TYPE Original Research

PUBLISHED 15 September 2023

DOI 10.3389/fpsyt.2023.1196866

Exploring the risk of glycemic

OPEN ACCESS variability in non-diabetic
depressive individuals: a
EDITED BY
Chi-Shin Wu,
National Health Research Institutes (Taiwan),
Taiwan

REVIEWED BY
cross-sectional GlyDep pilot study
Yang-Pei Chang,
Kaohsiung Medical University, Taiwan
Chen-Cheng Yang,
Shivang Mishra 1*, Anurag Kumar Singh 1*, Sumit Rajotiya 1,
Kaohsiung Municipal Siaogang Hospital, Taiwan Pratima Singh 2, Preeti Raj 1, Hemant Bareth 1, Mahaveer Singh 3*,
*CORRESPONDENCE Tushar Jagawat 4, Deepak Nathiya 1,5,6* and Balvir Singh Tomar 5,6,7
Shivang Mishra
[email protected] 1
Department of Pharmacy Practice, Institute of Pharmacy, Nims University Rajasthan, Jaipur, India,
Anurag Kumar Singh 2
School of Public Health, University of Alberta, Edmonton, AB, Canada, 3 Department of Endocrinology,
[email protected] National Institute of Medical Sciences, Nims University Rajasthan, Jaipur, India, 4 Department of
Mahaveer Singh Psychiatry, National Institute of Medical Sciences, Nims University Rajasthan, Jaipur, India, 5 Department
[email protected] of Clinical Studies, Fourth Hospital of Yulin (Xingyuan), Yulin, Shaanxi, China, 6 Department of Clinical
Deepak Nathiya Sciences, Shenmu Hospital, Shenmu, Shaanxi, China, 7 Institute of Pediatric Gastroenterology and
[email protected] Hepatology, Nims University Rajasthan, Jaipur, India
RECEIVED 30 March 2023
ACCEPTED 29 August 2023
PUBLISHED 15 September 2023

CITATION Background: Data on the correlation between glycemic variability and depression
Mishra S, Singh AK, Rajotiya S, Singh P, Raj P, in nondiabetic patients remain limited. Considering the link between increased
Bareth H, Singh M, Jagawat T, Nathiya D and
glycemic variability and cardiovascular risks, this relationship could be significant
Tomar BS (2023) Exploring the risk of glycemic
variability in non-diabetic depressive in depressed patients.
individuals: a cross-sectional GlyDep pilot
Methods: In this single-center pilot study, we utilized Flash Glucose Monitoring
study.
Front. Psychiatry 14:1196866. (Abbott Libre Pro) to study glycemic variability. The CES-D (Center for
doi: 10.3389/fpsyt.2023.1196866 Epidemiological Studies– Depression) scale was employed to measure depression
COPYRIGHT levels. Based on CES-D scores, patients were classified into two groups: those with
© 2023 Mishra, Singh, Rajotiya, Singh, Raj, scores ≥ 33 and those with scores < 33. We analyzed various glycemic variability
Bareth, Singh, Jagawat, Nathiya and Tomar.
This is an open-access article distributed under
indices, including HBGI, CONGA, ADDR, MAGE, MAG, LI, and J-Index, employing
the terms of the Creative Commons Attribution the EasyGV version 9.0 software. SPSS (version 28) facilitated the data analysis.
License (CC BY). The use, distribution or
reproduction in other forums is permitted,
Results: We screened patients with depression visiting the department of
provided the original author(s) and the psychiatry, FGM was inserted in eligible patients of both the groups which yielded
copyright owner(s) are credited and that the a data of 196 patient-days (98 patient-days for CES-D ≥ 33 and 98 patient-days
original publication in this journal is cited, in
accordance with accepted academic practice.
for CES-D < 33). The glycemic variability indices CONGA (mg/dl), (76.48 ± 11.9
No use, distribution or reproduction is vs. 65.08 ± 7.12) (p = 0.048), MAGE (mg/dl) (262.50 ± 25.65 vs. 227.54 ± 17.72)
permitted which does not comply with these (p = 0.012), MODD (mg/dl) (18.59 ± 2.77 vs. 13.14 ± 2.39) (p = 0.002), MAG(mg/dl)
terms.
(92.07 ± 6.24vs. 63.86 ± 9.38) (p = <0.001) were found to be significantly higher in
the CES-D ≥ 33 group.
Conclusion: Patients with more severe depressive symptoms, as suggested by
CES-D ≥ 33, had higher glycemic variability.

KEYWORDS

depression, glycemic variability, risk of diabetes, FGM, CES-D, glycemic variability

indices

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1. Introduction 2.1. Design and participants

Diabetes mellitus, a global health issue, stands as one of the The present study, called GlyDep, is a primary quantitative
prevalent non-communicable diseases impacting millions exploratory research project aimed at analyzing glycemic variability (GV)
worldwide. Beyond the well-researched complications of in individuals with depressive disorder. Recruitment of participants, aged
neuropathy, nephropathy, retinopathy, and cardiovascular 18 years and older, diagnosed with depression (ICD-10) was conducted
sequelae, there emerges a significant shadow of psychological at the Department of Psychiatry, National Institute of Medical Science and
morbidity, most profoundly depression. This complex Research in Jaipur, India, from April 2022 to November 2022. Diagnosis
relationship is substantiated by recent meta-analyses, such as of incident depression was based on ICD-10 codes F32 (all mild to severe
those conducted by Mezuk et al. (1) and Chireh et al. (2), which depressive episodes) or F33 (all recurrent depressive disorders) with
indicate that diabetes increases the risk of developing depression cognitive behavioral therapy for management of diabetes (7). The study
by approximately 25% (1, 2). The relationship between diabetes utilized a set of inclusion and exclusion criteria. Inclusion criteria
and depression is bidirectional. Diabetes can elevate the risk of consisted of a proven diagnosis of depression, glycated hemoglobin
developing depression, and similarly, depression can predispose indices A1c (HbA1c) levels <5.6%, and willingness to give consent for the
one to diabetes. When they coexist in an individual, it’s not just study. Patients were excluded if they did not meet the clinical diagnosis
a simple overlap. This confluence exacerbates the progression and according to ICD-10, had unstable severe medical conditions such as
complicates the outcomes of both disorders. active malignant diseases, heart failure, or chronic liver diseases, were
Depression, characterized by pervasive mood disturbances, below 18 years of age, or had HbA1c levels above 5.6%.
underpins profound implications for metabolic health, particularly
glycemic control. A confluence of pathophysiological mechanisms
including inflammation, neuroendocrine dysfunction, and alterations 2.2. Data collection and recruitment of the
in insulin dynamics have been implicated in mediating this association study population
(3). Longitudinal studies further emphasize the chronic impact of
depression on glycemic variability (GV), a parameter depicting 2.2.1. Demographic factors
fluctuations in blood glucose levels that has been linked to Customized data collection forms were designed and used to
microvascular complications and oxidative stress (4). collect the study data. Participants’ age, gender, marital status,
However, the majority of these studies are conducted in diabetic smoking habits, and educational status were documented in the
populations and rely on traditional glucose monitoring systems, data collection forms. Weight and height were measured as per
which may not accurately capture the day to day spectrum of protocol and the body mass index (BMI) was calculated. The
GV. Recent innovations like the FreeStyle Libre flash glucose criteria established by the World Health Organization for
monitoring system offer a more nuanced window into these overweight (23.0 kg/m2) and obesity (25.0 kg/m2) were used to
fluctuations, yet there is a paucity of research exploring the determine BMI status (8). Body composition was assessed with
depression-GV nexus in non-diabetic individuals using this waist and hip measurements, which was obtained from standard
technology. Observational studies have highlighted the potential measuring tape. Waist-to-hip ratio (WHR) was calculated by
connections, but more targeted research is needed (5). dividing the waist circumference by the hip circumference (9).
The objective of this research is to fill this research gap through
a pilot study examining the relationship between depression 2.2.2. Laboratory parameters
severity and GV in non-diabetic individuals, employing the The participants lipid profile was assessed, including Low-Density
advanced FreeStyle Libre system. This cross-sectional GlyDep Pilot Lipoprotein (LDL), High-Density Lipoprotein (HDL), and
Study seeks to extend the current understanding of this complex Triglycerides (TG), following the guidelines of the American Heart
interplay by focusing on a population often overlooked in Association (AHA) (10). Additionally, Blood Urea Nitrogen (BUN),
conventional research. By shedding light on the mechanisms at Serum Creatinine (SCr), Aspartate Aminotransferase (AST), and
play in non-diabetic individuals, the findings may pave the way for Alanine Transaminase (ALT) levels were measured. These particular
early interventions and personalized therapeutic strategies that measurements are integral for monitoring kidney function and liver
account for both mental and metabolic health. By engaging with health, ensuring a comprehensive evaluation of the participants’
cutting-edge technology and a novel demographic, this study overall metabolic health.
endeavors to contribute a fresh perspective to the ongoing
discourse surrounding depression, GV, and their broader 2.2.3. Glucose assessment
implications for public health (6).
2.2.3.1. HbA1c measurement
HbA1c serves as a sensitive indicator of long-term glycemic
2. Methodology control, reflecting average blood glucose levels over a period of
approximately 2 to 3 months. In this study, HbA1c levels were
The present study was conducted in compliance with the ethical measured via high-performance liquid chromatography (HPLC) of
principles of the Declaration of Helsinki, and approval for the study hemolysates from whole blood (<5.6%) which is a reliable and gold
was obtained from the Institutional Review Board (approval number: standard technique for HbA1C determination. Glucose levels in
NIMSUR/IEC/2022/211). All study subjects provided informed fasting serum samples were assessed using glucose oxidase peroxidase
consent for this observational analysis. and a Siemens Dimension EXL 200 analyzer.

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2.2.3.2. Flash glucose monitoring (Freestyle libre Pro) we explored alternative methods. Non-parametric tests, known for
In this study, the ambulatory glucose profile was calculated using their reliability with limited data, became suitable choices.
interstitial sensor glucose data obtained from the Freestyle Libre Pro We emphasize awareness of assumptions and limitations in both
system (Abbott Diabetes Care, Oxon, UK). The system comprised a parametric and non-parametric analyses. Furthermore, Microsoft
sensor worn by patients for 2 weeks, which tested interstitial glucose Excel 2015 facilitated data visualization.
levels at 15-min intervals (11). All study participants were instructed
to wear the sensor for the entire two-week period, resulting in a total
of 196 patient-days. 3. Results
Glycemic variability indices, such as mean sensor glucose and its
standard deviation (SD), absolute means of daily differences 3.1. Study population
(MODD), continuous overall net glycemic action (CONGA), mean
amplitude of glycemic excursion (MAGE), high blood glucose index At the psychiatry outpatient department of NIMS hospital,
(HBGI), mean absolute glucose (MAG), liability index (LI), average we screened 62 patients for our study. Out of 62 patients with
daily risk ratio (ADRR), and J-Index were among the glycemic depression, thirty-one patients were found to be eligible for the study.
variability indices. EasyGV version 9.0 software (University of Out of thirty-one, thirteen patients were excluded from the study. The
Oxford, OX2 6GG, United Kingdom) was utilized to compute reasons for the exclusion were as follows: (1) difficulty in interviewing
the above indices using the data collected for 196 patient-days patients due to aggressive or irregular behavior (n = 3); (2) refusal to
(Review Supplementary Table 1) (12–17). use FGMS (n = 6); (3) refusal to participate in the study (n = 4). Finally,
eighteen patients were enrolled, with a loss of follow-up (n = 4). The
2.2.4. Measures for depressive symptoms (CES-D) study flow chart is shown in Figure 1.
The Center for Epidemiological Research Depression Scale The study included 14 participants with a total of 196 patient-
(CES-D) was devised by the National Institute of Mental Health in the days. Of 14 participants 10 were males and 4 were females with an
1970s. Its primary intent was to assess depressive symptomatology in average age of 29.53 ± 1.77 years. We made two groups depicting the
the general population, bridging the gap between clinical diagnosis severity of depression: CES-D scores≥33 (6 males, 1 female) and < 33
and population-based assessment. Over the years, it has been adapted (4 males, 3 females). The overall CES-D score was 33.46 ± 7.32 (range:
for various subpopulations and has become one of the widely accepted 0–60), 39.71 ± 3.81 for the CES-D ≥ 33 group, and 27.00 ± 2.70 for the
tools for screening depression symptoms in epidemiological studies. CES-D < 33 group. The comparison of the data of patients who had
Compared to other depression scales, CES-D uniquely CES-D > 33 to those who had CES-D < 33 is shown in Table 1. Age and
incorporates a range of symptoms, capturing diverse domains such as HbA1C were significantly higher in the patients with CES-D ≥ 33
mood, somatic complaints, and interpersonal interactions. This (Table 1).
holistic approach ensures a comprehensive understanding of an
individual’s depressive state. The Center for Epidemiological Research
Depression Scale (CES-D) was employed to screen for depression 3.2. Distribution of glycemic variability
symptoms under the guidance of a designated psychiatrist (18) The indices
CES-D contains 20 items commonly used in screening for depression
and depressive symptoms. The CES-D response options were based Supplementary Table 2 shows an explanatory version of the
on recent symptoms and a 4-point Likert scale ranging from “rarely measures of glycemic variability, along with their mean and standard
or none of the time” to “most or all of the time.” The scale goes from 0 deviations. The standard deviation of the blood glucose, a marker of
to 60, with a higher score indicating more significant depressive glycemic variability, was higher in CES-D ≥ 33 group (Figures 2A,B).
symptoms (19).
Cronbach’s alpha was 0.85 in reliability testing (20). Furthermore,
significant correlations with other depression measurement scales 3.3. Glycemic variability and depression
were observed, supporting the convergent validity of the CES-D, and
construct validity was established by differences between psychiatric We compared the glycemic variability indices of the patients who
inpatients and the general population (19). had CES-D ≥ 33 to those who had CES-D < 33. The HbA1c was higher
in the patients who had CES-D ≥ 33 (5.52 ± 0.34 vs. 4.82 ± 0.59)
(p = 0.020) (Table 1).
2.3. Statistical analysis CONGA (mg/dl) was higher in CES-D ≥ 33 group (76.48 ±
11.9 mg/dL vs. 65.08 ± 7.12 mg/dL) (p = 0.048) (Figure 3A). Likewise,
We used IBM SPSS version 28.0 from Chicago, IL, United States HBGI (mg/dl) and MAGE (mg/dl) values were also higher (50.41 ±
for our statistical analysis. We summarized continuous variables with 5.21 vs. 36.89 ± 4.09) (p = <0.001), (262.50 ± 25.65 vs. 227.54 ± 17.72)
mean and standard deviation, while categorical variables were (p = 0.012) respectively (Figures 3B,C) Other glycemic variability
presented as frequency and percentage. To compare differences indices like J-Index (mg/dl) (4296.49 ± 777.98 vs. 2822.79 ± 526.53)
between groups, we used t-tests for continuous variables and Fisher’s (p = 0.001), MODD (mg/dl) (18.59 ± 2.77 vs. 13.14 ± 2.39) (p = 0.002),
exact test for categorical variables. Acknowledging our cautious LI(mg/dl) (766.74 ± 266.28vs. 384.41 ± 72.98) (p = 0.003), ADDR
approach toward our small sample’s uniqueness and potential data (mg/dl) (384.14 ± 15.43 vs. 332.71 ± 17.21) (p = <0.001) and MAG
non-normality, we found non-parametric statistical methods to (mg/dl) (92.07 ± 6.24vs. 63.86 ± 9.38) (p = <0.001) were also found to
be necessary. Since finding non-diabetic participants posed challenges, be significantly higher in the CES-D ≥ 33 group (Figures 3D–H).

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FIGURE 1
Study flow chart showing enrollment and exclusion of the study subjects.

TABLE 1 Baseline comparison of the patients as per the CES-D score, a score used to depict the severity of depression.

Variables < 33 (n = 7) ≥ 33 (n = 7) p- value

Age, (years) 24.14 (4.05) 36.42 (4.10) 0.047

Male, n (%) 4 (40) 6 (60) 0.559

Married, n (%) 4 (40) 6 (60) 0.559

Education status

Primary school, n (%) 0 (0) 1 (14.2) 0.510

Intermediate, n (%) 5 (71.42) 4 (57.14)

Graduate or Post graduate, n (%) 2 (28.57) 2 (28.57)

Smokers, n (%) 2 (28.57) 4 (57.14) 0.290

BMI, (kg/m2) 22.17 (2.56) 23.20 (4.24) 0.594

WHR, mean ± SD 0.91 ± 0.03 0.92 ± 0.03 0.599

HbA1c (%) 4.82 ± 0.59 5.52 ± 0.34 0.020

LDL, (mg/dl), mean ± SD 85.74 ± 21.85 89.42 ± 24.16 0.770

HDL (mg/dl), mean ± SD 45.37 ± 16.41 53.08 ± 14.56 0.371

TG (mg/dl), mean ± SD 143.42 ± 143.76 152.00 ± 72.75 0.890

(Continued)

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TABLE 1 (Continued)

Variables < 33 (n = 7) ≥ 33 (n = 7) p- value

BUN (mg/dl), mean ± SD 10.82 ± 3.42 10.81 ± 3.38 0.998

SCr (mg/dl), mean ± SD 0.77 ± 0.26 0.85 ± 0.17 0.489

AST (U/L), mean ± SD 42.14 ± 43.73 21.14 ± 7.88 0.235

ALT (U/L), mean ± SD 68.14 ± 71.00 35.14 ± 9.52 0.246

All the data is presented in mean ± standard deviation (SD) or number (n) and percentage (%).
BMI, Body Mass Index; WHR, Waist Hip Ratio; HbA1c, Glycated Hemoglobin; LDL, Low-Density Lipoprotein; HDL, High-Density Lipoprotein; TG, Triglycerides; BUN, Blood Urea
Nitrogen; SCr, Serum Creatinine; AST, Aspartate aminotransferase; ALT, Alanine transaminase; CES-D, Center for Epidemiologic Studies– Depression.

FIGURE 2
(A) Detailed day-wise tracing of the sensor glucose values of 196 patient-days. (B) The Mean glucose level and Standard deviation of all the patients
with their CES-D scores.

These findings show that glycemic variability was higher in patients 2 weeks, which generated an ambulatory glucose profile of 196 patient-
with a CES-D score ≥ 33. days. The glycemic indices were calculated via the utilization of EasyGV
version 9.0 software. Depression was assessed using the CES-D scale,
which has been validated in the Indian population. Patients were
4. Discussion assigned to two groups based on their CES-D scores, with scores <33
and scores ≥33. The results of this study reveal that patients with CES-D
This research endeavors to fill the void of understanding concerning scores ≥33 exhibited increased glycemic variability.
glycemic variability in non-diabetic patients with depression. To assess The etiology of elevated glycemic variability in individuals with
the patients’ glycemic variability, the FGMS was utilized for a period of depression is multifactorial. In depression, there is an upsurge in stress

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FIGURE 3
Comparison between Glycemic variability indices (A) CONGA (B) HBGI (C) MAGE (D) J-INDEX (E) MODD (F) LI (G) ADDR (H) MAG of both CES-D
groups.

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hormones, particularly cortisol, which can be severe enough to result in stigma surrounding depression in India, which also served as a
pseudo- cushing syndrome (21). The elevated cortisol acts on the significant contributing factor to the attrition of study participants.
subcortical area, including the hippocampus and hypothalamus (22).
These two areas are crucial for the control of the autonomic nervous
system regulation. Autonomic dysfunction, as observed in patients with 5. Conclusion
diabetes, has been linked to elevated glycemic variability. This has been
seen in patients with diabetes, who have autonomic dysfunction, and had Patients who have more severe depression (CES-D scores≥33)
high glycemic variability (23, 24). The glycemic variability was also found have high glycemic variability (SD, MAGE, CONGA, and MODD)
to be associated with incident depression. In a retrospective study from than the patients who have less severe depression (CES < 33).
the Korean National Health Insurance Service–National Health Screening
Cohort from 2002 to 2007, patients (n-264,480) who have at least three
fasting serum glucose were later observed during 2008–2013 (n-198,267), Data availability statement
and their hazard ratios (HR) of incident depression were calculated. After
adjustment, it was found that the highest glycemic variability was The data collected and/or evaluated in this study are intended for
associated with a 9% increased risk of depression (HR, 1.09; 95% CI, academic research and can be accessed upon suitable request to the
1.02–1.16). The risk of incident depression heightened with increasing corresponding authors.
GV (p for trend < 0.001) (22). In our pilot study, we tried to explore the
glycemic variability in depressive patients. Our pilot study had the
objective of exploring glycemic variability among non-diabetic individuals Ethics statement
with depression. The heightened glycemic variability observed in patients
with CES-D scores ≥33 suggests an elevation in stress hormone levels. The study was conducted in accordance with the Declaration of
Additionally, there exists a connection between glycemic variability Helsinki, and approved by the Institutional Ethics Committee, NIMS
and endothelial dysfunction, which is a precursor to atherosclerosis and University Rajasthan, Jaipur (IEC Approval number: NIMSUR/
cardiovascular incidents. Notably, depression itself is also linked to IEC/2022/211) on 26 March 2022 for studies involving humans. The
endothelial dysfunction. The coexistence of both conditions may participants provided their written informed consent to participate
potentially contribute to an increased risk of cardiovascular events. in this study.
In summary, our pilot study illuminates the correlation between
glycemic variability and depression in individuals without diabetes. The
noted rise in stress hormones among those exhibiting higher CES-D Author contributions
scores highlights the importance of this link. Moreover, the interaction
among glycemic variability, endothelial dysfunction, and depression MS: conceptualization, investigation, validation, and writing—
underscores potential repercussions for cardiovascular well-being (25). original draft. SM: conceptualization, investigation, validation, and
writing—original draft. PS: methodology and project administration.
DN: conceptualization, validation, resources, writing—original draft,
4.1. Future recommendations supervision, and funding. SR and AS: investigation, validation, and
writing—original draft. PR: investigation, formal analysis, and writing—
In this study, our objective is to underscore patient education and original draft. HB: investigation, formal analysis, writing, reviewing, and
awareness initiatives that highlight the link between glycemic editing. TJ: investigation, writing, reviewing, and editing. BT:
variability and depression. Advocating for holistic care includes conceptualization, resources, writing, reviewing, editing, supervision, and
integrating comprehensive management strategies and funding. All authors contributed to the article and approved the
interdisciplinary consultations. Expanding this research to a larger, submitted version.
diverse cohort is imperative to bolster the association regarding
glycemic variability, particularly in non-diabetic populations. Our
recommendation is to enhance robust methodologies by controlling Funding
confounders and predictors, encompassing dietary habits, physical
activity, medication usage, and lifestyle factors. Embracing these This work was supported by Nims University Rajasthan, Jaipur,
approaches propels progress in patient care and scientific India. No other funding source was involved in the study. All the
understanding, ultimately enhancing overall well-being. decisions on design, data collection, analysis, interpretation and
publication were independent of the funding source.
4.2. Limitations

This pilot research represents a pioneering application of a flash Acknowledgments

glucose monitoring system to evaluate glycemic variability among
patients afflicted with depression, who do not suffer from diabetes. All the authors would like to express their sincere gratitude and
Moreover, the glycemic variability is analyzed relative to the severity appreciation to the staff and doctors of Department of Psychiatry and
of the depression. Nevertheless, certain constraints were observed Department of Endocrinology, Nims hospital, Jaipur for their
during the study. The principal restriction was the restricted sample unwavering support and guidance throughout our journey. We would
size, which may limit the generalizability of the findings. Additionally, also like to thank all the professors of the Pharmacy department for
the low screening-to-enrollment ratio was attributed to the social their constant support and help.

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Mishra et al. 10.3389/fpsyt.2023.1196866

Conflict of interest organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may
The authors declare that the research was conducted in the be made by its manufacturer, is not guaranteed or endorsed by
absence of any commercial or financial relationships that could the publisher.
be construed as a potential conflict of interest.

Supplementary material
Publisher’s note
The Supplementary material for this article can be found online
All claims expressed in this article are solely those of the authors at: https://www.frontiersin.org/articles/10.3389/fpsyt.2023.1196866/
and do not necessarily represent those of their affiliated full#supplementary-material

References
1. Mezuk B, Eaton WW, Albrecht S, Golden SH. Depression and type 2 diabetes over diabetes using self-monitoring blood glucose data. Diabetes Technol Ther. (2003)
the lifespan: a meta-analysis. Diabetes Care. (2008) 31:2383–90. doi: 10.2337/dc08-0985 5:817–28. doi: 10.1089/152091503322527021
2. Chireh B, Li M, D'Arcy C. Diabetes increases the risk of depression: a systematic review, 14. Kovatchev BP, Otto E, Cox D, Gonder-Frederick L, Clarke W. Evaluation of a new
meta-analysis and estimates of population attributable fractions based on prospective studies. measure of blood glucose variability in diabetes. Diabetes Care. (2006) 29:2433–8. doi:
Prev Med Rep. (2019) 14:100822. doi: 10.1016/j.pmedr.2019.100822 10.2337/dc06-1085
3. Merabet N, Lucassen PJ, Crielaard L, Stronks K, Quax R, Sloot PM, et al. How 15. Wójcicki JM. “J”-index. A new proposition of the assessment of current glucose
exposure to chronic stress contributes to the development of type 2 diabetes: a control in diabetic patients. Horm Metab Res. (1995) 27:41–2. doi: 10.1055/s-2007-979906
complexity science approach. Front Neuroendocrinol. (2022) 65:100972. doi: 10.1016/j.
16. McDonnell CM, Donath SM, Vidmar SI, Werther GA, Cameron FJ. A novel
yfrne.2021.100972
approach to continuous glucose analysis utilizing glycemic variation. Diabetes Technol
4. Zhou Z, Sun B, Huang S, Zhu C, Bian M. Glycemic variability: adverse clinical Ther. (2005) 7:253–63. doi: 10.1089/dia.2005.7.253
outcomes and how to improve it? Cardiovasc Diabetol. (2020) 19:1–4. doi: 10.1186/
17. Service FJMolnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean
s12933-020-01085-6
amplitude of glycemic excursions, a measure of diabetic instability. Diabetes. (1970)
5. O’Neil M, Berkman N, Hartling L, Chang S, Anderson J, Motu’apuaka M, et al. 19:644–55.
Observational evidence and strength of evidence domains: case examples. Syst Rev.
18. Zich JM, Attkisson CC, Greenfield TK. Screening for depression in primary care
(2014) 3:1–8. Available at: https://www.ncbi.nlm.nih.gov/books/NBK202087/
clinics: the CES-D and the BDI. Int J Psychiatry Med. (1990) 20:259–77. doi: 10.2190/
6. Reddy N, Verma N, Dungan K. Monitoring technologies-continuous glucose LYKR-7VHP-YJEM-MKM2
monitoring, mobile technology, biomarkers of glycemic control. Endotext [Internet].
19. Carleton RN, Thibodeau MA, Teale MJ, Welch PG, Abrams MP, Robinson T, et al.
(2020). Available at: https://www.ncbi.nlm.nih.gov/books/NBK279046/
The center for epidemiologic studies depression scale: a review with a theoretical and
7. ICD-10 Version:2019 [Internet]. [cited 2023 Mar 11]. Available at: https://icd.who. empirical examination of item content and factor structure. PLoS One. (2013) 8:e58067.
int/browse10/2019/en doi: 10.1371/journal.pone.0058067
8. Tham KW, Abdul Ghani R, Cua SC, Deerochanawong C, Fojas M, Hocking S, et al. 20. Marbaniang I, Borse R, Sangle S, Kinikar A, Chavan A, Nimkar S, et al.
Obesity in south and Southeast Asia—a new consensus on care and management. Obes Development of shortened HIV-related stigma scales for young people living with HIV
Rev. (2023) 24:e13520. doi: 10.1111/obr.13520 and young people affected by HIV in India. Health Qual Life Outcomes. (2022) 20:1. doi:
10.1186/s12955-022-02030-9
9. Talati KN, Parmar A, Zalavadiya D, Shinde M, Madan-Patel G. Epidemiological
insights into anthropometric indices and their correlates among college students 21. Stetler C, Miller GE. Depression and hypothalamic-pituitary-adrenal activation: a
through a university-level screening program in Western India. Indian J Community quantitative summary of four decades of research. Psychosom Med. (2011) 73:114–26.
Med. (2022) 47:445–8. doi: 10.4103/ijcm.ijcm_1219_21 doi: 10.1097/PSY.0b013e31820ad12b
10. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 22. Kim JJ, Diamond DM. The stressed hippocampus, synaptic plasticity and lost
AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA memories. Nat Rev Neurosci. (2002) 3:453–62. doi: 10.1038/nrn849
guideline on the management of blood cholesterol: a report of the American College of
23. Kim HJ, Kim SM, Lee G, Choi S, Son JS, Oh YH, et al. Association between visit-
Cardiology/American Heart Association task force on clinical practice guidelines.
to-visit fasting glycemic variability and depression: a retrospective cohort study in a
Circulation. (2019) 139:e1082–143. doi: 10.1161/CIR.0000000000000625
representative Korean population without diabetes. Sci Rep. (2022) 12:4. doi: 10.1038/
11. Blum A. Freestyle Libre Glucose Monitoring System. Clinical Diabetes. (2018) s41598-022-27160-4
36:203–4. doi: 10.2337/cd17-0130
24. Fleischer J. Diabetic autonomic imbalance and glycemic variability. J Diabetes Sci
12. Schlichtkrull J, Munck O, Jersild M. The m-valve, an index of blood-sugar control Technol. (2012) 6:1207–15. doi: 10.1177/193229681200600526
in diabetics. Acta Med Scand. (1965) 177:95–102. doi: 10.1111/j.0954-6820.1965.
25. Lai YR, Huang CC, Chiu WC, Liu RT, Tsai NW, Wang HC, et al. HbA1C variability
tb01810.x
is strongly associated with the severity of cardiovascular autonomic neuropathy in
13. Kovatchev BP, Cox DJ, Kumar A, Gonder-Frederick L, Clarke WL. Algorithmic patients with type 2 diabetes after longer diabetes duration. Front Neurosci. (2019)
evaluation of metabolic control and risk of severe hypoglycemia in type 1 and type 2 13:458. doi: 10.3389/fnins.2019.00458

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