] The result showed that membrane fluidity increased with increasing temperature but the increase in fluidity was greatest when either chromium picolinate or chromium nicotinate, pyridine carboxylate isomer complexes, was added to the medium used for preparation of the liposomes. The increase in fluidity produced by chromium picolinate was much greater than that produced by chromium nicotinate; chromium picolinate is several times more soluble in chloroform (lipophilic) than the nicotinate complex. Thus, the lipophilic complexes used in these experiments produced the most dramatic alterations in membrane fluidity and the most lipophilic of these, chromium picolinate, produced the largest increase in membrane fluidity and also resulted in a marked increase in insulin internalization in cultured cells.

REFERENCES CITED IN EXAMPLE 1

[0059] Syed S, Michalski E S, Tangpricha V, Chesdachai S, Kumar A, Prince J, Ziegler T R, Suchdev P S, Kugathasan S. (2017). Vitamin D status is associated with hepcidin and hemoglobin concentrations in children with inflammatory bowel disease. Inflammation Bowel Discovery 23(9):1650-1658. [0060] Zughaier S M, Alvarez J A, Sloan J H, Konrad R J, Tangpricha V. (2014). The role of vitamin D in regulating the iron-hepcidin-ferroportin axis in monocytes. J Clinical Translational Endocrinol. 1(1):19-25. [0061] Y. Barenholz, D. Gibbes, B. J. Litman, J. Goll, T. E. Thompson, Carlson F. D. (1977). Biochemistry. 16, 2806. [0062] Suurkuusk J., Lentz B. R., Barenholz Y., R. L. Biltonen R. L., and Thompson T. E. (1976). Biochemitry. 15, 1393. [0063] M. Shin&&y, A. C. Dianouz, C. Gilter, and G. Weber, Biochemistry 10, 2106 (1971).

Example 2

[0064] A single oral dose of glucose (2 g/kg bw) was orally administered to each animal and thereafter blood glucose was measured at 0 (just before glucose ingestion), 30 and 60 min after the glucose ingestion using a portable glucometer (Glucoplus Inc., Saint-Laurent, Quebec, Canada).

[0065] The result showed that although erythritol did not significantly influence the glucose tolerance ability of normal animals, it significantly improved (p<0.05) the glucose tolerance ability of diabetic animals, especially at 30 and 60 min after the glucose ingestion. On the other hand, erythritol did not significantly influence serum insulin levels in normal animals, but it appreciably increased (p=0.178) diabetes-induced serum insulin depletion of diabetic animals.

References Cited in Example 2

[0066] Chika Ifeany Chukwuma, Ramgopal Mopuri, Savania Nagiah, Anil Amichund Chuturgoon, Md. Shahidul Islam (2018). Erythritol reduces small intestinal glucose absorption, increases muscle glucose uptake, improves glucose metabolic enzymes activities and increases expression of Glut-4 and IRS-1 in type 2 diabetic rats. Eur J Nutr 57:2431-2444.

[0067] Therefore, those skilled in the art will appreciate that the conceptions and specific embodiments disclosed in this description may be readily utilized as a basis for modifying or designing other embodiments for carrying out the same purposes of the present invention. Those skilled in the art will also appreciate that such equivalent embodiments do not depart from the spirit and scope of the invention as set forth in the appended claims.

[0068] Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to describe more fully the state of the art to which this invention pertains.

[0069] As various modifications could be made to the exemplary embodiments, as described above with reference to the corresponding illustrations, without departing from the scope of the invention, it is intended that all matter contained in the foregoing description and shown in the accompanying drawings shall be interpreted as illustrative rather than limiting. Thus, the breadth and scope of the present invention should not be limited by any of the above described exemplary embodiments, but should be defined only in accordance with the following claims appended hereto and their equivalents.

References

[0070] Al-Ali, A., Alkawajah, A., Randhawa, M A., Shaikh, NA. (2008). Oral and intraperitoneal LD50 of thymoquinone, an active principle of Nigella sativa in mice and rats. J Ayub Medicine College Abbottabad, 20:23-27. [0071] Bourgou, S., Ksouri, R., Bellila. A., Skandrani. FH, Marzouk, B. (2008). Phenolic composition and biological activities of Tunisia Nigella Sativa L. shoots and roots. C R Biol, 331:48-55. [0072] Badary, OA., Al-Shabana, OA., Nagi, M N., Al Bekairi, A M. (1998). Acute and subchronic toxicity of thymoquinone in mice. Drug Development Resources, 44:56-61. [0073] Ibrahim, R. M., Hamdan, N. S., Mahmud, R., Imam, M. U., Saini, S. M., Rashid, S. N., Abd Ghafar S. A., Latiff, L. A., Ismail, M. (2014). A randomised controlled trial on hypolipidemic effects of Nigella sativa seeds powder in menopausal women. Journal of Translational Medicine, 12:82. [0074] Najmi, A., Nasiruddin, M., Khan, R. A., Haque, S. F. (2008). Effect of Nigella sativa oil on various clinical and biochemical parameters of insulin resistance syndrome. International Journal Diabetes Development Countries, 28:11-14. [0075] El-Mahmoudy, A., Shimizu, Y., Shiina, T., Matsuyama, H., El-Sayed, M., Takewaki, T. (2005) Successful abrogation by thymoquinone against induction of diabetes mellitus with streptozotocin via nitric oxide inhibitory mechanism. International Immunopharmacology, 5:195-207. [0076] Farah, K. M., Atoji, Y., Shimizu, Y., Shiina, T., Nikami, H., Takewaki, T. (2004). Nigella sativa L. oil in streptozotocin-induced diabetic hamsters. Mechanisms of the hypoglycaemic and immune potentiating effects. Res Vet Sci, 77:123-129 [0077] Vincent, JB. (2017). New evidence against chromium as an essential trace element. Journal Nutrition, 147:2212-19. [0078] Salem, M. L. (2005). Immunomodulatory and therapeutic properties of the Nigella Sativa L. Seed. International Immunopharmacology, 5:1749-1770. [0079] Ahmad, A., Husain, A., Mujeeb, M., Khan, S. A., Najmi, A. K., Siddique, N. A., Damanhouri, Z. A., Anwar, F. (2013). A review on therapeutic potential of Nigella sativa: a miracle herb. Asian Pac. J. Trop. Biomed, 3 (5): 337-352. [0080] Anderson R A, Kozlovsky, A. S. (1985). Chromium intake, absorption and excretion of subjects consuming self-selected diets. Am. J Clin Nutr., 41(6):1177-83. [0081] Kubota T, Imaizumi T, Oyama J, et al. (1997). L-arginine increases exercise-induced vasodilation of the forearm in patients with heart failure. Jpn Circ J, 61:471-480. [0082] Chen J., Cui X., Zacharek A., et al. (2007). Niaspan increases angiogenesis and improves functional recovery after stroke. Ann Neurol, 62:49-58. [0083] Penberthy, W. T., (2007). The Niacin flush pathway in recovery from Schizophrenia and how Arginine and Glutamine may provide added benefit. JOM, 27:35-36. [0084] Fararh K, Atoji Y, Shimizu Y, Shiina T, Nikami H, Takewaki T. (2004). Mechanisms of the hypoglycaemic and immunopotentiating effects of Nigella sativa L. oil in streptozotocin-induced diabetic hamsters. Res Vet Sci., 77(2):123-129. [0085] Benhaddou-Andaloussi A, Martineau L C, Spoor D, et al (2008). Antidiabetic activity of Nigella sativa. Seed extract in cultured pancreatic β-cells, skeletal muscle cells, and adipocytes. Pharm Biol., 46(1-2):96-104. [0086] Alimohammadi S, Hobbenaghi R, Javanbakht J, et al (2013). Protective and antidiabetic effects of extract from Nigella sativa on blood glucose concentrations against streptozotocin (STZ)-induced diabetic in rats: an experimental study with histopathological evaluation. Diagn Pathol., 8(1):818. [0087] Kanter M, Meral I, Yener Z, Ozbek H, Demir H (2003). Partial regeneration/proliferation of the B-cells in the Islets of Langerhans by Nigella sativa L. in streptozotocin-induced diabetic rats. Tohoku J Exp Med., 201(4):213-219. [0088] Daryabeygi-Khotbehsaraa R., Golzaranda M., Payam Ghaffarib M., Kurosh Djafarian K. (2017). Nigella sativa improves glucose homeostasis and serum lipids in type 2 diabetes: A systematic review and meta-analysis. Complementary Therapies in Medicine, 35:6-13. [0089] Pari L, Sankaranarayanan C. (2009). Beneficial effects of thymoquinone on hepatic key enzymes in streptozotocin-nicotinamide induced diabetic rats. Life Sci., 85(23):830-834. [0090] Alkharfy K. M., Ahmad A., Khan R. M., Al-Shagha W. M. (2015). Pharmacokinetic plasma behaviors of intravenous and oral bioavailability of thymoquinone in a rabbit model, Eur. J. Drug Metab. Pharmacokinet, 40 (3) 319-323. [0091] Rania R. et al (2018). Improvement of antihyperglycemic activity of nano-thymoquinone in rat model of type-2 diabetes. Chemico-Viological Interactions, 295:119-112. [0092] Zebrowska A, Wo_zniacka A, Juczyn_ska K, et al (2017). Correlation between IL36a and IL17 and activity of the disease in selected autoimmune blistering diseases. Mediators Inflammation, 1-10. https://doi.org/10.1155/2017/8980534. [0093] Kistowska M, Meier B, Proust T, et al (2015). Propionibacterium acnes promotes Th17 and Th17/Th1 responses in acne patients. Journal Investment Dermatology, 135: 110-118. [0094] Xiao S, Jin H, Korn T, et al (2008). Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. Journal of Immunology, 181: 2277-2284. [0095] Hentze M W, Muckenthaler M U, Galy B, Camaschella C. (2010). Two to tango: regulation of Mammalian iron metabolism. Cellular, 142(1):24-38. [0096] Papanikolaou G, Tzilianos M, Christakis J I, et al. (2005). Hepcidin in iron overload disorders. Blood, 105(10):4103-4105. [0097] Kremastinos D T, Farmakis D. (2011). Iron overload cardiomyopathy in clinical practice. Circulation, 124(20):2253-2263. [0098] Deugnier Y, Turlin B. (2007). Pathology of hepatic iron overload. World J Gastroenterol, 13(35):4755-4760. [0099] Rajpathak S N, Crandall J P, Wylie-Rosett J, Kabat G C, Rohan T E, Hu F B. (2009). The role of iron in type 2 diabetes in humans. Biochim Biophys Acta., 1790(7):671-681. [0100] Baudrand R, Gupta N, Garza A E, et al. (2016). Caveolin 1 Modulates Aldosterone-Mediated Pathways of Glucose and Lipid Homeostasis. J Am Heart Association, 5(10):e003845. [0101] Kerkela R, Grazette L, Yacobi R, et al. (2001). Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006; 12(8):908-916. 42. van Oosterom A T, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet, 358(9291):1421-1423. [0102] Cumming D C, Yang J C, Rebar R W, Yen S S. (1982). Treatment of hirsutism with spironolactone. JAMA, 247(9):1295-1298. [0103] Ouzan J, Perault C, Lincoff A M, Carre E, Mertes M. (2002). The role of spironolactone in the treatment of patients with refractory hypertension. Am J Hypertens, 15(4 Pt 1):333-339. [0104] Corvol P, Michaud A, Menard J, Freifeld M Mahoudeau J. (1975). Antiandrogenic effect of spirolactones: mechanism of action. Endocrinology, 97(1):52-58. [0105] Palloshi A., Fragasso G. F., Monti L D., Setola E., Valsecchi G et al. (2004). Effect of oral L-Arginine on blood pressure and symptoms and endothelial function in patients with systematic hypertension, positive exercise tests, and normal coronary arteries. Am J Cardiol, 93(7):933-5. [0106] Palmer R M J, Ashton D S, Moncada S. (1988). Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature, 333: 664-6. [0107] Newsholme P, Homem De Bittencourt P I, O'Hagan C, De Vito G, Murphy C, Krause M S. (2010). Exercise and possible molecular mechanisms of protection from vascular disease and diabetes: the central role of ROS and nitric oxide. Clin Sci (Lond), 118(5):341-9. [0108] Iyengar R, Stuehr D J, Marietta M A. (1987). Macrophage synthesis of nitrite, nitrate, and N-nitrosamines: precursors and role of the respiratory burst. Proc Natl Acad Sci USA, 84:6369-73. [0109] Forstermann U, Closs E I, Pollock J S, Nakane M, Schwarz P, Gath I, et al. (1994). Nitric oxide synthase isozymes. Characterization, purification, molecular cloning, and functions. Hypertension, 23:1121-31. [0110] Wascher T C, Graier W F, Dittrich P, Hussain M A, Bahadori B, Wallner S, et al. (1997). Effects of low dose L-arginine on insulin-mediated vasodilatation and insulin sensitivity. Eur J Clin Investment, 27:690-5. [0111] M. Morita, M. Sakurada, F. Watanabe, et al. (2013). Effects of oral L-citrullinesupplementation on lipoprotein oxidation and endothelial dysfunction in humans with vasospastic angina, Immunol. Endocr. Metab. Agents Med. Chemistry, 13:214-220. [0112] N. Kameda, T. Okigawa, T. Kimura, et al. (2011). The effect of L-citrulline ingestion on ECG QT interval and autonomic nervous system activity, J. Physiol. Anthropology, 30: 41-45. [0113] M. J. Romero, D. H. Platt, R. B. Caldwell, et al. (2006). Therapeutic use of citrulline in cardiovascular disease, Cardiovasc. Drug Rev, 24:275-290. [0114] S. Pollock, U. Forstermann, J. A. Mitchell, et al. (1991). Purification and characterization of particulate endothelium-derived relaxing factor synthase from cultured and native bovine aortic endothelial cells, Proc. Natl. Acad. Sci. U.S.A., 88:10480-10484. [0115] S. Shin, S. Mohan, H. L. Fung (2011). Intracellular L-arginine concentration does not determine NO production in endothelial cells: implications on the “L-arginine paradox”, Biochem. Biophys. Res. Community, 414:660-663. [0116] Ahlborg G, Bjorkman O. (1900). Carbohydrate utilization by exercising muscle following pre-exercise glucose ingestion. Clin Phys 7: 181-195. [0117] Ahlborg G, Felig P, Hagenfeldt L, Hendler R, Wahren J. (1974). Substrate turnover during prolonged exercise in man. Splanchinc and leg metabolism of glucose, free fatty acids and amino acids. J Clin Invest 53: 1080-1090. [0118] Antonescu C N, Thong F S L, Niu W, Karnieli E, Klip A. (2011). To be or not to be: regulation of the intrinsic activity of GLUT4. Curr Med Chem Immun Endoc Metab Agents 5: 175-187. [0119] Felig P, Cherif A, Minagawa A, Wahren J. (1982). Hypoglycemia during prolonged exercise in normal men. N Engl J Med 306: 895-900. [0120] Goodyear L J, Hirshman M F, Napoli R, Calles J, Markuns J F, Ljungqvist O, Horton E S. (1996). Glucose ingestion causes GLUT4 translocation in human skeletal muscle. Diabetes 45: 1051-1056. [0121] Greiwe J S, Hickner R C, Hansen P A, Racette S B, Chen M M, Holloszy J O. (1999). Effects of endurance exercise training on muscle glycogen accumulation in humans. J Appl Physiol 87: 222-226. [0122] Guma A, Zierath J R, Wallberg-Henriksson H, Klip A. Insulin induces translocation of GLUT-4 glucose transporters in human skeletal muscle. Am J Physiol Endocrinol Metab 268: E613-E622, 1995. [0123] Holloszy J O, Narahara H T. (1965). Studies of tissue permeability. J Biol Chem 240: 3493-3500. [0124] Holloszy J O, Narahara H T. (1967). Nitrate ions: potentiation of increased permeability to sugar associated with muscle contractions. Science 155: 573-575. [0125] Henriksen E J, Bourey R E, Rodnick K J, Koranyi L, Permutt M A, Holloszy J O. (1990). Glucose transporter protein content and glucose transport capacity in rat skeletal muscles. Am J Physiol Endocrinol Metab 259: E593-E598. [0126] Jeukendrup A E, Raben A, Gijsen A, Stegen J H, Brouns F, Saris W H, Wagenmakers A J. (1990). Glucose kinetics during prolonged exercise in highly trained human subjects: effect of glucose ingestion. J Physiol 515: 579-589. [0127] MacLean D A, Bangsbo J, Saltin B. (1999). Muscle interstitial glucose and lactate levels during dynamic exercise in humans determined by microdialysis. J Appl Physiol 87: 1483-1490. [0128] McConell G, Fabris S, Proietto J, Hargreaves M. (1994). Effect of carbohydrate ingestion on glucose kinetics during exercise. J Appl Physiol 77: 1537-1541. [0129] McCoy M, Proietto J, Hargreaves M. (1996). Skeletal muscle GLUT-4 and postexercise mus cleglycogen storage in humans. J Appl Physiol 80: 411-415. [0130] Zaid H, Talior-Volodarsky I, Antonescu C, Liu Z, Klip A. (2009). GAPDH binds GLUT4 reciprocally to hexokinase-II and regulates glucose transport activity. Biochem J 419: 475-484. [0131] Dugani, C. B. & Klip, A. (2005). Glucose transporter 4: cycling, compartments and controversies. EMBO Rep 6, 1137-1142. [0132] Qi Zhoua Xinzhou Yangb Mingrui Xionga Xiaolan Xuc Li Zhenc Weiwei Chena Yan Wanga Jinhua Shena Ping Zhaoa Qing-Hua L. (2016). Chloroquine Increases Glucose Uptake via Enhancing GLUT4 Translocation and Fusion with the Plasma Membrane in L6 Cells. Cellular Physiology and Biochemistry, 38: 2030-2040.