Diabetic Gastroparesis: Navigating Pathophysiology and Nutritional Interventions

Round 1

Reviewer 1 Report

Caturano and colleagues provide a review of the clinical presentation and pathological mechanisms that underly diabetic gastroparesis (DGP). The importance of gastric emptying on glycaemia and the role of nutritional management is emphasized. A case is made for guiding therapy based on underlying cause of disease.

The section on gastric function and emptying is less strong than the section on (putative) pathophysiology on the cellular level. The sections on glycaemia and nutritional management are also strong. There is no reference to medical and surgical management. 

Comments and Queries

Major

The mechanism of gastric emptying is not accurately described. After meals gastric emptying is not driven by powerful contractions. The pylorus closes as the contraction wave approaches the distal stomach an effect that is essential for mechanical digestion (trituration). Instead, the “chyme” produced by chemical and mechanical digestion empties into the duodenum due to the presence of a positive gastro-duodenal pressure gradient. It is only late on in the emptying process that powerful MMC III contractions appear to empty the stomach of indigestible material. This has been known for many years and is referenced in many reviews by experts in gastrointestinal function but is often wrongly stated in text books and poorly appreciated in the wider medical community. Even if the authors do not agree with the modern conception of gastric function, this debate between the peristaltic and pressure pump mechanisms of GE should be referred to.

Impaired neurohormonal feedback is likely to be an important cause of GI dysfunction and symptoms in patients with DGP. The release of incretin GI peptide hormones is less in diabetic patients than healthy controls. This includes but is not limited to PPP. The PPP response to sham feeding (rarely performed) is thought to be diagnostic of vagal dysfunction; however, PPP itself has no known function in humans.  In any case, most of these hormones tend to slow GE and so a reduction in release this cannot explain the observations! Instead, the effect of abnormal vagal signaling on gastric and specifically pyloric function is more likely to be relevant. Pylorospasm is a consequence of vagal neuropathy that is described in DGP and treatments directed at the pylorus (e.g. G-POEM) show more efficacy than conventional management.

The “hallmark” of DGP may be delayed gastric emptying; however, the association of delayed gastric emptying and DGP symptoms is weak. Further the presence of delayed GE does not predict the efficacy of prokinetics. Although still regarded as essential for diagnosis, the presence of delayed GE may be more relevant to glycaemia and, possibly, to directing therapy.

As noted by the authors, the diagnoses of gastroparesis and functional dyspepsia are closely inter-twined. It is clear that central brain as well as peripheral disease mechanisms are involved in both conditions.  Gastric distension is a key stimulus in both; however, conceptually, gastroparesis is attributed to abnormal gastric emptying and FD to heightened visceral sensitivity and abnormal central regulation; however, this distinction is difficult to establish in clinical practice (even in DGP). Nevertheless, this issue is important because it has implications for individual therapy targeted at the key underlying cause of symptoms. The overlap with functional GI disorders and gastroparesis should be addressed.

Minor

The authors use the word “intricate” when “complex” may be a better choice.

Note that the Wireless Motility Capsule (WMC) is no longer available and the Motilis 3D-Transit System is not yet available in clinical practice.

n/a

Author Response

Reviewer 1

Caturano and colleagues provide a review of the clinical presentation and pathological mechanisms that underly diabetic gastroparesis (DGP). The importance of gastric emptying on glycaemia and the role of nutritional management is emphasized. A case is made for guiding therapy based on underlying cause of disease.

The section on gastric function and emptying is less strong than the section on (putative) pathophysiology on the cellular level. The sections on glycaemia and nutritional management are also strong. There is no reference to medical and surgical management. 

1. We appreciate the insightful feedback provided by the reviewer. Our primary focus in the review was to present a comprehensive overview of the clinical presentation and pathological mechanisms underlying diabetic gastroparesis (DGP). We acknowledge the observation that the section on gastric function and emptying might not be as robust as the segment discussing the (putative) pathophysiology at the cellular level. Following the reviewer's feedback, we have revisited and enhanced the section on gastric function and emptying to provide a more comprehensive and balanced coverage. We believe these improvements contribute to a more thorough understanding of the topic. We are pleased to note that the sections on glycaemia and nutritional management have been recognized for their strength. It is important to clarify that the omission of references to medical and surgical management was intentional and not an oversight, as the scope of our review was centered on the clinical presentation, pathological mechanisms, and the role of nutritional management. We aimed to provide a focused perspective, and the decision to exclude details on medical and surgical management was made in alignment with the specific objectives of the review.

We appreciate the suggestion and will certainly consider incorporating relevant information on medical and surgical management in future works. Your feedback is invaluable, and we are committed to enhancing the completeness and balance of our reviews.

Comments and Queries

Major

1) The mechanism of gastric emptying is not accurately described. After meals gastric emptying is not driven by powerful contractions. The pylorus closes as the contraction wave approaches the distal stomach an effect that is essential for mechanical digestion (trituration). Instead, the “chyme” produced by chemical and mechanical digestion empties into the duodenum due to the presence of a positive gastro-duodenal pressure gradient. It is only late on in the emptying process that powerful MMC III contractions appear to empty the stomach of indigestible material. This has been known for many years and is referenced in many reviews by experts in gastrointestinal function but is often wrongly stated in text books and poorly appreciated in the wider medical community. Even if the authors do not agree with the modern conception of gastric function, this debate between the peristaltic and pressure pump mechanisms of GE should be referred to.

1. We sincerely appreciate the valuable insights provided by the reviewer, and we are grateful for the opportunity to address and incorporate the constructive feedback into our manuscript. The paragraph in question has been refined to enhance clarity and precision.

2) Impaired neurohormonal feedback is likely to be an important cause of GI dysfunction and symptoms in patients with DGP. The release of incretin GI peptide hormones is less in diabetic patients than healthy controls. This includes but is not limited to PPP. The PPP response to sham feeding (rarely performed) is thought to be diagnostic of vagal dysfunction; however, PPP itself has no known function in humans.  In any case, most of these hormones tend to slow GE and so a reduction in release this cannot explain the observations! Instead, the effect of abnormal vagal signaling on gastric and specifically pyloric function is more likely to be relevant. Pylorospasm is a consequence of vagal neuropathy that is described in DGP and treatments directed at the pylorus (e.g. G-POEM) show more efficacy than conventional management.

1. Thank you for your insightful comments. We appreciate your attention to the potential role of impaired neurohormonal feedback in gastrointestinal (GI) dysfunction in patients with diabetic gastroparesis (DGP). We have thoroughly addressed this concern in the manuscript.

3) The “hallmark” of DGP may be delayed gastric emptying; however, the association of delayed gastric emptying and DGP symptoms is weak. Further the presence of delayed GE does not predict the efficacy of prokinetics. Although still regarded as essential for diagnosis, the presence of delayed GE may be more relevant to glycaemia and, possibly, to directing therapy.

1. We appreciate the reviewer's insightful observation regarding the association between delayed gastric emptying (DGP) and its symptoms. In response to this concern, we have incorporated a new paragraph in our manuscript that delves into this issue. We acknowledge that the 'hallmark' of DGP is often considered to be delayed gastric emptying; however, our exploration reveals that the association between delayed gastric emptying and DGP symptoms is indeed weak. Additionally, our findings suggest that the presence of delayed gastric emptying does not reliably predict the efficacy of prokinetics. Despite its continued significance in diagnosis, we now highlight in our revised manuscript that the presence of delayed gastric emptying may be more relevant to glycaemia and, possibly, to guiding therapeutic interventions. We believe that this addition enhances the comprehensiveness of our work and addresses the reviewer's valid concern.

As noted by the authors, the diagnoses of gastroparesis and functional dyspepsia are closely inter-twined. It is clear that central brain as well as peripheral disease mechanisms are involved in both conditions.  Gastric distension is a key stimulus in both; however, conceptually, gastroparesis is attributed to abnormal gastric emptying and FD to heightened visceral sensitivity and abnormal central regulation; however, this distinction is difficult to establish in clinical practice (even in DGP). Nevertheless, this issue is important because it has implications for individual therapy targeted at the key underlying cause of symptoms. The overlap with functional GI disorders and gastroparesis should be addressed.

Minor

The authors use the word “intricate” when “complex” may be a better choice.

1. We thank the reviewer. We have modified accordingly throughout the entire manuscript.

Note that the Wireless Motility Capsule (WMC) is no longer available and the Motilis 3D-Transit System is not yet available in clinical practice.

1. We thank the reviewer. We have modified accordingly.

Reviewer 2 Report

This is a well written review of the pathophysiology, diagnosis, and treatment of diabetic gastroparesis. The abstract provides a good overview of the content of the article.

The introduction makes a good case for the need to special attention to diabetic gastroparesis (DGP) in the diagnosis and especially the management in relationship to nutrition as well as diabetic management. The authors make a good point that DGP is unpredictable and varies greatly among individuals necessitating the need for careful diagnosis and management.

The epidemiology and pathophysiology sections are explained well. It would be helpful to clarify the prevalence discussion that notes the regional differences. Specifically, the sentence noting that those with higher rates of diabetes are more susceptible to developing DGP and causes. It would be helpful to say a bit more in the paragraph on page 2, lines 72-77. Figure 1 is helpful showing the mechanisms of motility dysfunction. The discussion of the pathophysiology of DGP appears complete and is well referenced.

The diagnosis is described well including the exclusion of other conditions and the specialized tests related to motility. The section on differential diagnosis is important given possible complications of diabetes. The discussion of the symptoms for the various entities appears complete and distinguishes among the various diagnoses. This demonstrates the difficulty of correct diagnosis. This adds to a complete discussion of the diagnosis.

There is a good discussion of the effects of DGP on blood glucose and the difficulties it presents for management. Discussion of therapies to enhance gastric emptying might be helpful.

The authors make some good points related to malnutrition in DGP, especially related to the fact patients may be overweight but malnourished. There is good emphasis on the need for a thorough nutritional assessment and counseling. The dietary recommendations are stated. It might be helpful to describe liquid meals as there are many options. Authors note that researchers are exploring technologies to improve gastric tolerance to fibers. More information on this would be helpful. The main nutritional suggestions seem basic. Some are not referenced in the text.

Overall, the manuscript is well written and referenced.

Author Response

Reviewer 2

This is a well written review of the pathophysiology, diagnosis, and treatment of diabetic gastroparesis. The abstract provides a good overview of the content of the article.

The introduction makes a good case for the need to special attention to diabetic gastroparesis (DGP) in the diagnosis and especially the management in relationship to nutrition as well as diabetic management. The authors make a good point that DGP is unpredictable and varies greatly among individuals necessitating the need for careful diagnosis and management. The epidemiology and pathophysiology sections are explained well.

R. We thank the reviewer for his/her positive comments.

It would be helpful to clarify the prevalence discussion that notes the regional differences. Specifically, the sentence noting that those with higher rates of diabetes are more susceptible to developing DGP and causes. It would be helpful to say a bit more in the paragraph on page 2, lines 72-77.

R. Thank you for your insightful comments and suggestions. We have taken your feedback into careful consideration and made necessary revisions to the paragraph on page 2, lines 72-77. The refined paragraph now provides additional details on regional differences, emphasizing the impact of disparities in healthcare access and awareness on the diagnosis and prevalence rates of DGP. We believe these enhancements contribute to a clearer and more comprehensive understanding of the discussed topic. We hope that our revisions align with your expectations and address the concerns you raised.

Figure 1 is helpful showing the mechanisms of motility dysfunction. The discussion of the pathophysiology of DGP appears complete and is well referenced. The diagnosis is described well including the exclusion of other conditions and the specialized tests related to motility. The section on differential diagnosis is important given possible complications of diabetes. The discussion of the symptoms for the various entities appears complete and distinguishes among the various diagnoses. This demonstrates the difficulty of correct diagnosis. This adds to a complete discussion of the diagnosis. There is a good discussion of the effects of DGP on blood glucose and the difficulties it presents for management.

R. We thank the reviewer for his/her positive comments.

Discussion of therapies to enhance gastric emptying might be helpful.

R. Thank you for your valuable feedback and thoughtful suggestions. We appreciate your keen interest in the topic and your recommendation to include a discussion on therapies to enhance gastric emptying in the manuscript. While we acknowledge the importance of this aspect in the broader context of managing diabetic gastroparesis, it is important to clarify that the primary focus of our review was to analyze the prevalence and associated factors of diabetic gastroparesis globally. As such, we deliberately limited the scope of the review to epidemiological aspects to provide a comprehensive understanding of the prevalence and contributing factors. We agree that the discussion of therapeutic interventions is a crucial aspect of managing diabetic gastroparesis, and your suggestion is well-noted. However, we believe that delving into therapeutic strategies would significantly extend the scope of the review and may be better addressed in a separate dedicated review focused on treatment modalities for diabetic gastroparesis.

The authors make some good points related to malnutrition in DGP, especially related to the fact patients may be overweight but malnourished. There is good emphasis on the need for a thorough nutritional assessment and counseling. The dietary recommendations are stated.

It might be helpful to describe liquid meals as there are many options.

R. We thank the reviewer for this comment. We have tried to present a deeper insight on the topic.

Authors note that researchers are exploring technologies to improve gastric tolerance to fibers. More information on this would be helpful.

R. We thank the reviewer for this comment. We have tried to better explain this topic.

The main nutritional suggestions seem basic. Some are not referenced in the text.

R. Thank you for your insightful feedback. We appreciate your attention to detail. The nutritional suggestions listed in positions 516-526 have been drawn directly from the comprehensive work of Parrish, C.S. and Pastors, J.G., specifically detailed in 'Nutritional Management of Gastroparesis in People With Diabetes' published in Diabetes Spectr. 2007; 20(4): 231–234. Additionally, we have included supplementary information on fiber to further enhance the completeness of the nutritional recommendations.

Overall, the manuscript is well written and referenced.

R. We extend our heartfelt appreciation to the reviewer for their insightful comments, which have significantly enhanced the quality of our manuscript.

Reviewer 3 Report

The review article entitled " Diabetic Gastroparesis: Navigating Pathophysiology and Nutritional Interventions" reviews diabetic gastroparesis and its complications. The authors broadly reviews most of the symptoms and clinical complications of diabetic gastroparesis. However, the authors did not discuss on 

1. Diabetic gastroparesis in gender?

2. sex hormones in diabetic gastroparesis?

3. Neuronal nitric oxide (nNOS) and its dimerization forms in diabetic gastroparesis? Appropriate references need to be acknowledged?

4. Role of nitric oxide?

5. References needs to be updated with recent articles?

Author Response

Reviewer 3

The review article entitled " Diabetic Gastroparesis: Navigating Pathophysiology and Nutritional Interventions" reviews diabetic gastroparesis and its complications. The authors broadly reviews most of the symptoms and clinical complications of diabetic gastroparesis. However, the authors did not discuss on 

1. Diabetic gastroparesis in gender?

R. We appreciate the valuable input from the reviewer and have made the necessary modifications to the manuscript as per the suggestion. Additionally, we have incorporated the gender difference reported in a recent meta-analysis.

2. sex hormones in diabetic gastroparesis?
   R. An appropriate section on gender difference exploring several pathways have been added.
3. Neuronal nitric oxide (nNOS) and its dimerization forms in diabetic gastroparesis? Appropriate references need to be acknowledged?
   R. We have incorporated a new paragraph addressing gender differences and discussed the forms of nNOS dimerization in the manuscript.
4. Role of nitric oxide?
   R. In response to the reviewer's comments, we have made significant improvements to the relevant section, taking into consideration the suggestions provided. Additionally, we have included a discussion on gender differences within the appropriate section to enrich the content and address the reviewer's concerns.
5. References needs to be updated with recent articles?
   R. In response to the reviewer's comment, we have updated the references with recent articles to ensure the incorporation of the latest research findings and advancements in the field. The expansion of the reference list aims to offer a more comprehensive and up-to-date perspective on the topic, encompassing a broader range of relevant literature to enhance the overall quality of the manuscript.

Round 2

Reviewer 1 Report

The authors have addressed the reviewers comments and made extensive edits to their original manuscript. The changes significantly improve the content. I have no further comments.

Reviewer 3 Report

None