The aim of the present study was to evaluate the potential antidiabetic effects of two-component drug Subetta and its components (release-active dilutions of antibodies to β-subunit insulin receptor (RAD of Abs to β-InsR) and to endothelial nitric oxide synthase (RAD of Abs to eNOS)) in Goto-Kakizaki (Paris colony) (GK/Par) diabetic rats. Subetta was administered orally for 28 days once daily (5？mL/kg) and compared to its two components (2.5？mL/kg), Rosiglitazone (5？mg/kg), and vehicle (5？mL water/kg). At day 28, fasting plasma glucose levels were significantly decreased only in Subetta and Rosiglitazone groups as compared to vehicle ( ): ？mg/dL and ？mg/dL and ？mg/dL, respectively. The data of glucose tolerance test showed that Subetta and RAD of Abs to β-InsR (similar to Rosiglitazone) prevented significantly ( ) the age-related spontaneous deterioration of glucose tolerance as seen in the control group. Subetta and RAD of Abs to β-InsR did not significantly modify the glucose-induced insulin secretion. Chronic administration of Subetta and RAD of Abs to β-InsR improves glucose control, to an extent similar to that of Rosiglitazone. We hypothesize that Subetta and RAD of Abs to β-InsR mostly act via an insulin-sensitizing effect upon target tissues. 1. Introduction According to the WHO (2012), more than 347 million people worldwide suffer from diabetes mellitus, and among these 90% have type 2 diabetes. That is why type 2 diabetes is ranked high in prophylactic, therapeutic, and rehabilitation programs worldwide. Despite the high efficacy of per oral antidiabetic drugs in treatment of type 2 diabetes, there are a number of limitations associated with their side effects (hypoglycemia, heart failure, body weight gain, lactic acidosis, low tolerability of some drugs, necessity of multiple-dose administration, etc.). The search for new targets, as well as development of innovative approaches for effective and safe action on these targets remains a topical issue. The use of the release-activity phenomenon, which consists in the modifying action exerted by specifically processed ultradilutions on the starting substance [1, 2], could lay the foundation for one of those innovative methods. The drugs of this class containing the so-called release-active dilutions of antibodies [3] demonstrated a fundamentally new pro-antigen (cotargeted with antigen) targeted activity, based on the ability of release-active dilutions of antibodies to modify the nature of antigen-target (molecule-target) interaction via the mechanism of conformational modification. The efficacy
References
[1]
O. I. Epstein, Ultra-Low Doses (History of One Study), Publishing House of RAMN, Moscow, Russia, 2008.
[2]
O. I. Epstein, “Possible mechanisms of action of potentiated drugs and some of the questions of functioning of biosystems,” Bulletin of the Siberian Branch of the Russian Academy of Medical Sciences, vol. 1, pp. 132–149, 1999 (Russian).
[3]
O. I. Epstein, “Release-activity: a long way from the phenomenon to new drugs,” Bulletin of Experimental Biology and Medicine, vol. 154, pp. 54–58, 2012.
[4]
X. Chu, E. S. Zhavbert, J. L. Dugina, et al., “Effects of chronic treatment with the eNOS stimulator Impaza on penis length and sexual behaviors in rats with a high baseline of sexual activity,” International Journal of Impotence Research, 2013.
[5]
J. Nicoll, E. Gorbunov, S. Tarasov, and O. I. Epstein, “Subetta treatment increases adiponectin secretion by mature human adipocytes in vitro,” International Journal of Endocrinology, vol. 2013, Article ID 925874, 4 pages, 2013.
[6]
S. A. Tarasov, V. V. Zarubaev, E. A. Gorbunov, S. A. Sergeeva, and O. I. Epstein, “Activity of ultra-low doses of antibodies to gamma-interferon against lethal influenza A, (H1N1) 2009 virus infection in mice,” Antiviral Research, vol. 93, pp. 219–224, 2012.
[7]
I. A. Kheyfets, A. A. Spasov, M. P. Voronkova, J. L. Dugina, and O. I. Epstein, “Study of antidiabetic activity of subetta and Rosiglitazone on the model of streptozotocin diabetes in rats,” Bulletin of Experimental Biology and Medicine, vol. 153, pp. 54–56, 2012.
[8]
L. V. Sizova, “Treatment of early arthritis using arthrofoon (ultra-low doses of antibodies to tumor necrosis factor-α),” Indian Journal of Pharmacology, vol. 43, pp. 724–725, 2011.
[9]
P. D. Lisachev, M. B. Shtark, O. O. Sokolova, V. O. Pustylnyak, M. Y. Salakhutdinova, and O. I. Epstein, “A comparison of the dynamics of S100B, S100A1, and S100A6 mRNA expression in Hippocampal CA1 area of rats during long-term potentiation and after low-frequency stimulation,” Cardiovascular Psychiatry and Neurology, vol. 2010, Article ID 720958, 6 pages, 2010.
[10]
V. V. Andrianov, O. I. Epstein, T. K. Gainutdinova, M. B. Shtark, A. K. Timoshenko, and K. L. Gainutdinov, “Antibodies to calcium-binding S100B protein block the conditioning of long-term sensitization in the terrestrial snail,” Pharmacology Biochemistry and Behavior, vol. 94, no. 1, pp. 37–42, 2009.
[11]
V. Castagne, M. Lemaire, I. Kheyfets, J. L. Dugina, S. A. Sergeeva, and O. I. Epstein, “Antibodies to S100 proteins have anxiolytic-like activity at ultra-low doses in the adult rat,” Journal of Pharmacy and Pharmacology, vol. 60, no. 3, pp. 309–316, 2008.
[12]
X. Chu and A. ？gmo, “Sexual incentive motivation in old male rats: the effects of sildenafil and a compound (Impaza) stimulating endothelial NO synthase,” Pharmacology Biochemistry and Behavior, vol. 89, no. 2, pp. 209–217, 2008.
[13]
X. Chu, E. S. Zhavbert, J. L. Dugina et al., “Sildenafil and a compound stimulating endothelial NO synthase modify sexual incentive motivation and copulatory behavior in male wistar and fisher 344 rats,” Journal of Sexual Medicine, vol. 5, no. 9, pp. 2085–2099, 2008.
[14]
O. I. Epstein, “Introducing a new class of pharmaceuticals,” Pharmaceutical Executive, vol. 27, p. S14, 2007.
[15]
A. V. Kalueff, “Antibodies to S-100 protein in anxiety-depressive disorders in experimental and clinical conditions,” in Animal Models in Biological Psychiatry, Nova Science, New York, NY, USA, 2006.
[16]
J. L. Dugina, V. I. Petrov, A. R. Babayeva et al., “A randomized, open-label, comparative, 6-month trial of oral ultra-low doses of antibodies to tumor necrosis factor-α and diclofenac in rheumatoid arthritis,” International Journal of Tissue Reactions, vol. 27, no. 1, pp. 15–21, 2005.
[17]
O. I. Epstein, N. A. Beregovoy, N. S. Sorokina et al., “Membrane and synaptic effects of anti-S-100 are prevented by the same antibodies in low concentrations,” Frontiers in Bioscience, vol. 8, pp. A79–A84, 2003.
[18]
G. V. Karpova, T. I. Fomina, T. V. Vetoshkina et al., “Preclinical studie of general toxic properties of preparations containing ultralow doses of antibodies to endogenous regulators,” Bulletin of Experimental Biology and Medicine, vol. 148, no. 3, pp. 543–546, 2009.
[19]
B. Portha, M. H. Giroix, P. Serradas et al., “β-cell function and viability in the spontaneously diabetic GK rat: information from the GK/Par colony,” Diabetes, vol. 50, no. 1, pp. S89–S93, 2001.
[20]
K. S. Polonsky, B. D. Given, L. J. Hirsch et al., “Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus,” The New England Journal of Medicine, vol. 318, no. 19, pp. 1231–1239, 1988.
[21]
S. I. Taylor, D. Accili, and Y. Imai, “Insulin resistance or insulin deficiency: which is the primary cause of NIDDM?” Diabetes, vol. 43, no. 6, pp. 735–740, 1994.
[22]
B. Portha, “Programmed disorders of β-cell development and function as one cause for type 2 diabetes? The GK rat paradigm,” Diabetes/Metabolism Research and Reviews, vol. 21, no. 6, pp. 495–504, 2005.
[23]
B. Portha, M. H. Giroix, C. Tourrel-Cuzin, H. Le-Stunff, and J. Movassat, “The GK rat: a prototype for the study of non-overweight type 2 diabetes?” in Animal Models of Diabetes Research, H. G. Joost, A. Schürmann, and H. Al-Hasani, Eds., Humana Press, New-York, NY, USA, 2012.
[24]
N. Yasuda, T. Inoue, T. Nagakura et al., “Metformin causes reduction of food intake and body weight gain and improvement of glucose intolerance in combination with dipeptidyl peptidase IV inhibitor in Zucker fa/fa rats,” Journal of Pharmacology and Experimental Therapeutics, vol. 310, no. 2, pp. 614–619, 2004.
[25]
S. J. Dunmore and J. E. Brown, “The role of adipokines in β-cell failure of type 2 diabetes,” Journal of Endocrinology, vol. 216, pp. T37–T45, 2013.
[26]
E. B. Mazo, S. Gamidov, and R. I. Ovchinnikov, “Viagra, cialis, impase—which of them, to whom, when and how?” Urologiia, no. 5, pp. 42–48, 2004 (Russian).
[27]
J. F. Youngren, “Regulation of insulin receptor function,” Cellular and Molecular Life Sciences, vol. 64, no. 7-8, pp. 873–891, 2007.
[28]
A. Shehzad, W. Iqbal, O. Shehzad, and Y. S. Lee, “Adiponectin: regulation of its production and its role in human diseases,” Hormones, vol. 11, no. 1, pp. 8–20, 2012.
[29]
B. Zhang, G. Salituro, D. Szalkowski et al., “Discovery of a small molecule insulin mimetic with antidiabetic activity in mice,” Science, vol. 284, no. 5416, pp. 974–977, 1999.
[30]
R. Luo, X. Li, R. Jiang, X. Gao, Z. Lü, and W. Hua, “Serum concentrations of resistin and adiponectin and their relationship to insulin resistance in subjects with impaired glucose tolerance,” Journal of International Medical Research, vol. 40, pp. 621–630, 2012.
[31]
M. Stumvoll, B. J. Goldstein, and T. W. van Haeften, “Type 2 diabetes: principles of pathogenesis and therapy,” The Lancet, vol. 365, no. 9467, pp. 1333–1346, 2005.
[32]
H. Tilg and A. R. Moschen, “Adipocytokines: mediators linking adipose tissue, inflammation and immunity,” Nature Reviews Immunology, vol. 6, no. 10, pp. 772–783, 2006.
[33]
K. Srinivasan, P. S. Patole, C. L. Kaul, and P. Ramarao, “Reversal of glucose intolerance by pioglitazone in high fat diet-fed rats,” Methods and Findings in Experimental and Clinical Pharmacology, vol. 26, no. 5, pp. 327–333, 2004.
[34]
C. M. O'Rourke, J. A. Davis, A. R. Saltiel, and J. A. Cornicelli, “Metabolic effects of troglitazone in the Goto-Kakizaki rat, a non-obese and normolipidemic rodent model of non-insulin-dependent diabetes mellitus,” Metabolism, vol. 46, no. 2, pp. 192–198, 1997.
[35]
Y. Zhang, R. Proenca, M. Maffei, M. Barone, L. Leopold, and J. M. Friedman, “Positional cloning of the mouse obese gene and its human homologue,” Nature, vol. 372, no. 6505, pp. 425–432, 1994.
[36]
R. V. Considine, M. K. Sinha, M. L. Heiman et al., “Serum immunoreactive-leptin concentrations in normal-weight and obese humans,” The New England Journal of Medicine, vol. 334, no. 5, pp. 292–295, 1996.
[37]
J. L. Halaas, K. S. Gajiwala, M. Maffei et al., “Weight-reducing effects of the plasma protein encoded by the obese gene,” Science, vol. 269, no. 5223, pp. 543–546, 1995.
[38]
M. Maffei, J. Halaas, E. Ravussin et al., “Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects,” Nature Medicine, vol. 1, no. 11, pp. 1155–1161, 1995.
[39]
H. J. Kim, S. K. Kim, W. S. Shim et al., “Rosiglitazone improves insulin sensitivity with increased serum leptin levels in patients with type 2 diabetes mellitus,” Diabetes Research and Clinical Practice, vol. 81, no. 1, pp. 42–49, 2008.
[40]
F. S. Chou, P. S. Wang, S. Kulp, and J. J. Pinzone, “Effects of thiazolidinediones on differentiation, proliferation, and apoptosis,” Molecular Cancer Research, vol. 5, no. 6, pp. 523–530, 2007.
[41]
C. Berthelier, M. Kergoat, and B. Portha, “Lack of deterioration of insulin action with aging in the GK rat: a contrasted adaptation as compared with nondiabetic rats,” Metabolism, vol. 46, no. 8, pp. 890–896, 1997.
[42]
J. Movassat, D. Bailbé, C. Lubrano-Berthelier et al., “Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion,” American Journal of Physiology—Endocrinology and Metabolism, vol. 294, no. 1, pp. E168–E175, 2008.
