PONE-D-21-16275

Evidence that Human Oral Glucose Detection Involves A Sweet Taste Pathway and A Glucose Transporter Pathway

PLOS ONE

Dear Dr. Breslin,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Dear Dr. Breslin and coauthors,

You have done a superb job addressing most of the concerns raised by the reviewers. In particular, I commend you for conducting the additional experiments. As you note, they strengthen your study and provide robust support for the central claim of your study--that SGLT1 is involved in oral glucose detection in humans. This is clearly a novel and important finding. 

Overall, I believe that you have addressed the majority of the reviewers' original concerns. You will see, however, that Reviewer 1 has some remaining concerns that need to be addressed in your revision. I also have a few editorial suggestions. 

1. Your current title is: "Evidence that Human Oral Glucose Detection Involves A Sweet Taste Pathway and A Glucose Transporter Pathway." This title implies that you have identified two pathways for detecting glucose in the oral cavity. This is not the case. What you have established is that one can systematically alter glucose detection thresholds by modulating the activity of SGLT1. While I do not mean to diminish the importance of this finding, you currently do not know whether modulating the activity of SGLT1 alters downstream voltage-sensitive events in the T1r2-r3 pathway or whether it activates a T1r2-r3-independent pathway. Thus, I recommend that you scale back the scope of your title.

2. End of first paragraph of Introduction: You state: "Clearly sugars engage a second signaling pathway for calories that noncaloric sweeteners fail to engage post-prandially." I do not think that this statement follows logically from the five reasons you provide for why "...diet sodas have never captured a major share of the beverage market." Reviewer 1 has raised additional concerns about this statement.

3. Line 1, second paragraph of Introduction: Change "mice" to "mouse"

4. Line 4, second paragraph of Introduction: The following phrase seems awkward: "...the transportation of glucose". I think that it is more conventional to say "...the transport of glucose"

5. Line 5, second paragraph of Introduction: Why don't you refer directly to the GLUTs? That would seem to be clearer than a vague reference to "...other transporters". 

6. Lines 5-6, second paragraph of Introduction: I think that the following wording is accurate: "...the conversion of glucose into several ATP molecules..." Glucose is not actually converted into ATP molecules. The energy in the glucose molecule is used by glycolysis, krebs cycle and oxidative phosphorylation to add high-energy phosphate bonds to AMP and ADP.

7. Line 10, second paragraph of Introduction: I recommend changing "mouse tissue" to "mouse taste bud cells."

8. Lines 10-13, second paragraph of Introduction: I do not think that the prior literature has established that "taste bud cells in the mouth of mice are capable of identifying when a “sweetener” is metabolizable." Instead, I think this literature has established that murine taste bud cells may be able to detect elevations in salivary glucose via a T1r2+r3-independent mechanism.

9. In the last paragraph of the Introduction, you state: "Were such a signaling system to exist and be functional in the human mouth, it would have implications for oral signaling of metabolizable sugars and could help explain why humans overwhelmingly prefer sugared beverages to non-caloric beverages." I recommend that you dial-back this statement a bit for two reasons. First, because your paper addresses threshold (not suprathreshold) effects of SGLT1, you are creating false expectations in your readers. Second, the use of "metabolizable sugar" is a bit confusing. As noted by Reviewer 1, fructose may not be metabolized in taste cells, but it is certainly metabolized in the liver. Thus, fructose is a metabolizable sugar that does not activate SGLT1.

10. I was surprised that you did not incorporate the findings from a recent mouse paper [Yasumatsu K, Ohkuri T, Yoshida R, Iwata S, Margolskee RF, Ninomiya Y (2020) Sodium-glucose cotransporter 1 as a sugar taste sensor in mouse tongue. Acta Physiologica 230: e13560. doi: 10.1111/apha.13529], as it is highly relevant and supportive of your general hypothesis.

Please submit your revised manuscript by Jul 23 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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John I. Glendinning, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: This revised manuscript is substantially enhanced by the addition of MDG and fructose experiments which support the involvement of SGLT1 sensing in oral glucose detection in humans. However, the characterization of this oral SGLT1-glucose sensing pathway as a "caloric" or " metabolic signaling pathway" is misleading. The SGLT1 pathway does not respond to fructose which is a "caloric" and "metabolizable" sugar. It is also unclear how much sucrose activates the SGLT1 taste pathway given that sucrose must be first hydrolyzed to glucose in the mouth to have this action. The authors should revise their description of the SGLT1 taste pathway. Also, for completeness, the authors should mention that galactose is a ligand for SGLT1 although, given the relatively low amount of free galactose in foods, this sugar may have minimal effects on the oral SGLT1 pathway.

The authors describe MDG as a ligand for SGLT1 but don't mention that it is also a ligand for the T1R2/T1R3 receptor and thus has a sweet taste to humans as it apparently has to mice as judged by their avidity for this glucose analog. The authors speculate that the SGLT1 taste pathway may contribute to the sweetness (or palatability) of sugars in humans and contribute to their preference for sugars over non-nutritive sweeteners. However, this does not appear to be the case in mice. SGLT1 KO and WT mice showed identical preferences for MDG over water in 3-min, 2-bottle tests (Sclafani, Koepsell and Ackroff, 2016). Furthermore, SGLT1 KO and WT mice showed similar preferences for a glucose + saccharin solution over a saccharin in a 1-h choice test. The KO mice consumed less glucose and MDG than WT mice which was attributed to their failure to normally absorb these sugars in the intestine. The authors should acknowledge that the oral glucose-sensing SGLT1 pathway does not appear to mediate oral sugar preference in mice although, as discussed next, it is essential for post-oral glucose preference conditioning. This does not preclude them from speculating about a role of SGLT1 taste pathway in sugar preference in humans.

The following statement in the Introduction should be supported with citations: "Clearly sugars engage a second signaling pathway for calories that noncaloric sweeteners fail to engage post-prandially." Presumably, the authors are referring to rodent and human studies showing that the post-oral actions of glucose and glucose-containing carbohydrates (sucrose, maltodextrin) condition preferences. However, describing this post-prandial pathway as "for calories" is questionable given the many rodent studies showing that glucose is much more effective than fructose in activating the post-prandial pathway. Of particular relevance here are studies showing that mice learn to prefer glucose but not isocaloric fructose over non-nutritive sweeteners (sucralose, Ace K), an outcome thought to be mediated by intestinal SGLT1 signaling (e.g., Sclafani & Ackroff, 2017; Tan et al., 2020). The effectiveness of post-prandial fructose in conditioning sugar preferences in humans is uncertain because the few published human conditioning studies all used maltodextrins.

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Evidence that Human Oral Glucose Detection Involves A Sweet Taste Pathway and A Glucose Transporter Pathway

PONE-D-21-16275R1

Dear Dr. Breslin,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

John I. Glendinning, PhD

Academic Editor

PLOS ONE

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