The novel oral drug Subetta exerts an antidiabetic effect in the diabetic Goto-Kakizaki rat: comparison with rosiglitazone
Authors: Oleg Epstein
Sergey Tarasov
Erwann Philippe
Evgeniy Gorbunov
Bernard Portha
Danielle Bailbé
Journal: Journal of diabetes research (2013)
Discipline: CLINICAL MEDICINE
Keywords: antidiabetic effects; Subetta; RAD of Abs to β -InsR; RAD of Abs to eNOS; Goto-Kakizaki diabetic rats
Affiliations: Laboratoire B2PE (Biologie et Pathologie du Pancréas Endocrine), Unité BFA (Biologie Fonctionnelle et Adaptive), Equipe 1, Université Paris-Diderot et CNRS EAC 4413, 4 rue Lagroua Weill Hallé, Paris Cedex 13, France.

Abstract:  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 (P &lt; 0.01): 147 ± 4 mg/dL and 145 ± 4 mg/dL and 165 ± 4 mg/dL, respectively. The data of glucose tolerance test showed that Subetta and RAD of Abs to β -InsR (similar to Rosiglitazone) prevented significantly (P &lt; 0.01) 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. 

Retracted: No

PubPeer comments:
 In their article Bailbe et al. conclude, that u201cSubetta and release-active dilutions (RAD) of antibodies to u03b2-subunit insulin receptor treatments are effective to significantly improve glucose homeostasis in GK Par diabetic ratsu201d and that u201cchronic oral administration of Subetta and RAD of Abs to u03b2-InsR significantly attenuated fasting hyperglycemia and improved glucose homeostasis in GK Par ratsu201d. However, they fail to mention that Subetta is made from antibodies diluted beyond Avogadrou2019s limit (12 consecutive dilutions of 1:100, see Google patents US8535664) and thus contains no active molecules. The authors do not mention homeopathy in their article, but this clearly is a homeopathic drug. The results obtained by the authors are likely false positives (due to some technical artifact are human biases) considering the very low prior probability of a drug with no active molecules having any specific effect on Human Adipocytes. The authors have not attempted to use any randomization or blinding techniques to account for such possibilities. More over, the data presented in the original paper does not support the abovementioned conclusion, as far as after correct statistical analysis antidiabetic effect of Subetta, can not be distinguished from the effect of water control. Apparently, Subetta did not exert an antidiabetic effect in diabetic Goto-Kakizaki rats in this study. On the ethical side, the authors did not declare conflict of interests, though OOO  NPF  MATERIA MEDICA HOLDING is a Russian Company that markets a number of drugs which contain active ingredients diluted beyond Avogadrou2019s limit, including Subetta. Three out of four authors work for this company. Furthermore, Oleg Epstein is CEO of the abovementioned Company. , 
 2019 expression of concern. https: www.hindawi.com journals jdr 2019 2938413 Journal of Diabetes Research Volume 2019, Article ID 2938413, 2 pages https: doi.org 10.1155 2019 2938413 Expression of Concern Expression of Concern on u201cThe Novel Oral Drug Subetta Exerts an Antidiabetic Effect in the Diabetic Goto-Kakizaki Rat: Comparison with Rosiglitazoneu201d Journal of Diabetes Research Received 28 April 2019; Accepted 28 April 2019; Published 16 June 2019 Copyright u00a9 2019 Journal of Diabetes Research. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Journal of Diabetes Research would like to express concern with the article titled u201cThe Novel Oral Drug Subetta Exerts an Antidiabetic Effect in the Diabetic Goto-Kakizaki Rat: Comparison with Rosiglitazoneu201d [1]. After issues were raised by several different parties [2u20134] and we consulted editors, concerns were found with conflicts of interest, the nature of the therapy as related to homeopathy, text reuse from other authors, and the methods and reporting. Details are as follows. 1. Conflicts of Interest Subetta (in Russian, u0421u0443u0431u0435u0442u0442u0430), specifically u201crelease-active dilutions of antibodies to u03b2-subunit insulin receptor (RAD of Abs to u03b2-InsR) and to endothelial nitric oxide synthase (RAD of Abs to eNOS)u201d, is a proprietary remedy owned by a company several of the authors are affiliated to, OOO u201cNPFu201d Materia Medica Holding; Sergey Tarasov is the Head of Research Analytical Department, Oleg Epstein (also known as Epshtein) is the founder and CEO and holds related patents [5, 6], and Evgeniy Gorbunov is also affiliated. Though affiliations to and funding from OOO u201cNPFu201d Materia Medica Holding were stated in the article, this was not declared as a conflict of interest. 2. Homeopathy The nature of Subetta as related to homeopathy should have been made clear. The serial dilutions used, C12, C30, and C200, make it likely none of the original substance was left in the preparations. At C12, one molecule might remain; below this, none are likely to remain. Dr. Epstein and colleagues have published on this topic since the late 1990s, first referring to u201cultra-dilute potentized antibodiesu201d and later coining the term u201crelease-active dilutionsu201d (RAD). The authors say RAD is not homeopathy [7] and some particles may be retained even at ultra-dilutions [8], but the description of the preparation is clearly related to homeopathy and RAD have been previously reported as related to homeopathy by this group: for example, a 2006 article stated that u201cultralow concentrations of the antibody were obtained using routine homeopathic methodsu201d and referred to their previous work as u201cdrugs obtained by homeopathic methodsu201d [9], the patents notes that the treatment is u201cprepared according to homeopathic technologyu201d [5] and u201chomeopathically potentizedu201d [6], and a 2013 article by Dr. Epstein discusses homeopathy as a form of u201crelease activityu201d and notes that production of RAD uses u201cHahnemannu2019s methodu201d [10], i.e. homeopathic preparation, named after the founder of homeopathy Samuel Hahnemann. Despite concerns over the plausibility of ultra-dilute antibodies having activity, in 2016 the United Kingdom High Court overturned a decision of the hearing officer of the Intellectual Property Office to refuse patents to Dr. Epsteinu2019s products [11]. 3. Text Reuse and Prior Work The article reused around 250 words without citation from Tahara et al., 2011 [12]. The effects of rosiglitazone, a drug formerly used in diabetes treatment, in that previous diabetes mouse model were not the same as in the present study, in which it was used as a positive control. The authors have apologised for the lack of citation. An article from 2012 studying rosiglitazone in GK rats was also not discussed (Gao and Jusko, 2012) [13]. Those results of those two articles could have been compared to the current study, though the authors noted the different models, species, pathogenesis, doses, and duration of treatment, and that the aim of their study was not to study rosiglitazone. This work is similar to a study published by one of the same authors, Dr. Epstein, in reference 7 (Kheyfets et al., 2012) [14], that used a different rat model of diabetes. Streptozotocin-induced diabetes was used in that study, while GK rats were used in this one. Though that article is cited there is no discussion of how the results compare; the authors argued during the review process that this was not necessary because the models are different. 4. Methods and Reporting No blinding is reported, though the authors say the analysis was blinded. There are no statistical adjustments for multiple hypothesis testing, though the authors provided an analysis adjusted using the Benjamini-Hochberg procedure that maintained statistical significance. Panchin et al. [2] argued, in the supplementary material, that the authors should have used a regression analysis and that after adjustment for the false discovery rate there is no significant effect of Subetta; the author Dr. Tarasov replied that the assumptions by Panchin et al. are not supported [8]. Samples of Subetta were stored at room temperature, but u201cstorage at room temperature often leads to antibody degradation and or inactivity, usually resulting from microbial growthu201d [15]. If the action of Subetta were dependent on antibody activity following ultra-dilution, storage at room temperature would have affected the results. The abstract says fasting plasma glucose decreased in rosiglitazone versus vehicle, but this was not so when compared to the appropriate control, carboxy-methyl-cellulose (CMC). Therefore, the intended positive control, rosiglitazone, was no better than the negative control at reducing plasma glucose. Some marginal, inconsistent, or negative results were not highlighted: (i)tThe lack of effect of Subetta on adiponectin, leptin, or glucagon is not mentioned in the abstract (ii)tNo treatment affected HbA1c or GLP-1 other than marginal evidence of increased HbA1c with RAD Abs to eNOS and increased GLP-1 with RAD Abs to beta-insulin receptor versus water (Table 2); (iii)tOnly rosiglitazone increased adiponectin levels (Table 3); this is the opposite of an in vitro study by the authors, but this discrepancy is not discussed (iv)tRosiglitazone had lower leptin levels than vehicle, CMC (Table 3), but this is only indicated as significant at day 1 and not day 28, though the text indicates a significant reduction at day 28. References D. Bailbu00e9, E. Philippe, E. Gorbunov, S. Tarasov, O. Epstein, and B. 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Epstein, u201cStudy of hypoglycemic activity of Subetta and rosiglitazone on the model of Streptozotocin-induced diabetes mellitus in rats,u201d Bulletin of Experimental Biology and Medicine, vol. 153, no. 1, pp. 54u201356, 2012. View at Publisher u00b7 View at Google Scholar u00b7 View at Scopus M. Johnson, u201cAntibody shelf life how to store antibodies,u201d Materials and Methods, vol. 2, p. 120, 2012. View at Publisher u00b7 View at Google Scholar , 
 Retraction Note Published: 23 June 2020 Retraction to: International Journal of Impotence Research https: doi.org 10.1038 ijir.2013.12 The editor has retracted this article because there are concerns about the scientific validity of the study. Specifically, the reagent is diluted beyond the point to which any active molecules are expected to be present and there is no molecular analysis to support the presence of molecules at these dilutions. These concerns have caused the editor to lose faith in the reliability of the findings. ,