Convicting a wrong molecule?

Sok-Ja Janket; Jukka H. Meurman; Eleftherios P. Diamandis

doi:10.1515/dx-2023-0129

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Convicting a wrong molecule?

Sok-Ja Janket , Jukka H. Meurman and Eleftherios P. Diamandis

Published/Copyright: November 1, 2023

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From the journal Diagnosis Volume 11 Issue 2

Keywords: artificial sweeteners; T-cell dysfunction; platelet activation; confounding; epiphenomenon

To the Editor,

Dr. Tilg’s brilliant insights on metabolic diseases are well-known. However, we do not agree with his commentary on artificial sweeteners appeared in the New England Journal of Medicine [1]. The results presented by numerous bench scientists require a focused re-appraisal, because these scientists are not familiar with confounding or biases [2]. For example, Dr. Tilg quoted the report by Zani et al. that sucralose inhibited T-cell mobilization in mice. Since sugar is the key energy source for immune-activation [3], this study proves that sucralose is not a major source of sugar. The second article Dr. Tilg quoted was by Suez et al. who fed mice a high fat diet and saccharin and observed glucose intolerance. High fat diet is an independent risk factor for glucose intolerance [4]. Thus, we cannot blame saccharin as the true culprit of glucose intolerance when two risk factors coexist. The third article Dr. Tilg cited was Witkowski and colleagues’ report [5]. They claimed that erythritol increased platelet activation. However, the process generating platelet-rich-plasma which Witkowski et al. used can activate platelets [6]. Moreover, erythritol can be synthesized endogenously from glucose via the pentose-phosphate-pathway and those who developed obesity have 15-fold higher blood erythritol levels than those without obesity [7]. Thus, glucose may be the key contributor to obesity which activates platelets. When we examined the distribution of CVD risk factors per erythritol levels from Witkowski et al.’s supplementary table (our Table 1), highly positive correlations between cardiovascular risk factors and erythritol levels emerged. Thus, it is likely that major cardiac events in the study of Witkowski et al. [5]. may be due to the underlying cardiovascular risk factors and erythritol may be an epiphenomenon.

Table 1:

Distribution of CVD risk factors per erythritol levels in US validation cohorts.

	Erythritol Q1	Erythritol Q2	Erythritol Q3	Erythritol Q4	p-Value
Diabetes mellitus, %	12.4	15.7	23.9	36.6	<0.001
CAD, %	66.7	71.1	77.4	85.0	<0.001
Heart failure, %	16.1	21.2	26.7	37.9	<0.001
History of MI, %	30.9	35.9	41.2	50.1	<0.001
Triglycerides, mg/dL	103	111	119	131	<0.001

Adapted from supplementary table of Witkowski et al. [5].

Corresponding author: Eleftherios P. Diamandis, MD, PhD, FRCP(C), Lunenfeld-Tanenbaum Research Institute, Sinai Health System, ACDC Lab, Room L6-201, 60 Murray St., Toronto, ON, M5T 3L9, Canada, Phone: 416-586-8443, Mobile: 416-505-2844, Fax: 416-619-5521 Email: diamandis@lunenfeld.ca

Research ethics: Not applicable.
Informed consent: Not applicable.
Author contributions: The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Competing interests: The authors state no conflict of interest.
Research funding: None declared.
Data availability: Not applicable.

References

1. Tilg, H, Adolph, TE. Sucralose and erythritol – not too sweet. N Engl J Med 2023;389:859–61. https://doi.org/10.1056/NEJMcibr2303516.Search in Google Scholar PubMed

2. Janket, SJ, Benwait, J, Isaac, P, Ackerson, LK, Meurman, JH. Oral and systemic effects of xylitol consumption. Caries Res 2019;53:491–501. https://doi.org/10.1159/000499194 [Epub 2019 May 6].Search in Google Scholar PubMed

3. Tucey, TM, Verma, J, Harrison, PF, Snelgrove, SL, Lo, TL, Scherer, AK, et al.. Glucose homeostasis is important for immune cell viability during Candida challenge and host survival of systemic fungal infection. Cell Metabol 2018;27:988–1006.e7. https://doi.org/10.16/j.cmet.2018.03.019.Search in Google Scholar

4. Scheja, L, Heese, B, Zitzer, H, Michael, MD, Siesky, AM, Pospisil, H, et al.. Acute-phase serum amyloid A as a marker of insulin resistance in mice. Exp Diabetes Res 2008;2008:230837.10.1155/2008/230837Search in Google Scholar PubMed PubMed Central

5. Witkowski, M, Nemet, I, Alamri, H, Wilcox, J, Gupta, N, Nimer, N, et al.. The artificial sweetener erythritol and cardiovascular event risk. Nat Med 2023;29:710–8. https://doi.org/10.1111/j.365-2125.1990.tb03762.x.Search in Google Scholar

6. Greaves, M. Platelet function tests in the assessment of antithrombotic agents. Br J Clin Pharmacol 1990;30:175–7. https://doi.org/10.1111/j.365-2125.1990.tb03762.x.Search in Google Scholar

7. Hootman, KC, Trezzi, JP, Kraemer, L, Burwell, LS, Dong, X, Guertin, KA, et al.. Erythritol is a pentose-phosphate pathway metabolite and associated with adiposity gain in young adults. Proc Natl Acad Sci USA 2017;114:E4233–40. https://doi.org/10.1073/pnas.1620079114 [Epub 2017 May 8].Search in Google Scholar PubMed PubMed Central

Received: 2023-09-29

Accepted: 2023-10-02

Published Online: 2023-11-01

This work is licensed under the Creative Commons Attribution 4.0 International License.

Articles in the same Issue

https://doi.org/10.1515/dx-2023-0129

Keywords for this article

artificial sweeteners; T-cell dysfunction; platelet activation; confounding; epiphenomenon

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