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Inflammation and central adiposity as mediators of depression and uncontrolled diabetes in the study on global AGEing and adult health (SAGE)

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Abstract

Objectives Diabetes and depression are commonly present in the same individuals, suggesting the possibility of underlying shared physiological processes. Inflammation, as assessed with the biomarker C‐reactive protein (CRP), has not consistently explained the observed relationship between diabetes and depression, although both are associated with inflammation and share proposed inflammatory mechanisms. Central adiposity has also been associated with both conditions, potentially by causing increased inflammation. This study uses the World Health Organization's Study on global AGEing and adult health (SAGE) Mexico Wave 1 biomarker data (n = 1831) to evaluate if inflammation and central adiposity mediate the relationship between depression and diabetes. Methods Depression was estimated using a behavior‐based diagnostic algorithm, inflammation using venous dried blood spot (DBS) CRP, central adiposity using waist‐to‐height ratio (WHtR), and uncontrolled diabetes using venous DBS‐glycated hemoglobin (HbA1c). Results The association between depression and uncontrolled diabetes was partially mediated by CRP before but not after WHtR was considered. When WHtR was added to the model, it partially mediated the relationship between diabetes and depression while fully mediating the relationship between depression and CRP. Conclusions These findings suggest that central adiposity may be a more significant mediator between diabetes and depression than inflammation and account for the relationship between these disorders and inflammation. Depression may cause an increase in central adiposity, which then may lead to diabetes, but the increase in known systemic inflammatory pathways caused by central adiposity may not be the key pathological mechanism.
ORIGINAL RESEARCH ARTICLE
Inflammation and central adiposity as mediators
of depression and uncontrolled diabetes in the study
on global AGEing and adult health (SAGE)
Allison C. Dona
1
| Alicia M. DeLouize
1
| Geeta Eick
1
| Elizabeth Thiele
2
|
Aarón Salinas Rodríguez
3
| Betty Soledad Manrique Espinoza
3
|
Ricardo Robledo
4
| Salvador Villalpando
4
| Nirmala Naidoo
5
|
Somnath Chatterji
5
| Paul Kowal
1,5,6
| J. Josh Snodgrass
1
1
Department of Anthropology, University
of Oregon, Eugene, Oregon
2
Department of Biology, Vassar College,
Poughkeepsie, New York
3
Centre for Evaluation Research and
Surveys, National Institute of Public
Health, Mexico
4
Nutrition and Health Investigation
Center, National Institute of Public
Health Laboratory, Cuernavaca, Morelos,
Mexico
5
Department of Health Statistics and
Information Systems, World Health
Organization SAGE, Geneva, Switzerland
6
Research Centre for Generational Health
and Ageing, University of Newcastle,
Newcastle, Australia
Correspondence
J. Josh Snodgrass, Department of
Anthropology, 1218 University of Oregon,
Eugene, OR 97403.
Email: jjosh@uoregon.edu
Funding information
Ministry of Health in Mexico; NIH NIA
Interagency Agreement YA1323-08-CN-
0020
Abstract
Objectives: Diabetes and depression are commonly present in the same
individuals, suggesting the possibility of underlying shared physiological
processes. Inflammation, as assessed with the biomarker C-reactive protein
(CRP), has not consistently explained the observed relationship between diabe-
tes and depression, although both are associated with inflammation and share
proposed inflammatory mechanisms. Central adiposity has also been associ-
ated with both conditions, potentially by causing increased inflammation. This
study uses the World Health Organization's Study on global AGEing and adult
health (SAGE) Mexico Wave 1 biomarker data (n= 1831) to evaluate if inflam-
mation and central adiposity mediate the relationship between depression and
diabetes.
Methods: Depression was estimated using a behavior-based diagnostic algo-
rithm, inflammation using venous dried blood spot (DBS) CRP, central adipos-
ity using waist-to-height ratio (WHtR), and uncontrolled diabetes using
venous DBS-glycated hemoglobin (HbA1c).
Results: The association between depression and uncontrolled diabetes was
partially mediated by CRP before but not after WHtR was considered. When
WHtR was added to the model, it partially mediated the relationship between
diabetes and depression while fully mediating the relationship between depres-
sion and CRP.
Conclusions: These findings suggest that central adiposity may be a more sig-
nificant mediator between diabetes and depression than inflammation and
account for the relationship between these disorders and inflammation.
Depression may cause an increase in central adiposity, which then may lead to
diabetes, but the increase in known systemic inflammatory pathways caused
by central adiposity may not be the key pathological mechanism.
Received: 10 April 2019 Revised: 22 February 2020 Accepted: 9 March 2020
DOI: 10.1002/ajhb.23413
Am J Hum Biol. 2020;112. wileyonlinelibrary.com/journal/ajhb © 2020 Wiley Periodicals, Inc. 1
1|INTRODUCTION
Mental health conditions are major contributors to long-
term morbidity and disability globally. Hundreds of mil-
lions of people suffer from mental health conditions such
as depression, yet the resources allocated to respond to
morbidity and associated impairment are disproportion-
ately low, particularly in low- and middle-income coun-
tries (Eaton et al., 2011; Saraceno et al., 2007).
Conventional public health metrics also fail to account
for the risk of acquiring a second health disorder.
Multiple studies have found that mental health conditions
including depression, substance abuse, suicide, and post-
traumatic stress disorder (PTSD)are related to physical
illness (Farmer, Kim, Kleinman, & Basilico, 2013) includ-
ing cardiovascular diseases, respiratory diseases, chronic
pain conditions, gastrointestinal illnesses, and cancer
(Jones et al., 2004; Sareen et al., 2007; Van der Kooy
et al., 2007).
Type 2 diabetes and depressionwhich impact over
400 million (WHO, 2018) and 250 million (WHO, 2019)
people worldwide, respectivelyare commonly present
in the same people (Roy & Lloyd, 2012) and may share
underlying physiological mechanisms and social determi-
nants. This relationship is thought to be bidirectional
because of similarities in the underlying pathological mech-
anisms in these conditions, including inflammation, as well
as health behaviors, psychosocial factors, and brain-derived
neurotrophic factor. People with depression have also been
shown to have higher rates of diabetes and vice versa
(Berge & Riise, 2015; Stuart & Baune, 2012). The present
study was designed to investigate potential key underlying
mechanisms in the comorbidity between diabetes and
depression as well as to identify relationships related to
aging and sociodemographic parameters. We specifically
consider if depression is associated with greater inflamma-
tion and/or central adiposity and then if the inflammation
and/or central adiposity are associated with uncontrolled
diabetes.
The number of individuals with comorbid diabetes and
depression varies greatly between studies. This is in part
because of methodological differences and limitations,
including self-reported prevalence data vs biomarker or
clinical assessment, samples that do not distinguish
between type 1 and type 2 diabetes, lack of documentation
regarding relevant factors associated with the disease state,
and population differences such as race/ethnicity (Katon,
2008). In a 39-study meta-analysis, 11% of patients with
diabetes met the criteria for comorbid major depressive
disorder and 31% experienced significant depressive symp-
toms. Furthermore, depression prevalence in patients with
diabetes was significantly higher in women than men, and
the odds of having depression were twice as great in
patients with diabetes as in their nondiabetic counterparts
(Anderson, Freedland, Clouse, & Lustman, 2001).
Although the relationship between depression and diabe-
tes is bidirectional, the risk of developing diabetes after a
depression diagnosis is higher than the risk of developing
depression after a diabetes diagnosis (Mezuk, Eaton,
Albrecht, & Golden, 2008). This pattern highlights the
need to identify underlying physiological mechanisms
linking the two disorders, as the relationship is not entirely
due to the stressors of illness causing depression. In addi-
tion, individuals with type 2 diabetes and comorbid
depression have increased incidence of overall poor health
outcomes (Anderson et al., 2001; Black, Markides, & Ray,
2003) as well as worse diet and medication regimen adher-
ence, functional impairment, and higher healthcare costs
(Ciechanowski, Katon, & Russo, 2000; Katon, 2008).
Understanding how depression could lead to diabetes
physiologically could help prevent this disorder from
developing in some people, improving patient outcomes.
Epidemiological and animal studies suggest that inflam-
mation is an important mediator of the comorbidity between
diabetes and depression. Levels of both pro-inflammatory
and anti-inflammatory cytokines in the peripheral circulation
and central nervous system have been reported to rise during
depression and other brain disorders (Schwarz, Chiang,
Müller, & Ackenheil, 2001). Chronic subclinical elevation of
interleukin 6 (IL-6), C-reactive protein (CRP), orosomucoid,
and sialic acid (all of which play a role in the inflammatory
process) might be causes of diabetes in middle-aged adults
(Duncan et al., 2003).
In particular, CRP is one component of the inflamma-
tory process that may be most directly related to this
comorbidity. The liver secretes CRP into the blood after
macrophages and T cells secrete IL-6 as a typical
response to cell damage, pathogens, burns, heart attack,
cancer, and other damage. The main biological function
of CRP appears to be host defense against bacterial path-
ogens and clearance of apoptotic and necrotic cells
(Volanakis, 2001). Chronically elevated CRP levels are
associated with many physical health conditions, includ-
ing depression and diabetes, as well as cardiovascular dis-
ease (Dehghan et al., 2007; Howren, Lamkin, & Suls,
2009; Pearson et al., 2003; Pradhan, Manson, Rifai,
Buring, & Ridker, 2001), although its role as a causal fac-
tor remains debated (Li & Fang, 2004; Yousuf et al., 2013;
Zimmermann et al., 2014). Depression has also been
associated with CRP in patients with type 1 and type
2 diabetes (Herder et al., 2018). However, adjustment for
markers of inflammation (including CRP) has not consis-
tently attenuated the positive association between diabe-
tes and depression, although diabetes and depression are
each associated with inflammation and share proposed
inflammatory mechanisms (Stuart & Baune, 2012).
2DONA ET AL.
Central adiposity may influence this comorbidity and
account for CRP involvement. Diabetes and depression
are both associated with obesity (Luppino et al., 2010;
Mokdad et al., 2003; Pan et al., 2012; Yudkin, Stehouwer,
Emeis, & Coppack, 1999) and specifically central adipos-
ity (Bray et al., 2008; Thakore, Richards, Reznek,
Martin, & Dinan, 1997; Vogelzangs et al., 2008), although
depression has been associated with being underweight
as well (Carey et al., 2014). Depressive symptoms have
been shown to predict greater abdominal obesity inde-
pendent of overall obesity, indicating that specific patho-
logical mechanisms of depression may lead to visceral
fat accumulation (Vogelzangs et al., 2008). Multiple
measures of central adiposity have been shown to predict
diabetes as well (Bray et al., 2008). CRP and systemic
inflammation may be a part of central adiposity pathol-
ogy; adipose tissue secretes IL-6 into circulation, which
stimulates CRP production by the liver (Trayhurn &
Wood, 2004; Voleti & Agrawal, 2005; Wisse, 2004;
Yudkin et al., 1999). However, a recent study found that
change in IL-6 was not associated with change in depres-
sive symptoms in individuals with type 1 or type 2 diabe-
tes, even when CRP was (Herder et al., 2018). Another
study showed that when controlling for central adipos-
ity, only IL-6, and not CRP, predicted the development
of type 2 diabetes (Duncan et al., 2003). These incon-
sistencies could be due to multicollinearity, which can
be detected and further understood with mediation
analyses.
Metabolic syndromewhich generally involves
increased blood pressure, high blood sugar, central adi-
posity, and abnormal cholesterol or triglyceride levels
(Huang, 2009)combines the variables investigated in
the present article and more; therefore, related research
may provide insight into the comorbidity of diabetes and
depression. Increased oxidative stress, defined as a distur-
bance in the balance between the production of reactive
oxygen species (free radicals) and antioxidant defenses
(Betteridge, 2000), in accumulated fat has been shown to
be an early instigator of metabolic syndrome (Furukawa
et al., 2017). In addition, CRP is significantly elevated in
metabolic syndrome and is a predictor of multiple meta-
bolic disorders including type 2 diabetes (Ridker, 2003;
Sattar et al., 2003). A prospective study found that indi-
viduals with both depressive symptoms and metabolic
dysregulation at baseline were at higher risk for develop-
ing diabetes than participants with only one of the condi-
tions, and this increase was more than the sum of the
individual effects (Schmitz et al., 2016). Overall, central
adiposity may be a pathological mechanism causing both
diabetes and depression, and each condition may also
increase central adiposity and through this pathway bidi-
rectionally put individuals at greater risk for the other.
The present study investigates uncontrolled diabetes
and depression comorbidity in older Mexican adults
using biomarker data (CRP and HbA1c [glycated hemo-
globin]) from the World Health Organization's Study on
global AGEing and adult health (SAGE) (Kowal et al.,
2012). Specifically, we evaluate CRP and waist-to-height
ratio (WHtR) as mediators of this comorbidity to better
understand the pathology of both diseases. This study
focuses on adults over 50 in Mexico because most major
studies have been conducted in Europe and the United
States (Herder et al., 2018; Schmitz et al., 2016; Stuart &
Baune, 2012), diabetes and depression are highly preva-
lent in the Mexican population (IHME, 2019; WHO,
2016), and socioeconomic differences and similarities to
previous studies may contribute to meaningful cross-
study comparison. In Mexico, type 2 diabetes is the lead-
ing cause of death and disability, with more than 13 of
the 127 million people (10.4%) living with diabetes
(WHO, 2016). In addition, 12.5% of the population, over
15 million people, experienced major depressive disor-
der in 2002. Older adults are burdened disproportion-
ately; depression prevalence in individuals over 80 years
old has been estimated to range from 21.7% to 25.3%
(Alvarez-Monjaras & Gonzalez, 2016).
The aims of this article are twofold. First, we will
evaluate if CRP mediates the relationship between
uncontrolled diabetes and depression. Second, we will
evaluate if central adiposity mediates the comorbidity
between uncontrolled diabetes and depression and if it
impacts CRP as a mediator. We hypothesize that the first
model will show that depression is associated with higher
levels of CRP, which will then be associated with the
presence of uncontrolled diabetes. In the second model,
we predict that depression will be associated with greater
central adiposity, which then will be associated with the
presence of uncontrolled diabetes. We also expect that
the positive association between central adiposity and
CRP will mediate the co-occurrence of depression and
uncontrolled diabetes.
2|METHODS
2.1 |Study on global AGEing and adult
health (SAGE)
SAGE is a comprehensive longitudinal study of the
health and well-being of older adult populations and
the aging process in six middle income nations. It was
approved by the World Health Organization's Ethical
Review Committee and review bodies within each coun-
try (Kowal et al., 2012). The present study uses biomarker
data from SAGE Mexico Wave 1 to examine if CRP and
DONA ET AL.3
WHtR mediate the relationship between depression and
diabetes.
2.2 |Participants
A subset of people participating in the SAGE study in
Mexico underwent biomarker analysis (n= 1831). Exclu-
sions included 13 people for incomplete data and 173 peo-
ple for having an elevated CRP value that might indicate
injury or infection. The sample was 60% women. Partici-
pant ages for this analysis ranged from 50 to 94 years old
(M= 67.32, SD = 8.91) and education ranged from 0 to
25 years (M= 4.38, SD = 4.14). Mean education is partic-
ularly low because 20% of the sample had no formal edu-
cation. Participants were mostly married (58%), followed
by widowed (23%), never married (9%), divorced (6%),
and cohabiting (4%).
2.3 |Sociodemographic measures
Trained interviewers performed face-to-face computer-
assisted personal interviews and undertook anthropomet-
ric measurement. The interviews took place from 2009 to
2010 in the participants' homes and lasted approximately
1.5 hours on average (Kowal et al., 2012). The self-report
depression diagnosis, answers to depression symptoms
questions, and participant demographic information were
used in the present study.
Gender,age,maritalstatus,education,perceived
health, and wealth were determined using standard
measures (Kowal et al., 2012). The wealth variable was a
standardized composite variable including household
assets and housing amenities used to assess wealth inde-
pendently of employment status. It included a 21-item
self-report measure that asked about items owned by
the household and household characteristics such as
typeoffloors,walls,watersupply,andsanitation.
2.4 |Biomarkers
Venous blood was collected in an EDTA tube using stan-
dard venipuncture. These whole blood samples were then
homogenized before being pipetted in 20 μL aliquots onto
standard Whatman 903 filter paper so that they could be
analyzed using DBS procedures (Brindle, O'Connor, &
Garrett, 2014; de Waal, Driver, & Warner, 2019; Lacher,
Berman, Chen, & Porter, 2013; Lehmann, Delaby,
Vialaret, Ducos, & Hirtz, 2013; Li & Lee, 2014; McDade
et al., 2012). The samples were analyzed after 24 hours of
drying at room temperature. A 6 mm spot was punched
out from the DBS card and eluted for 14 hours with
250 μL of PBS buffer pH = 7. DBS eluates were analyzed
using the Abbott Architect CI8200 chemistry analyzer for
CRP (Lacher et al., 2013). In addition, CRP values were
obtained from an additional serum separator tube col-
lected from 91 participants for comparison and analyzed
using the Architect CI8200. To create serum equivalents,
CRP DBS values were regressed onto CRP serum controls
for the comparison subsample using a Passing and
Bablok regression. The regression equation was:
CRP serum = 2:41 CRP DBSðÞ1:38
The CRP DBS values and the CRP serum values were
highly correlated, indicating sufficient validity for analy-
sis, Pearson's r= 0.99. Participants were excluded for pos-
sible infection/injury if they had a serum conversion
value greater than 5 mg/L. Analyses run with a cutoff of
10 mg/L produced similar results, indicating the model is
robust to the choice of CRP cutoff value. All analyses
were run using raw DBS CRP values; however, serum
conversion values are reported in the manuscript (unless
otherwise noted) for ease of interpretation.
HbA1c was run via blood chemistry analysis using the
Architect CI8200 (de Waal et al., 2019; Lacher et al., 2013).
A 6 mm DBS punch was eluted 14 hours in 400 μLMUL-
TIAGEN Hemoglobin Denaturant. A cuvette with the elu-
ent was loaded into the Architect blood chemistry analyzer,
where HbA1c and total hemoglobin were each determined
by measuring absorbance at 700 nm and 604 nm, respec-
tively. Percent HbA1c was calculated by the analyzer's pro-
gram as [(HbA1c/TotHb) ×100] 3+(0.2 ×TotHb).
Elevated levels of HbA1c can indicate type 1 and type 2 dia-
betes; therefore, we were not able to distinguish between
them in this study. A 6.5% cutoff value was used to create
the diabetes variable for analyses. Participants who were
diagnosed with diabetes but had an HbA1c below 6.5%
were not included in the diabetes variable because treat-
ments that lower HbA1c also lower inflammation.
2.5 |Depression
Two methods were used to identify the presence of
depression. First, participants were considered to have
depression if they answered yes to, Have you ever been
diagnosed with depression?Second, because depression
is often underreported and underdiagnosed, symptoms
for depression were also assessed using the World Mental
Health Survey version of the Composite International
Diagnostic Interview (Kessler & Üstün, 2004). This mea-
sure was then transformed to a symptom-based diagnos-
tic variable using a previously validated algorithm to
4DONA ET AL.
include participants who had a depressive episode in the
past 12 months but no diagnosis. Participants who
responded yesto the first question or had a positive result
for depression as indicated by the diagnostic interview were
categorized into the depression group. This combined mea-
sure has also been used in previous studies, including others
from SAGE (eg, Hsieh, 2015; Kamenov et al., 2016).
2.6 |Anthropometrics
Height and waist circumference were recorded using
standard measures (Kowal et al., 2012). Waist circumfer-
ence was measured at the top of the iliac crest. More
detailed information about measurements can be found
online in the SAGE survey manual (https://www.who.
int/healthinfo/survey/SAGESurveyManualFinal.pdf).
WHtR has been used in previous studies and has been
shown to be an effective indicator of diabetes risk and
other health conditions (Ashwell, Gunn, & Gibson, 2012;
Browning, Hsieh, & Ashwell, 2010; Łopaty
nski,
Mardarowicz, & Szcze
sniak, 2003; Sayeed et al., 2003).
2.7 |Statistical analyses
Before analysis, depression and wealth composites were com-
puted. To evaluate the diagnostic validity of the symptom-
based depression variable, slightly different variations of an
algorithm computing the DSM-IV diagnoses for a depressive
episode were created. They were then compared to the clini-
cal diagnoses of a separate sample of participants. The algo-
rithm that was most consistent with the clinical diagnosis of
the sample population was used. For the wealth variable,
each question was treated as an independent observation of
wealth. The data were then reshaped, a pure random effects
model was fit, and data were transformed using Bayes post-
estimation to create a standardized composite wealth variable
(Schrock et al., 2017).
A hierarchical linear regression was performed in SPSS
v. 25, and mediation analyses were performed using struc-
tural equation modeling (SEM) in the lavaan package
(Rosseel, 2012) with diagonally weighted least squares esti-
mation in R (R Core Team, 2019). The alpha level was set at
0.05. Statistical assumptions were checked prior to analysis.
Variable skewness ranged from 0.47 to 1.86, and kurtosis
ranged from 1.78 to 3.61, which indicates sufficient nor-
mality (Warner, 2012). However, review of the histograms
showed that CRP was exponentially distributed; there-
fore, it was ln-transformed. In addition, all variables
were approximately linear in relation to one another
and appeared homoscedastic. There were no multivari-
ate outliers. Therefore, all assumptions were met.
A hierarchical regression was performed to, first, eval-
uate if the health variables of interest, depression and
diabetes were related to CRP in the presence of demo-
graphic controls (model 3). Second, the hierarchical
regression detected potential mediation relationships by
evaluating the extent of suppression effects between
depression and diabetes (models 1 and 2) and between
health variables, depression, diabetes, and CRP (models
3 and 4). Four models were compared to evaluate the
suppression effects between depression and diabetes and
on depression and diabetes by WHtR. Depression was
included as a predictor of CRP in model 1, diabetes was
added as a predictor in model 2, demographics were
added in model 3, and self-reported health and WHtR
were added in model 4. CRP was the outcome in all four
models.
The first mediation analysis explores the potential
mediation of depression and diabetes by CRP. The SEM
for the i
th
person, where xis the predictor, zis the media-
tor, and yis the outcome is as follows:
Diabetesi=β0y+βzylnCRPi+βxyDepi+εyi
lnCRPi=β0z+βxz Depi+εzi
The second mediation analysis explores whether the
links between CRP, depression, and diabetes are further
mediated by WHtR. The SEM for the i
th
person, where
xis a predictor, vis the mediation by WHtR, zis the
mediation by CRP, and yis the outcome is as follows:
Diabetesi=β0y+βzylnCRPi+βxyDepi+βvy WHtRi+εyi
lnCRPi=β0z+βxz Depi+βvzWHtRi+εzi
WHtRi=β0v+βxvDepi+εvi
CRP Bvalues were converted to serum equivalents
with the following equation:
serum CRP B =2:41 eDBS lnCRP B

1:38:
3|RESULTS
Uncontrolled diabetes and depression both pose a signif-
icant health burden to people living in Mexico, with an
estimated 26% and 17% of individuals from this study
suffering from these conditions, respectively (Table 1).
DONA ET AL.5
The median HbA1c value was 5.8% (the diabetic range is
6.5% or higher; Table 2). The median CRP value in the
sample was 1.79 mg/L; there is currently no cutoff stan-
dard, but generally low risk for cardiovascular disease is
considered to be a CRP concentration of <1.0 mg/L, aver-
age risk a CRP concentration between 1.0 and 3.0 mg/L,
and high risk a CRP concentration > 3.0 mg/L (Nehring &
Patel, 2018; Pearson et al., 2003). WHtR in the population
averaged 0.63 (0.56 and above is considered high; Rodea-
Montero et al., 2014).
Using hierarchical regression, all models accounted
for a significant portion of the variance in CRP
(F's = 4.48-9.61, P's < 0.05). Model 1 showed that the
presence of depression increased CRP by an average of
1.44 mg/L (t= 2.22, P= 0.03). This value remained sig-
nificant in model 2, when controlling for diabetes
(t= 2.02, P= 0.04). The presence of diabetes increased
CRP by 1.49 mg/L (t= 2.78, P= 0.005). Diabetes
maintained its significance as a predictor in model 3, even
after controlling for demographic variables (t= 2.42,
P= 0.02). Diabetes did, however, become nonsignificant
in model 4 when WHtR was controlled for (t= 1.26,
P= 0.21). This indicates that WHtR may be more closely
related to inflammation than depression or diabetes risk.
For every 0.10 increase in WHtR, CRP increased by
3.38 mg/L (t= 8.08, P< 0.001; Table 3).
In the first mediation model, the results for direct
effects showed that the presence of depression was associ-
ated with higher CRP levels (z= 2.46, P= 0.01), higher
CRP levels were associated with the presence of diabetes
(z= 3.32, P< 0.001), and the presence of depression was
associated with the presence of diabetes (z= 2.53,
P= 0.01). The indirect effect indicated that there was par-
tial mediation of the relationship between depression and
diabetes by CRP (z= 1.98, P< 0.05; Figure 1). Because
the model was saturated, no fit statistics are reported.
WHtR was then added to the model. Adjusted direct
effects showed that the presence of depression was no
longer associated with higher CRP levels (z= 1.59,
P= 0.08). New paths showed that the presence of depres-
sion was associated with a higher WHtR (z= 4.00,
P< 0.001), and a higher WHtR was associated with
higher CRP values (z= 10.03, P< 0.001) and the pres-
ence of diabetes (z= 5.57, P< 0.001). In the mediation of
depression and inflammation by waist-to-height ratio,
the presence of WHtR accounts for an average of
1.15 mg/L of the higher CRP values seen with the pres-
ence of depression (indirect effect β= 0.02, z= 3.71,
P< 0.001). In addition, the presence of depression and
diabetes was partially mediated by WHtR (indirect effect
β= 0.02, z= 3.25, P= 0.001). However, the positive rela-
tionship between depression and diabetes was not medi-
ated by the path through WHtR and CRP (indirect effect
β= 0.002, z= 1.71, P= 0.09), and the positive relation-
ship between depression and diabetes was not mediated
by CRP (indirect effect β= 0.003, z= 1.22, P= 0.22).
Because the model was saturated, no fit statistics are
reported (Figure 2).
4|DISCUSSION
Our results suggest that central adiposity may be a more
significant mediator between diabetes and depression
TABLE 1 HbA1c and CRP statistics for the sample population
Measure Median Min Max Lower quartile Upper quartile
HbA1c 5.80% 3.97% 14.97% 5.42% 6.57%
CRP (DBS) 1.21 mg/L 0.09 mg/L 4.72 mg/L 0.76 mg/L 2.06 mg/L
CRP (serum equivalent) 1.53 mg/L 0.00 mg/L 10.00 mg/L 0.45 mg/L 3.57 mg/L
TABLE 2 Population percentage in risk categories for HbA1c,
CRP (serum equivalent), and WHtR before exclusion for infection/
injury
Measure/risk category Cut-off values
Population
percentage (%)
HbA1c
Diabetes 6.50% 24
Impaired glucose
tolerance
5.70-6.49% 28
Normal <5.70 48
CRP (serum equivalent)
High 10.00 mg/L 9
Medium/high 3.00-9.99 mg/L 27
Medium/low 1.00-2.99 mg/L 29
Low <1.00 mg/L 36
Waist to height ratio
High 0.56 81
Low <0.56 19
Note: Waist-to-height ratio (WHtR) reference ranges (Rodea-Montero, Evia-
Viscarra, & Apolinar-Jiménez, 2014; WHO, 2011b), C-reactive protein (CRP)
reference ranges (Nehring & Patel, 2018; Pearson et al., 2003), and HbA1c
reference ranges (WHO, 2011a).
6DONA ET AL.
than inflammation and account for the relationship
between these disorders and inflammation. The first
mediation model is consistent with the hypothesized rela-
tionship that depression is associated with higher levels
of CRP, which is then associated with uncontrolled dia-
betes. When WHtR was not considered, the relationship
between diabetes and depression was partially mediated
by CRP, although the association was modest. However,
when WHtR was included in the second mediation
model, CRP was no longer a significant mediator of the
comorbidity between depression and diabetes. Instead,
central adiposity mediated the relationship between
depression and uncontrolled diabetes.
The results from the second model were partially con-
sistent with the second hypothesis that central adiposity
would mediate depression and diabetes as well as that
TABLE 3 Regression table of serum C-reactive protein (CRP) B and standardized βvalues predicting lnCRP
Model 1 Model 2 Model 3 Model 4
Variables of interest
Depression 1.45 (0.06)* 1.41 (0.05)* 1.18 (0.02) 1.08 (0.01)
Diabetes 1.49 (0.07)** 1.42 (0.06)** 1.23 (0.03)
Demographic
Age 1.02 (0.04) 1.02 (0.04)
Female 1.84 (0.13)*** 1.55 (0.09)**
Education 1.01 (0.03) 1.02 (0.01)
Wealth 1.06 (0.01) 0.99 (0.01)
Marital status (married vs)
Never married 0.60 (0.05) 0.77 (0.03)
Cohabiting 1.49 (0.03) 1.46 (0.03)
Separated/divorced 0.89 (0.01) 0.90 (0.01)
Widowed 0.80 (0.04) 0.79 (0.04)
General health
Waist/height 33.84 (0.20)***
Current health 1.17 (0.04)
R
2
0.00 0.01 0.03 0.07
ΔR
2
0.00 0.01 0.02 0.04
F4.91* 6.34** 4.49*** 9.61***
*P< 0.05.; **P< 0.01.; ***P< 0.001. All Bvalues were transformed to represent changes in serum CRP.
Depression Diabetes
lnCRP
.08*
.11***
.06*
E1
E2
FIGURE 1 Mediation model, including βvalues, showing
diabetes and depression were mediated by lnCRP. (Indirect effect
β= 0.01 P< 0.05.) *P< 0.05, **P< 0.01, and ***P< 0.001
.04
.19***
WHtR
Depression
lnCRP
Diabetes
.09***
.25***
.07
.07*
E1
E3
E2
FIGURE 2 Waist-to-height ratio (WHtR) was added to the
mediation model with βvalues for direct effects noted. This model
shows that WHtR mediated the positive relationship between
depression and lnCRP (Indirect effect β= 0.02, P< 0.001), WHtR
partially mediated the positive relationship between depression and
diabetes (Indirect effect β= 0.02, P= 0.001), the path through
WHtR and lnCRP did not mediate the positive relationship
between depression and diabetes (Indirect effect β= 0.002,
P= 0.09), and lnCRP did not mediate the positive relationship
between depression and diabetes (Indirect effect β= 0.003,
P= 0.22) *P< 0.05 **P< 0.01 ***P< 0.001
DONA ET AL.7
the positive association between central adiposity and
CRP would mediate depression and diabetes. As
predicted, the presence of depression was associated with
a greater WHtR, and a greater WHtR was associated with
the presence of diabetes. However, CRP no longer medi-
ated the relationship between depression and diabetes
and the positive association between WHtR and CRP did
not mediate the relationship between depression and
diabetes. Therefore, the relationship between depression
and uncontrolled diabetes appears to have a central adi-
posity component but not a systemic inflammatory com-
ponent as indicated by CRP. In addition, the relationship
between depression and CRP was fully mediated by
WHtR. This suggests that central adiposity may be a
more significant mediator of the relationship between
uncontrolled diabetes and depression as well as account
for the observed mediation of depression and diabetes
by CRP.
These results suggest that central adiposity is one of
the causal factors in the relationship between depression
and diabetes: the presence of depression may cause an
increase in visceral adipose tissue, which then may cause
an increase in diabetes risk. It is also possible that this
relationship could be bidirectional. Although inflamma-
tion did appear to be an intermediate pathway step
between these two diseases when assessed alone, central
adiposity fully accounted for the previously observed rela-
tionship between depression and CRP, supporting that
this inflammation results from central adiposity and is
not involved in the association between depression and
diabetes. However, CRP no longer mediating central adi-
posity and diabetes suggests that other pathways caused
by central adiposity should also be further evaluated as
potential mediators of the two disorders.
Although some of these findings are comparable to
previously published studies, others are inconsistent.
First, the association between WHtR and diabetes found
in this study using HbA1c to identify participants with
diabetes suggests that the results of an earlier analysis of
SAGE Wave 1 datawhich did not observe an associa-
tion between WHtR and diabetes in Mexico (but did
observe this relationship in other countries) (Tyrovolas
et al., 2015)may have been due to self-report bias or
lack of reliable reporting of clinical diagnosis in the sam-
ple (biomarker data were unavailable at the time of that
publication). Second, although previous studies indicate
that inflammation could be a causal factor in the comor-
bidity of diabetes and depression, the present study does
not and suggests that central adiposity is a more signifi-
cant factor in mediating the relationship between inflam-
mation and depression as well as depression and
diabetes. Although many studies have shown the rela-
tionship between chronic illness and inflammation, not
all studies share these results. For example, several stud-
ies from the Tsimane Health and Life History Project
have found that higher levels of inflammation, and spe-
cifically CRP, co-occur with better health outcomes such
as lower cholesterol levels and coronary artery calcium,
potentially because of parasitic burden driving high CRP
and protective lifestyle factors keeping chronic disease
risk low (Gurven et al., 2017; Kaplan et al., 2017). These
studies as well as the present study indicate that the rela-
tionship between inflammation and chronic disease is
complex and that inflammation is not always the key
pathophysiological mechanism.
Furthermore, this study adds to the field of mental
health and aging research from middle-income countries.
Infact,itmaybethefirsttousealargesampleofolder
adults in a middle-income nation with biomarker informa-
tion to investigate physiological processes that might be
involved in diabetes and depression. This is significant
because studies of populations from low- and middle-
income countries are underrepresented in high-impact
psychiatry journals (Farmer et al., 2013). Indeed, a 2001 sur-
vey found that, in six leading psychiatry journals, only 6%
of the papers originated from countries outside of Western
Europe, North America, Australia, and New Zealand.
Within this 6%, 4% of published studies were from Latin
America (0.0024% of the total papers) (Patel & Sumathipala,
2001). Although representation of research from low- and
middle-income countries is improving, these limitations
were also identified in papers investigating comorbid diabe-
tes and depression, namely the need for research in
populations that are not of European descent and not from
high-income nations (Herder et al., 2018; Schmitz et al.,
2016). This study begins to clarify conflicting relationships
between these conditions observed in smaller and/or less
diverse samples (Herder et al., 2018; Hood et al., 2012). In
addition, the worldwide number of people aged 60 years
and older is growing faster than all younger age groups and
is expected to more than double by 2050 and to more than
triple by 2100, rising from 962 million globally in 2017 to
2.1 billion in 2050 and 3.1 billion in 2100 (United Nations,
2017). With the number of older people increasing world-
wide, making additional years healthy is critical.
4.1 |Limitations
The main limitations of this study are that directionality
cannot be assessed without longitudinal data, and these
results cannot demonstrate causation based on our study
design and data. In other words, although we were able
to demonstrate that diabetes was associated with an
increase in WHtR and diabetes, we were not able to con-
clude that depression causes an increase in WHtR, which
8DONA ET AL.
in turn causes diabetes or vice versa (indeed, this path-
way might be bidirectional). In addition, this study may
only be representative of Mexico, and the results cannot
necessarily be generalized to all countries and communi-
ties. Overall, though, the diversity and size of the sample
are strength of this study.
Another limitation is the identification of a partici-
pant's sex. Because the interviewer made a determination
of sex based on appearance and recorded either Maleor
Female,this variable is a measure of the participant's
gender presentation as perceived by the interviewer, not a
measure of biological sex. This measure would be consis-
tent with biological sex for most individuals; however, it
fails to take into account transgender, non-binary, and
intersex individuals. Therefore, this variable has been
renamed gender for the purposes of this article, and the
limitation of true gender identification due to the method-
ology is noted.
Finally, this study was unable to differentiate between
type 1 and type 2 diabetes, as HbA1c levels increase in both
conditions. The underlying pathological mechanisms differ
significantly between type 1 and type 2 diabetes (Cnop
et al., 2005), and it is possible that the inability to distin-
guish between the two could have increased our analyses'
variance and made our results less significant. However, we
would expect type 2 diabetes to be vastly more common,
especially in older Mexican individuals. Other health condi-
tions have also been shown to impact HbA1c levels, includ-
ing iron deficiency among adults without diabetes (Kim,
Bullard, Herman, & Beckles, 2010). In addition, we did not
differentiate between people being treated for uncontrolled
diabetes (HbA1c > 6.5%) and people who were not.
4.2 |Summary and conclusions
In summary, this study found that, although CRP alone
partially mediated the co-occurrence of depression and
diabetes, controlling for WHtR showed that CRP is not
involved in the mediation of diabetes and depression and
only appears associated at first because of its strong rela-
tionship with central adiposity. Instead, central adiposity
alone mediated the relationship between depression and
diabetes. In addition, central adiposity fully mediated the
relationship between depression and CRP. These results
suggest that depression may cause an increase in central
adiposity which then leads to diabetes and is incidentally
associated with systemic inflammation. Because CRP did
not mediate the relationship between central adiposity
and diabetes, it is possible that there are other pathways
that are also causally involved in the presence of both
depression and diabetes. Knowledge of how central
adiposity contributes to this comorbidity may help in the
design of preventative strategies or improve treatment.
ACKNOWLEDGMENTS
We thank all the participants in this study. SAGE was
supported by NIH NIA Interagency Agreement
YA1323-08-CN-0020 and the Ministry of Health in
Mexico.
AUTHOR CONTRIBUTIONS
Allison C. Dona: Writing of abstract, introduction, parts of
methods, and discussion; data interpretation; and main
editor/composer of manuscript. Alicia M. DeLouize: Statis-
tical analysis, writing of most of the methods and results
sections; data interpretation; and critical feedback to
manuscript. Geeta Eick: Important biomarker insight
and critical feedback to manuscript. Elizabeth Thiele:
SAGE consultant and biomarker insight. Aarón Salinas
Rodríguez, Betty Soledad Manrique Espinoza, Ricardo
Robledo, Salvador Villalpando: Data collection and
biomarker analysis. Paul Kowal: SAGE co-director and
critical feedback to manuscript. Nirmala Naidoo: SAGE
co-director. Somnath Chatterji: SAGE co-director. Josh
Snodgrass: Project management and critical feedback to
manuscript.
ORCID
Allison C. Dona https://orcid.org/0000-0002-5830-626X
Geeta Eick https://orcid.org/0000-0001-7512-3265
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12 DONA ET AL.
... Inflammation has the capability to impact the brain and neurotransmitter levels, potentially contributing to the development of depression. The overproduction of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, has been observed in cases of depression [47,48]. Additionally, metabolic diseases have the potential to disrupt the hypothalamic-pituitary-adrenal (HPA) axis, resulting in the dysregulation of stress response and cortisol production. ...
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Background Studies suggest a correlation between excessive sedentary behavior, insufficient physical activity, and an elevated likelihood of experiencing psychiatric disorder. Nonetheless, the precise influence of sedentary behavior and physical activity on psychiatric disorder remains uncertain. Hence, the objective of this research was to investigate the possible causal relationship between sedentary behavior, physical activity, and the susceptibility to psychiatric disorder (depression, schizophrenia and bipolar disorder), utilizing a two-sample Mendelian randomization (MR) approach. Methods Potential genetic instruments related to sedentary leisure behaviors were identified from the UK Biobank database, specifically a summary-level genome-wide association study (GWAS) involving 422,218 individuals of European descent. The UK Biobank database also provided the GWAS data for physical activity. Primary analysis was performed using inverse variance weighting (IVW) to assess the causal relationship between sedentary behavior, physical activity, and the risk of psychiatric disorder (depression, schizophrenia and bipolar disorder). Sensitivity analysis was conducted using Cochran’s Q test, the MR–Egger intercept test, the MR-pleiotropy RESidual sum and outlier test, leave-one-out analysis, and funnel plot analysis. Results According to the IVW analysis, there was a significant association between genetically predicted leisure television watching and an increased risk of depression (odds ratio [OR] = 1.027, 95% confidence interval [CI]: 1.001–1.053; P = 0.04). The IVW analysis also indicated that there was a decreased risk of depression associated with fraction accelerations of > 425 milligravities, as measured by accelerometers (OR = 0.951, 95%CI: 0.914–0.989; P = 0.013). The other MR methods obtained consistent but non-significant results in the same direction. However, there was no evidence of a causal association between genetic liability for moderate-to-vigorous physical activity, accelerometer-assessed physical activity, computer use, or driving and the risk of depression. Furthermore, IVW analysis has also found that driving has a slight effect in reducing the risk of schizophrenia (OR = 0.092, 95%CI: 0.010–0.827; P = 0.033), while leisure television viewing has a significant protective effect against the onset of bipolar disorder (OR = 0.719, 95%CI: 0.567–0.912; P = 0.006). Conclusion The study provides compelling evidence of a link between depression, bipolar disorder, and excessive TV watching. Furthermore, it suggests that higher accelerometer-assessed fraction accelerations of > 425 milligravities can serve as a genetic protective factor against depression. To mitigate the risk of developing depression, it is advisable to reduce sedentary activities, particularly television watching, and prioritize engaging in vigorous physical exercise.
... Several psychiatric disorders associated with increased risk of SUD share comorbidity with metabolic disorders (Luppino et al., 2010;Jimenez et al., 2019;Trevino-Alvarez et al., 2023). For example, MDD is often comorbid with type 2 diabetes (T2D), and several lines of evidence point to a core metabolic pathology across mood disorders (Fagiolini et al., 2002;Dona et al., 2020;Norwitz et al., 2020). Additionally, conditions associated with metabolic disorders such as painful diabetic neuropathy are commonly managed with opioid medications, which pose a risk of addiction (Callaghan et al., 2012;Jensen et al., 2021). ...
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Substance use disorders are a global health problem with increasing prevalence resulting in significant socioeconomic burden and increased mortality. Converging lines of evidence point to a critical role of brain extracellular matrix (ECM) molecules in the pathophysiology of substance use disorders. An increasing number of preclinical studies highlight the ECM as a promising target for development of novel cessation pharmacotherapies. The brain ECM is dynamically regulated during learning and memory processes, thus the time course of ECM alterations in substance use disorders is a critical factor that may impact interpretation of the current studies and development of pharmacological therapies. This review highlights the evidence for the involvement of ECM molecules in reward learning, including drug reward and natural reward such as food, as well as evidence regarding the pathophysiological state of the brain's ECM in substance use disorders and metabolic disorders. We focus on the information regarding time-course and substance specific changes in ECM molecules and how this information can be leveraged for the development of therapeutic strategies.
... Depressive disorders and impaired mental health-related quality of life are more prevalent among people with T2DM [11]. The relationship between T2DM and depression is thought to be bidirectional because of similar underlying pathological features in these conditions, including inflammation [12]. Higher serum levels and expression of inflammatory and pro-inflammatory markers in depressed patients with T2DM have been reported [13]. ...
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Background Using functional foods in the prevention and treatment of type 2 diabetes mellitus (T2DM) has increased across the world owing to their availability, cultural acceptability, and lower side effects. The present study will aim to examine the impact of bitter almond ( Amygdalus communis L. var. Amara) gum as a functional food on metabolic profile, inflammatory markers, and mental health in women with T2DM. Methods We will conduct a randomized, triple-blind, placebo-controlled trial. A total of 44 women with T2DM will be randomly allocated into two groups: an intervention group ( n = 20) and a placebo group ( n = 20). Patients will receive either 5 g/d of bitter melon gum or a placebo for 8 weeks. Clinical and biochemical outcome parameters which include glycemic indices, lipid profile, inflammatory markers, oxidative stress indices, tryptophan (Trp), kynurenine (KYN), cortisol, glucagon-like peptide 1 (GLP-1), leptin, adiponectin, ghrelin, peroxisome proliferator-activated receptor (PPAR) gene expression, brain-derived neurotrophic factor (BDNF), endothelial cell adhesion molecules, plasminogen, cluster deference 4 (CD4), cluster deference 8 (CD8), anthropometric indices, blood pressure, dietary intake, and mental health will be measured at the baseline and end of the study. Statistical analysis will be conducted using the SPSS software (version 24), and P value less than 0.05 will be considered statistically significant. Discussion The present randomized controlled trial will aim to investigate any beneficial effects of bitter almond gum supplementation on the cardio-metabolic, immune-inflammatory, and oxidative stress biomarkers, as well as mental health in women with T2DM. Ethics and dissemination The study protocol was approved by the Ethical Committee of the Tabriz University of Medical Sciences (IR.TBZMED.REC.1399.726). Trial registration Iranian Registry of Clinical Trials ( www.irct.ir/IRCT20150205020965N7 )
... [16] Researches have proved that depression may make the body in a low-grade inflammation state, and C-reactive protein, as an inflammatory-related factors, partially mediates the relationship between depression and diabetes. [17] Negative emotional state could be changed by mind-body therapies. As a non-drug approach for T2DM, mind-body therapies have gained more attention than ever before, which could also help reduce social medical costs. ...
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Background: Type 2 diabetes mellitus is intimately linked to chronic stress. Meditation programs belong to mind-body therapies, which could benefit patients' disease management. Though some clinical trials have proved that meditation programs have the ability to improve level of blood glucose quality of life, body mass index and blood indexes related to metabolism in individuals with type 2 diabetes mellitus, the efficacy of meditation programs needs further confirmation. Thus we will conduct this systematic evaluation and meta-analysis to summarize and analyze all the results included to obtain reliable evidence. Methods: We will search several English and Chinese databases for relevant clinical trials published up to July 2021, and randomized controlled trials or controlled trials among adults with type 2 diabetes mellitus are included. Two reviewers will extract data and assess the quality of included studies independently. The main outcomes of this research are glycosylated hemoglobin level and fasting blood glucose level. The secondary outcomes are high-density lipoprotein, low-density lipoprotein, body mass index, remission of depression and anxiety, and quality of life. Stata v.14.0 and Review Manager V5.3 will be used to synthesize and analyze all data included. Results: Grading of Recommendations Assessment, Development, and Evaluation will be used to evaluate the quality of the assessments. Our study will be disseminated through publications in peer-reviewed journals. Conclusion: This systematic review is the first to analyze the efficacy of different types of meditation for type 2 diabetes mellitus, which could provide evidence for the use of mediation programs as non-drug approaches. Trial registration number: PROSPERO CRD42021274508.
... In China and South Africa, dried blood spot samples were collected using finger-prick capillary blood spotted onto standard filter paper, following established procedures (25). In Mexico, the values were obtained through dried blood spots collected by spotting whole blood collected by venipuncture onto standard filter paper (26). For all countries, the biomarkers were analyzed using enzyme-linked immunosorbent assays. ...
... DM is reciprocally linked to depression through many ways [17]. Researches have proved that depression may make the body in a low-grade in ammation state, and C-reactive protein (CRP), as an in ammatory-related factors, partially mediates the relationship between depression and diabetes [18]. Negative emotional state could be changed by mind-body therapies. ...
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Background Type 2 diabetes mellitus is intimately linked to chronic stress. Meditation programs belong to mind-body therapies, which could benefit patients’ disease management. Though some clinical trials have proved that meditation programs have the ability to improve level of blood glucose, quality of life, body mass index and blood indexes related to metabolism in individuals with type 2 diabetes mellitus, the efficacy of meditation programs needs further confirmation. Thus, we will conduct this systematic evaluation and meta-analysis to summarize and analyze all the results included to obtain reliable evidence.Method We will search several English and Chinese databases for relevant clinical trials published up to July 2021, and randomized controlled trials or controlled trials among adults with type 2 diabetes mellitus are included. Two reviewers will extract data and assess the quality of included studies independently. The main outcomes of this research are glycosylated hemoglobin level and fasting blood glucose level. The secondary outcomes are high-density lipoprotein, low-density lipoprotein, body mass index, remission of depression and anxiety, and quality of life. Stata v.14.0 and Review Manager V5.3 will be used to synthesize and analyze all data included.DiscussionThis systematic review is the first to analyze the efficacy of different types of meditation for type 2 diabetes mellitus, which could provide evidence for the use of mediation programs as non-drug approaches. Lack of enough randomized controlled trials is the main limitation of this protocol. So, we will gradually finish this protocol in the future and reduce the risk of bias.Registrationhttps://doi.org/10.37766/inplasy2021.10.0008. NO. 2021100008.
... Inflammation was associated with the risk for diabetes (Wang et al., 2013), and depression was associated with a higher degree of inflammation (Dowlati et al., 2010). In one mediation analysis (Dona et al., 2020), central adiposity (quantified by waist-to-height ratio) and inflammation (quantified by CRP) were suggested to mediate the relationship between depression and glycemic control (quantified by HbA1c). Inflammatory markers fall reliably with physical activity (Swardfager et al., 2012), which might also be considered as a mediator considering depression and insulin resistance (Rethorst, Bernstein, & Trivedi, 2014). ...
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Background Bidirectional longitudinal relationships between depression and diabetes have been observed, but the dominant direction of their temporal relationships remains controversial. Methods The random-intercept cross-lagged panel model decomposes observed variables into a latent intercept representing the traits, and occasion-specific latent ‘state’ variables. This permits correlations to be assessed between the traits, while longitudinal ‘cross-lagged’ associations and cross-sectional correlations can be assessed between occasion-specific latent variables. We examined dynamic relationships between depressive symptoms and insulin resistance across five visits over 20 years of adulthood in the population-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Possible differences based on population group (Black v. White participants), sex and years of education were tested. Depressive symptoms and insulin resistance were quantified using the Center for Epidemiologic Studies Depression (CES-D) scale and the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. Results Among 4044 participants (baseline mean age 34.9 ± 3.7 years, 53% women, 51% Black participants), HOMA-IR and CES-D traits were weakly correlated ( r = 0.081, p = 0.002). Some occasion-specific correlations, but no cross-lagged associations were observed overall. Longitudinal dynamics of these relationships differed by population groups such that HOMA-IR at age 50 was associated with CES-D score at age 55 ( β = 0.076, p = 0.038) in White participants only. Longitudinal dynamics were consistent between sexes and based on education. Conclusions The relationship between depressive symptoms and insulin resistance was best characterized by weak correlations between occasion-specific states and enduring traits, with weak evidence that insulin resistance might be temporally associated with subsequent depressive symptoms among White participants later in adulthood.
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Background Low hemoglobin levels are a significant biomarker in the prognosis of sarcopenia. Anemia and sarcopenia are frequent and disabling conditions in the older adult population, but little is known about the role of anemia in the onset and progression of sarcopenia. This study aimed to determine whether prospective changes in anemia are associated with the incidence and persistence of sarcopenia. Methods Data come from the second and third waves (2014, 2017) of the World Health Organization (WHO) Study on global AGEing and adult health (SAGE) in Mexico. SAGE-Mexico is a dynamic cohort with national representativeness, including a follow-up sample and new enrollments. For this study, 1,500 older adults (aged 50 or above) with measurements in both waves were included. Sarcopenia was defined as having low muscle quantity and either/both slow gait speed and weak handgrip strength. Anemia was defined according to hemoglobin concentrations, adjusted for altitude, as recommended by the WHO, <120 g/L for women and <130 g/L for men. Multinomial logistic regression was used to estimate the association between anemia and prospective changes in sarcopenia. Results The baseline prevalence of anemia was 17.4%, and that of sarcopenia was 12.1%. The incidence and persistence of anemia were 10.6% (95% CI: 7.3–15.0%) and 6.9% (95% CI: 4.7–9.8%), respectively, and for sarcopenia, they were 5.3% (95% CI: 3.7–7.7%) and 9.2% (95% CI: 6.4–13.0%), respectively. Incident anemia was associated with incident (RRR = 3.64, 95% CI: 1.18–11.19) but not with persistent (RRR = 0.75, 95% CI: 0.18–3.20) sarcopenia. Persistent anemia was significantly associated with persistent (RRR = 3.59, 95% CI: 1.14–11.27) but not incident (RRR = 1.17, 95% CI: 0.30–4.54) sarcopenia. Conclusion Changes in anemia are significantly associated with incident and persistent sarcopenia. Primary actions to promote a healthy diet rich in antioxidants, high-quality proteins, and micronutrients, as well as moderate physical activity and maintaining a healthy weight, are crucial for the aging population to delay the deleterious effects of anemia and sarcopenia.
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Background The comorbidity between diabetes mellitus and depression was revealed, and diabetes mellitus increased the prevalence of depressive disorder, which ranked 13th in the leading causes of disability‐adjusted life‐years. Insulin resistance, which is common in diabetes mellitus, has increased the risk of depressive symptoms in both humans and animals. However, the mechanisms behind the comorbidity are multi‐factorial and complicated. There is still no causal chain to explain the comorbidity exactly. Moreover, Selective serotonin reuptake inhibitors, insulin and metformin, which are recommended for treating diabetes mellitus‐induced depression, were found to be a risk factor in some complications of diabetes. Aims Given these problems, many researchers made remarkable efforts to analyze diabetes complicating depression from different aspects, including insulin resistance, stress and Hypothalamic–Pituitary–Adrenal axis, neurological system, oxidative stress, and inflammation. Drug therapy, such as Hydrogen Sulfide, Cannabidiol, Ascorbic Acid and Hesperidin, are conducive to alleviating diabetes mellitus and depression. Here, we reviewed the exact pathophysiology underlying the comorbidity between depressive disorder and diabetes mellitus and drug therapy. Methods The review refers to the available literature in PubMed and Web of Science, searching critical terms related to diabetes mellitus, depression and drug therapy. Results In this review, we found that brain structure and function, neurogenesis, brain‐derived neurotrophic factor and glucose and lipid metabolism were involved in the pathophysiology of the comorbidity. Obesity might lead to diabetes mellitus and depression through reduced adiponectin and increased leptin and resistin. In addition, drug therapy displayed in this review could expand the region of potential therapy. Conclusions The review summarizes the mechanisms underlying the comorbidity. It also overviews drug therapy with anti‐diabetic and anti‐depressant effects.
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Subclinical inflammation has been implicated in the development of depression, a common comorbidity of type 1 diabetes (T1D) and type 2 diabetes (T2D). This study aimed to characterise the relationships between biomarkers of inflammation and depressive symptoms in T1D and T2D. Biomarkers of inflammation were measured in serum of participants with elevated depressive symptoms and T1D (n = 389, mean age 38 years, diabetes duration 15 ± 11 years) or T2D (n = 204, mean age 56 years, diabetes duration 13 ± 8 years). Subclinical depression was examined using three questionnaires (Center for Epidemiologic Studies Depression [CES-D], Patient Health Questionnaire-9 [PHQ-9], 5-item World Health Organization Well-Being Index [WHO-5]). In T1D, levels of interleukin-1 receptor antagonist (IL-1RA) were positively associated with two depression scores (CES-D, PHQ-9), and high-sensitivity C-reactive protein (hsCRP) was positively associated with depression for one score (WHO-5) after adjustment for age, sex, body mass index, diabetes duration, metabolic variables, medication and comorbidities (P = 0.008-0.042). In T2D, IL-18 and IL-1RA were positively associated with depression for two scores (IL-18: PHQ-9, WHO-5; IL-1RA: CES-D, WHO-5), hsCRP was associated with one depression score (PHQ-9), and adiponectin showed an inverse association with one depression score (PHQ-9) after adjustment (P = 0.006–0.048). No associations were found for IL-6 and CC-chemokine ligand 2 (CCL2). In conclusion, we observed associations between hsCRP, IL-1RA and depressive symptoms in patients with diabetes. In T2D, there was additional evidence for associations of IL-18 and (inversely) adiponectin with depressive symptoms. The strength of the associations appeared to depend on diabetes type and the method used to asssess depressive symptoms.
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Objective: Our objective was to test whether food insecurity mediates cross-sectional associations between social disadvantage and body composition among older adults (aged 50+) in India (n = 6556). Methods: Adjusting for key sociodemographic and dietary variables, we examined whether markers of social disadvantage (lower educational attainment, lower household wealth, belonging to a disadvantaged caste/tribe, and belonging to a minority religion) were associated with food insecurity. We then examined whether food insecurity, in turn, was associated with anthropometric measures of body composition, body mass index (BMI), and waist circumference (WC). We also tested whether food insecurity mediated the relationship between social disadvantage and body composition. Results: In adjusted models, lower household wealth [lowest quintile (Q5) vs highest quintile (Q1): odds ratio (OR) = 13.57, P < .001], having less than a high-school education (OR = 2.12. P < .005), being Muslim (OR = 1.82, P < .001), and being in a scheduled caste (historically marginalized) (OR = 1.49, P < .005) were associated with greater food insecurity. Those who were severely food insecure had greater odds of being underweight (OR = 1.36, P < .01) and lower odds of high WC (OR = 0.70, P < .01). Mediation analyses estimated that food insecurity explained 4.7%-29.7% of the relationship between social disadvantage and body composition, depending on the variables considered. Conclusions: Our results are consistent with the hypothesis that food insecurity is a mechanism linking social disadvantage and body composition among older adults in India. These analyses contribute to a better understanding of processes leading to variation in body composition, which may help enhance the design of interventions aimed at improving population nutritional status.
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Mental health in Mexico is recognized as one of the main unresolved issues within the government’s health policy agenda. Statistics from the National Institute of Statistics and Geography showed that the number of deaths due to mental disorders has increased by 33% between 2008 and 2014. Depressive disorders in Mexico create a comparable disease burden to that of interpersonal violence, road injuries, or congenital anomalies, and a greater burden than that of cerebrovascular disease, and HIV/AIDS. In 2002, one out of eight Mexican citizens suffered a depressive disorder and, in 2012, studies found the prevalence was even higher in individuals over 80 years of age. This suggests that mental health issues in Mexico will become more relevant as the country undergoes a demographic transition to an older population. In addition to the stigma, discrimination, and low public awareness of mental health issues, Mexico faces two large obstacles for the treatment of these disorders: (1) the lack of specialized human resources and (2) the general budget restrictions on health care initiatives. The present article reviews the state of affairs of depression in Mexico and discusses the most relevant challenges the Mexican mental health system is facing in managing the burden of disease.
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Background: The study aimed to identify the most burdensome functioning domains in depression and their differential impact on the quality of life (QoL) of individuals from nine countries in Asia, Africa, Europe, and Latin America. Materials and Methods: Data from two multi-country projects—the World Health Organization’s Study on Global Ageing and Adult Health (SAGE) and the Collaborative Research on Ageing in Europe (COURAGE)—were analyzed. Eight functioning domains (pain, mobility, self-care, cognition, interpersonal activities, domestic life, and work, sleep and energy, and affect) and QoL were assessed in 4051 individuals with depression. Results: The analyses of the pooled sample showed that affect (ß = –0.21, p < 0.001), domestic life and work (ß = –0.16, p < 0.001) and interpersonal activities (ß = –0.15, p < 0.001) were the most affected functioning domains. When the analysis was stratified by gender, women showed similar patterns to the total sample, whereas mobility, self-care, cognition and pain were not significant amongst men. The cross-national analysis revealed that difficulties in affect and interpersonal activities were common across countries, whereas the rest of the domains showed country variability. In addition, being a woman (ß = –0.05), being older (ß = 0.07), being married (ß = 0.05), not having a comorbid condition (ß = –0.03) and having a higher education (ß = 0.04) were all factors associated with higher levels of QoL. Conclusion: There was a variation in the level of decrements in different functioning domains across countries. This is in line with the growing evidence that reporting functioning sum-scores obscures potential differences among people. Functioning tools should capture the distinctiveness among individuals in order to provide tailored responses.
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The Tsimane Health and Life History Project, an integrated bio-behavioral study of the human life course, is designed to test competing hypotheses of human life-history evolution. One aim is to understand the bidirectional connections between life history and social behavior in a high-fertility, kin-based context lacking amenities of modern urban life (e.g. sanitation, banks, electricity). Another aim is to understand how a high pathogen burden influences health and well-being during development and adulthood. A third aim addresses how modernization shapes human life histories and sociality. Here we outline the project's goals, history, and main findings since its inception in 2002. We reflect on the implications of current findings and highlight the need for more coordinated ethnographic and biomedical study of contemporary nonindustrial populations to address broad questions that can situate evolutionary anthropology in a key position within the social and life sciences.
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Background: Conventional coronary artery disease risk factors might potentially explain at least 90% of the attributable risk of coronary artery disease. To better understand the association between the pre-industrial lifestyle and low prevalence of coronary artery disease risk factors, we examined the Tsimane, a Bolivian population living a subsistence lifestyle of hunting, gathering, fishing, and farming with few cardiovascular risk factors, but high infectious inflammatory burden. Methods: We did a cross-sectional cohort study including all individuals who self-identified as Tsimane and who were aged 40 years or older. Coronary atherosclerosis was assessed by coronary artery calcium (CAC) scoring done with non-contrast CT in Tsimane adults. We assessed the difference between the Tsimane and 6814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). CAC scores higher than 100 were considered representative of significant atherosclerotic disease. Tsimane blood lipid and inflammatory biomarkers were obtained at the time of scanning, and in some patients, longitudinally. Findings: Between July 2, 2014, and Sept 10, 2015, 705 individuals, who had data available for analysis, were included in this study. 596 (85%) of 705 Tsimane had no CAC, 89 (13%) had CAC scores of 1-100, and 20 (3%) had CAC scores higher than 100. For individuals older than age 75 years, 31 (65%) Tsimane presented with a CAC score of 0, and only four (8%) had CAC scores of 100 or more, a five-fold lower prevalence than industrialised populations (p≤0·0001 for all age categories of MESA). Mean LDL and HDL cholesterol concentrations were 2·35 mmol/L (91 mg/dL) and 1·0 mmol/L (39·5 mg/dL), respectively; obesity, hypertension, high blood sugar, and regular cigarette smoking were rare. High-sensitivity C-reactive protein was elevated beyond the clinical cutoff of 3·0 mg/dL in 360 (51%) Tsimane participants. Interpretation: Despite a high infectious inflammatory burden, the Tsimane, a forager-horticulturalist population of the Bolivian Amazon with few coronary artery disease risk factors, have the lowest reported levels of coronary artery disease of any population recorded to date. These findings suggest that coronary atherosclerosis can be avoided in most people by achieving a lifetime with very low LDL, low blood pressure, low glucose, normal body-mass index, no smoking, and plenty of physical activity. The relative contributions of each are still to be determined. Funding: National Institute on Aging, National Institutes of Health; St Luke's Hospital of Kansas City; and Paleocardiology Foundation.