Rapid glycemic regulation in poorly controlled patients living with diabetes, a new associated factor in the pathophysiology of Charcot's acute neuroarthropathy.

OBJECTIVE: Aggressive antidiabetic therapy and rapid glycemic control are associated with diabetic neuropathy. Here we investigated if this is also the case for Charcot neuroarthropathy. RESEARCH DESIGN AND METHODS: HbA1c levels and other relevant data were extracted from medical databases of 44 cases of acute Charcot neuroarthropathy.
RESULTS: HbA1c levels significantly declined from 8.25% (67mmol/mol) [7.1%-9.4%](54-79mmol/mol), at -6 months (M-6), to 7.40%(54mmol/mol) [6.70%-8.03%] (50-64 mmol/mol) during the six months preceding the diagnosis of Charcot neuroarthropathy (P <0.001).
CONCLUSIONS: HbA1c levels significantly declined during the six months preceding the onset of Charcot neuroarthropathy. This decline seems to be a associated factor with the appearance of an active phase of Charcot neuroarthropathy in poorly controlled patients with diabetic sensitive neuropathy.

Introduction

Aggressive antidiabetic therapy and rapid glycemic control may result in a diabetic neuropathy called treatment-induced neuropathy of diabetes (TIND) [1, 2]. On the other hand, Charcot neuroarthropathy is a chronic, devastating and destructive disease of the bone structure and joints in patients with neuropathy. It is characterised by painful or painless bone and joint destruction in limbs that have lost sensory innervation [3, 4]; we have reported a case developed following rapid glycemic control [5]. In this project, we accessed databases of three diabetes centres, extracted a clinically significant number of cases of Charcot neuroarthropathy, and investigated whether its onset was associated with rapid glycemic control. We aimed to investigate this association for better understanding of the physiology of this complication.

Research design and methods

We retrospectively analyzed medical records of persons with diabetes and acute Charcot neuroarthropathy, who had been referred to three hospital centres (Department of Diabetes, Sud-Francilien Hospital, Corbeil-Essonnes, France; Podology Unit, Cochin Hospital, Paris, France; and Department of Diabetes, Pitie-Salpetriere Hospital, Paris) from 2008 to 2018. Patients with suspected active Charcot neuroarthropathy were referred by general practitioners, diabetologists or emergency services of these centres.

Patients

The inclusion criteria were: (i) a diagnosis of acute Charcot neuroarthropathy based on the clinical presentation of a hot and red foot with associated joint oedema and confirmed by radiological examination and nuclear magnetic résonance (MRI), and (ii) patients with HbA1c values (measured in their usual laboratories or at the hospital) at 6 and 3 months before the diagnosis of Charcot neuroarthropathy, and at the time of diagnosis.

The type of Charcot neuroarthropathy was determined according to the classification of Sanders and Frykberg [6, 7]. In Practice, The data of the radiology departments from already mentioned hospitals were screened in order to identify patients having practiced MRI with the diagnosis of active phase neuroarthropathy, the authors then included only patients with sensitive neuropathy and having performed three HbA1c tests within the time specified in the inclusion criteria, the clinical records were consulted for this information. (S1 Fig).

Out of 59 files screened by the three radiology departments, 44 files compliant with the inclusion criteria were finally included (the necessary population size according to the workforce calculation used in the statistical method was 43 patients). It is also important to note that patients with a diagnosis of OAN in active phase can also perform their MRI outside the hospital radiology department), all data were monitored by the clinical research unit of the Centre hospitalier sud Francilien, all three radiology departments used the classification of Eichenholtz [8] to determine an active phase of OAN, (MRI showing signs of microfracture, oedema of the bone marrow and bone contusion to determine an active phase of OAN.

Study design

The study adhered to the Declaration of Helsinki and the state laws of France. According to the national law and the research guidelines of local hospitals, a retrospective study with treatment administered as a part of routine clinical practice does not require the approval of an institutional review board. According to the French law (Decree No. 2016–1872 of December 26, 2016), a file was submitted to the INDS (Institut National des Données de Santé; National Institute of Health Data) and the CEREES (Comité d’Expertise pour les Recherches, les Etudes et les Evaluations dans le domaine de la Santé; Committee of Expertise for Research Studies and Evaluations in the Field of Health).

For each record selected, one of us (DD) collected data in an Excel file using a password-protected computer, without Internet access.

Statistical analysis

To demonstrate an HbA1c reduction of at least 2 points (within six months before the onset of Charcot neuroarthropathy) with an estimated variance of 2.5, we hypothesized that a population size of 43 patients was needed. Statistical analyses were performed with R software (version 3.6.1, The R Foundation for Statistical Computing, Vienna, Austria).

Data are presented as median and interquartile ranges. Statistical analysis for numeric variables was performed according to the non-parametric Friedman and Wilcoxon tests. Pairwise comparisons between time levels were performed using the Bonferonni-Holms method for p-value adjustment. Categorical variables were compared using Fisher’s exact test. Kernel density estimates were used to investigate multimodality [9].

Results

A total of 44 patients diagnosed with diabetes and acute Charcot neuroarthropathy were included in the study. Patients median age was 60 years (interquartile range = 50–71 years); 29 were males and 15 females living with diabetes for 16±3,2 years. Among patients with a foot deformity, 29 had a distortion in the tarsometatarsal joints and 13 in the metatarsophalangeal joints; the remaining two had knee or ankle disease. All subjects had diabetic sensitive neuropathy; only three patients had reported a previous autonomic neuropathy diagnosed before the onset of acute Charcot neuroarthropathy.

HbA1c levels

HbA1c levels declined from 8.25% (67mmol/mol) [7.1%–9.4%](54-79mmol/mol), at -6 months (M-6), to 7.80%(62mmol/mol) [7.15%–8.25%](55-67mmol/mol) at -3 months (M-3) and 7.40%(54mmol/mol) [6.70%–8.03%] (50–64 mmol/mol) at the time of diagnosis of Charcot neuroarthropathy (M0) (S1 Fig). This decrease in HbA1c level was highly significant (p <0.001).

Of the 44 included patients, 15 presented with T1DM and 29 with TD2M (S1 Table). HbA1c levels significantly decreased in patients with T1DM (-1.78% p <0.01) but not in patients with T2DM (-0.74%, not significant).(S2 Fig).

Recent intensification of treatment

Thirty-three patients underwent an intensification of antidiabetic treatment (16 with insulin, fou with liraglutide and six with oral antidiabetics (OADs). Intensification of antidiabetic treatment was unknown for seven patients) and one patient received a pancreas transplant (S1 Table). Of the 16 patients receiving insulin intensification, ten had T1DM, and six had T2DM (S1 Table).

Significant heterogeneity was found in the magnitude of HbA1c reduction with treatment intensification. Kernel density estimates [9] showed that the HbA1c reduction data (x-axis intervals of 0.2%) was well fitted with two normal distributions, one for the mean HbA1c reduction = 0.86% ± 1.66% and the second one for the HbA1c reduction = 4.23% ± 3.61%.

Discussion

In our study, HbA1c levels significantly declined during the six months before the onset of acute Charcot neuroarthropathy. HbA1c levels decreased more in patients with T1DM compared to patients with T2DM (S2 Fig). Significant heterogeneity was found in the magnitude of HbA1c reduction with treatment intensification (S3 Fig). Taking a cut-off of 2 points for the decrease in HbA1c% in six months, seventeen participants (two with T1DM and fifteen with T2DM) had an HbA1c reduction equal to or higher than the cut-off.

We included 44 diabetic patients with acute Charcot neuroarthropathy, a large sample size for an unusual disorder (its prevalence in patients with diabetes is 0.1% and 0.4% [10,11]). As expected, all included subjects had diabetic sensitive neuropathy. The distribution of HbA1c reduction among the included patients was bimodal. Therefore, we used a cut-off point (HbA1c reduction of more than 2 points in six months) similar to the one used by Gibbons et al. [1, 2] to define TIND (HbA1c reduction of more than 2 points in three months) [1]. In our study, we have a similar reduction, but in over six months, the clinical presentation of CN is longer than that of TNID.

Interestingly, the prevalence of TIND reported by Gibbons et al. (up to 10%) [1, 2] is similar to ours (11.4% of treatment-associated acute Charcot neuroarthropathy).

The Charcot neuroarthropathy (CN) is a rare and devastating disorder presenting with peripheral and/or autonomic neuropathy that affects people with diabetes [3, 4], [in our study only three patients had reported a diagnosis of autonomic neuropathy]. A late diagnosis of CN can have serious consequences, including amputation. The physiopathology of this disorder is poorly known. A new series of experiments was carried on the evolution of bone modelling factors in the appearance of Charcot neuroarthropathy with the implication of the receptor activator of nuclear factor-B ligand (RANKL) and its natural antagonist, osteoprotegerin (OPG) [12,13], it has already been described the value of OPG can vary after insulin treatment in patients living with type 1 diabetes [14], this may refine the hypotheses and the results of our study, however, the RANKL value was not evaluated in that study [14].

More, a diagnosis of neuroarthropathy in particular circumstances which can be linked to rapid correction of the glycemic balance without treating the subject directly has been described, as the onset of Charcot neuroarthropathy during weight loss after bariatric surgery [15] and after kidney and pancreas transplantation [16], it is for the first time we can clearly describe an association type relationship and not a direct causality between the onset of acute CN with the rapid glycemic control, a study tackled the level of HbA1C as a predictive factor in the onset of an OAN, but without conclusive results [17], in other words, one thinks that this rapid reduction in HbA1C levels contributes to the month in a partial way to the activation of the inflammatory phenomena which are currently the triggers of OAN [18]

Study limitations include: (i) The single-group design often employed in retrospective studies limits the researchers’ ability to determine cause and effect. Although it is usually impossible to include a control group in a retrospective study, whenever possible a control group should be included to help establish the cause-and-effect relationship; (ii) data extraction was centre-based, potentially ignoring site-specific factors.

In conclusion, HbA1c levels significantly declined during the six months preceding the onset of acute Charcot neuroarthropathy. This prevalence is similar to the prevalence of up to 10% reported by Gibbons et al. [1, 2] for TIND. Our results suggest that rapid glycemic control in chronically unbalanced patients with diabetic neuropathy is an associated factor for acute Charcot neuroarthropathy.

Decrease in HbA1c levels before the onset of Charcot neuroarthropathy.

Values are given as median [interquartile ranges]. Statistical significance was tested with the non-parametric Friedman’s test.

(DOCX)

Click here for additional data file.

Reduction in HbA1c levels according to the type of diabetes.

(DOCX)

Click here for additional data file.

Heterogeneity of the magnitude of HbA1c reduction in the 6 months preceding the onset of Charcot neuroarthropathy.

(non parametric Friedman test).

(DOCX)

Click here for additional data file.

Therapeutic aspects of the included patients.

(DOCX)

Click here for additional data file.

Fow chart of collecting data.

(DOCX)

Click here for additional data file.

Transfer Alert

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1 Apr 2020

PONE-D-20-06583

Rapid glycemic regulation in poorly controlled patients living with diabetes, a new approach ginger-module-highlighter-mistake-type-3" id="gwmw-15856881875558206946191">in understanding the pathophysiology of Charcot's acute ginger-module-highlighter-mistake-type-1" id="gwmw-15856881875558947104717">neuroarthropathy

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Based on the constructive and valued reviewers’ comments, the authors should address, in addition, the following concerns:

- Provide more information about the inclusion and exclusion process, screening of cases etc. A flow chart would be most helpful as the patient-group in question is a heterogenous one and too little data are presented regarding this issue.

- Provide a fully plausible and validated biological model for the described association. Otherwise, the authors should point to this issue in the study shortcomings for the readers.

- Acknowledge the fact that data speak describe an association and not a causality.

- Sufficiently address in their study limitations all the possible pitfalls that stem from drawing conclusions from retrospective data.

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Reviewer #1: To the authors:

Thank you for the opportunity to review this ginger-module-highlighter-mistake-type-1" id="gwmw-15856882294543587272824">intersting paper by Dardari et al.

The paper touches upon a very interesting and largely overlooked problem in ginger-module-highlighter-mistake-type-1" id="gwmw-15856882307373516530623">glycaemic regulation, namely the complications that can arise from too rapid/aggressive blood glucose treatment.

While the issues regarding cardiovascular and retinal disease in this regard ginger-module-highlighter-mistake-type-3" id="gwmw-15856882316763224509431">is ginger-module-highlighter-mistake-type-1" id="gwmw-15856882316764421058823">wellknown, the problems with ginger-module-highlighter-mistake-type-1" id="gwmw-15856882316763873544039">neuropathic patients are more elusive.

Below, I have listed my comments on the paper as a whole. Unfortunately, my copy does not contain line ginger-module-highlighter-mistake-type-6" id="gwmw-15856882331351905120624">numbering and so I cannot address my comments to any specific line.

1) More information about the data collection and quality of the database would be helpful. Considering the time period and multiple sites, one wonders about the ginger-module-highlighter-mistake-type-1" id="gwmw-15856882346266953796452">homogenicity of the charts/electronic systems. How were data logged and retrieved?

2) In the same ginger-module-highlighter-mistake-type-6" id="gwmw-15856882366210285016844">vein it would be helpful if the paper included a ginger-module-highlighter-mistake-type-1" id="gwmw-15856882366218889101846">flowchart of patients screened, excluded and so on. How were the data ginger-module-highlighter-mistake-type-1" id="gwmw-15856882384425905003395">entried validated/controlled? How was the diagnosis confirmed?

The 44 cases have been gathered over a 10 year time period, which makes me think that a lot of borderline cases were removed (unless we're talking about smaller hospitals). Thus, it appears the authors had a good and solid screening of cases. However, this is not apparent in the manuscript.

3) What timeline was used to give the diagnosis acute Charcot foot? When was it considered chronic instead? What was the temperature spread? Any bilateral feet? Recurrences?

4) What was the spread in dates from HbA1c analyses at each time point?

5) Since all the patients had Charcot, they probably all had neuropathy before onset. Is it possible that only 3 cases with registered painful neuropathy is due to insufficient data quality.

6) Were there any of the cases with other ginger-module-highlighter-mistake-type-6" id="gwmw-15856882457538292147058">possible plausible listed causes of Charcot foot? For instance trauma, physical stress or surgery?

7) It would be helpful to list HbA1c values in IFCC units as well as DCCT.

8) Did every single patient decrease in HbA1c, or did someone increase as well? If so, were there any differences between the two groups?

9) A change from 66.7 mmol/ginger-module-highlighter-mistake-type-1" id="gwmw-15856882488674427369829">mol to 57.4 mmol/ginger-module-highlighter-mistake-type-1" id="gwmw-15856882488672406722665">mol is relatively small, and unavoidable in clinical practice. Do you have any indication about ginger-module-highlighter-mistake-type-3" id="gwmw-15856882503155184797133">frequency of Charcot arthropathy being associated with such a change in HbA1c? Do you have any suggestions about how to effectively mitigate this issue in high risk patients?

10) Why did the patients get a better HbA1c before Charcot onset? You write that 26ginger-module-highlighter-mistake-type-6" id="gwmw-15856882522164014636389">(27) of 44 patients with altered medication – what happened to the rest? Maybe expand the table to say a bit more about these cases. Did they for instance get hospital control instead of GP control? Did they change lifestyle/lose weight? Is it possible to elaborate further since it's very important?

11) It seems that ginger-module-highlighter-mistake-type-3" id="gwmw-15856882552605569563017">data support an association to better regulation especially in T1DM group. What happens if you remove the T2DM patients from the analysis completely. Why do you think this is the case? Could it be a different ginger-module-highlighter-mistake-type-3" id="gwmw-15856882564132405105517">mechanisms?

12) The authors have found an interesting association between acute Charcot foot and ginger-module-highlighter-mistake-type-2" id="gwmw-15856882572213929706917">resent decrease in HbA1c. But of course association does not mean causality. Could you speculate about other factors that might contribute to this ginger-module-highlighter-mistake-type-2" id="gwmw-15856882582869979896254">find?

Would you be able to design a model to predict or adjust for any such confounding factors to your dataset?

13) At the bottom of page 8, the authors write that the reduction is mainly due to insulin intensification. Has any analysis done ginger-module-highlighter-mistake-type-3" id="gwmw-15856882602814557116714">of this and/or i.e. ginger-module-highlighter-mistake-type-1" id="gwmw-15856882605807033556421">contributing factors?

14) Do you know if any of the patients complained about TIND?

Reviewer #2: Introduction

1- Definition of Charcot neuroarthropathy is needed

2- Clear statement to describe why this research is important.

Methods

1-More justification why the authors select ginger-module-highlighter-mistake-type-3" id="gwmw-15856882635276213516370">retrospective approach and more information about selection of participants

Findings and discussion

Can the authors discuss more about the contributions the study makes to existing knowledge or literature?

**********

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Reviewer #1: No

Reviewer #2: No

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16 Apr 2020

Dear Editor, Dear Reviewer

First of all, I want to thank you for your support for the potential publication of our manuscript. We have taken into account all of your relevant remarks, with particular emphasis on the fact that we are describing an association and not a causality. Presenting our responses and a new version of our manuscript, I will be happy to consider your future comments.

Kindly regards

Dured Dardari

Additional Editor Comments

Based on the constructive and valued reviewers’ comments, the authors should address, in addition, the following concerns:

1- Provide more information about the inclusion and exclusion process, screening of cases etc. A flow chart would be most helpful as the patient-group in question is a heterogeneous one, and too little data are presented regarding this issue.

Answer from Dardari

I hope the modifications made in the Research Design and Methods respond to your important remarks.

2- Provide a fully plausible and validated biological model for the described association. Otherwise, the authors should point to this issue in the study shortcomings for the readers. Acknowledge the fact that data speak describe an association and not a causality.

Answer from Dardari

We have emphasized that our results represent an association and not a direct causality in the discussion section.

3- Sufficiently address in their study limitations all the possible pitfalls that stem from drawing conclusions from retrospective data.

Answer from Dardari

Done.

Reviewer #1

1) More information about the data collection and quality of the database would be helpful. Considering the time period and multiple sites, one wonders about the homogeneity of the charts/electronic systems. How were data logged and retrieved?

2) In the same vein, it would be helpful if the paper included a flowchart of patients screened, excluded, and so on. How were the data entered validated/controlled? How was the diagnosis confirmed?

The 44 cases have been gathered over a 10 year time period, which makes me think that a lot of borderline cases were removed (unless we are talking about smaller hospitals). Thus, it appears that the authors had a good and solid screening of cases. However, this is not apparent in the manuscript

Answer from Dardari

The data from the radiology departments of 3 hospitals were questioned in order to identify the patients who performed MRI during the period selected with the diagnosis of active phase neuroarthropathy. The authors then took into account only the patients having a sensitive neuropathy according to the information in the medical file and a presence of the three assays of HbA1c performed in the times indicated in the inclusion criteria. In this sense, 59 files were delivered by the three radiology departments, 44 files corresponding to the inclusion criteria were finally included (the number necessary according to the workforce calculation used in the statistical method for 43 patients). It is also important to note that patients with a diagnosis of OAN in active phase prove also perform their MRI outside the hospital radiology department, all data were monitored by r the clinical research unit of the southern francilein hospilatier centre.

3) What timeline was used to give the diagnosis of acute Charcot foot? When was it considered chronic instead? What was the temperature spread? Any bilateral feet? Recurrences?

Answer from Dardari

All three radiology departments used the classification of Eichenholtz (8) to determine an active phase of OAN. MRI was used to determine an active phase of OAN: signs of microfracture, oedema of the bone marrow, and bone contusion.

4)What was the spread in dates from HbA1c analyses at each time point?

Answer from Dardari

HbA1c levels declined from 8.25% [7.1%–9.4%] at -6 months (M-6), to 7.80% [7.15%–8.25%] at -3 months (M-3) and 7.40% [6.70%–8.03%] at the time of diagnosis of Charcot neuroarthropathy (M0) (Supplementary Figure 2).

5) Since all the patients had Charcot, they probably all had neuropathy before onset. Is it possible that only 3 cases with registered painful neuropathy are due to insufficient data quality?

Answer from Dardari

We wanted to know if the patients described the presence of painful neuropathy in the moment of the presentation of acute Charcot. Only three patients had already known neuropathy-related pain. Unfortunately, we do not have more information on this issue.

6) Were there any of the cases with other possible plausible listed causes of Charcot's foot? For instance, trauma, physical stress or surgery?

Answer from Dardari

As you have pointed out, it is believed that the rapid reduction of an HbA1c is associated with the other factors already described in the physiopathology of the OAN so we studied only the patient files looking for the main criterion of our study.

7) It would be helpful to list HbA1c values in IFCC units as well as DCCT

Answer from Dardari

Thank you for this comment, we have given the values in IFCC.

8) Did every single patient decrease in HbA1c, or did someone increases as well? If so, were there any differences between the two groups?

Answer from Dardari

Significant heterogeneity was found in the magnitude of HbA1c reduction with treatment intensification (Figure 1). Kernel density estimates showed that the HbA1c reduction data (x-axis intervals of 0.2%) was well fitted with two normal distributions, one of mean HbA1c reduction = 0.86% ± 1.66% and the second one of HbA1c reduction = 4.23% ± 3.61%. Taking a cut-off of 2 points for the decrease in HbA1c% in six months, twenty participants had an HbA1c reduction equal to or higher than the cut-off (Figure 3).

9) Change from 66.7 mmol/mol to 57.4 mmol/mol is relatively small, and unavoidable in clinical practice. Do you have any indication about frequency of Charcot arthropathy being associated with such a change in HbA1c? Do you have any suggestions about how to effectively mitigate this issue in high risk patients?

Answer from Dardari

After the publication of this retrospective study, we wish to set up a prospective evaluation of the bone modulating factors under similar conditions, which one can say that the return towards a “normal level of HbA1c In patients with a chronic glycemic balance must be progressive in the presence of peripheral neuropathy (+/-osteoporosis as a high risk example), this have to be indicated even if the patients have no retinal complication or other reason to indicate a gradual return, it may also be thought that preventive measures prove to be recommended to patients considered at risk, such as adapting footwear, etc., there is a real need to educate clinicians on this therapeutic aspect.

10) Why did the patients get a better HbA1c before Charcot onset? You write that 26(27) of 44 patients with altered medication – what happened to the rest? Maybe expand the table to say a bit more about these cases. Did they for instance get hospital control instead of GP control? Did they change lifestyle/lose weight? Is it possible to elaborate further since it is very important?

Answer from Dardari

The clear and precise information on the therapeutic evolution was obtained only for the patients noted in the table. We do not have information on this question.

11) It seems that data support an association with better regulation, especially in the T1DM group. What happens if you remove the T2DM patients from the analysis completely. Why do you think this is the case? Could it be different mechanisms?

Answer from Dardari

We added the differential measure between type 1 and type 2, the potency on HbA1c is probably linked to the effectiveness of insulin therapy in reducing the level of HbA1c, however on think that the impact of the correction of HbA1c on the causation of the OAN is the same in the two types of diabetes.

12) The authors have found an interesting association between acute Charcot foot and a recent decrease in HbA1c. Nevertheless, of course, association does not mean causality. Could you speculate about other factors that might contribute to this find?

Would you be able to design a model to predict or adjust for any such confounding factors to your dataset?

Answer from Dardari

W.J. Jeffcoate Theories concerning the pathogenesis of the acute Charcot foot suggest that trauma is the basis for triggering inflammatory factors in OAN. We share this opinion, although not all patients with diabetes and trauma develop OAN, so the association of our results and already known factors appears to be interesting and justified.

13) At the bottom of page 8, the authors write that the reduction is mainly due to insulin intensification. Has any analysis done of this and/or, i.e. contributing factors?

Answer from Dardari

We wrote this sentence because the reduction in HbA1c levels was greater in patients with T1D.

14) Do you know if any of the patients complained about TIND?

Answer from Dardari

Unfortunately, we do not have this information.

Reviewer #2

1) Definition of Charcot neuroarthropathy is needed

Answer from Dardari

Many thanks for your suggestion; the modification was done.

2) A clear statement to describe why this research is important

Answer from Dardari

Done.

3) More justification why the authors select retrospective approach and more information about selection of participants

Answer from Dardari

Taking into account the reduced prevalence of this devastating complication, we opted for a retrospective study first in order to prove the concept. We will be delighted to inform you of the results of our prospective phase.

4) Can the authors discuss more the contributions the study makes to existing knowledge or literature?

Answer from Dardari

Done.

30 Apr 2020

Rapid glycemic regulation in poorly controlled patients living with diabetes, a new associated factor in the pathophysiology of Charcot's acute neuroarthropathy

PONE-D-20-06583R1

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7 May 2020

PONE-D-20-06583R1

Rapid glycemic regulation in poorly controlled patients living with diabetes, a new associated factor in the pathophysiology of Charcot's acute neuroarthropathy

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