|Ahead of print
|Increased expression of BDNF and inflammatory biomarkers in type 2 diabetes-related claustrophobia: A case report
Ankita Srivastava1, Bashair M Mussa2, Salahedeen Abusnana3
1 Sharjah Institute for Medical Research, University of Sharjah, Sharjah, UAE
2 Basic Medical Science Department, College of Medicine, University of Sharjah, Sharjah, UAE
3 Diabetes and Endocrinology Department, University Hospital Sharjah, Sharjah, UAE; Clinical Sciences Department, College of Medicine, University of Sharjah, Sharjah, UAE
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|Date of Submission||24-Mar-2022|
|Date of Decision||20-May-2022|
|Date of Acceptance||24-May-2022|
|Date of Web Publication||08-Jul-2022|
Type 2 diabetes mellitus (T2DM) is widely known to cause damage to several organ systems resulting in complications such as neuropathy, nephropathy, and retinopathy. A characteristic feature of T2DM is hyperglycemia, which can adversely affect the brain and cause psychological disorders such as anxiety and depression. Although several studies have reported a strong association between T2DM and psychological disorders, it is surprising that the latter is not well investigated. Therefore, the main objectives of this case report are to (i) emphasize the association between psychological disorders and T2DM and (ii) investigate the expression of brain-derived neurotrophic factor (BDNF) and inflammatory markers in a case of T2DM-related claustrophobia. By investigating the blood and saliva samples of a 40-year-old male suffering from T2DM and claustrophobia, we report a highly significant increase in BDNF expression and inflammatory biomarkers interleukin-6 and monocyte chemoattractant protein-1 along with a concomitant decrease in interleukin-8 and transforming growth factor-beta. Based on these observations, we propose the presence of a correlation between increased BDNF expression, inflammation, and diabetes-related claustrophobia. Outcomes from this report further highlight the significance of considering T2DM-related psychological disorders as an essential diagnostic measure.
Keywords: BDNF, claustrophobia, diabetes mellitus, inflammatory markers, psychological disorders
|How to cite this URL:|
Srivastava A, Mussa BM, Abusnana S. Increased expression of BDNF and inflammatory biomarkers in type 2 diabetes-related claustrophobia: A case report. Adv Biomed Health Sci [Epub ahead of print] [cited 2022 Aug 8]. Available from: http://www.abhsjournal.net/preprintarticle.asp?id=350313
| Background|| |
Diabetes mellitus (DM) is a chronic metabolic disorder with an exceptionally high prevalence (24%) in the United Arab Emirates (UAE) . This makes UAE ranks second on the list of countries with the highest DM prevalence worldwide, which is highly concerning [1,2]. Typically, type 2 DM (T2DM) is characterized by increased blood glucose levels (hyperglycemia) due to either insulin resistance or inefficient insulin production from the pancreas. Eventually, this increase in blood glucose levels affects several organ systems such as the nervous, circulatory, and inflammatory systems, resulting in T2DM-related complications such as cardiovascular diseases, hyperlipidemia, neuropathy, hypertension, and retinopathy ,,,,,,. In addition, T2DM can also cause a significant effect on the mental status of the patients, resulting in neuropsychiatric complications such as major depressive disorder, mood- and anxiety-related disorders, and phobias . Within the UAE population, few studies have investigated the association of T2DM with depression ,,. These studies have revealed high incidences of T2DM and anxiety-related disorders in this population. Despite this evidence, it is surprising that no study has investigated the association of T2DM with claustrophobia, which is a commonly occurring anxiety-related disorder.
A characteristic feature of anxiety disorders is the disruption of neurotransmission within the brain . One of the primary regulators of this neurotransmission is brain-derived neurotrophic factor (BDNF) [15,16]. BDNF has a crucial role in brain development and plasticity and is involved in the pathogenesis of several conditions, including stress and anxiety ,,. This highlights the critical role of BDNF as a gene of interest in anxiety-related disorders and stress conditions, which are also correlated with inflammatory responses [10,20-22]. Interestingly, BDNF is also known to bridge neuroplasticity and inflammation . Therefore, in the present study, we aimed to report a case of a patient with T2DM and claustrophobia and investigate their association, if any, with a focus on the involvement of the BDNF. The main aims of the present study are to (i) examine the levels of BDNF and the inflammatory profile of the patient with T2DM and claustrophobia, (ii) compare the findings of the latter with a T2DM patient who has no other complications (T2DM) and an age-matched healthy subject (control), and (iii) identify the role of BDNF and inflammatory biomarkers in diabetes-related claustrophobia.
| Case report|| |
A 40-year-old man diagnosed with T2DM (duration > nine years) with hyperlipidemia, vitamin D deficiency, and primary hypertension visited a diabetes clinic in Sharjah, UAE, with a complaint of claustrophobia in May 2015. Since then, he is also being monitored for depressive disorder by a psychiatrist. In 2019, his body weight was recorded at 138.4 kg with a body mass index (BMI) of 53.393 kg/m2 and HbA1c at 6.9% (Supplementary Material, Section 1A). However, his most recent anthropometric measurements in January 2021 showed a decrease in his body weight to 120.8 kg, and correspondingly, his BMI to 42.3 kg/m2 with regulated glucose metabolism (fasting glucose—5.2 mmol/L, HbA1c—5.9%; Supplementary Material, Sections 1B and 2). Demographic data of all three subjects involved in the study are included in the Supplementary material, Section 1A, whereas the psychiatry notes and medications of the patient with T2DM and claustrophobia are mentioned in Sections 3 and 4, respectively.
The primary organ in the brain that is responsible for processing phobias is the amygdala. Thus, dysfunction of the amygdala could be one of the leading causes of claustrophobia. Other causes could also include a traumatic event or familial history. Patients with claustrophobia often experience mild or severe anxiety that could lead to panic attacks when left in a closed, tight, or confined space due to fear of being trapped. Interestingly, animal studies have revealed BDNF as one of the primary mediators responsible for developing susceptibility to the conditioning of fear responses . Therefore, it was of great interest to investigate the expression of BDNF in the patient with T2DM and claustrophobia compared with a T2DM patient without any complications and a healthy subject.
Gene expression analysis of BDNF using blood and saliva
Usually, BDNF is found to be decreased in neurodegenerative diseases such as Huntington’s, Alzheimer’s, and Parkinson’s, as well as in psychological disorders such as depression and claustrophobia [10, 16, 18, 23-26]. In contrast, some studies have reported increased levels of BDNF in autoimmune neurodegenerative diseases such as experimental autoimmune encephalomyelitis and multiple sclerosis, proposing a neuroprotective role for BDNF in such cases [27,28]. However, no study has investigated the role of BDNF in T2DM with the psychological complication of claustrophobia.
In the present case, gene expression analysis of BDNF in both blood and saliva samples was conducted using quantitative real time-polymerase chain reaction (qRT-PCR) (Supplementary Material, Section 5). Results revealed significant upregulation in the levels of BDNF in a patient with T2DM and claustrophobia (T2DM+Claustrophobia) when compared to a patient with T2DM without any related complications (T2DM; blood: P < 0.0001 [Figure 1](a); saliva: P = 0.0003 [Figure 1](b)) and an age-matched healthy control (control; blood: P < 0.0001 [Figure 1(a)]; saliva: P = 0.0062 [Figure 1(b)]).
|Figure 1: Gene expression analysis of BDNF in blood and saliva samples. (a) A highly significant upregulation (P < 0.0001) was observed in the expression of BDNF in the patient with T2DM+Claustrophobia compared with the control subject (control) and patient with T2DM without any complications (T2DM). (b) Similarly, significant upregulation was also observed in the saliva sample of the patient with T2DM+Claustrophobia compared with the control subject (control; P = 0.0062) and patient with T2DM without any complications (T2DM; P = 0.0003) (data are represented as dCt values of three independent experiments with average of two duplicates each; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001).|
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Profiling and analysis of cytokines
BDNF also acts as a bridge between neuroplasticity and inflammation . Cytokines, chemokines, and other pro- or anti-inflammatory molecules are vital regulators and modulators of inflammatory responses. Examining the expression of these regulators in the present case study is essential in understanding their potential role as biomarkers of inflammation.
Using the enzyme-linked immunosorbent assay (ELISA), which is regarded as the standard method for analysis of cytokines in serum samples, we measured the protein levels of the following cytokines and chemokines: interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), and transforming growth factor-beta (TGF-β) as per the manufacturer’s protocol (Supplementary Material, Section 5). For the patient with T2DM and claustrophobia, a significant increase was observed in the levels of proinflammatory cytokine IL-6 (P < 0.0001 vs. both control and T2DM [Figure 2](a)) and the chemokine MCP-1 (P < 0.0001 vs. both control and T2DM [Figure 2](b)), indicating the presence of an inflammatory response. Moreover, there was a significant decrease in the levels of IL-8 vs. control (P < 0.01 [Figure 2](c)), whereas it was non-significant vs. T2DM patient without complications (T2DM; ns [Figure 2(c)]). As for TGF-β, a highly significant decrease was observed vs. control (P < 0.0001 [Figure 2](d)), which was non-significant vs. the T2DM patient without any complications (T2DM; ns [Figure 2(d)]).
|Figure 2: Protein expression analysis of serum cytokines. (a) A highly significant upregulation (P < 0.0001) was observed in the protein expression of IL-6 in the patient with T2DM+Claustrophobia compared with the control subject (control) and patient with T2DM without any complications (T2DM). (b) A significant increase in the expression of MCP-1 was observed in the patient with T2DM+Claustrophobia compared with both control and T2DM. (c) Expression of IL-8 decreased significantly for the patient with T2DM+Claustrophobia compared with control, which was non-significant when compared with the T2DM patient without complications. (d) TGF-β expression was observed to decrease significantly for both T2DM and T2DM+Claustrophobia patients when compared with control (data are represented as concentration in pg/mL; **P < 0.01, ***P < 0.001, ****P < 0.0001).|
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| Discussion|| |
Several studies have investigated the complications of diabetes; however, its association with psychological disorders remains poorly evaluated. Based on the findings from De Ornelas Maia et al. , psychological disorders such as anxiety and depression were significantly detected in patients with both type 1 and type 2 diabetes, highlighting the need for more investigatory studies in this group of patients. However, no study has investigated the association of claustrophobia with T2DM yet. Therefore, to the best of our knowledge, outcomes from the present report are the first to suggest a correlation among BDNF, inflammatory biomarkers, and diabetes-related claustrophobia.
We reported a case of T2DM with claustrophobia in a 40-year-old man with a history of depressive disorder, hypertension, and obesity. The present investigation has revealed a significant upregulation of BDNF gene expression in the blood and saliva samples of the patient with T2DM and claustrophobia compared with a patient with T2DM without complications and a healthy control. Supporting these findings, Xie et al.  have also reported a significant involvement of BDNF in the pathophysiology of phobic disorders in a Chinese cohort. Furthermore, Ibarra et al.  detected an epigenetic association between BDNF polymorphism (Val66Met) and phobic anxiety coupled with somatization. These findings suggest a significant correlation between BDNF levels in phobic disorders that remains underexplored.
Interestingly, studies have found a similar trend in BDNF expression in other psychiatric disorders [10,32]. However, these studies measured BDNF in serum samples, which is vulnerable to processing factors such as storage, temperature, and handling . Therefore, investigating gene expression of BDNF in blood and saliva RNA using qRT-PCR provided us with higher accuracy and sensitivity and can thus be regarded as a more precise representation. Supporting our results further, several studies have proposed BDNF as a predictive marker for neurodegenerative diseases in both animals and humans, emphasizing the correlation of BDNF levels in the blood with the brain ,,. Similar outcomes were observed using saliva samples; however, the conclusion was contradictory as most of these studies used ELISA to measure protein expression compared with gene expression using qRT-PCR ,,.
Through this case report, we have suggested the involvement of BDNF in fear responses, glucose metabolism, and neuroinflammation. Several factors can affect the encephalic expression of BDNF. Still, given the pathogeneses of diabetes and psychological disorders, the exact frequency with which the levels of BDNF fluctuate within the brain remains unknown [10,40]. Therefore, further investigation is warranted to examine the involvement of BDNF in psychological disorders associated with T2DM.
Measuring inflammatory markers has revealed a significant upregulation in the expression of IL-6 and MCP-1 and a concomitant decrease in IL-8 and TGF-β in the patient with T2DM+Claustrophobia compared with T2DM without complications and healthy control. Given the pathophysiology of T2DM, the presence of inflammation is not surprising. This outcome is in line with observations from Brennan et al.  that reported a significant correlation between increased levels of inflammatory markers with phobic anxiety in women with diabetes. Although TGF-β is classically known as an anti-inflammatory mediator, in the presence of IL-6, it can stimulate the activation of T helper 17 (Th17) cells, causing an inflammatory response . Based on a review by Karina Braga Gomes , the role of TGF-β is paradoxical as it is dependent on several other pro- and anti-inflammatory mediators of T2DM. Furthermore, the decrease in IL-8 and TGF-β observed in our study could also be a consequence of diabetic complications, a novel finding that has been reported in the studied population by our group previously .
Based on these observations, we propose the presence of a correlation among increased BDNF expression, inflammation, and diabetes-related claustrophobia using blood and saliva samples from a patient with T2DM and claustrophobia. Although some studies have investigated the relationship between diabetes and fear, the present case is the first to report an association between diabetes and claustrophobia [11,44]. Therefore, the absence of previous studies of claustrophobia in T2DM further highlights the importance and novelty of this study.
To understand the frequency of BDNF upregulation, measuring the corresponding levels of BDNF, inflammatory markers, and claustrophobia over an extended period would result in a more comprehensive investigation. Moreover, designing a study with a larger sample size and gender-matched population would provide more substantial outcomes as the expression of BDNF also depends on sex hormones and steroids [45,46]. Furthermore, evaluating the medications taken by the patients would be vital in understanding their effect on the levels of BDNF, if any.
| Conclusion|| |
We observed a highly significant upregulation in the genetic expression of BDNF using blood and saliva samples and serum proteomic expression of inflammatory biomarkers IL-6 and MCP-1 in a patient with T2DM-related claustrophobia compared with a patient with T2DM without complications and a healthy control. Outcomes from this study suggest a correlation between BDNF and T2DM-related claustrophobia along with inflammation. Thus, it is highly recommended to include psychological evaluation as a parameter in the treatment regime of diabetic patients.
The authors would like to thank all the participants who were involved in the present study for their valuable participation. In addition, the authors would like to thank Ms. Abeer AlHabshi and Ms. Asma Obaideen for their help in sample processing and verification of the medical records, respectively.
AS designed the study, conducted the experiments, and analyzed the data. BMM validated the study design, results, and analysis. The study is supported by research grants to BMM. AS prepared the report. BMM and SA edited and reviewed the report.
The study was approved by the Ethics Committee of UOS (REC-19-01-21-02) and UHS (UHS 10032019) and conducted in accordance with the Declaration of Helsinki. All participants were requested to sign an informed-consent form written in their native language that was approved by the Ethics Committee prior to the recruitment process.
Financial support and sponsorship
This study was supported by Targeted Grant (No. 1801090137) from University of Sharjah and Al Jalila Foundation (AJF2018082) to BMM.
Conflict of interest
The authors declare no conflict of interest.
Data availability statement
All the data used to support the findings of the study are included in the report.
Declaration of patient consent
All patients signed an informed consent in their native languages prior to the recruitment process. The signed forms are available on request.
| Supplementary Material|| |
1. DEMOGRAPHIC ANALYSIS OF SUBJECTS
A. All subjects in 2019
B. T2DM+Claustrophobia in 2021
2. BLOOD REPORT (SUBJECT WITH T2DM+ CLAUSTROPHOBIA; JANUARY 2021)
RBC: 7.76 × 106/µL
Hemoglobin: 14.3 g/dL
MCV: 62 fL
MCH: 18.4 pg
MCHC: 29.5 g/dL
Platelet count: 325 × 103/µL
WBC: 8.1 × 103/µL
Neutrophils: 3.9 × 109/L
Lymphocytes: 3.6 × 109/L
Monocyte: 0.5 × 109/L
Eosinophils: 0.09 × 109/L
Basophils: 0.04 × 109/L
Creatinine: 64 µmol/L
Estimated GFR, male: 227 mL/min
Estimated GFR, female: 193 mL/min
Albumin: 44 g/L
Alanine aminotransferase: 31 U/L
Alkaline phosphatase: 47 U/L
Aspartate aminotransferase: 19 U/L
Bilirubin—total: 14 µmol/L
Bilirubin—direct: 5 µmol/L
Gamma glutamyl transferase: 16 U/L
Protein (total): 72 g/L
Potassium: 4.2 mmol/L
Sodium—plasma or serum: 137 mmol/L
Thyroid-stimulating hormone—3rd generation: 0.887 mIU/L
Urea (BUN): 4.0 mmol/L
LDL: 1.69 mmol/L
Cholesterol—total: 3.50 mmol/L
Glucose—fasting: 5.2 mmol/L
Triglycerides: 0.79 mmol/L
3. PSYCHIATRY NOTES (PATIENT WITH T2DM+CLAUSTROPHOBIA)
Came with complaint of fear on closed places.
He did not go to the therapist and stopped the medication for few days. He said that he has improved a little as his mood is better. His wife said that the patients is lazy and does not like to do anything. He is afraid to get on the escalator. But wanting to get better but he has his mother to care for.
- Psychoeducation for him and his wife and reassurance;
- To restart medication and increase to 40 mg Fluoxetine and Inderal once a day;
- Strongly advised to see the therapist.
4. MEDICATION (PATIENT WITH T2DM+CLAUSTROPHOBIA)
COVERSYL, ASPIRIN, JANUMET, JARDIANCE, VITA-D, LIPITOR, ZESTRIL, VICTOZA, SIDERAL FORTE, STATIX 10, BETASERC, PEPSOLAN, CURAM, KLACID, PROFINAL, VICTOZA, FASTUM, CARMELLOSE, GLYCERINE, SODIUM HYALURONATE-OPTIVE FUSION, BETASERC, NASONEX, CLARITINE, MUCOLYTE, JALRA M, PANTOZOL, CIPRALEX
The present cross-sectional study was conducted at the University Hospital Sharjah (UHS) and Sharjah Institute for Medical Research (University of Sharjah, UOS). From a cohort of 102 patients with confirmed diagnosis of T2DM (for more than 5 years) recruited from the diabetes clinic in UHS, one patient was also diagnosed with claustrophobia. For comparison, we chose a patient with confirmed T2DM without any complications (T2DM) and a healthy Emirati control subject without any diseases (Control).
The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committees of UHS and UOS. All participants were requested to sign an informed-consent form written in their native language, which was approved by the Ethics Committees prior to the recruitment process.
For all participants, the demographic and clinical data were acquired from the UHS electronic medical records system which included age, gender, and anthropometric measurements—height (cm), weight (kg), and BMI (kg/m2). In addition, vital signs including systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate were also measured and recorded.
Blood sample collection
From each subject, about 8 mL of blood sample was collected once and the following laboratory tests were conducted: hemoglobin A1c (HbA1c, %), fasting blood glucose, insulin levels (mU/L), total cholesterol (mmol/L), triglycerides (mmol/L), high-density lipoprotein (HDL, mmol/L), low-density lipoprotein (LDL, mmol/L), C-reactive protein (mg/L), creatinine (mmol/L), and c-peptide (nmol/L). Furthermore, RNA was extracted from these blood samples using the Qiazol® method (Qiagen, Hilden, Germany) as per the manufacturer’s instructions.
Saliva sample collection
Subjects were asked to donate about 5 mL of saliva over 10 min in 15 mL falcon tubes (Nunc, Roskilde, Denmark) containing 1 mL of RNAlater™ (Qiagen, Hilden, Germany) for long-term preservation. Samples were collected using the passive drool technique which involved moving their jaws for a few seconds enacting mastication and then gently pooling the saliva into the collection tubes . Samples were stored at 4°C until they were processed. RNA was extracted from these saliva samples using the Qiazol® method (Qiagen, Hilden, Germany) as per the manufacturer’s instructions.
Gene expression using qRT-PCR
Isolated RNA from the blood and saliva samples was quantified by the Nanodrop2000 spectrophotometer (Thermo Fisher Scientific, Waltham, MA, USA). Purity was determined by the A260/A280 ratio and then the RNA samples were reverse transcribed to 100 ng of cDNA using the High-capacity cDNA Synthesis kit (Applied Biosystems, Foster City, CA, USA). From this, 1 µL of cDNA was used to perform quantitative PCR using the PowerUp™ SYBR™ green master mix (Thermo Fisher Scientific, Waltham, MA, USA) in a total reaction volume of 10 µL, containing 5 µL of the master mix, 1 µL of 10 µM forward primer, 1 µL of 10 µM reverse primer, and 2 µL of nuclease free water per sample. The reaction was set up in duplicates and the experiment was performed three times for reproducibility using the QuantStudio 3 Real-Time PCR system (Applied Biosystems, Foster City, CA, USA). Cycling parameters were followed as per the manufacturer’s protocol for a standard reaction. [Table 1] enlists the primer sequences used for glyceraldehyde 3-phosphate dehydrogenase (GAPDH; house-keeping gene) and brain-derived neurotrophic factor (BDNF; gene of interest).
|Table 1: Primer pairs used for quantitative real-time polymerase chain reaction.|
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Protein expression using ELISA
Soon after collection, the whole blood samples were left undisturbed for about 15–30 min at room temperature to allow clotting. Clotted blood samples were then centrifuged at 2000 RPM for 10 min at 4°C to obtain serum. The serum then was used to detect the levels of the following inflammatory biomarkers: IL-6 (Cat. No. E-EL-H0102), MCP-1 (Cat. No. E-EL-H6005), IL-8 (Cat. No. E-EL-H0048), and TGF-β (Cat. No. E-EL-H0110) using human enzyme-linked immunosorbent assay (ELISA) kits (Elabscience, Guangzhou, China), following the manufacturer’s protocol.
For gene expression analysis, data are represented as dCt values where each dot represents the average of duplicates from three independent experiments. For protein expression analysis, data are represented as the concentration of each inflammatory biomarker in pg/mL. Ordinary one-way ANOVA was performed to calculate significance between the three groups using Tukey’s multiple comparison in the GraphPad Prism 9 software. P-value of less than 0.05 was considered significant.
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Bashair M Mussa,
Basic Medical Science Department, College of Medicine, University of Sharjah, Sharjah, P. O. Box 27272
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]
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