Godoy-Matos et al.

Diabetology & Metabolic Syndrome (2025) 17:218 Diabetology & Metabolic

https://doi.org/10.1186/s13098-025-01796-4
Syndrome

REVIEW Open Access

CARDIAL-MS (CArdio-Renal-DIAbetes-Liver-
Metabolic Syndrome): a new proposition
for an integrated multisystem metabolic
disease
Amélio F. Godoy-Matos1,2,7* , Cynthia Melissa Valério1,2 , Wellington S. Silva Júnior1,3 , João Marcello de Araujo-
Neto4 , Andrei C. Sposito5 and José Hermógenes Rocco Suassuna6

Abstract
Background Metabolic Syndrome—a constellation of insulin resistance, cardiovascular risk factors as hyperglycemia,
hypertension, and dyslipidemia, and systemic metabolic dysfunction—may be driven by dysregulation of adipose
tissue, which manifests as adiposopathy (pathogenic adipose tissue expansion or maldistribution), ectopic fat
deposition (in the liver, muscle, pancreas, and cardiorenal systems), and altered secretion of adipokines/hepatokines.
Weight gain, obesity, and/or unfavorable fat distribution create a scenario wherein the type, size, location, secretions,
or even scarcity of adipocytes drive pathophysiological mechanisms leading to hepatic steatosis and steatohepatitis,
type 2 diabetes, and heart and kidney disease. While recent frameworks, such as cardiovascular-kidney-metabolic
syndrome, emphasize holistic staging, the central role of metabolic dysfunction-associated steatotic liver disease
(MASLD) in multisystem morbidity remains underrecognized.
Main text This narrative review synthesizes evidence linking MASLD and diabetes to cardiovascular and kidney
diseases through shared pathways of adiposopathy, ectopic lipid accumulation, and dysregulated adipokine/
hepatokine signaling. We propose CARDIAL-MS (CArdio-Renal-DIAbetes-Liver-Metabolic Syndrome), an expanded
pathophysiological model that unifies these interactions into four progressive stages: (1) weight gain and
dysfunctional adipose tissue; (2) metabolic risk factors and markers of risk; (3) cardiometabolic diseases and chronic
kidney disease; and (4) advanced cardio-renal-liver-metabolic disease. By integrating MASLD as a pivotal component,
CARDIAL-MS reframes metabolic syndrome as a continuum of interconnected organ injuries rather than isolated risk
factors.
Conclusion CARDIAL-MS provides a staging model to identify patients at critical transition points—from reversible
metabolic disturbances to irreversible organ damage. This model emphasizes early interventions targeting adipose
tissue health and ectopic fat deposition to mitigate the progression of metabolic cardiorenal diseases. By recognizing

*Correspondence:
Amélio F. Godoy-Matos
[email protected]
Full list of author information is available at the end of the article

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the syndromic nature of these conditions, CARDIAL-MS offers clinicians an actionable paradigm for risk stratification,
timely diagnosis, and personalized prevention strategies.
Keywords Obesity, Adiposopathy, Ectopic fat, Metabolic dysfunction-associated steatotic liver disease, Type 2
diabetes, Cardiovascular disease, Chronic kidney disease

Introduction between adiposity and CV diseases (CVD). Utilizing data

It is well established that cardiometabolic and renal dis- from 501 cohorts, 12 systematic reviews, 53 meta-anal-
eases (CMRDs) have a complex pathophysiology involv- yses, and 12 MR studies, involving 30 million individu-
ing multiple cardiometabolic risk factors (CMRFs) and als, the authors confirmed an association and a causal
interconnected systems. Recognizing the interrelation- relationship between high adiposity and CV outcomes
ship between several conditions such as obesity, type 2 [7]. BMI was directly related to coronary artery disease
diabetes (T2D), and metabolic syndrome (MS), and the (CAD), heart failure (HF), atrial fibrillation (AF), all-
subsequent risk of cardiovascular (CV) and renal out- cause stroke, hemorrhagic stroke, ischemic stroke, hyper-
comes, the American Heart Association (AHA) intro- tension, aortic valve stenosis, pulmonary embolism, and
duced the concept of Cardiovascular-Kidney-Metabolic venous thromboembolism. All these outcomes, except
(CKM) syndrome in a 2023 scientific statement [1]. stroke, were causally related to adiposity, as MR studies
Although the AHA has considered the liver involvement showed. A dose-response relationship has been demon-
in CKM syndrome, noting that metabolic dysfunction- strated between BMI and CV outcomes, and the evalua-
associated steatotic liver disease (MASLD) “further tion of central adiposity, assessed by waist circumference
amplifies systemic inflammation and insulin resistance (WC) and waist-to-hip ratio (WHR), corroborated these
(IR),” [1] we speculate that this major metabolic organ is a findings [7].
determinant for the development of T2D and CMRDs [2, Nonetheless, not all metabolic conditions typically
3]. Thus, aiming to expand the pathophysiological bases associated with excess adiposity are present in indi-
that lead to increased CV and renal risk, we propose a viduals with obesity, and those with BMI-based normal
new concept: the CArdio-Renal-DIAbetes-Liver-Meta- weight are not exempt from adiposity-related complica-
bolic Syndrome (CARDIAL-MS). tions and disorders [8, 9]. The distribution of body fat and
The CARDIAL-MS considers that (i) adiposopathy ectopic fat accumulation may provide insights into this
(excess adipose tissue or unfavorable fat distribution), (ii) paradox [9]. The two primary fat storage sites in humans
ectopic fat deposition (in liver, muscle, pancreas, peri- are subcutaneous adipose tissue (SAT) and visceral adi-
cardial/epicardial adipose tissues, and perirenal adipose pose tissue (VAT). However, VAT is not an appropriate
tissues), and (iii) adipo/hepatokines are pivotal elements site for fat storage, as it is pathophysiological linked to
for the increased morbidity and mortality related to IR and MS [9, 10]. In recent years, strong evidence has
CMRDs. This narrative review proposes the CARDIAL- been accumulated defining VAT, measured by magnetic
MS, an expanded and unifying pathophysiological model resonance imaging (MRI) or computed tomography, as
that delineates the interplay of key mechanisms driving an independent risk factor for T2D and cardiometabolic
CMRDs—the world’s primary cause of death. morbidity and mortality [11].
SAT is the most appropriate local for fat storage due to
Adiposopathy: the trigger for the development of its expandability and plasticity [12], and the gluteofemo-
the CARDIAL-MS ral adipose tissue (G-FAT) is generally considered to be
Obesity (body mass index [BMI] ≥ 30 kg/m²) and its metabolically protective [8, 9, 13, 14]. Indeed, Agrawal et
related conditions are established as a public health epi- al. [14] have recently confirmed, through a deep learning
demic. Between 1980 and 2014, the prevalence of obe- model that analyzed body MRI data from 40,032 individ-
sity doubled in 73 countries, reaching approximately uals in the UK Biobank, that: (i) VAT is associated with
603.7 million adults [4]. In 2021, 1.00 billion (95% uncer- an increased risk of T2D and CAD; (ii) G-FAT is linked
tainty interval [UI] 0.989–1.01) men and 1.11 billion to a reduced risk; and (iii) abdominal SAT (Ab-SAT) is
(1.10–1.12) women were classified as overweight (BMI mainly neutral, all adjusted for BMI [14]. Therefore, a
of 25–29.9 kg/m²) or obese [5]. Following current trends, scarcity of G-FAT leads to diminished storage capac-
overweight and obesity combined (i.e., BMI ≥ 25 kg/m²) ity, which has been etiologically and genetically associ-
are projected to affect nearly 3 billion adults (about 50% ated with IR and CMRDs [9, 15, 16]. Although VAT is
of the world’s adult population) by 2030 [6]. metabolically important, among the SAT compartments,
Kim et al. [7] published the first umbrella review and G-FAT is of utmost significance for metabolic health [2,
meta-analysis that included observational and Mendelian 8, 9, 13].
randomization (MR) studies evaluating the association

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Lotta et al. [15] evidenced that specific risk loci (e.g., insulin-resistant adipose tissue may favor ectopic fat
loci near or within L3MBTL3, DNAH10, and CCDC92) deposition by releasing free fatty acids (FFA) [17–20].
influence adipose gene expression, resulting in impaired Thus, SAT plays a significant role in the availability of
adipogenesis, reduced peripheral fat depots, and, ulti- circulating FFA, which are ultimately directed to ectopic
mately, increased risk of CMRDs. In parallel with the sites [17]. This process is outlined in Fig. 1 [2, 8–10, 12,
genetic predisposition for unfavorable distribution of 13, 17–20].
body fat, increased availability, accessibility, and afford- Schleh et al. [20] conducted an elegant and compre-
ability of energy-dense foods and reduced opportunities hensive study demonstrating, through clamp technique,
for physical activity that have followed urbanization and abdominal MRI, and biopsies of Ab-SAT and muscle,
other changes in the built environment have been con- that the suppression of insulin-mediated fatty acid ratio
sidered as potential environmental drivers to weight gain of appearance was associated with insulin-mediated glu-
[4]. When the expansion capacity of the SAT is reached, cose uptake (r = 0.51; p < 0.01) and was negatively corre-
there is a compromise in fat storage in this location, lated with liver fat (r = -0.36; p < 0.01) and VAT (r = -0.42;
which favors visceral and ectopic deposition in tissues p < 0.01) [20].
unsuitable for accumulating fat, such as the liver, muscle, Once ectopic fat deposition occurs, disruption of
pancreas, heart, and kidneys [9]. Thus, VAT itself may be metabolic homeostasis is triggered, which includes dys-
regarded as an ectopic fat depot. Similarly, dysfunctional regulated adipokine/hepatokine signaling, inflammation,

Fig. 1 Weight gain, fat distribution, and dysfunctional insulin-resistant AT. Free fatty acids (FFA) are stored as triglycerides in adipose tissue, and these
triglycerides can be broken down to release FFA into the blood. When the expansion capacity of subcutaneous adipose tissue is exceeded, FFA are in-
creasingly mobilized, leading to visceral and ectopic fat deposition. Gluteofemoral adipose tissue plays a protective metabolic role by sequestering excess
FFAs and triglycerides. Visceral adipose tissue (VAT), due to its ectopic nature and proximity to vital organs, further contributes to systemic metabolic
dysfunction. Concurrently, insulin resistance and impaired lipid storage in adipose tissue exacerbate lipolysis, amplifying FFA release into circulation. VAT,
owing to its heightened insulin resistance and metabolic dysfunction, serves as a major source of FFA for the liver and systemic distribution. Excess FFA
can overwhelm organs such as the pancreas, skeletal muscle, heart, and kidneys, promoting ectopic lipid accumulation and associated pathologies. For
details, refer to the main text. AT: adipose tissue; EAT: epicardial adipose tissue; FFA: free fatty acids; MASLD: metabolic dysfunction-associated steatotic
liver disease; MS, muscular steatosis; PRAT: perirenal adipose tissue; PS: pancreatic steatosis; RSF: renal sinus fat; SAT: subcutaneous adipose tissue; VAT:
visceral adipose tissue. This image features content from BioRender

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 4 of 17

increased IR and impaired insulin secretion, endothelial A burning question in the complex relationship
dysfunction, tissue injury, and fibrosis, i.e., pathological between MASLD and CVD is whether there is a causal
processes that will lead to T2D, MASLD, and cardiorenal relationship or just an epidemiological and pathophysi-
diseases [2, 8–10, 12, 13, 17–20]. ological association. Considering that MR studies use
genetic variants as instrumental variables to estimate
Ectopic fat depots: disrupting metabolic causal effects, these studies may help to infer causal-
homeostasis in the CARDIAL-MS ity between MASLD and CVD [29, 30]. Miao et al. [29]
Steatotic liver disease identified 94 independent (R2 < 0.2) MASLD genome-
Liver fat or steatotic liver disease (SLD) is the most com- wide association study (GWAS) loci, of which 90 have
mon hepatic disease, affecting more than 30% of people not been identified before. Using a polygenic risk scor-
worldwide [21]. Due to its frequent association with ing model, the authors found a significant causal effect of
IR, obesity, and T2D, the acronym “MASLD” was pro- MASLD on CAD [29]. Ren et al. [30] performed a two-
posed as the most appropriate nomenclature, as well as sample MR analysis, and after exclusion of genetic vari-
“MASH” (metabolic dysfunction-associated steatohepa- ants implicated in impaired very low-density lipoprotein
titis), when steatohepatitis is histologically character- (VLDL) secretion, concluded for a robust association
ized [22]. The SLD associated with at least one of the five between genetically predicted elevated serum alanine
CMRFs defines MASLD and is considered the manifesta- aminotransferase (ALT), imaging-based, and biopsy-con-
tion of MS in the liver. These CMRFs are: (i) BMI ≥ 25 kg/ firmed MASLD and CAD.
m² or WC > 90 cm (men)/>80 cm (women) or ethnicity Finally, previous studies of the common genetic vari-
adjusted equivalent; (ii) prediabetes or T2D; (iii) blood ants associated with MASLD strongly suggest that
pressure ≥ 130/85 mmHg or specific antihypertensive plasma lipids are responsible for their differential effects
drug treatment; (iv) plasma triglycerides ≥ 150 mg/dl or on CVD risk [31]. The associations of single-nucleotide
lipid lowering treatment; (v) plasma high-density lipo- polymorphisms (SNPs) that affect fatty acid flux and de
protein (HDL)-cholesterol ≤ 40 mg/dl (men) and ≤ 50 mg/ novo lipogenesis with lipid-increasing effect (e.g., GCKR)
dl (women) or lipid lowering treatment [22]. In conso- may contribute to higher CAD risk. In contrast, those
nance with several scientific societies, the Brazilian Dia- carriers of genetic variants predisposing to MASLD
betes Society [23] and other Brazilian societies [24] also through impaired VLDL secretion (i.e., MTTP, PNPLA3,
adopted the terms SLD, MASLD, and MASH. and TM6SF2) simultaneously reduce plasma lipids,
Given MASLD’s metabolic pathophysiology, its asso- resulting in a more cardioprotective phenotype [31].
ciation with T2D, several CMRFs, and CMRDs is Accordingly, Ahmed et al. [32], recognizing the com-
unsurprising [2, 25, 26]. Furthermore, there is grow- plexity of MASLD pathophysiology and the limitations
ing evidence of a potential causal relationship between of some previous MR studies, conducted a genome-wide
MASLD and CVD. A meta-analysis of 36 prospective survey based on the UK Biobank MRI study. They identi-
cohort studies, involving more than 5.8 million middle- fied 13 genetic variants associated with increased liver fat
aged individuals, revealed that MASLD was associated content, most of which had been previously described.
with an increased risk of both fatal and non-fatal CV Genetic variants linked to enhanced de novo lipogenesis
outcomes (pooled random effects hazard ratio [HR] 1.45, revealed that liver fat-increasing alleles were associated
95% confidence interval [CI] 1.31–1.61) over a median with a higher risk of myocardial infarction and CAD (i.e.,
follow-up of 6.5 years [27]. Interestingly, this finding was TRIB1, GCKR, ADH1B, and CDHR4). In contrast, vari-
independent of age, sex, measures of adiposity, T2D, and ants associated with impaired hepatic triglyceride export
other common CMRFs. Additionally, the risk of CVD indicated a reduced risk of CAD and myocardial infarc-
increased with more advanced liver disease, particularly tion but an elevated risk of T2D (i.e., PNPLA3, TMS6SF2,
at higher fibrosis stages (pooled random effects HR 2.50, APOE, and SUGP1) [32].
95% CI 1.68–3.72) [27]. These findings suggest that MASLD is not only epide-
Regarding mortality, MASLD is associated with both miologically associated with CVD but also causally linked
liver-specific and non-specific deaths. However, CV to it, despite genetic heterogeneity. Nonetheless, geneti-
mortality frequently contributes to severe outcomes. cally increased liver fat content raises the risk of T2D,
According to data from 13,099 patients with MASLD, cirrhosis, hepatocellular carcinoma, and intrahepatic
matched with up to 10 controls from the general popu- bile duct and gallbladder cancers, demonstrating a dose-
lation, MASLD was linked to higher all-cause mortality dependent relationship, regardless of the mechanism.
(HR 1.85, 95% CI 1.74–1.96) [28]. The highest estimated
15-year cumulative incidence of death was attributed to MALSD as a cause of CVD: mediating factors
cancer (non-hepatocellular carcinoma) and CV disease The increased influx of FFA into the liver results from
(7.3% and 7.2%, respectively) [28]. adiposopathy and IR, i.e., the increased release of FFA

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 5 of 17

from adipose tissue and reduced uptake in skeletal mus- (ApoC-III), resulting in a longer time in the circula-
cle. These factors reinforce/exacerbate the insulin sig- tion (before undergoing hydrolysis by lipoprotein lipase
naling dysregulation, in a vicious circle that stimulates [LPL]) [34, 35] (Fig. 2). The increased secretion and
hepatic de novo lipogenesis, further promoting hepatic impaired clearance of TRL result in long exposure in the
lipid accumulation [33]. The long-lasting exposure to vessels, giving them a greater chance of crossing the vas-
high levels of FFA and de novo lipogenesis leads to the cular endothelium and being deposited in the form of
hepatic accumulation of lipotoxic lipid species, inducing plaques, triggering the inflammatory process that char-
mitochondrial dysfunction, impaired autophagy, oxida- acteristically accompanies atherosclerosis [35, 36]. The
tive stress, inflammasome activation, hepatocyte injury, interplay of these diverse mechanisms (the presence of
and apoptosis. Subsequent wound healing responses MASLD and the ectopic adiposopathy), in the context of
marked by stellate cell activation drive collagen deposi- subclinical inflammation and atherogenic dyslipidemia,
tion, progressive fibrosis, and eventual end-organ failure promotes a metabolic phenotype with a high risk for
[27, 33]. vulnerable coronary plaque angiographic features such
Meanwhile, MASLD and VAT result in atherogenic as napkin-ring signs, positive arterial remodeling, high-
dyslipidemia and hypertriglyceridemia through 2 mecha- grade stenosis, triple vessel disease, and total occlusions
nisms: (i) increased hepatic secretion of large, triglycer- [34, 37, 38].
ide-rich VLDL cholesterol molecules and (ii) impaired
clearance of triglyceride-rich lipoproteins (TRL) asso-
ciated with increased levels of apolipoprotein C-III

Fig. 2 Hypertriglyceridemia is associated with abdominal obesity and liver steatosis. ApoC-III: apolipoprotein C-III; TRL: triglyceride-rich lipoproteins; VAT:
visceral adipose tissue; VLDL: very low-density lipoprotein. This image features content from BioRender.
Adapted from Björnson E et al. [35].

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 6 of 17

The role of hepatocytes in the induction of inflammation A multiomics and multitissue integration connects
and IR in adipose tissue Proteobacteria with jejunal deoxycholic acid and jejunal
Inflammation of VAT in obesity is a well-recognized and VAT genes involved in actin cytoskeleton, insulin,
pathological process. However, the source of this inflam- and T-cell signaling. Fasting glucose was consistently
mation remains under investigation, and a hepatic- associated with interferon-induced genes and antiviral
derived circulating factor (a hepatokine) may be involved responses in the intestine and VAT. Evidence suggests
[39]. For instance, Ghorpade et al. [40] highlighted the an interaction between serum bile acids and CVD within
clinically evident interaction between the liver and VAT the biliary tree. Recently, Kipp et al. [44] described that
in metabolic diseases, demonstrating that obesity in mice urobilin is frequently elevated in the urine of individu-
stimulates hepatocytes to synthesize and secrete dipep- als with CVD. This is just one example of how this new
tidyl peptidase 4 (DPP4), which interacts with plasma pathophysiological axis links the liver to MS and CVD,
factor Xa to promote inflammation of adipose tissue and it is as intriguing as it is uncertain [44]. They posi-
macrophages and IR. They showed that soluble DPP4 tion the liver as the protagonist, further reinforcing the
activates the caveolin-1 pathway in adipose tissue mac- concept of CARDIAL-MS, human microbiota, MASLD,
rophages. Alongside the activation of the protease-acti- and adiposopathy.
vated receptor two pathway by factor Xa, both pathways
synergistically stimulate the extracellular signal-regulated May the liver drive T2D?
protein kinases 1 and 2 and the nuclear factor kappa The global prevalence of MASLD in T2D is rising. A
B, which are distal inflammatory signaling molecules. pooled global prevalence of MASLD in individuals with
Silencing DPP4 expression in hepatocytes suppressed T2D has reached 65.33% (95% CI 62.35–68.2), ranging
VAT and IR inflammation, while pharmacological inhibi- from 53.1% in Africa to 80.6% in Eastern Europe [45].
tion of DPP4 did not [40]. These findings suggest that the The relationship between the liver and T2D has been
liver, through hepatokines, may initiate inflammation and recognized for over a century [46]. Indeed, as early as
IR in adipose tissue, potentially leading to obesity-related 1906, a possible origin of T2D in liver cirrhosis was sug-
CMRDs. gested, and the term “hepatogenous diabetes” was pro-
posed (reviewed by Kumar R [46]). Nonetheless, the
The gut-liver-adipose axis in the CARDIAL-MS strongest association between MS and T2D has been
The gut-liver-adipose axis connects human microbiota with MASLD.
to MASLD and adiposopathy. The gut microbiota is rec- Observational studies have shown that a modest ele-
ognized as an “invisible organ” interconnected with vari- vation of ALT, aspartate aminotransferase (AST), and
ous other tissues. The liver is the primary source of blood gamma-glutamyltransferase (GGT) is associated with
drainage from the gut, maintaining a continuous connec- an increased risk of subsequently developing T2D. Sev-
tion to microbiota health. Additionally, the liver connects eral meta-analyses have confirmed the association of
back to the intestine through the biliary tract [41]. MASLD with the incidence of T2D [47–49]. Ballestri et
It is well known that intestinal products, such as host al. [47] conducted a systematic review and meta-analysis
and/or microbial metabolites and microbial-associated involving 117,020 patients across 20 studies, followed for
molecular patterns, are transported to the liver and can a median of 5 years (3–14.7 years). MASLD was linked to
modulate liver function [42]. Some researchers advocate an increased risk of incident T2D; using ALT, AST, and
for an intricate interplay among the gut microbiota, the GGT as the diagnostic criterion for MASLD, the relative
intestine, and adipose tissue that influences liver action risks were 1.97 (95% CI 1.80–2.15), 1.58 (95% CI 1.43–
on insulin [43]. In a comprehensive multiomics, multitis- 1.74), and 1.86 (95% CI 1.71–2.03), respectively [47]. The
sue, cross-cohort integrative approach that encompasses presence of steatosis, as evaluated by ultrasonography,
transcriptomics of the intestine, liver, and adipose tissue conferred a relative risk of 1.86 (95% CI 1.76–1.95) [47].
(both visceral and subcutaneous), while incorporating An updated meta-analysis comprising 33 studies and
plasma metabolomics, lipidomics, and metagenomics, including 501,022 individuals, among whom there were
along with a hyperinsulinaemic-euglycaemic clamp, fast- 27,953 cases of incident T2D over a median of 5 years
ing glucose measurements, and glycated hemoglobin (IQR: 4.0–19 years), demonstrated a higher risk among
(HbA1c), Castells-Nobau et al. [43] presented a series of patients with MASLD compared to those without (n = 26
intriguing results. Several genera and species from the studies; random effects HR 2.19, 95% CI 1.93–2.48;
Proteobacteria phylum were consistently negatively asso- I² 91.2%) [48]. Interestingly, the risk was even greater
ciated with insulin sensitivity. Transcriptomic analysis of among individuals with advanced liver disease and mark-
the jejunum, ileum, and colon revealed T-cell-related sig- edly across the severity of liver fibrosis (5 studies; ran-
natures positively linked to insulin sensitivity [43]. dom-effects HR 3.42, 95% CI 2.29–5.11; I² 44.6%) [48].

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 7 of 17

To investigate the longitudinal outcomes associated reduction in risk per 1 standard deviation (OR 0.76, 95%
with MASLD, a comprehensive systematic review and CI 0.62–0.94) [53]. Despite these findings, the research-
meta-analyses evaluated 129 studies involving thousands ers were unable to identify a genetic association between
of participants [49]. The incidences of T2D (HR 2.56, pancreatic fat and the risk of T2D.
95% CI 2.10–3.13, p < 0.01), prediabetes (HR 1.69, 95%
CI 1.22–2.35, p < 0.01), and MS (HR 2.57, 95% CI 1.13– Hepatokines: liver-derived proteins linked to CMRDs
5.85, p < 0.02) were higher in people with MASLD than The liver produces and releases approximately thirteen
in those without. Furthermore, in a subgroup of patients proteins associated with metabolic disturbances. At least
with advanced liver disease, the incidence of T2D was six of these may be particularly significant for CARDIAL-
even more pronounced (HR 3.60, 95% CI 2.10–6.18, MS: fetuin-A, fibroblast growth factor 21 (FGF-21), sex
p < 0.01). The same pattern was observed in those with hormone binding globulin (SHBG), angiopoietin-like 3
less severe MASLD when compared to non-MASLD (HR (ANGPTL3), selenoprotein P, and DPP4 [40, 54]. Among
1.63, 95% CI 1.00–2.45, p < 0.02) [49]. Taken together, this group, only SHBG and FGF-21 are reduced in SLD.
there appears to be a dose-response relationship between Most hepatokines are associated with IR, inflammation,
the incidence of T2D and the presence and severity of β-cell dysfunction, and cardiometabolic risk regardless
MASLD. of the presence or absence of obesity (reviewed by Stefan
Conversely, the presence of T2D results in more severe [54]).
MASLD. In a study involving 713 Duke NAFLD clinical Associations with incident T2D have been reported
database patients, each 1% increase in HbA1c recorded 1 for fetuin-A (also known as alpha 2-Heremans-Schmid),
year before liver biopsy was associated with an odds ratio a hepatokine predominantly synthesized by the liver.
(OR) of 1.15 (95% CI 1.01–1.31) for increased fibrosis Fetuin-A plays a crucial role in essential pathophysi-
stage [50]. T2D is also an important risk factor for com- ological processes, such as insulin receptor signaling,
plications related to cirrhosis. In a retrospective Japanese adipocyte dysfunction, inflammation, liver fibrosis, lipid
study involving patients with MASLD, the presence of toxicity, triacylglycerol production, macrophage phe-
T2D was associated to a high risk for developing hepato- notype modification, promotion of angiogenesis, β-cell
cellular carcinoma (HR 3.21, 95% CI 1.09–9.50, p < 0.05) damage, apoptosis, and Toll-like receptor 4 (TLR4) acti-
[51]. vation, which are vital for liver integrity and function
Despite the consistent pathophysiologic and epide- [54–56]. Fetuin-A levels are elevated in MASLD and
miologic relationship between MASLD and T2D, most linked to MS and its components. Interestingly, it seems
evidence comes from observational studies, limiting the to precede the onset of MS. Furthermore, several obser-
conclusion about the existence of a causal relationship. vational studies have established its correlation with the
Therefore, some researchers have utilized MR to infer risk of T2D (meta-analyzed by Guo et al. [57]).
a probable causal effect of liver function biomarkers or Despite findings from mechanistic, preclinical, obser-
liver fat [52, 53]. De Silva et al. [52] analyzed data from vational studies, and meta-analyses suggesting a clear
up to 64,094 T2D cases and 607,012 control subjects in causal connection with fetuin-A and T2D, MR studies
a MR study, using genetic variants associated with liver remain controversial [58, 59]. Using data from the EPIC-
parameters (ALT, AST, alkaline phosphatase [ALP], and InterAct case-cohort study, based on 12,403 subjects
GGT) and with T2D or fasting insulin, to evaluate a pos- with newly diagnosed T2D, Kröger et al. [58] could not
sible bidirectional effect. Genetically predicted higher identify a strong association between a genetic score
levels of circulating ALT and AST were associated with involving SNPs in the fetuin-A-encoding AHSG gene and
an increased risk of T2D. Higher genetic predisposition incident T2D. However, a subsequent MR study, which
to fasting insulin, but not T2D, correlated with increased featured a larger number of participants, with longer fol-
circulating ALT [52]. These findings support MASLD as low-up, and employed newly identified genetic variants
a cause of T2D, or IR resulting in MASLD, which in turn associated with fetuin-A, found that increased levels of
increases the risk of T2D. Moreover, these findings also genetically predicted fetuin-A correlate with an elevated
support the Twin-Cycle hypothesis [52]. This will be dis- risk of T2D (OR 1.21, 95% CI 1.13–1.30, p < 0.01) [59].
cussed in detail later. Moreover, its genetically predicted higher levels were
Martin et al. [53] utilized genetic variants associated connected to a higher risk of CAD in individuals with
with liver and pancreatic volume and fat content from T2D, but not in those without (p for interaction = 0,03)
MRI scans of UK Biobank participants. After conducting [59].
several sensitivity analyses, they concluded that hepatic Since individuals with MASLD predominantly die from
fat (OR 1.27, 95% CI 1.08–1.49) and lower pancreatic CVD, potential links between CVD and hepatokines
volume are causal factors in the higher risk of T2D. In have been investigated. Given its pleiotropic metabolic
turn, higher pancreatic volume was associated with 24% and inflammatory effects, fetuin-A is considered a likely

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 8 of 17

mediator (as summarized by Dogru [55]). Among the 12 recovery of β-cell function was demonstrated following
observational studies conducted, 7 reported associations dietary caloric restriction, an achievement that was tem-
with various CV manifestations [55]. porally coincident with rapid reductions in liver fat and a
more protracted decrease in PS [67–69]. Despite all this
Pancreatic steatosis evidence, not all studies have demonstrated an associa-
Pancreatic steatosis (PS) is a general term to describe the tion between MASLD and PS, indicating the existence of
accumulation of fat in the pancreas, ranging from fatty an alternative pathway of fatty acid deposition in the pan-
infiltration of the gland to the development of inflam- creas independent of hepatic triglyceride production and
mation and fibrosis [60]. Fat storage in the pancreas can potentially derived from a direct flow of FFA from adi-
be due to adipocyte infiltration (the most common situ- pose tissue [60].
ation) or the intracellular accumulation of fat droplets In a systematic review, meta-analysis, and meta-regres-
[61]. Although fatty infiltration can be reversed, irrevers- sion, PS was associated with an increased risk of T2D
ible fatty infiltration may also occur due to acinar cell (RR 2.08, 95% CI 1.44–3.00, p = 0.0001) and MS (RR 2.37,
death, a condition known as pancreatic liposubstitution 95% CI 2.07–2.71, p < 0.0001) [63]. A longitudinal study
[61]. also found that lean individuals with PS were more likely
PS was first described in the medical literature by Ogil- to develop T2D than those without PS after a 6-year fol-
vie in 1933 [62]. In the 1980s, an autopsy study showed low-up [60]. However, the presence of PS was not a risk
that fat replacement of more than 25% of the pancreas factor for T2D in individuals with obesity, suggesting that
was associated with an increased risk of generalized ath- different T2D phenotypes may have distinct associations
erosclerosis and T2D, drawing attention to the fact that with PS [60].
PS was not a harmless finding [63]. Interestingly, the metabolic context determines the role
Pooling data on PS from eleven studies (12,675 indi- of pancreatic fat in the function of β-cells. PS does not
viduals) yielded the prevalence of 33% (95% CI 24–41%) appear to compromise insulin secretion per se. In experi-
[64]. Weight gain, prediabetes or T2D, MS, MASLD, mental models, pancreatic adipocytes modulate this
advancing age, and alcohol consumption are some of the secretion by releasing FFA, which can increase insulin
main factors that affect the accumulation of pancreatic secretion via FFA receptor 1 (FFAR1, also called GPR40)
fat [60, 61]. The presence of one or more MS components in β-cells [70]. However, increased PS is associated with
was associated with a 37% increase in the prevalence impaired insulin secretion under some metabolic cir-
of PS [65]. Other factors, including male sex, low birth cumstances, such as prediabetes. Genetic variants that
weight, and monogenic diseases, may also be involved in mediate IR, but not insulin secretion capacity, appear
PS. Notably among these monogenic conditions is matu- responsible for this interaction [60].
rity-onset diabetes of the young type 8 (MODY 8), a spe- In summary, insulin secretion seems to be impaired
cific form of diabetes associated with severe pancreatic by the PS only in individuals genetically predisposed to
lipomatosis since childhood [61]. T2D. It is thought that the mechanism involved is the
Although adipocyte infiltration of the exocrine pan- paracrine action of metabolites or substances such as
creas is the most common degenerative change in the cytokines, chemokines, and adipokines secreted by pan-
gland, lipid infiltration can also occur in the endocrine creatic adipocytes. Furthermore, prolonged exposure of
pancreas. The involvement of the islets of Langerhans by β-cells to long-chain saturated fatty acids promote intra-
fat increases with advancing age and the development of cellular changes, including ceramide production, oxida-
T2D [61]. Moreover, utilizing MRI, our group evidenced tive and endoplasmic reticulum stress, mitochondrial
increased pancreatic fat content in 11 female patients dysfunction, and activation of protein kinases. These
with type 2 partial familial lipodystrophy vs. 8 healthy factors can compromise insulin secretion and glucose
matched controls, and it was inversely related to β-cell homeostasis, contributing to the onset of T2D [60].
function, measured by the disposition index (DI) [16].
Roy Taylor et al. [66, 67] elaborated a hypothesis asso- Cardiovascular steatosis
ciating liver and pancreatic steatosis with T2D genesis As discussed, hypertrophic triglyceride-rich adipocytes
(the Twin Cycle hypothesis). According to this hypoth- experience cellular stress, contributing to inflamma-
esis, increased hepatic triglyceride production would lead tion and IR in adipose tissue. At the same time, the acti-
to fat accumulation in the pancreas, resulting in β-cell vation of Toll-like receptors (TLRs) and the secretion
dysfunction (lipotoxicity), impaired insulin secretion, of proinflammatory cytokines, such as tumor necro-
and increased blood glucose levels; consequently, these sis factor alpha (TNF-α) and interleukin 6 (IL-6), fur-
changes lead to a self-reinforcing cycle. In subsequent ther impair insulin sensitivity. This cascade enhances
years, the Twin Cycle hypothesis was tested through a lipolysis, increasing the release of FFA into circulation,
series of elegant studies (reviewed by Taylor [67–69]); accumulating in ectopic tissues, worsening local IR and

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 9 of 17

inflammation. Additionally, abnormalities in intracellu- hemodynamics or diabetes, is strongly linked to ultra-

lar fatty acid metabolism—potentially linked to IR and structural abnormalities, including fibrosis, sarcomere
hyperinsulinemia—synergistically promote intracellular disruption, increased lysosomal/phagosomal activity, and
fatty acid accumulation, fostering a pro-inflammatory mitochondrial structure alterations.
milieu [71]. Epicardial adipose tissue (EAT) is a unique fat depot
In the CV system, cardiomyocytes, epicardial adi- between the myocardium and the visceral epicardium.
pose tissue, and endothelial cells are key targets for Composed primarily of adipocytes, EAT also contains
inter-tissue FFA transfer. Endothelial cells (ECs) take up nerve cells, inflammatory cells (mainly macrophages
circulating FFA via albumin and TRL, including chylomi- and mast cells), stromal cells, vascular cells, and immune
crons (CMs) and VLDL [72]. LPL facilitates FFA release cells. While classified as white adipose tissue, it retains
from these lipoproteins, enabling their uptake through brown and beige fat-like properties and expresses a dis-
multiple pathways. Once inside ECs, FFA are primar- tinct transcriptome compared to other visceral and
ily converted into triglycerides via enzymatic processes subcutaneous fat depots [78–80]. EAT distribution is
involving diacylglycerol O-acyltransferase (DGAT). region-specific, with distinct transcriptomic and pro-
ECs also possess the machinery to form and metabolize teomic profiles depending on location. EAT surrounding
intracellular lipid droplets (LDs), which serve as buffers the left atrium differs from that infiltrating the coronary
against lipotoxicity and reservoirs for FFA, supplying arteries, influencing adjacent cardiac structures differ-
both ECs and adjacent parenchymal cells [73]. The mobi- ently [79].
lization of FFA from triglycerides within LDs is initiated No muscle fascia separates EAT from the myocar-
by adipose triglyceride lipase (ATGL), and its dysregula- dium, leading to a shared microcirculation. It plays a
tion, either through excessive lipid intake or ATGL defi- dual role: exerting cardioprotective effects through its
ciency, leads to LD accumulation. This, in turn, promotes thermogenic, brown fat-like function while promoting
endothelial dysfunction through mechanisms such as cardiac dysfunction via paracrine and vasocrine secre-
reduced endothelial nitric oxide synthase (eNOS) expres- tion of pro-inflammatory and profibrotic cytokines. The
sion due to decreased eNOS messenger ribonucleic acid thermogenic function of EAT declines from childhood
(mRNA) stability, increased endoplasmic reticulum (ER) to adulthood but continues to provide energy and heat to
stress, and endothelial inflammation. These pathologi- the heart [81]. However, in pathological conditions such
cal changes contribute to atherosclerosis progression as CAD, T2D, HF, and AF, EAT shifts towards a pro-ath-
and heighten vascular tone, ultimately predisposing to erogenic and pro-arrhythmogenic phenotype. This tran-
arterial hypertension [74, 75]. In a serial study of human sition is further worsened in advanced cardiac disease
heart transplant recipients, intracellular lipid accumula- and aging, with a concomitant increase in profibrotic and
tion in cardiomyocytes—specifically triacylglycerol and pro-apoptotic gene expression.
ceramide—was inversely associated with homeostasis Coronary EAT exhibits dense inflammatory infil-
model assessment of insulin resistance (HOMA-IR) val- tration in CAD, dominated by pro-inflammatory M1
ues, suggesting a link between lipid deposition and IR macrophages [82]. It secretes cytokines (monocyte che-
[76]. Moreover, myocardial triacylglycerol and ceramide moattractant protein-1 [MCP-1], IL-6, TNF-α) and adi-
accumulation in the transplanted hearts was further pokines (chemerin, intelectin-1/omentin-1, resistin, and
associated with both early diastolic and systolic dysfunc- serglycin) into the coronary lumen, amplifying systemic
tion, independent of BMI, at 12 months after transplanta- and local coronary atherosclerotic plaque inflammation.
tion [76]. EAT is also implicated in AF, influencing its development
Increased lipid droplet accumulation in the myocar- and recurrence post-ablation [83]. Increased EAT volume
dium is also observed in patients and animal models or thickness is associated with atrial conduction abnor-
of diabetes and obesity, reflecting impaired fatty acid malities, including prolonged P-wave duration, interatrial
homeostasis and lipotoxicity. In obesity-related HF with conduction block, and extended P–R interval [84]. This
preserved ejection fraction (HFpEF), lipid droplet accu- interaction likely involves genetic and neural factors,
mulation exceeds that seen in hypertensive HFpEF, high- inflammation, fibrosis, fatty infiltration, and atrial struc-
lighting a distinct metabolic pathology where lipotoxicity tural and electrical remodeling. Importantly, the asso-
plays a more prominent role than hypertrophy and pres- ciation between cardiac fat and AF appears partially or
sure overload [77]. Diabetes can independently contrib- entirely independent of obesity.
ute to this myocardial pathology, and in HFpEF, T2D is In HF, EAT contributes to pathogenesis via inflamma-
highly prevalent alongside obesity. However, BMI, rather tion, fibrosis, autonomic dysregulation, and mechanical
than diabetes status, demonstrates a stronger associa- effects of fibrotic fat deposits [85]. Its secretome plays a
tion and emerges as the primary predictor of this his- key role in HF, particularly with HFpEF [86]. The asso-
topathology [77]. Indeed, obesity, more than cardiac ciation between EAT thickness or volume and HFrEF

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 10 of 17

remains controversial, with studies reporting increased from shared metabolic and inflammatory pathways or
and, more frequently, decreased EAT volume compared whether a direct pathophysiological connection also
to healthy individuals [87, 88]. Consequently, EAT vol- exists, potentially contributing to CV complications
ume assessment in HFrEF lacks clinical usefulness in [98]. In fact, CKD markedly increases the risk of CVD
guiding management decisions. through a multifactorial pathophysiological process
involving hemodynamic, neurohormonal, metabolic, and
Perirenal adipose tissue, renal sinus fat, and chronic kidney inflammatory pathways. Traditional risk factors such as
disease hypertension, diabetes, dyslipidemia, and obesity are
The reciprocal interplay between obesity, MS, MASLD, highly prevalent in CKD and accelerate atherosclerosis
T2D, and CVD has been extensively explored. It is well [99]. Additionally, activation of the renin-angiotensin-
established that the kidneys are susceptible to various aldosterone system and sympathetic nervous system
disorders linked to these conditions. These disorders contributes to left ventricular hypertrophy and heart
range from direct effects, such as obesity-related glomer- failure [100]. Metabolic disturbances, including uremic
ulopathy [89], to secondary complications arising from toxin accumulation and calcium-phosphate imbalance,
obesity-driven systemic diseases, including T2D and further promote vascular calcification and myocardial
hypertension [90]. The epidemiology and pathophysiol- fibrosis [100]. In addition, CKD also induces endothe-
ogy of classical diabetic nephropathy are well character- lial dysfunction and chronic inflammation, which create
ized and will not be further discussed here. However, a prothrombotic and proatherogenic environment [101,
the causal pathways linking obesity, MASLD, and MS 102]. Coronary microvascular dysfunction and impaired
to kidney damage remain an active and evolving area of nitric oxide bioavailability contribute to myocardial isch-
research. emia, even in the absence of epicardial coronary disease
Recent large-scale studies have demonstrated robust [103]. Finally, using clinical, laboratory, and baseline
associations between obesity and chronic kidney disease proteomic data from the EQUAL Study, three proteins—
(CKD), independent of diabetes and hypertension. For receptor protein-tyrosine phosphatase sigma, FCN2, and
instance, in a cohort of 1,405,016 adults from English IGFBP6—were identified as being associated with esti-
primary care records, the risk of developing advanced mated glomerular filtration rate (eGFR) decline in two
CKD increased in a log-linear fashion with rising BMI, independent cohorts of older adults with advanced CKD
from overweight to obesity to severe obesity, regard- [104]. These findings suggest a potential link between
less of the presence of T2D, hypertension, or CVD [91]. elevated expression of proteins related to fibrosis and the
Similarly, using advanced MR techniques in a dataset of complement cascade and progressive kidney function
337,422 individuals of European ancestry from the UK loss. Collectively, these interrelated mechanisms explain
Biobank, in combination with GWAS of human adipos- the heightened CVD burden in CKD and are well-docu-
ity traits, Xu et al. [92] demonstrated significant causal mented in contemporary research.
effects of genetic traits related to BMI, WC, and obesity Nevertheless, as one of the core tenets of epidemiology
on a composite measure of renal function, referred to as states, establishing causality from these observations is
the kidney health index. Notably, T2D and blood pres- inherently challenging due to overlapping traditional risk
sure accounted for only 26–34% of the causal association factors for MASLD and CKD.
between BMI/WC and the kidney health index, suggest- The hypothesis of a direct causal link between hepatic
ing that most of the obesity’s impact on kidney health fat infiltration and CKD is relatively recent, and accu-
occurs independently of these comorbidities. Interest- mulating clinical and mechanistic evidence supports its
ingly, another large-scale MR study revealed a strong plausibility. Several putative factors have been impli-
association between obesity and renal dysfunction but cated, including genetic predisposition, intestinal
found no significant association with albuminuria in the dysbiosis, liver-driven IR, low-grade inflammation, pro-
absence of T2D [93]. This finding suggests the presence thrombotic states, hyperuricemia, reduced adiponectin
of distinct and complex pathways of kidney injury within production, activation of the renin-angiotensin system,
the broader framework of metabolic-mediated kidney impaired antioxidant defenses, nephrotoxicity of liver-
damage. derived metabolites, and the secretion of harmful hepa-
As mentioned above, MASLD is increasingly recog- tokines [105–108]. One interesting and relatively recent
nized as a systemic metabolic disorder extending beyond development is that the accumulation of renal fat depos-
hepatic pathology. Several large-scale meta-analyses have its may contribute to renal damage mediated by obesity
reinforced the epidemiological link between MASLD and and MASLD. Perirenal adipose tissue (PRAT) and renal
kidney disease [94–97]. sinus fat (RSF) are compartments of VAT surrounding
A key question regarding the association between the kidneys. PRAT is the only adipose tissue enclosed by
MASLD and CKD is whether this relationship results a tough fibrous membrane; therefore, excessive adiposity

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 11 of 17

in this non-distensible compartment can encapsulate and six clusters of individuals at elevated risk for developing
compress the kidneys (the Renal Tamponade hypothesis) T2D in the Tübingen Family Study and Tübingen Lifestyle
[109]. The kidney is surrounded by an adherent renal Program (TUEF/TULIP) and replicated their findings in
capsule, a serosal layer composed of collagen and elastin the Whitehall II study cohort. Among these clusters, two
that encloses most of the renal parenchyma but is discon- subgroups were marked by elevated VAT and MASLD or
tinuous at the hilum, where vessels, nerves, and the renal VAT and RSF (clusters 5 and 6, respectively). The latter
pelvis pass through. At the hilum, PRAT extends inward subgroups faced heightened risks for CKD and mortality,
to form RSF, which intersperses with and surrounds these although with a distinct risk for imminent diabetes [118].
structures, as well as the distal portions of the papillae. As discussed above, these studies add to the discussion of
RSF can be seen as a unique variety of VAT and a partic- the interconnection of T2D and ectopic fat deposition in
ular type of perivascular adipose tissue, being vascular- liver and surrounding kidneys.
ized, innervated, endowed with lymphatic drainage, and
possessing a functional adrenergic system [110, 111]. CARDIAL-MS stages
Excess RSF can infiltrate and compress the renal papil- Identifying patients at risk of developing downstream
lae at the hilum and its main vessels, exerting mechani- metabolic complications could streamline early detec-
cal and endocrine/paracrine effects that may contribute tion. Figure 4 outlines the four stages of CARDIAL-
to renal injury [109, 112]. Mechanistically, RSF com- MS, with anthropometric cut-offs defined as follows:
pression of the kidney may increase intrarenal pressure, WHR ≥ 0.95 (men)/≥0.85 (women), fat mass ratio [(the
impair renal perfusion, activate the renin-angiotensin ratio between truncal and lower limbs fat evaluated by
system, increase sodium reabsorption, impair glomerular DXA); (FMR) ≥ 1.7 (men)/≥1.2 (women)], and waist-to-
filtration, and enhance susceptibility to ischemic injury height ratio > 0.5 (both sexes) [119–122]. Beyond anthro-
[113, 114]. Additionally, RSF is metabolically active and pometrics, CMRFs align with the International Diabetes
responds to systemic cues through direct lipotoxicity, Federation MS criteria [123]. We strongly recommend
local and systemic adipocytokines, hepatokines, oxida- incorporating fasting and/or 1-hour post-load glucose
tive stress, and endothelial dysfunction, which can fur- tests to assess impaired glucose tolerance and T2D detec-
ther exacerbate renal damage [26]. tion [124, 125].
Recent findings highlight PRAT inflammation as an
emerging and independent CMRF [114]. This could Imaging methods for evaluating ectopic fat sites
explain, at least in part, why patients with early stages The most used imaging methods for hepatic and pancre-
of CKD have a high risk of CV events. PRAT contains a atic fat include ultrasound, computed tomography, and
mixture of brown and white adipocytes, which usually MRI [126–128]. However, because CKD has a distinct
display an immunoregulatory phenotype in response to origin and pathophysiology, MRI has proven to be more
inflammation but may switch to an inflammatory pheno- informative. It is important to note that the biomarkers
type characterized by increased secretion of pro-inflam- most frequently used in clinical practice (eGFR and albu-
matory cytokines (TNF-α, IL-6, MCP-1) and reduced minuria) only appear when the disease is already estab-
production of protective adipokines such as adiponectin lished and/or advanced, providing limited information
[114, 115]. This inflammatory shift may lead to endo- about pathophysiology or early detection. Therefore, new
thelial dysfunction, fibrosis, and tubular injury, linking methods of functional MRI have become increasingly
PRAT dysfunction to CKD progression. effective and valuable.
Figure 3 details the proposed complex pathophysiology MRI can estimate in vivo renal volume, glomerular per-
of CARDIAL-MS, which includes adiposopathy, ectopic fusion rate, glomerular sclerosis rate, function, metabo-
lipid accumulation, and dysregulated adipokine/hepato- lism, perfusion, oxygenation, and detect microstructural
kine signaling, leading to T2D, MASLD, and cardiorenal changes and fibrosis at early stages without requiring
diseases contrast media [127, 128]. Examples of these new tech-
niques include T1 and T2-weighted mapping, phase-con-
Adult-onset diabetes phenotypes and ectopic fat trast MRI, BOLD (blood oxygenation level-dependent)
Some studies have introduced a new concept for sub- MRI, diffusion MRI, and Arterial Spin Labeling (ASL-
phenotyping adult-onset diabetes, both clinically and MR). Finally, multiparametric MRI, which incorporates
genetically, beyond a binary classification of type 1 diabe- several of these techniques, may become the gold stan-
tes (T1D) and T2D [116, 117]. By subclassifying individu- dard in studying kidneys and kidney diseases [127].
als with adult-onset diabetes into six distinct clusters,
Ahlqvist et al. [116] observed that a sub-phenotype exhib- Final considerations
iting greater IR was linked to an increased risk of devel- Following the AHA’s publication of the CKM syndrome
oping CKD. Furthermore, Wagner et al. [118] identified [1], we propose a more comprehensive definition to

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 12 of 17

Fig. 3 Proposed pathophysiology of Cardio-Renal-Diabetes and Liver-Metabolic Syndrome (CARDIAL-MS). For details, refer to the main text. AT: adipose
tissue; EAT: epicardial adipose tissue; FFA: free fatty acids; IR, insulin resistance; MASLD: metabolic dysfunction-associated steatotic liver disease; MS, mus-
cular steatosis; PRAT: perirenal adipose tissue; PS: pancreatic steatosis; RSF: renal sinus fat; SAT: subcutaneous adipose tissue; T2D, type 2 diabetes; VAT:
visceral adipose tissue. This image features content from BioRender

capture the frequent clustering of MS, CV, kidney, and diseases associated with high morbidity and mortal-
liver diseases, prediabetes, and T2D. This led us to intro- ity, the acronym is limited by its focus on downstream
duce a new model: CARDIAL-MS. events. The occurrences within the CKM model transpire
While preparing this proposal and review, Theodorakis well after the triggering factors emerge, indicating that
& Nikolaou [129] independently suggested incorporat- preventive and therapeutic interventions would likely be
ing MASLD into their expanded framework, the Cardio- much more effective at an earlier stage. Ultimately, rec-
vascular-Renal-Hepatic-Metabolic (CRHM) syndrome. ognizing CARDIAL-MS as a novel pathophysiological
Given that T2D is a well-established CMRF and is likely framework for MS and its distinct stages could enable
causally linked to MASLD, we argue that CARDIAL-MS earlier diagnosis and timely preventive interventions for
aligns with their perspective while offering a more inclu- CMRDs, addressing our foremost global health challenge.
sive definition.

Conclusions
The acronym CKM was introduced to describe the final
pathway of CV and renal complications from meta-
bolic diseases [1]. While it is crucial to acknowledge the
complex health issues stemming from these metabolic
disorders, related to energy supply and accumulation,
for developing guidelines for investigating and treating

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 13 of 17

Fig. 4 Stages of CARDIAL-MS. AF: atrial fibrillation; ASCVD: atherosclerotic cardiovascular disease; AT: adipose tissue; CARDIAL-MS: cardio-renal-diabetes-
liver-metabolic syndrome; CKD: chronic kidney disease; FMR: fat mass ratio (the ratio between truncal and lower limbs fat evaluated by DXA); HF: heart
failure; IGT: impaired glucose tolerance; MALO: major adverse liver outcomes; MASH: metabolic dysfunction-associated steatohepatitis; MASLD: metabolic
dysfunction-associated steatotic liver disease; T2D: type 2 diabetes; WHR: waist-to-hip ratio; WHtR: waist-to-height ratio. This image features content from
BioRender

Abbreviations ER endoplasmic reticulum

Ab-SAT abdominal SAT FFAR1 free fatty acid receptor 1
AF atrial fibrillation FFA free fatty acids
AHA American Heart Association FGF-21 fibroblast growth factor 21
ALP alkaline phosphatase FMR fat-to-muscle ratio
ALT alanine aminotransferase G-FAT gluteofemoral adipose tissue
ANGPTL3 angiopoietin-like 3 GGT gamma-glutamyltransferase
ApoC-III apolipoprotein C-III GWAS genome-wide association study
ASCVD atherosclerotic cardiovascular disease HbA1c glycated hemoglobin
ASL-MRI arterial spin labeling magnetic resonance imaging HDL high-density lipoprotein
AST aspartate aminotransferase HF heart failure
AT adipose tissue HFpEF heart failure with preserved ejection fraction
ATGL adipose triglyceride lipase HOMA-IR homeostasis model assessment of insulin resistance
BMI body mass index HR hazard ratio
BOLD blood oxygenation level-dependent IGT impaired glucose tolerance
CAD coronary artery disease IL-6 interleukin-6
CARDIAL-MS cardio-renal-diabetes-liver-metabolic syndrome IR insulin resistance
CI confidence interval LDs lipid droplets
CKD chronic kidney disease LPL lipoprotein lipase
CKM syndrome Cardiovascular-Kidney-Metabolic syndrome MALO major adverse liver outcomes
CM chylomicron MASH metabolic dysfunction-associated steatohepatitis
CMRDs cardiometabolic and renal diseases MASLD metabolic dysfunction-associated steatotic liver disease
CMRFs cardiometabolic risk factors MCP-1 monocyte chemoattractant protein-1
CRHM syndrome Cardiovascular-Renal-Hepatic-Metabolic syndrome MODY 8 maturity-onset diabetes of the young type 8
CV cardiovascular MR Mendelian randomization
CVD cardiovascular disease MRI magnetic resonance imaging
DGAT diacylglycerol O-acyltransferase mRNA messenger ribonucleic acid
DI disposition index MS metabolic syndrome
DPP4 dipeptidyl peptidase 4 OR odds ratio
EAT epicardial adipose tissue PRAT perirenal adipose tissue
EC endothelial cell PS pancreatic steatosis
eGFR estimated glomerular filtration rate RR relative risk
eNOS endothelial nitric oxide synthase RSF renal sinus fat

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Godoy-Matos et al. Diabetology & Metabolic Syndrome (2025) 17:218 Page 14 of 17

SAT subcutaneous adipose tissue 3. Katsiki N, Kolovou G, Melidonis A, Banach M. The Cardiac-Kidney-Liver
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VLDL very low-density lipoprotein y​​.​o​r​​g​/​p​​u​b​l​i​​c​a​​t​i​o​n​s​/​?​c​a​t​=​2​3
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figures, and revised the manuscript; JMA-N drafted, formatted, and revised the 9. Silva Júnior WS. Under new criteria for clinical obesity, is metabolic obesity
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the manuscript. All the authors read and approved the final manuscript. nol Obes Med. 2025;1(1):62–70. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​​1​0​8​9​​/​d​​t​o​m​.​2​0​2​5​.​0​0​1​5.
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AFG-M received grants from AstraZeneca, Eli Lilly, and Novo Nordisk. CMV genomic analysis implicates limited peripheral adipose storage capacity in
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and Novo Nordisk. WSSJ received grants from Abbott, AstraZeneca, Eli Lilly, t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​​1​0​3​8​​/​n​​g​.​3​7​1​4.
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no conflicts of interest to declare. JHRS has no conflicts of interest to declare. with Familial partial lipodystrophy. Diabetol Metab Syndr. 2018;10:71. ​h​t​t​p​​s​:​/​​/​
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