Type 1 Diabetes and Addison’s Disease: When the Diagnosis Is Suggested by the Continuous Glucose Monitoring System

Round 1

Reviewer 1 Report

This submission by Vinci, et.al. is a brief case report describing the clinical course and CGM changes of a 13 year old patient with type 1 diabetes mellitus and Addison’s disease.  The authors highlight the CGM findings of early morning hypoglycemia as one of the clues to her diagnosis though there were additional clinical manifestations (symptom and physical exam findings) that were present as well.  The authors should be commended on highlighting a relatively rare (1% or less) co-morbidity in the type 1 population that has potentially life-threatening consequences.  However, there was nothing particularly novel about this case presentation or findings on CGM.  This case report is a good review of a known association but otherwise did not carve much of a niche in the literature.

Introduction

The authors should introduce Schmidts syndrome so the reader is aware of this association before introducing this diagnosis in the last line of the introduction

Internet of Things (IoT) in this reviewers understand is a slang term for the movement of industry to embed technology in their services and devices rather than a “tool”.  While CGM devices could be considered to fall under this umbrella, its not clear why this term is being used and probably would be better left out as it does not add to the introduction.

Case Report

How was autoimmune thyroidits confirmed?

There is no information includd about when the patient was first diagnosed.  This has relevance to her underlying insulin requirement and whether she could have been in her honeymoon.

“Self glycemic control” should be changed to “glucose monitoring”

The authors report that the patient was started on thyroid hormone.  Were the symptoms of adrenal insufficiency worsened?  Was there any evidence of hypotension at clinic visits.  Thyroid hormone can precipitate an adrenal crisis in an untreated Addisonian patient, and the authors may want to highlight this fact as part of their manuscript.

It might be helpful for readers who are not used to looking at a Dexcom report to point out the concerning area on the 14 day average figure.  The authors could include arrows to point out the falls in BG level in the am.

Discussion

While celiac disease and hypothyroidism are recommended screening tests in type 1 diabetes, additional routine screens for other autoimmune disease are not routinely recommended unless a clinical suspicion is present.  It was not clear what  “all 104 autoimmune diseases” that the authors were referring to in their commentary.  In addition, Addison’s is not a routine screening test according to the ADA.

Author Response

POINT 1: The authors should introduce Schmidts syndrome so the reader is aware of this association before introducing this diagnosis in the last line of the introduction.

ANSWER 1: I added the information about Schmidts syndrome in the introduction as you suggested.

POINT 2: Internet of Things (IoT) in this reviewers understand is a slang term for the movement of industry to embed technology in their services and devices rather than a “tool”.  While CGM devices could be considered to fall under this umbrella, its not clear why this term is being used and probably would be better left out as it does not add to the introduction.

ANSWER 2: Agree with your suggestion.

POINT 3 Case Report: How was autoimmune thyroidits confirmed? There is no information includ about when the patient was first diagnosed.  This has relevance to her underlying insulin requirement and whether she could have been in her honeymoon.

ANSWER 3: I added the information about autoimmune thyroiditis diagnosis. We meet our patient for the first time in April 2019, when she was 13 years old and diagnosed with diabetes since the age of 10 (2016) [page 1, line 44-45] so honeymoon was escluded.

POINT 4: “Self glycemic control” should be changed to “glucose monitoring”

ANSWER 4: Agree with your suggestion.

POINT 5: The authors report that the patient was started on thyroid hormone.  Were the symptoms of adrenal insufficiency worsened?  Was there any evidence of hypotension at clinic visits.  Thyroid hormone can precipitate an adrenal crisis in an untreated Addisonian patient, and the authors may want to highlight this fact as part of their manuscript.

ANSWER 5: Agree with your suggestion. I added the information about that (supported by two additional references).

POINT 6: It might be helpful for readers who are not used to looking at a Dexcom report to point out the concerning area on the 14 day average figure.  The authors could include arrows to point out the falls in BG level in the am.

ANSWER 6: Agree with your suggestion. I provided.

POINT 7: Discussion: While celiac disease and hypothyroidism are recommended screening tests in type 1 diabetes, additional routine screens for other autoimmune disease are not routinely recommended unless a clinical suspicion is present.  It was not clear what  “all 104 autoimmune diseases” that the authors were referring to in their commentary.  In addition, Addison’s is not a routine screening test according to the ADA.

ANSWER 7:I apologize about that, "104" was a typing error.

Author Response File: Author Response.docx

Reviewer 2 Report

This case report aims to demonstrate how continuous glucose monitoring can be used to identify early primary adrenal insufficiency as well as better manage patients during steroid therapy. Visualizing CGM trends in an adrenally insufficient patient is a valuable addition to current published literature. However, the report lacks the detail needed to sufficiently demonstrate this. Showing the trends over time in other factors such as insulin use (rather than single discrete time points), % hypoglycemia, weight would be important to see if CGM is a necessary tool or if the diagnosis could have been suspected without seeing this CGM trend. Also, the differential for the CGM pattern and work-up to exclude other causes of decreased insulin needs in the early am after hyperglycemia in the evening was not explored. The discussion would be better spent exploring these things than providing education on details about adrenal insufficiency.

Page 1 Line 26 Internet of Things is not a commonly used term, and I would not use it in this report. It is especially confusing to start the introduction with this sentence.

Page 2 Line 65 – The time in range goals are not consistent with current consensus statement guidelines. Please cite where goals are derived from.

Page 2 Line 77-81. It would be helpful to know how much basal was increased prior to her dawn hypoglycemia as wellas the last time she ate/bolused insulin at night. Was c-peptide ever checked? You can see this pattern in some children who are honeymooning.

FIGURE 1 – Can you show CGM trend progression over a few months prior to diagnosis, or is that data unavailable? It would also be interesting to see how CGM looks once steroids are repleted.

Page 3 Line 91 – There is no discussion of how CGM was helpful in titrating hydrocortisone and insulin needs.

Page 3 Line 117-119 does not make sense

Page 3 Line 120 – don’t need to mention autoimmune gastritis again as discussed previously

Page 4 Line 144-145 Would be good to discuss more details around food eaten and insulin taken as well as bigger differential diagnosis for this pattern as there are other plausible explanations beyond Addison’s disease.

Author Response

POINT 1: This case report aims to demonstrate how continuous glucose monitoring can be used to identify early primary adrenal insufficiency as well as better manage patients during steroid therapy. Visualizing CGM trends in an adrenally insufficient patient is a valuable addition to current published literature. However, the report lacks the detail needed to sufficiently demonstrate this. Showing the trends over time in other factors such as insulin use (rather than single discrete time points), % hypoglycemia, weight would be important to see if CGM is a necessary tool or if the diagnosis could have been suspected without seeing this CGM trend. Also, the differential for the CGM pattern and work-up to exclude other causes of decreased insulin needs in the early am after hyperglycemia in the evening was not explored. The discussion would be better spent exploring these things than providing education on details about adrenal insufficiency.

ANSWER 1: We want point out that CGM can be used not only for the glicometabolic control of the patient affected by type 1 diabetes, but also for prompt recognition of potentially life-threatening condition like addisonian crisis. The aim of the report is to enlight that adrenal insufficiency can be suspected, although latent or pauci-symptomatic, through periodic and careful evaluation of CGM data, which is an unusual (or at least a less known) use of this tool.

POINT 2: Page 1 Line 26 Internet of Things is not a commonly used term, and I would not use it in this report. It is especially confusing to start the introduction with this sentence.

ANSWER 2: Agree with your suggestion.

POINT 3: Page 2 Line 65 – The time in range goals are not consistent with current consensus statement guidelines. Please cite where goals are derived from.

ANSWER 3: Agree with your suggestion. I provided.

POINT 4: Page 2 Line 77-81. It would be helpful to know how much basal was increased prior to her dawn hypoglycemia as well as the last time she ate/bolused insulin at night. Was c-peptide ever checked? You can see this pattern in some children who are honeymooning.

ANSWER 4: Agree with your suggestion. I added some informations about insuline intake, weight and daily insuline requirement. I added some information also about c-peptide (found indosable at the time of diagnosis). Honeymooning was escluded becouse 3 years and a half had passed since the debut.

POINT 5: FIGURE 1 – Can you show CGM trend progression over a few months prior to diagnosis, or is that data unavailable?

ANSWER 5: The first figure refers to april 2019 (few months prior to diagnosis), the second one to august 2019 (moment of diagnosis). We have available some data of february 2019, but they are comparable to april 2019 (TIR 57%, TBR 3%, TAR 40%).

POINT 6: It would also be interesting to see how CGM looks once steroids are repleted.

ANSWER 6: Agree with your suggestion. I provided.

POINT 7: Page 3 Line 91 – There is no discussion of how CGM was helpful in titrating hydrocortisone and insulin needs.

ANSWER 7: Agree it was a poorly expressed concept. I prefere leave it out.

POINT 8: Page 3 Line 117-119 does not make sense

ANSWER 8: I hope i managed to fix it.

POINT 9: Page 3 Line 120 – don’t need to mention autoimmune gastritis again as discussed previously

ANSWER 9: Agree with your suggestion.

POINT 10: Page 4 Line 144-145 Would be good to discuss more details around food eaten and insulin taken as well as bigger differential diagnosis for this pattern as there are other plausible explanations beyond Addison’s disease.

ANSWER 10: I added some informations about insulin requirement and basal insuline modifications between april 2019 and august 2019. I'm sorry, i can't provide more details around food eaten at the time.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The authors have addressed the critiques to the best of their capability. As a case report, the authors highlight the utility of CGM to identify unexplained hypoglycemia as a potential etiology for Addison's disease.  They are successful with this objective.  There remains some sentences that are difficult to understand (e.g. the sentence around c-peptide) and others should have a grammatical review.  Otherwise, the paper is improved from the original submission.

Author Response

Dear reviewer 1,

Based on your suggestions we have performed further revision of the English language and grammatics. I hope you'll find it improved from the original submission.

Author Response File: Author Response.docx