Introduction: Frailty is prevalent among older adults with diabetes mellitus. Elevated serum levels of the soluble receptor for advanced glycation-end products (sRAGE) predict mortality in frail older adults. The evidence that sRAGE is also related to higher mortality in older adults with diabetes mellitus is inconsistent. Therefore, this study explored if frailty status influences the relationship between sRAGE and mortality in older adults with this condition. Methods: We analysed data of 391 participants with diabetes mellitus (median age, 76 years) from four European cohorts enrolled in the FRAILOMIC project. Frailty was evaluated at baseline using Fried’s criteria. Serum sRAGE was determined by ELISA. Participants were stratified by frailty status (n = 280 non-frail and 111 frail). Multivariate Cox proportional hazards regression and Kaplan-Meier survival analysis were used to assess the relationship between sRAGE and mortality. Results: During 6 years of follow-up, 98 participants died (46 non-frail and 52 frail). Non-survivors had significantly higher baseline levels of sRAGE than survivors (median [IQR]: 1,392 [962–2,043] pg/mL vs. 1,212 [963–1,514], p = 0.008). High serum sRAGE (>1,617 pg/mL) was associated with increased mortality in the whole diabetes sample after adjustment for relevant confounders (HR 2.06, 95% CI: 1.36–3.11, p < 0.001), and there was an interaction between sRAGE and frailty (p = 0.006). Accordingly, the association between sRAGE and mortality was stronger in the frail group compared to the non-frail group (HR 2.52, 95% CI: 1.30–4.90, p = 0.006 vs. HR 1.71, 95% CI: 0.91–3.23, p = 0.099, respectively). Likewise, Kaplan-Meier curves showed a significant difference in survival rates between frail participants with high sRAGE and those with low sRAGE (p = 0.001), whereas no survival difference was seen in the non-frail group (p = 0.09). Conclusions: Frailty status influences the relationship between sRAGE and mortality in older adults with diabetes mellitus. Determination of sRAGE in this population could be a useful tool for risk stratification.

1.
Hanlon
P
,
Faure
I
,
Corcoran
N
,
Butterly
E
,
Lewsey
J
,
McAllister
D
, et al
.
Frailty measurement, prevalence, incidence, and clinical implications in people with diabetes: a systematic review and study-level meta-analysis
.
Lancet Healthy Longev
.
2020
;
1
(
3
):
e106
16
. doi: .
2.
Clegg
A
,
Young
J
,
Iliffe
S
,
Rikkert
MO
,
Rockwood
K
.
Frailty in elderly people
.
Lancet
.
2013
;
381
(
9868
):
752
62
. doi: .
3.
Castro-Rodriguez
M
,
Carnicero
JA
,
Garcia-Garcia
FJ
,
Walter
S
,
Morley
JE
,
Rodriguez-Artalejo
F
, et al
.
Frailty as a major factor in the increased risk of death and disability in older people with diabetes
.
J Am Med Dir Assoc
.
2016
;
17
(
10
):
949
55
. doi: .
4.
American Diabetes Association Professional Practice Committee
.
2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2022
.
Diabetes Care
.
2022
;
45
(
Suppl 1
):
S17
38
. doi: .
5.
Schafer
MJ
,
Zhang
X
,
Kumar
A
,
Atkinson
EJ
,
Zhu
Y
,
Jachim
S
, et al
.
The senescence-associated secretome as an indicator of age and medical risk
.
JCI Insight
.
2020
;
5
(
12
):
e133668
. doi: .
6.
Gomez-Cabrero
D
,
Walter
S
,
Abugessaisa
I
,
Minambres-Herraiz
R
,
Palomares
LB
,
Butcher
L
, et al
.
A robust machine learning framework to identify signatures for frailty: a nested case-control study in four aging European cohorts
.
GeroScience
.
2021
;
43
(
3
):
1317
29
. doi: .
7.
Angioni
D
,
Lu
WH
,
Sourdet
S
,
Macaron
T
,
Takeda
C
,
Guyonnet
S
, et al
.
Biomarkers of age-related frailty and frailty related to diseases: an exploratory, cross-sectional analysis from the MAPT study
.
J Nutr Health Aging
.
2022
;
26
(
6
):
545
51
. doi: .
8.
Fielding
RA
,
Atkinson
EJ
,
Aversa
Z
,
White
TA
,
Heeren
AA
,
Achenbach
SJ
, et al
.
Associations between biomarkers of cellular senescence and physical function in humans: observations from the lifestyle interventions for elders (LIFE) study
.
GeroScience
.
2022
;
44
(
6
):
2757
70
. doi: .
9.
Kierdorf
K
,
Fritz
G
.
RAGE regulation and signaling in inflammation and beyond
.
J Leukoc Biol
.
2013
;
94
(
1
):
55
68
. doi: .
10.
Erusalimsky
JD
.
The use of the soluble receptor for advanced glycation-end products (sRAGE) as a potential biomarker of disease risk and adverse outcomes
.
Redox Biol
.
2021
;
42
:
101958
. doi: .
11.
Butcher
L
,
Carnicero
JA
,
Gomez Cabrero
D
,
Dartigues
JF
,
Peres
K
,
Garcia-Garcia
FJ
, et al,
FRAILOMIC Consortium
.
Increased levels of soluble Receptor for Advanced Glycation End-products (RAGE) are associated with a higher risk of mortality in frail older adults
.
Age Ageing
.
2019
;
48
(
5
):
696
702
. doi: .
12.
Nin
JW
,
Jorsal
A
,
Ferreira
I
,
Schalkwijk
CG
,
Prins
MH
,
Parving
HH
, et al
.
Higher plasma soluble Receptor for Advanced Glycation End Products (sRAGE) levels are associated with incident cardiovascular disease and all-cause mortality in type 1 diabetes: a 12-year follow-up study
.
Diabetes
.
2010
;
59
(
8
):
2027
32
. doi: .
13.
Thomas
MC
,
Soderlund
J
,
Lehto
M
,
Makinen
VP
,
Moran
JL
,
Cooper
ME
, et al
.
Soluble receptor for AGE (RAGE) is a novel independent predictor of all-cause and cardiovascular mortality in type 1 diabetes
.
Diabetologia
.
2011
;
54
(
10
):
2669
77
. doi: .
14.
Klein
R
,
Horak
K
,
Lee
KE
,
Danforth
L
,
Cruickshanks
KJ
,
Tsai
MY
, et al
.
The relationship of serum soluble receptor for advanced glycation end products (sRAGE) and carboxymethyl lysine (CML) to the incidence of diabetic nephropathy in persons with type 1 diabetes
.
Diabetes Care
.
2017
;
40
(
9
):
e117
9
. doi: .
15.
Colhoun
HM
,
Betteridge
DJ
,
Durrington
P
,
Hitman
G
,
Neil
A
,
Livingstone
S
, et al
.
Total soluble and endogenous secretory receptor for advanced glycation end products as predictive biomarkers of coronary heart disease risk in patients with type 2 diabetes: an analysis from the CARDS trial
.
Diabetes
.
2011
;
60
(
9
):
2379
85
. doi: .
16.
Fujisawa
K
,
Katakami
N
,
Kaneto
H
,
Naka
T
,
Takahara
M
,
Sakamoto
F
, et al
.
Circulating soluble RAGE as a predictive biomarker of cardiovascular event risk in patients with type 2 diabetes
.
Atherosclerosis
.
2013
;
227
:
425
8
. doi: .
17.
Thomas
MC
,
Woodward
M
,
Neal
B
,
Li
Q
,
Pickering
R
,
Marre
M
, et al
.
Relationship between levels of advanced glycation end products and their soluble receptor and adverse outcomes in adults with type 2 diabetes
.
Diabetes Care
.
2015
;
38
(
10
):
1891
7
. doi: .
18.
Lazo
M
,
Halushka
MK
,
Shen
L
,
Maruthur
N
,
Rebholz
CM
,
Rawlings
AM
, et al
.
Soluble receptor for advanced glycation end products and the risk for incident heart failure: the Atherosclerosis Risk in Communities Study
.
Am Heart J
.
2015
;
170
(
5
):
961
7
. doi: .
19.
Yang
ZK
,
Shen
Y
,
Shen
WF
,
Pu
LJ
,
Meng
H
,
Zhang
RY
, et al
.
Elevated glycated albumin and reduced endogenous secretory receptor for advanced glycation endproducts levels in serum predict major adverse cardio-cerebral events in patients with type 2 diabetes and stable coronary artery disease
.
Int J Cardiol
.
2015
;
197
:
241
7
. doi: .
20.
Katakami
N
,
Matsuhisa
M
,
Kaneto
H
,
Matsuoka
TA
,
Sakamoto
K
,
Yasuda
T
, et al
.
Serum endogenous secretory RAGE level is an independent risk factor for the progression of carotid atherosclerosis in type 1 diabetes
.
Atherosclerosis
.
2009
;
204
:
288
92
. doi: .
21.
Waden
JM
,
Dahlstrom
EH
,
Elonen
N
,
Thorn
LM
,
Waden
J
,
Sandholm
N
, et al
.
Soluble receptor for AGE in diabetic nephropathy and its progression in Finnish individuals with type 1 diabetes
.
Diabetologia
.
2019
;
62
(
7
):
1268
74
. doi: .
22.
Sabbatinelli
J
,
Castiglione
S
,
Macri
F
,
Giuliani
A
,
Ramini
D
,
Vinci
MC
, et al
.
Circulating levels of AGEs and soluble RAGE isoforms are associated with all-cause mortality and development of cardiovascular complications in type 2 diabetes: a retrospective cohort study
.
Cardiovasc Diabetol
.
2022
;
21
(
1
):
95
. doi: .
23.
Pérès
K
,
Matharan
F
,
Allard
M
,
Amieva
H
,
Baldi
I
,
Barberger-Gateau
P
, et al
.
Health and aging in elderly farmers: the AMI cohort
.
BMC Public Health
.
2012
;
12
:
558
. doi: .
24.
Ferrucci
L
,
Bandinelli
S
,
Benvenuti
E
,
Di Iorio
A
,
Macchi
C
,
Harris
TB
, et al
.
Subsystems contributing to the decline in ability to walk: bridging the gap between epidemiology and geriatric practice in the InCHIANTI study
.
J Am Geriatr Soc
.
2000
;
48
(
12
):
1618
25
. doi: .
25.
Rodríguez-Artalejo
F
,
Graciani
A
,
Guallar-Castillón
P
,
León-Muñoz
LM
,
Zuluaga
MC
,
López-García
E
, et al
.
Rationale and methods of the study on nutrition and cardiovascular risk in Spain (ENRICA)
.
Rev Esp Cardiol
.
2011
;
64
(
10
):
876
82
. doi: .
26.
Garcia-Garcia
FJ
,
Gutierrez Avila
G
,
Alfaro-Acha
A
,
Amor Andres
MS
,
De Los Angeles De La Torre Lanza
M
,
Escribano Aparicio
MV
, et al
.
The prevalence of frailty syndrome in an older population from Spain. The Toledo Study for Healthy Aging
.
J Nutr Health Aging
.
2011
;
15
(
10
):
852
6
. doi: .
27.
Erusalimsky
JD
,
Grillari
J
,
Grune
T
,
Jansen-Duerr
P
,
Lippi
G
,
Sinclair
AJ
, et al
.
In search of “omics”-based biomarkers to predict risk of frailty and its consequences in older individuals: the FRAILOMIC initiative
.
Gerontology
.
2016
;
62
(
2
):
182
90
. doi: .
28.
Katz
S
,
Ford
AB
,
Moskowitz
RW
,
Jackson
BA
,
Jaffe
MW
.
Studies of illness in the aged. The index of adl: a standardized measure of biological and psychosocial function
.
JAMA
.
1963
;
185
:
914
9
. doi: .
29.
Folstein
MF
,
Folstein
SE
,
McHugh
PR
.
Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician
.
J Psychiatr Res
.
1975
;
12
(
3
):
189
98
. doi: .
30.
Levey
AS
,
Stevens
LA
,
Schmid
CH
,
Zhang
YL
,
Castro
AF
3rd
,
Feldman
HI
, et al
.
A new equation to estimate glomerular filtration rate
.
Ann Intern Med
.
2009
;
150
(
9
):
604
12
. doi: .
31.
Fried
LP
,
Tangen
CM
,
Walston
J
,
Newman
AB
,
Hirsch
C
,
Gottdiener
J
, et al
.
Frailty in older adults: evidence for a phenotype
.
J Gerontol A Biol Sci Med Sci
.
2001
;
56
(
3
):
M146
156
. doi: .
32.
Butcher
L
,
Carnicero
JA
,
Peres
K
,
Colpo
M
,
Gomez Cabrero
D
,
Dartigues
JF
, et al,
FRAILOMIC Consortium
.
Higher sRAGE levels predict mortality in frail older adults with cardiovascular disease
.
Gerontology
.
2021
;
67
(
2
):
202
10
. doi: .
33.
Kallner
A
.
Bayes’ theorem, the ROC diagram and reference values: definition and use in clinical diagnosis
.
Biochem Med
.
2018
;
28
(
1
):
010101
. doi: .
34.
McGuire
LC
,
Ford
ES
,
Ajani
UA
.
The impact of cognitive functioning on mortality and the development of functional disability in older adults with diabetes: the second longitudinal study on aging
.
BMC Geriatr
.
2006
;
6
:
8
. doi: .
35.
Thein
FS
,
Li
Y
,
Nyunt
MSZ
,
Gao
Q
,
Wee
SL
,
Ng
TP
.
Physical frailty and cognitive impairment is associated with diabetes and adversely impact functional status and mortality
.
Postgrad Med
.
2018
;
130
(
6
):
561
7
. doi: .
36.
Sparvero
LJ
,
Asafu-Adjei
D
,
Kang
R
,
Tang
D
,
Amin
N
,
Im
J
, et al
.
RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation
.
J Transl Med
.
2009
;
7
:
17
. doi: .
37.
Nakamura
K
,
Yamagishi
S
,
Adachi
H
,
Kurita-Nakamura
Y
,
Matsui
T
,
Yoshida
T
, et al
.
Serum levels of sRAGE, the soluble form of receptor for advanced glycation end products, are associated with inflammatory markers in patients with type 2 diabetes
.
Mol Med
.
2007
;
13
(
3–4
):
185
9
. doi: .
38.
Grant
RW
,
Dixit
VD
.
Mechanisms of disease: inflammasome activation and the development of type 2 diabetes
.
Front Immunol
.
2013
;
4
:
50
. doi: .
39.
Schmidt
AM
.
Soluble RAGEs: prospects for treating and tracking metabolic and inflammatory disease
.
Vascul Pharmacol
.
2015
;
72
:
1
8
. doi: .
40.
Huo
L
,
Magliano
DJ
,
Rancière
F
,
Harding
JL
,
Nanayakkara
N
,
Shaw
JE
, et al
.
Impact of age at diagnosis and duration of type 2 diabetes on mortality in Australia 1997–2011
.
Diabetologia
.
2018
;
61
(
5
):
1055
63
. doi: .
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