Sage Journals: Discover world-class research

Abstract

Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition marked by insulin resistance, decreased insulin production, and persistent low-grade inflammation. The prevalence of T2DM has increased significantly in recent decades; as a result, it is now regarded as one of the fastest-growing public health concerns worldwide. Long-term micro- and macrovascular problems such as nephropathy, retinopathy, neuropathy, and cardiovascular disease can be caused by poor blood glucose control. Therefore, developing reliable diagnostic indicators for early diagnosis and investigating new treatment targets are critical for addressing the increasing prevalence of T2DM. Several novel diagnostic approaches have been created by targeting endogenous proteins, with fetuin-A being one of the most promising targets. Human fetuin-A, also referred to as alpha-2-Heremans Schmid glycoprotein, is a liver-produced glycoprotein that is abundantly secreted into the bloodstream and seems to be involved in insulin resistance, metabolic syndrome, and inflammation. Clinical studies have shown that circulating fetuin-A levels are closely associated with T2DM and its complications, underscoring its potential as both a biomarker and a therapeutic target. This narrative review provides a detailed overview of the evolving role of fetuin-A in the development of T2DM and its associated complications, as well as its future perspectives.

Plain language summary

The evolving roles of fetuin-A in type 2 diabetes mellitus and its potential clinical implications

Type 2 diabetes mellitus (T2DM) is a long-term condition in which the body does not use insulin properly (a problem called insulin resistance) and cannot make enough of it. This leads to high blood sugar levels and ongoing low-grade inflammation. Over time, poorly controlled diabetes can cause serious health problems, including kidney disease, eye disease, nerve damage, and heart disease. Because T2DM is becoming more common worldwide, finding better ways to detect it early and to prevent complications is very important. One protein of particular interest is fetuin-A, which is made in the liver and released into the blood. Fetuin-A has been linked to insulin resistance, inflammation, and metabolic syndrome. Studies show that circulating fetuin-A levels are closely linked with T2DM and its complications. Therefore, fetuin-A may serve as a useful biomarker (a measurable substance that signals disease risk or progression) and may also be a potential target for treatment. In this review, we look at the current evidence on the role of fetuin-A in T2DM and its complications, and discuss how it may be used in the future to improve patient care.

Keywords

biomarker clinical implications fetuin-A hepatokine insulin resistance insulin signaling metabolic inflammation type 2 diabetes mellitus

Introduction

Diabetes mellitus (DM) is typically described as a metabolic condition characterized by elevated blood sugar levels, which may arise from issues with insulin secretion, insulin function, or a combination of both. Type 2 diabetes mellitus (T2DM) includes people who exhibit insulin resistance and typically have a relative deficiency in insulin production.¹ According to the 11th edition (2025) of the Diabetes Atlas, T2DM has become a significant global public health concern. An estimated 589 million adults aged 20–79 are currently living with the disease worldwide, a figure expected to increase to about 853 million by 2050.² There are a number of distinct mechanisms underlying the pathogenesis of T2DM. It is crucial to elucidate the intricate pathophysiology of this disease, which is important for the management and development of prevention strategies.

Fetuin-A, previously referred to as α2-Heremans-Schmid glycoprotein (AHSG) in humans and phosphorylated protein 63 (PP63) in rats, is a 64 kDa negatively charged plasma protein. It is encoded by a gene located on chromosome 3q27 and is primarily expressed by hepatocytes.³ The concentration of fetuin-A in serum varies between 0.5 and 1.0 g/L, with a half-life of 1–2 days.⁴ Fetuin-A has been demonstrated to play a crucial role in various physiological cellular functions, including the metabolism of proteins and fatty acids, the regulation of acute inflammatory responses, bone mineralization, and the metabolism of calcified matrices. It also influences neutrophil degranulation, lymphocyte recruitment, thyroid hormone activity, and calcium ion homeostasis, among other processes.⁵

Glycoproteins such as fetuin-A have recently been proposed to play a role in the molecular connections between obesity, nonalcoholic fatty liver disease (NAFLD), insulin resistance, and metabolic syndrome, as they have been associated with the inhibition of insulin receptor activity, leading to a disruption of insulin signaling pathways.^6,7 Beyond its metabolic functions, fetuin-A also plays a pivotal role in inflammatory processes.^8,9 Since chronic low-grade inflammation underlies both T2DM and its complications,^10–12 this shared inflammatory milieu highlights the importance of examining the role of fetuin-A in the pathogenesis of T2DM and its complications. Currently, fetuin-A has been identified as having a potential new role in the pathogenesis of T2DM. Given its pathological involvement in the development of T2DM, the clinical application of fetuin-A as a diagnostic marker and therapeutic target in T2DM is now underway. Therefore, this review article primarily focuses on the role of fetuin-A in the pathogenesis of T2DM and its potential clinical applications.

Methodology

This review included studies from research databases such as PubMed, PubMed Central, Web of Science, Google Scholar, and Cochrane Library. The keywords used included fetuin-A, AHSG, structural features of fetuin-A, the role of fetuin-A in T2DM, the relationship between fetuin-A and complications of T2DM, and the clinical application of fetuin-A in patients with T2DM. The studies included were published in or translated into English. There was no specific time frame for study inclusion, but the authors preferred recently published papers. However, studies on fetuin-B and those focused on type 1 DM, gestational DM, and other types of DM were not included in this review article.

Structural features of fetuin-A

Fetuin-A is primarily expressed in embryonic and adult liver cells, with lower levels in adipocytes and immune cells.¹³ It is a heterodimeric plasma glycoprotein encoded by the AHSG gene on chromosome 3q27.3, which comprises multiple exons and introns.¹⁴ The gene is transcribed into a single messenger ribonucleic acid (mRNA) strand coding for a 367-amino-acid preprotein (pre-fetuin-A).¹⁵ This precursor contains two polypeptide chains: the A-chain (282 amino acids), the B-chain (27 amino acids), along with an 18-amino-acid signal sequence (SS) and a 40-amino-acid connecting peptide (CP),^3,15 The A-chain of mature fetuin-A consists of three domains: two cystatin-like domains, D1 and D2, and a third domain, D3, which is further divided into the proline-rich subdomain D3a and the C-terminal subdomain D3b. D1 and D2 (116–118 residues) form α-helices, β-sheets, and reverse turns, comprising 29%, 24%, and 26% of the structure, respectively. Functionally, D1 has binding sites for calcium, TGF-β, and bone morphogenic protein; D2 hinders cysteine protease¹⁶; and D3 binds to the insulin receptor.¹⁷

Mature fetuin-A results from proteolytic processing and undergoes posttranslational modifications, including glycosylation, phosphorylation, and sulfation.³ Processing yields a 321-residue heavy chain and a 27-residue light chain, linked by disulfide bonds.¹⁸ Occasionally, cleavage omits 40 residues from the heavy chain’s C-terminus, with the B-chain identical to the light chain.¹⁹ Fetuin-A has two phosphorylation sites (in the A-chain and CP), two N- and two O-glycosylation sites on the A-chain, and one O-glycosylation site on the B-chain.^20,21 These modifications are likely to affect the expression, biological stability, and activity of fetuin-A.²² In particular, phosphorylation plays a critical role in fetuin-A’s interaction with the insulin receptor (Figure 1).

Figure 1.

Basic structure of fetuin-A.

The relationship of fetuin-A with T2DM

Numerous recent studies have highlighted a substantial association between fetuin-A and the progression of T2DM, suggesting its potential role in the pathogenesis of the disease, although its specific role remains uncertain. Evidence from prospective cohort studies indicates that elevated fetuin-A predicts the development of T2DM and contributes to disease progression by inhibiting insulin receptor signaling and promoting toll-like receptor 4 (TLR4)-mediated inflammation.^17,23,24 Conversely, hepatic steatosis, inflammation, and metabolic dysregulation can elevate fetuin-A levels, suggesting that its increase may also result from the metabolic disturbances characteristic of T2DM and its complications.^25–27 These findings underscore the need for large-scale experimental studies to clarify the relationship between fetuin-A and T2DM.

A significant amount of data indicates that individuals with T2DM exhibit significantly higher serum levels of fetuin-A compared to healthy controls. For instance, findings from the Health, Ageing and Body Composition Study (Health ABC) and the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study demonstrated that individuals with elevated fetuin-A levels had an increased risk of developing diabetes.²⁸ Interestingly, a positive correlation between fetuin-A and T2DM has also been observed in individuals with elevated, yet nondiabetic, blood glucose levels. However, this association was not evident among individuals with strictly normal glucose levels.^23,29 Supporting this, a systematic review and meta-analysis by Guo et al.³⁰ reported that each standard deviation increase in fetuin-A concentration was associated with a 23% higher risk of developing T2DM. Similarly, a multiethnic cohort study of middle-aged to older adults without clinically apparent cardiovascular disease (CVD) at baseline found that higher fetuin-A concentrations were significantly associated with increased diabetes risk in women.³¹

In contrast to these findings, some studies have reported an inverse association, where fetuin-A levels were lower in individuals with T2DM compared to healthy counterparts.^32–34 For example, Wojtysiak-Duma et al.³⁴ found significantly lower serum fetuin-A concentrations in patients with T2DM. This result was echoed by another case-control study, which also reported reduced fetuin-A levels in diabetic individuals.³² Table 1 summarizes key studies exploring the relationship between fetuin-A levels and T2DM in the current literature.

Table 1.

A summary table on the relationship between fetuin-A and T2DM.

Design	Sample size	Findings	References
Case-control study	1116 (558 patients with T2DM and 558 controls)	Patients with T2DM had a significantly higher fetuin-A level than control groups.	Wang et al.³⁵
	150 (75 T2DM patients and 75 control).		Beigi et al.³⁶
	90 (60 men with T2DM and 30 healthy men controls)		Ahmed et al.³⁷
	150 (50 were known T2DM, 50 were having impaired fasting glycaemia and 50 were normal healthy individuals).	Serum fetuin-A levels were significantly higher in known T2DM as compared to impaired fasting glycemics and controls.	Fatima et al.³⁸
	200 (100 T2DM patients and 100 NGT controls)	Fetuin-A levels were observed to be higher in patients with new-onset T2DM than in the NGT group.	Yin et al.³⁹
	940 (470 women with T2DM and 470 healthy women control)	Positive association was noted between elevated fetuin-A levels and an increased diabetes risk.	Sun et al.⁴⁰
	80 (40 patients with T2DM and 40 healthy controls)	Elevated serum fetuin-A level is strongly linked to insulin resistance and glycemic control in T2DM patients.	Ahmed et al.⁴¹
	84 (43 patients with T2DM and 41 controls)	Patients with T2DM had significantly lower fetuin-A levels than healthy controls.	Karajibani et al.³²
	88 (44 T2DM patients and 44 controls).		Gouda et al.³³
Cohort study	5227 (2008 NGT, 1621 impaired glucose regulation, and 1598 T2DM)	The level of fetuin-A was markedly elevated in patients with T2DM compared to the control group.	Song et al.⁴²
Cross-sectional study	160 (40 T2DM patients without microvascular complications, 40 T2DM patients with nephropathy, 40 T2DM patients with retinopathy, and 40 controls).	Fetuin-A concentration was markedly elevated in all T2DM groups compared to the healthy controls.	Al-Said et al.⁴³
	200 (100 T2DM and 100 controls)	Patients with T2DM had significantly greater levels of fetuin-A compared to the control group.	Kurele et al.⁴⁴
	120 (40 patients without carbohydrate disturbance, 40 prediabetes, 40 T2DM)	Fetuin-A may serve as a predictive factor for the development of prediabetes and T2DM.	Karamfilova et al.⁴⁵
	240 (82 T2DM, 79 prediabetes, and 79 controls).	The difference in serum fetuin-A levels between the three studied groups was insignificant.	Almarashda et al.⁴⁶

NGT, normal glucose tolerance; T2DM, type 2 diabetes mellitus.

The role of fetuin-A in the pathogenesis of T2DM

Several mechanisms have been proposed to explain the role of fetuin-A in the development of T2DM, although further research is warranted. One key mechanism is its involvement in insulin resistance, a central feature in T2DM pathogenesis.⁴⁷ Fetuin-A suppresses insulin receptor tyrosine kinase activity by blocking the autophosphorylation of the receptor and insulin receptor substrate-1 (IRS-1), thereby impairing insulin signaling and reducing insulin sensitivity in the liver and muscle tissues.^22,48 In vitro studies using purified rat and bovine fetuin-A support this inhibitory effect. In humans, fetuin-A disrupts insulin-stimulated phosphorylation of the insulin receptor and IRS-1.^49–51 Moreover, in rat adipocytes overexpressing human AHSG, fetuin-A significantly reduced basal and insulin-stimulated phosphorylation of Elk-1, a transcription factor downstream of mitogen-activated protein kinase (MAPK), without affecting glucose transport-4 (GLUT-4) translocation.⁵² Conversely, Malin et al.⁵³ found that fetuin-A can directly impair glucose uptake by reducing GLUT-4 translocation in skeletal muscle.

Insulin receptor is a heterotetramer composed of two α and two β subunits. Insulin binds to the α-subunit, inducing a conformational change and autophosphorylation of tyrosine residues on the β-subunit, which activates downstream signaling pathways such as PI3K-Akt and Ras-MAPK.⁵⁴ Fetuin-A interacts with the tandem fibronectin type 3 (Fn3) domains located in the 194 amino acid residue extracellular region of the β-subunit of the insulin receptor, which is situated away from the high-affinity binding pocket produced by the two complementary α-subunits where insulin binds. Currently, only insulin and fetuin-A are known to bind directly to the receptor’s ectodomain, but with opposing effects: insulin activates, while fetuin-A inhibits, receptor function (Figure 2).⁵⁵

Figure 2.

The role of fetuin-A in T2DM pathogenesis.

Fetuin-A has been strongly linked to obesity. In obese rats, fetuin-A gene expression is significantly elevated,⁵⁶ while fetuin-A knockout mice are resistant to diet-induced obesity, highlighting its critical role in weight regulation.^57,58 In humans, several studies have shown a positive association between fetuin-A levels and both body mass index³⁹ and waist circumference.⁵⁸ Conversely, weight loss is associated with reduced fetuin-A levels,²⁸ suggesting its involvement in obesity-related metabolic disturbances.

In addition, fetuin-A is implicated in inflammation-associated insulin resistance.⁵⁹ Previous studies have shown that fetuin-A can stimulate the expression of proinflammatory cytokines at both mRNA and protein levels⁹ and facilitates lipid-induced insulin resistance by enhancing the binding of free fatty acids (FFAs) to TLR4 via its terminal galactoside moiety. Fetuin-A can directly interact with the Leu100-Gly123 and Thr493-Thr516 residues in TLR4, promoting adipose tissue inflammation and, consequently, insulin resistance.¹⁷ Consistent with this, a human study also confirmed the interaction between FFAs and fetuin-A in predicting insulin resistance.⁶⁰ Fetuin-A binds to FFAs and facilitates their interaction with TLR4 on adipocytes and macrophages, initiating proinflammatory signaling cascades such as the nuclear factor kappa B cells (NF-κB) and JNK pathways.^17,61 This activation leads to the upregulation of cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6, all of which interfere with insulin receptor signaling and impair glucose uptake in peripheral tissues. For instance, fetuin-A stimulates the TNF-α production in monocytes and adipocytes.⁹ Elevated TNF-α impairs insulin sensitivity and glucose metabolism, as shown in both animal and human studies,^62,63 with regulation occurring through the tissue inhibitor of metalloproteases 3/TNF-α converting enzyme signaling axis.^64,65 In addition to its role in TLR4 signaling, fetuin-A contributes directly to adipose tissue inflammation. It promotes the infiltration of monocytes into adipose depots and drives their polarization toward a proinflammatory M1 macrophage phenotype, thereby sustaining a local inflammatory environment.⁶⁶ This low-grade, chronic inflammation amplifies systemic insulin resistance and accelerates the progression of T2DM.⁶⁷

Finally, fetuin-A may suppress the expression of adiponectin, an adipokine known for its insulin-sensitizing and anti-inflammatory effects in adipose tissues.⁹ By downregulating adiponectin, fetuin-A diminishes these protective effects, thereby contributing to insulin resistance and metabolic dysfunction.^9,68 In summary, the collective evidence suggests that elevated fetuin-A levels contribute to insulin resistance, inflammation, obesity-related metabolic dysfunction, and ultimately, a higher risk of developing T2DM.

The relationship of fetuin-A with T2DM complications

The relationship between fetuin-A and complications of T2DM is complex. Both decreased and increased levels of fetuin-A have been associated with an increased risk of morbidity and mortality related to T2DM complications.^69–72 Previous cross-sectional investigations revealed inverse relationships between fetuin-A levels and macrovascular conditions, such as peripheral arterial disease (PAD) and the formation of atherosclerotic plaques in individuals with T2DM.^70,73,74 In addition, lower fetuin-A levels were linked to PAD in patients with advanced T2DM, independent of traditional cardiovascular risk factors, and tended to be even lower in those with more severe lower-extremity arterial calcification.⁷⁵ Conversely, longitudinal investigations such as the Rancho Bernardo Study and Cardiovascular Health Study reported that higher baseline fetuin-A levels in individuals with T2DM were associated with an increased risk of cardiovascular morbidity and mortality.^71,76

With respect to diabetic nephropathy, Sherif et al. reported that patients with this condition had significantly lower mean fetuin-A levels compared to those without nephropathy. In addition, patients with macroalbuminuria exhibited notably lower fetuin-A levels than those with micro and normoalbuminuria.⁷⁷ These findings align with a previous prospective study that indicated lower fetuin-A levels are associated with a higher risk of developing diabetic nephropathy.⁷² Furthermore, Mitkees et al.⁷⁸ discovered that diabetics without microalbuminuria had higher serum fetuin-A levels than those with microalbuminuria, revealing significant negative correlations between serum fetuin-A and albumin/creatinine ratios in both groups. Umapathy et al.⁷⁹ also reported that patients with persistent macroalbuminuria experienced a significant stepwise decline in circulating fetuin-A levels compared to those with micro- and normoalbuminuria. Conversely, a cross-sectional study indicated that diabetics with nephropathy had significantly higher fetuin-A levels than those without nephropathy.⁴³ Furthermore, T2DM patients with microalbuminuria had substantially elevated serum fetuin-A levels compared to those with normoalbuminuria, which was attributed to the influence of fetuin-A on insulin resistance, lipid profile abnormalities, and endothelial dysfunction.⁸⁰ Moreover, diabetic patients undergoing hemodialysis exhibited significantly higher fetuin-A levels than nondiabetic hemodialysis patients and healthy controls, suggesting that elevated circulating concentrations may contribute to the risk of kidney dysfunction.⁸¹

In a prospective study, it was reported that lower fetuin-A levels are associated with an increased risk of diabetic retinopathy.⁷² Similarly, another study found that serum fetuin-A levels were lower in cases of proliferative diabetic retinopathy compared to nonproliferative diabetic retinopathy and diabetics without retinopathy, although the differences among the groups were statistically insignificant.⁷⁷ However, in contrast to these findings, the fetuin-A levels in diabetic patients reportedly increased with the progression of diabetic retinopathy.^82,83 In addition, Priya et al.⁸⁴ reported that T2DM patients with diabetic retinopathy exhibited higher circulating fetuin-A levels compared to those without this complication. On the other hand, a study by Mostafa et al.⁸⁵ suggested that fetuin-A plays a non-significant role in the etiopathogenesis of diabetic retinopathy.

Birukov et al.⁷² found that lower levels of fetuin-A were associated with a higher incidence of neuropathy among diabetic patients. In a cross-sectional study, Sherif et al.⁷⁷ examined 160 patients with T2DM and reported that those with neuropathy had non-significantly lower mean fetuin-A levels compared to those without neuropathy. In contrast, Roos et al.⁷⁰ reported fetuin-A levels and their association with vascular disease in 149 T2DM patients with early diabetic nephropathy and found no association between fetuin-A levels and diabetic neuropathy. Finally, Jung et al. explored the associations between the levels of fetuin-A and diabetic microangiopathies (nephropathy, retinopathy, and peripheral neuropathy), including cardiac autonomic neuropathy in 172 T2DM subjects. Fetuin-A levels were not associated with diabetic neuropathy or cardiac autonomic neuropathy.⁸⁶

In light of these findings, the reasons for the differences in the effects of fetuin-A on macroangiopathies and microangiopathies remain unclear; several explanations have been suggested. One possibility is that the discrepancies may arise from differences in the study populations and the varying severity of complications among participants.⁸⁶ In addition, variations in fetuin-A concentrations suggest that fetuin-A secretion might serve as a feedback defense mechanism against vascular calcification in the early stages of diabetic and atherosclerotic diseases, while lipid disturbances and hyperinsulinemia could trigger hepatic release of fetuin-A.³⁴ Furthermore, it is essential to consider other factors that might account for the inconsistencies in the reports, such as the use of insulin-sensitizing medications like metformin, pioglitazone, and niacin; short-term dietary and exercise interventions; and differences in the ELISA kits used to measure serum fetuin-A levels.⁸⁷ These findings indicate that the relationship between fetuin-A and complications of T2DM is more complex; therefore, longitudinal studies with larger sample sizes are necessary to clarify the role of fetuin-A in the risk of developing T2DM-related complications. Table 2 summarizes the relationship between fetuin-A levels and T2DM complications.

Table 2.

Studies investigating the relationship of fetuin-A with T2DM complications.

Study design	Sample size	Associations of fetuin-A with T2DM complications	References
Diabetic macrovascular complication
Cross-sectional study	738 individuals	Low serum fetuin-A levels were linked to PAD in T2DM patients, regardless of traditional and novel cardiovascular risk factors	Eraso et al.⁷³
Cross-sectional study	153 patients	Reduced fetuin-A levels were linked to the presence of macrovascular disease in T2DM	Roos et al.⁷⁰
Comparative cross-sectional study	200 (100 T2DM patients and 100 NGT subjects)	Elevated serum fetuin-A levels were linked to macroangiopathy in cases of recent-onset T2DM	Yin et al.⁸⁸
Cross-sectional study	172 T2DM patients	A high level of plasma fetuin-A was significantly associated with arterial stiffness; however, there was no correlation with any microangiopathy in cases suffering from T2DM	Jung et al.⁸⁶
Comparative cross-sectional study	312 individuals (87 NGT, 51 IFG, 87 IGT, 87 NDD)	Elevated fetuin-A levels were associated with subclinical CVD as well as accidental or catastrophic CVD, as they exacerbate arterial stiffness in T2DM patients	Ou et al.⁸⁹
Cross-sectional study	(76 NGM-PAD, 129 T2DM–PAD, 40 T2DM-non-PAD)	Fetuin-A was higher in T2DM patients with PAD than in T2DM patients without PAD	Lorant et al.⁹⁰
Cross-sectional study	416 T2DM patients	Fetuin-A levels have been shown to be inversely related to the presence of calcified plaque in T2DM patients, regardless of recognized risk factors for atherosclerosis	Emoto et al.⁷⁴
Prospective cohort study	3810 community-living individuals	Higher baseline fetuin-A levels among T2DM patients were associated with a higher risk of cardiovascular morbidity and mortality	Jensen et al.⁷¹
Population-based prospective study	1658 individuals	Higher levels of fetuin-A were associated with CVD death only in patients with T2DM, whereas fetuin-A was inversely associated with CVD death in those without T2DM	Laughlin et al.⁷⁶
Case-control study	140 (70 T2DM and 70 controls)	Fetuin-A levels were significantly higher in the patients with T2DM than in the control group, and fetuin-A levels were found to be positively associated with blood pressure levels in the patients with T2DM	Dhanapriya et al.⁶⁹
Diabetic nephropathy
Cross-sectional study	88 T2DM patients	Patients with severe diabetic nephropathy (stages III and IV based on GFR) had higher levels of fetuin-A than diabetics without kidney disease	Mehrotra et al.⁹¹
Comparative cross-sectional study	75 (25 normoalbuminuric T2DM, 25 microalbuminuric T2DM and 25 healthy controls)	Serum fetuin-A levels were notably elevated in patients with microalbuminuria compared to those with normoalbuminuria or the healthy control group	El-Batch et al.⁸⁰
Comparative cross-sectional study	120 (40 micro-albuminuric, 40 normo-albuminuric, and 40 macro-albuminuric T2DM patients)	Serum fetuin-A levels were lower in microalbuminuria patients than in normo- and macroalbuminuric patients	Koluman et al.⁹²
Cross-sectional study	90 (30 T2DM without microalbuminuria, 30 T2DM with microalbuminuria, and 30 healthy controls)	Patients with T2DM without microalbuminuria had higher levels of serum fetuin-A than those with microalbuminuria	Mitkees et al.⁷⁸
Cross-sectional study	160 T2DM (80 patients with vascular complications and 80 patients without any vascular complications)	Patients with nephropathy had a significantly lower mean value of fetuin-A than those without nephropathy. Furthermore, patients with macroalbuminuria had markedly decreased mean fetuin-A levels compared to those with micro or normoalbuminuria	Sherif et al.⁷⁷
Prospective cohort study	587 T2DM patients	Lower levels of fetuin-A are associated with an increased risk of diabetic nephropathy	Birukov et al.⁷²
Cross-sectional study	160 (40 T2DM without microvascular complications, 40 T2DM with nephropathy, 40 T2DM with retinopathy, and 40 healthy controls).	Patients with nephropathy had considerably greater fetuin-A levels than the other groups.	Al-Said et al.⁴³
Cross-sectional study	975 (300 controls, 300 T2DM with normoalbuminuria, 195 T2DM with incipient microalbuminuria, 180 T2DM with persistent macroalbuminuria)	A notable gradual decrease was found in the circulatory fetuin-A among individuals with persistent macroalbuminuria when compared to those with micro and normoalbuminuria	Umapathy et al.⁷⁹
Diabetic neuropathy
Prospective cohort study	587 T2DM patients	Lower fetuin-A level was associated with a higher prevalence of neuropathy in patients with T2DM	Birukov et al.⁷²
Cross-sectional study	160 T2DM (80 patients with vascular complications and 80 patients without any vascular complications)	Patients with neuropathy have slightly lower mean levels of fetuin-A compared to patients without neuropathy, but the difference is statistically insignificant	Sherif et al.⁷⁷
Cross-sectional study	153 T2DM patients	There was no association between the level of fetuin-A and diabetic neuropathy	Roos et al.⁷⁰
Cross-sectional study	172 T2DM patients	There was no correlation between fetuin-A levels and diabetes neuropathy or cardiac autonomic neuropathy	Jung et al.⁸⁶
Diabetic retinopathy
Prospective cohort study	587 T2DM patients	Lower fetuin-A levels are linked to a higher occurrence of diabetic retinopathy	Birukov et al.⁷²
Prospective study	101 subjects (19 healthy controls, 26 T2DM without DR, 29 T2DM with nonproliferative diabetic retinopathy, 27 T2DM with proliferative diabetic retinopathy)	Fetuin-A value of T2DM patients increased based on the stage of diabetic retinopathy	Yilmaz et al.⁸³
Case-control study	45 participants (15 healthy controls, 15 T2DM without diabetic retinopathy, 15 T2DM with diabetic retinopathy)	Fetuin-A does not play a significant role in the development of diabetic retinopathy	Mostafa et al.⁸⁵
Cross-sectional study	160 T2DM (80 patients with vascular complications and 80 patients without any vascular complications)	Serum fetuin-A levels were somewhat lower in individuals with proliferative diabetic retinopathy compared to those with nonproliferative diabetic retinopathy and diabetics without retinopathy, but there was no significant difference between the groups	Sherif et al.⁷⁷
Diabetic foot ulcer
Cross-sectional study	137 (49 diabetes group, 57 diabetic foot group, and 31 control group)	Serum fetuin-A levels have a positive correlation with the development of diabetic foot ulcers	Ozenç et al.⁹³

CVD, cardiovascular disease; GFR, glomerular filtration rate; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; NDD, newly diagnosed diabetes; NGM, normal glucose metabolism; NGT, normal glucose tolerance; PAD, peripheral arterial disease; T2DM, type 2 diabetes mellitus.

The potential diagnostic implications of fetuin-A in T2DM

A growing body of evidence suggests that fetuin-A may serve as a valuable diagnostic marker for various clinical conditions. Numerous studies have revealed a significant association between fetuin-A and T2DM, indicating its possible role in disease onset and progression.^43,30,27 Additionally, other investigations have reported strong correlations between fetuin-A levels and T2DM-related complications.^70,72,77 Collectively, these findings suggest that fetuin-A may function both as a diagnostic marker and as an indicator of T2DM severity in clinical practice.

Both preclinical and clinical studies have shown that elevated fetuin-A levels are a strong early predictor of various metabolic disorders, including obesity, T2DM, NAFLD, nonalcoholic steatohepatitis, and insulin resistance.⁹⁴ Demirbaş et al.⁹⁵ identified fetuin-A as an emerging risk factor for CVD and proposed a connection between high levels of fetuin-A and atherosclerosis, supporting its proatherogenic effects through the enhancement of insulin resistance. Conversely, a study has indicated that lower fetuin-A levels are associated with increased atherosclerosis and plaque formation.⁷⁴ Supporting this, a recent meta-analysis reported significantly lower circulating fetuin-A concentrations in patients with aortic valve calcification or stenosis.⁹⁶ These findings suggest that diminished fetuin-A may facilitate vascular calcification, underscoring its potential as a biomarker for both atherosclerosis and vascular calcification.⁷⁴

A study by Werida et al.⁹⁷ found a significant positive correlation between fetuin-A levels, fasting blood glucose, and the atherogenic index, suggesting that fetuin-A may serve as a novel biological marker for diagnosing dyslipidemia and other metabolic disorders. However, the fluctuating relationship between fetuin-A and both the early and advanced stages of atherosclerosis, along with the biphasic association with CVD development, may limit its utility as a diagnostic biomarker in clinical practice.⁷⁰ To establish fetuin-A as a reliable clinical tool, more comprehensive and rigorous research is required to clarify these inconsistencies and confirm its diagnostic value in CVD.

A recent clinical investigation found that elevated serum fetuin-A levels were associated with the development of NAFLD and T2DM, potentially through the activation of NF-κB, which inhibits IRS function.⁹⁸ Yamasandhi et al.⁹⁹ reported that fetuin-A levels were significantly higher in newly diagnosed T2DM patients with NAFLD compared to those without, suggesting that increased fetuin-A may predict NAFLD development. Similarly, Stephen et al.⁴⁷ found a positive association between fetuin-A and liver fat content after adjusting for age and sex. However, a negative association has been observed between fetuin-A and severe liver damage, possibly due to decreased hepatic production of fetuin-A in advanced disease stages.⁸⁷ These findings suggest that fetuin-A may serve as a potential biomarker in the progression of NAFLD, reflecting structural liver damage.

Regarding diabetic microvascular complications, fetuin-A has emerged as a novel urinary biomarker for monitoring the progression of diabetic nephropathy in T2DM patients.¹⁰⁰ In an analysis of the human urine proteome database, Magalhães et al. identified fetuin-A peptides as being associated with impaired kidney function in individuals with T2DM. Specifically, fetuin-A levels showed a negative correlation with the estimated glomerular filtration rate (eGFR) slope, indicating declining kidney function. Furthermore, fetuin-A may allow for earlier detection of kidney dysfunction compared to traditional markers, such as albuminuria, supporting its potential as a novel marker.¹⁰¹ A large-scale proteomic analysis conducted as part of the Taiwan Renal Biomarker Study identified urinary concentrations of post-translationally modified, CP-containing fetuin-A fragments (uPTM-FetA) as promising markers of diabetic kidney disease in T2DM patients.¹⁰² In prospective cohorts of patients with T2DM, uPTM-FetA demonstrates a strong association with the decline in renal function, independent of factors such as albuminuria, eGFR, age, sex, and other risk factors.¹⁰³ Consistent with this, emerging data indicate that uPTM-FetA may serve as a novel and sensitive biomarker for renal injury in chronic kidney disease (CKD) patients regardless of diabetic status. It could also help distinguish diabetic-related CKD from other causes, especially in complex cases or when a kidney biopsy is not feasible.¹⁰⁴ In terms of diabetic retinopathy, Li et al. investigated galectin-3 and fetuin-A levels in 100 T2DM patients, including 50 with and 50 without diabetic retinopathy, aged between 30 and 75 years. The study found elevated levels of both markers in patients with diabetic retinopathy, indicating their potential utility in predicting disease onset. When used together, galectin-3 and fetuin-A offered greater diagnostic value.¹⁰⁵ Supporting this, a cross-sectional study by Zhao et al.⁸² demonstrated that serum and vitreous fetuin-A levels were significantly associated with the presence and progression of diabetic retinopathy. Furthermore, a recent meta-analysis by Das et al.¹⁰⁶ reported a significant increase in fetuin-A levels in patients with proliferative diabetic retinopathy. Similarly, another meta-analysis found that fetuin-A levels were significantly elevated in patients with diabetic retinopathy compared with both diabetic patients without diabetic retinopathy and nondiabetic controls. Fetuin-A concentrations were higher in individuals with proliferative diabetic retinopathy than in those with nonproliferative diabetic retinopathy.¹⁰⁷ Collectively, these findings provide strong evidence that circulating fetuin-A may serve as a novel biomarker for the diagnosis and monitoring of diabetic retinopathy. Regarding diabetic neuropathy, Karamfilova et al. assessed the relationship between fetuin-A and indicators of microangiopathy, including vibration perception threshold, neuropathy disability score, and autonomic neuropathy risk in 120 obese patients (40 patients without carbohydrate disturbances, 40 with prediabetes, and 40 with T2DM). The study revealed a positive correlation between fetuin-A and vibration perception threshold, and a negative correlation with the neuropathy disability score, highlighting a possible link between fetuin-A and diabetic neuropathy severity.⁴⁵

Beyond diabetes and its complications, recent studies have indicated that fetuin-A can be employed as a promising biological marker for cancer,¹⁰⁸ neurodegenerative diseases,¹⁰⁹ multiple sclerosis,¹¹⁰ leukemia,¹¹¹ cognitive decline,¹¹² liver cirrhosis,¹¹³ thoracic aortic aneurysms,¹¹⁴ and COPD¹¹⁵ in persons without T2DM.

Although fetuin-A is a promising potential diagnostic biomarker for T2DM and related conditions, several challenges hinder its practical use in clinical settings. These include the need for standardized assay methods, the high inter-individual and inter-population variability of fetuin-A levels, and the lack of clearly defined diagnostic cutoff values.^116,117 Therefore, there is a pressing need to standardize fetuin-A measurement techniques and establish consistent reference ranges to enable its reliable use in clinical practice.

The potential therapeutic implications of fetuin-A in T2DM

Fetuin-A has been identified as a potential target for treating various diseases, and it may also serve as a biomarker.¹¹⁸ Its growing importance in conditions such as T2DM underscores the necessity for therapies that can effectively manage fetuin-A levels.²⁷ Consequently, fetuin-A is predicted to emerge as a new therapeutic target for T2DM management. High levels of fetuin-A have been linked to insulin resistance and T2DM-related complications, such as CVD and NAFLD.²⁶ Studies have demonstrated that lowering fetuin-A levels or blocking its activity can enhance glucose tolerance and reduce systemic inflammation.^87,119 This indicates that therapies aiming at modifying fetuin-A’s activity could be a promising new approach to treating insulin resistance and metabolic dysregulation in T2DM.

Considerable efforts are being made to develop effective therapies for regulating fetuin-A levels. Recent studies have shown that both pharmacological agents, such as metformin and pioglitazone and natural compounds, such as resveratrol and niacin, can modulate circulating fetuin-A levels.^120,121 Specifically, treatment with pioglitazone and metformin has been associated with decreased fetuin-A levels. Esteghamati et al. conducted a 3-month follow-up study to compare the effects of metformin (1000 mg/day; 500 mg twice daily) and pioglitazone (30 mg/day; 15 mg twice daily) on circulating fetuin-A concentrations in patients with newly diagnosed T2DM. The findings revealed that pioglitazone significantly reduced fetuin-A levels independent of sex, whereas metformin exerted no measurable effect. Importantly, pioglitazone demonstrated superior efficacy in lowering fetuin-A levels, with the reduction being particularly pronounced in male patients.¹²⁰ Another study reported a non-significant decrease in fetuin-A levels in patients receiving metformin compared with newly diagnosed untreated T2DM patients, suggesting that the effect of metformin on fetuin-A may be limited.¹²² Besides, it appears that the release of fetuin-A reduces adiponectin release, whereas dietary intake of resveratrol seems to enhance adiponectin levels.¹²³ Decreased adiponectin secretion has been associated with an increased risk of several disorders, including NAFLD, insulin resistance, and obesity.^123,124 Thus, the interplay between fetuin-A and resveratrol may be mediated through their opposing effects on adiponectin release. Consistent with this, Lee et al.¹²⁵ reported that 4 weeks of resveratrol supplementation (8 mg/kg/day) increased serum adiponectin levels while simultaneously reducing fetuin-A levels in an in vivo study. Similarly, niacin treatment lowers serum fetuin-A levels, which coincides with favorable changes in blood lipids.^121,126

In an in vivo study, Hsu et al.¹²⁷ demonstrated that a 12 weeks of apigenin (20 mg/kg/day) administration suppresses fetuin-A mRNA expression by inhibiting NF-κB activation, a key transcription factor involved in immune responses and insulin resistance.¹²⁸ Apigenin counteracted the palmitic acid-induced increase in fetuin-A expression and formation of the fetuin-A–insulin receptor complex, thereby restoring insulin signaling and enhancing glucose uptake in hepatocytes.¹²⁷ In a randomized study of 67 patients, participants were assigned to three 12-week treatment groups: glimepiride 4 mg with placebo (n = 22), glimepiride 4 mg with curcumin 1100 mg (n = 23), and glimepiride 4 mg with fenofibrate 160 mg (n = 22). Both curcumin and fenofibrate, as adjuncts to glimepiride, improved glycemic control, lipid profiles, and inflammatory markers (fetuin-A and sirtuin 1), with fenofibrate demonstrating a more pronounced reduction in circulating fetuin-A.¹²⁹ Werida et al.⁹⁷ evaluated 70 patients with T2DM, of whom 40 received rosuvastatin 10 mg/day and 30 received a placebo for a duration of 3 months. The rosuvastatin dose was administered in accordance with ACC/AHA recommendations.¹³⁰ Rosuvastatin therapy significantly improved glycemic control and reduced fetuin-A levels, suggesting its potential role in improving lipid profiles and atherogenic indices. Notably, rosuvastatin therapy demonstrated greater efficacy in reducing fetuin-A levels compared with the placebo group, highlighting its additional metabolic benefits beyond lipid-lowering effects.⁹⁷ Similarly, research by Nag et al.¹³¹ found that vildagliptin dose-dependently suppressed palmitate-induced fetuin-A expression. Vildagliptin (20 mg/kg/day) inhibited the palmitate–fetuin-A-mediated activation of the TLR4–NF-κB pathway and decreased IL-1β release, thereby alleviating inflammation in pancreatic islet beta cells. Collectively, these findings support the hypothesis that targeting fetuin-A may offer substantial health benefits and represent a promising therapeutic strategy for more effective T2DM management.

Currently, numerous recent studies have shown that short-term dietary and exercise interventions can effectively reduce circulating fetuin-A levels in patients with T2DM.^132,133 For instance, Farsani et al. reported that combined intervention of ursolic acid supplementation (250 mg/kg/day) and resistance training significantly reduced circulating fetuin-A levels, whereas each intervention alone failed to elicit such an effect. This observation underscores a potential synergistic interaction between nutritional and exercise-based strategies in modulating fetuin-A.¹³³ Nevertheless, several studies have also demonstrated that exercise interventions alone can lower fetuin-A.^134–136 Keihanian et al.¹³⁵ reported that an 8 weeks program combining aerobic and resistance exercise effectively reduced serum fetuin-A levels in men with T2DM. Meta-analyses further support the role of exercise in improving glycemic outcomes by reducing fetuin-A levels in individuals with hyperglycemia and diabetes.¹³⁶ Moreover, in T2DM patients with nephropathy, moderate regular physical activity has proven more effective in lowering fetuin-A levels and improving associated renal impairment.¹³⁷ Several proposed processes explain why physical exercise reduces fetuin-A levels. The mechanisms underlying this effect may involve reductions in hepatic fat content and glucolipotoxicity, as well as mitigation of reactive oxygen species generation and proinflammatory signaling.^138,139 In addition, exercise-induced activation of the Akt signaling pathway can enhance glucose tolerance and reduce insulin resistance.¹⁴⁰ Overall, these findings underscore fetuin-A’s potential as a therapeutic target for managing T2DM and related metabolic disorders. However, additional studies are needed to validate these findings and fully elucidate the molecular mechanisms involved.

Although this review integrates findings from multiple studies and offers insights into the relationship between fetuin-A levels and T2DM, thereby contributing to a better understanding of the role of fetuin-A in T2DM pathology and its potential clinical implications, it also has certain limitations. First, as a narrative review, it has a limited scope and does not provide a comprehensive examination of the subject matter. Additionally, the lack of direct comparisons between studies diminishes the ability to critically evaluate the consistency and reliability of the findings related to fetuin-A and T2DM, which could affect the robustness of the conclusions. Furthermore, as a narrative review, this work is inherently prone to potential biases in literature selection and interpretation, since it does not adhere to the predefined methodological rigor of a systematic review. Moreover, the conclusions drawn from this review may be influenced by the authors’ perspectives, as they are not based on a thorough analysis of all available evidence, potentially limiting the objectivity of the findings.

Conclusion and future perspectives

Numerous studies have found a link between fetuin-A and T2DM and its associated complications, but the findings are inconsistent and inconclusive. More extensive research is needed to reconcile conflicting results and gain a better understanding of fetuin-A’s potential role in T2DM development. Fetuin-A is currently the focus of research efforts due to its potential clinical significance for diagnosis and treatment. It is proposed that fetuin-A be used as a diagnostic tool for T2DM and its associated complications in medical practices in the coming years. However, issues such as the necessity for standardized tests, dealing with variability in fetuin-A levels among groups, and determining particular cutoff values for diagnostic purposes impede its practical use. In addition, fetuin-A has been identified as a possible therapeutic target in T2DM. Currently, some drugs and natural compounds such as metformin, pioglitazone, resveratrol, apigenin, fenofibrate, rosuvastatin, and vildagliptin have been recognized as potential agents for modulating fetuin-A levels in patients with T2DM. Several recent studies also showed that short-term dietary and exercise interventions lead to a decrease in serum fetuin-A levels. Future research should concentrate on understanding the molecular mechanisms underlying the observed relationships as well as investigating novel treatment targets for improving clinical outcomes in T2DM patients. Furthermore, large-scale, multicentered cohort studies are necessary to confirm the diagnostic accuracy and clinical utility of fetuin-A in patients with T2DM.

Footnotes

Appendix

Acknowledgements

None.

Declarations

ORCID iDs

Mohammed Jemal

Bantayehu Addis Tegegne

References

American Diabetes Association Professional Practice Committee. 1. Improving care and promoting health in populations: standards of care in diabetes—2024. Diabetes Care 2023; 47: S11–S19.

IDF. Diabetes atlas, diabetesatlas.org (2025, accessed 21 August 2025).

Chekol Abebe

Tilahun Muche

Behaile

Mariam

, et al. The structure, biosynthesis, and biological roles of fetuin-A: a review. Front Cell Dev Biol 2022; 10: 945287.

Epitope Diagnostics Inc. EDI kit insert: H-fetuin ELISA. 2012.

Komsa-Penkova

Kovacheva

Golemanov

, et al. Fetuin-A–alpha2-Heremans-Schmid glycoprotein: from structure to a novel marker of chronic diseases part 2. Fetuin-A–A marker of insulin resistance and related chronic diseases. J Biomed Clin Res 2018; 11: 7–15.

Reinehr

Roth

CL.

Inflammation markers in type 2 diabetes and the metabolic syndrome in the pediatric population. Curr Diab Rep 2018; 18: 131.

Öner-İyidoğan

Koçak

Interaction of fetuin-A with obesity related insulin resistance and diabetes mellitus. Turk J Biochem 2025; 50: 170–182.

Di Lorenzo

Zoroddu

Mangoni

, et al. Circulating fetuin-A concentrations in rheumatic diseases: a systematic review and meta-analysis. Eur J Clin Invest 2025; 55: e14365.

Hennige

Staiger

Wicke

, et al. Fetuin-A induces cytokine expression and suppresses adiponectin production. PLoS One 2008; 3: e1765.

10.

Aktas

An overview of the role of serum uric acid to high-density lipoprotein cholesterol ratio in type 2 diabetes mellitus and in other inflammatory and metabolic conditions. Minerva Med. Epub ahead of print July 2025. DOI: 10.23736/S0026-4806.25.09712-5.

11.

Aktas

Serum C-reactive protein to albumin ratio as a reliable marker of diabetic neuropathy in type 2 diabetes mellitus. Biomol Biomed 2024; 24: 1380–1386.

12.

Pellegrini

La Grotta

Carreras

, et al. Inflammatory trajectory of type 2 diabetes: novel opportunities for early and late treatment. Cells 2024; 13: 1662.

13.

Gerst

Kemter

Lorza-Gil

, et al. The hepatokine fetuin-A disrupts functional maturation of pancreatic beta cells. Diabetologia 2021; 64: 1358–1374.

14.

Mori

Emoto

Inaba

Fetuin-A: a multifunctional protein. Recent Pat Endocr Metab Immune Drug Discov 2011; 5: 124–146.

15.

Osawa

Umetsu

Sato

, et al. Structure of the gene encoding human alpha2-HS glycoprotein (AHSG). Gene 1997; 196: 121–125.

16.

Komsa-Penkova

Golemanov

Radionova

, et al. Fetuin-A–alpha2-heremans-schmid glycoprotein: from structure to a novel marker of chronic diseases part 1. Fetuin-A as a calcium chaperone and inflammatory marker. J Biomed Clin Res 2017; 10: 90–97.

17.

Pal

Dasgupta

Kundu

, et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 2012; 18: 1279–1285.

18.

Jahnen-Dechent

Trindl

Godovac-Zimmermann

, et al. Posttranslational processing of human alpha 2-HS glycoprotein (human fetuin). Evidence for the production of a phosphorylated single-chain form by hepatoma cells. Eur J Biochem 1994; 226: 59–69.

19.

Lee

Bowman

Yang

FM.

Human alpha 2-HS-glycoprotein: the A and B chains with a connecting sequence are encoded by a single mRNA transcript. Proc Natl Acad Sci U S A 1987; 84: 4403–4407.

20.

Ricken

Can

Gräber

, et al. Post-translational modifications glycosylation and phosphorylation of the major hepatic plasma protein fetuin-A are associated with CNS inflammation in children. PLoS One 2022; 17: e0268592.

21.

Ren

Kim

Papizan

, et al. Phosphorylation status of fetuin-A is critical for inhibition of insulin action and is correlated with obesity and insulin resistance. Am J Physiol Endocrinol Metab 2019; 317: E250–E260.

22.

Auberger

Falquerho

Contreres

, et al. Characterization of a natural inhibitor of the insulin receptor tyrosine kinase: cDNA cloning, purification, and anti-mitogenic activity. Cell 1989; 58: 631–640.

23.

Stefan

Fritsche

Weikert

, et al. Plasma fetuin-A levels and the risk of type 2 diabetes. Diabetes 2008; 57: 2762–2767.

24.

Al Ali

van de Vegte

Said

, et al. Fetuin-A and its genetic association with cardiometabolic disease. Sci Rep 2023; 13: 21469.

25.

Roden

Shulman

GIJN

. The integrative biology of type 2 diabetes. Nature 2019; 576: 51–60.

26.

Dogru

Kirik

Gurel

, et al. The evolving role of fetuin-A in nonalcoholic fatty liver disease: an overview from liver to the heart. Int J Mol Sci 2021; 22: 6627.

27.

Bourebaba

Marycz

Pathophysiological implication of fetuin-A glycoprotein in the development of metabolic disorders: a concise review. J Clin Med 2019; 8: 2033.

28.

Brix

Stingl

Höllerl

, et al. Elevated fetuin-A concentrations in morbid obesity decrease after dramatic weight loss. J Clin Endocrinol Metab 2010; 95: 4877–4881.

29.

Sharma

Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: the roles of fetuin-A, adiponectin, and AMPK. J Am Soc Nephrol 2010; 21: 406–412.

30.

Guo

Cao

Cai

, et al. Fetuin-A levels and risk of type 2 diabetes mellitus: a systematic review and meta-analysis. Acta Diabetol 2018; 55: 87–98.

31.

Aroner

Mukamal

St-Jules

, et al. Fetuin-A and risk of diabetes independent of liver fat content: the multi-ethnic study of atherosclerosis. Am J Epidemiol 2017; 185: 54–64.

32.

Karajibani

Montazerifar

Sadeghi

, et al. Serum fetuin-A and adipsin levels in type II diabetes patients. Int J High Risk Behav Addict 2019; 8: e91963.

33.

Gouda

1005 Study of visfatin and fetuin-A in type 2 diabetes mellitus in children. J Arch Dis Child 2021; 106: A189–A190.

34.

Wojtysiak Duma

Malecha-Jȩdraszek

Burska

, et al. Serum fetuin-A levels in patients with type 2 diabetes mellitus. Curr Issues Pharm Med Sci 2010; 23(2): 93–99.

35.

Wang

Koh

Jensen

, et al. Plasma fetuin-A levels and risk of type 2 diabetes mellitus in a Chinese population: a nested case-control study. Diab Metab J 2019; 43: 474–486.

36.

Beigi

Shafaei

Khoshnia

, et al. Serum fetuin a level, liver enzymes activities and insulin resistance in patients with type 2 diabetes. J Med Sci 2015; 15: 229.

37.

Ahmed

Abdul Wahed

AMH

. Evaluation of fetuin A, hepassocin, selenoprotien P levels and number of biochemical variables in diabetes mellitus type 2 males’ patients. AIP Conf Proc 2024; 3097: 030029.

38.

Fatima

Zuberi

Noor

, et al. Role of fetuin-A in insulin resistance in type 2 diabetes mellitus. AASH KMDC 2013; 18: 58.

39.

Yin

Cai

W-J

Chang

X-Y

, et al. Association between fetuin‑A levels with insulin resistance and carotid intima‑media thickness in patients with new‑onset type 2 diabetes mellitus. Biomed Rep 2014; 2: 839–842.

40.

Sun

Cornelis

Manson

, et al. Plasma levels of fetuin-A and hepatic enzymes and risk of type 2 diabetes in women in the U.S. Diabetes 2013; 62: 49–55.

41.

Ahmed

Mousa

Mohamed

NAE-G

, et al. Fetuin-A and type II diabetes mellitus. Egypt J Intern Med 2014; 26: 157–161.

42.

Song

, et al. Serum fetuin-A associates with type 2 diabetes and insulin resistance in Chinese adults. PLoS One 2011; 6: e19228.

43.

Al-Said

Taha

Abdel-Aziz

, et al. Fetuin-A level in type 2 diabetic patients: relation to microvascular complications. Egypt J Intern Med 2018; 30: 121–130.

44.

Kurele

Dutta

Patne

The antagonistic relationship of fetuin-A and adiponectin in obese type 2 diabetes mellitus. Panacea J Med Sci 2023; 13: 521–524.

45.

Karamfilova

Nedeva

Gatev

, et al. Relationship of serum fetuin-A with metabolic and vascular parameters in patients with prediabetes and type 2 diabetes mellitus. Pharmacia 2023; 70: 1455–1461.

46.

Almarashda

Abdi

Yakout

, et al. Hepatokines fetuin-A and fetuin-B status in obese Saudi patient with diabetes mellitus type 2. Am J Transl Res 2022; 14: 3292–3302.

47.

Stefan

Hennige

Staiger

, et al. α2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 2006; 29: 853–857.

48.

Mathews

Chellam

Srinivas

, et al. α2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor. Mol Cell Endocrinol 2000; 164: 87–98.

49.

Rauth

Pöschke

Fink

, et al. The nucleotide and partial amino acid sequences of rat fetuin. Eur J Biochem 1992; 204: 523–529.

50.

Srinivas

Wagner

Reddy

, et al. Serum alpha 2-HS-glycoprotein is an inhibitor of the human insulin receptor at the tyrosine kinase level. Mol Endocrinol (Baltimore, MD) 1993; 7: 1445–1455.

51.

Mathews

Srinivas

Leon

, et al. Bovine fetuin is an inhibitor of insulin receptor tyrosine kinase. Life Sci 1997; 61: 1583–1592.

52.

Chen

Srinivas

Cong

, et al. Alpha2-Heremans Schmid glycoprotein inhibits insulin-stimulated Elk-1 phosphorylation, but not glucose transport, in rat adipose cells. Endocrinology 1998; 139: 4147–4154.

53.

Malin

Mulya

Fealy

, et al. Fetuin-A is linked to improved glucose tolerance after short-term exercise training in nonalcoholic fatty liver disease. J Appl Physiol (Bethesda, MD: 1985) 2013; 115: 988–994.

54.

Boucher

Kleinridders

Kahn

CR.

Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harbor Perspect Biol 2014; 6: a009191.

55.

Goustin

A-S

Abou-Samra

AB.

The “thrifty” gene encoding Ahsg/Fetuin-A meets the insulin receptor: insights into the mechanism of insulin resistance. Cell Signal 2011; 23: 980–990.

56.

Lin

Braymer

Bray

, et al. Differential expression of insulin receptor tyrosine kinase inhibitor (fetuin) gene in a model of diet-induced obesity. Life Sci 1998; 63: 145–153.

57.

Mathews

Rakhade

Zhou

, et al. Fetuin-null mice are protected against obesity and insulin resistance associated with aging. Biochem Biophys Res Commun 2006; 350: 437–443.

58.

Mathews

Singh

Ranalletta

, et al. Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. Diabetes 2002; 51: 2450–2458.

59.

Dandona

Aljada

Bandyopadhyay

Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004; 25: 4–7.

60.

Stefan

Häring

H-U.

Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat Med 2013; 19: 394–395.

61.

Tang

Jiang

Wang

, et al. TLR4/NF-κB signaling contributes to chronic unpredictable mild stress-induced atherosclerosis in ApoE^−/− mice. PLoS One 2015; 10: e0123685.

62.

Serino

Menghini

Fiorentino

, et al. Mice heterozygous for tumor necrosis factor-α converting enzyme are protected from obesity-induced insulin resistance and diabetes. Diabetes 2007; 56: 2541–2546.

63.

Hotamisligil

Shargill

Spiegelman

BM.

Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance. Science 1993; 259: 87–91.

64.

Federici

Hribal

Menghini

, et al. Timp3 deficiency in insulin receptor–haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-α. J Clin Invest 2005; 115: 3494–3505.

65.

Tripathy

Daniele

Fiorentino

, et al. Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3–TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study. Diabetologia 2013; 56: 2153–2163.

66.

Chatterjee

Seal

Mukherjee

, et al. Adipocyte fetuin-A contributes to macrophage migration into adipose tissue and polarization of macrophages. J Biol Chem 2013; 288: 28324–28330.

67.

Berbudi

Khairani

Tjahjadi

AI.

Interplay between insulin resistance and immune dysregulation in type 2 diabetes mellitus: implications for therapeutic interventions. Immunotargets Ther 2025; 14: 359–382.

68.

Agarwal

Chattopadhyay

Mukherjee

, et al. Fetuin-A downregulates adiponectin through Wnt-PPARγ pathway in lipid induced inflamed adipocyte. Biochim Biophys Acta Mol Basis Dis 2017; 1863: 174–181.

69.

Dhanapriya

Malarvizhi

Krishnaprabha

, et al. Exploring fetuin-A as a potential biomarker for type 2 diabetes mellitus: a case-control study. J Cardiovasc Dis Res 2024; 15.

70.

Roos

Oikonomou

von Eynatten

, et al. Associations of fetuin-A levels with vascular disease in type 2 diabetes patients with early diabetic nephropathy. Cardiovasc Diabetol 2010; 9: 48.

71.

Jensen

Bartz

Mukamal

, et al. Fetuin-A, type 2 diabetes, and risk of cardiovascular disease in older adults: the cardiovascular health study. Diabetes Care 2013; 36: 1222–1228.

72.

Birukov

Polemiti

Jäger

, et al. Fetuin-A and risk of diabetes-related vascular complications: a prospective study. Cardiovasc Diabetol 2022; 21: 6.

73.

Eraso

Ginwala

Qasim

, et al. Association of lower plasma fetuin-A levels with peripheral arterial disease in type 2 diabetes. Diabetes Care 2010; 33: 408–410.

74.

Emoto

Mori

Lee

, et al. Fetuin-A and atherosclerotic calcified plaque in patients with type 2 diabetes mellitus. Metabolism 2010; 59: 873–878.

75.

Eleftheriadou

Grigoropoulou

Kokkinos

, et al. Association of plasma fetuin-A levels with peripheral arterial disease and lower extremity arterial calcification in subjects with type 2 diabetes mellitus. J Diabetes Complications 2017; 31: 599–604.

76.

Laughlin

Cummins

Wassel

, et al. The association of fetuin-A with cardiovascular disease mortality in older community-dwelling adults: the Rancho Bernardo study. J Am Coll Cardiol 2012; 59: 1688–1696.

77.

Sherif

El Ahwal

Elsawy

, et al. Serum level of fetuin-A as a biomarker for vascular complications and severity of insulin resistance in individuals with type 2 diabetes. Int J Adv Res Med 2024; 6: 62–70.

78.

Mitkees

El-Sayed

Gad

, et al. Fetuin A as an early marker of diabetic nephropathy in patients with type 2 diabetes mellitus Al-Azhar Med J 2020; 49: 785–796.

79.

Umapathy

Subramanyam

Krishnamoorthy

, et al. Association of fetuin-A with Thr256Ser exon polymorphism of α2-Heremans Schmid glycoprotein (AHSG) gene in type 2 diabetic patients with overt nephropathy. J Diabetes Complications 2022; 36: 108074.

80.

El-Batch

Hamouda

Hassan

, et al. Preliminary study of biochemical role of serum fetuin-A level and its gene polymorphism in diabetic patients with microalbuminuria. J Diabetes Metab Disord Control 2015; 5: 158–164.

81.

Al Akad

Tawfeik

Kamel

, et al. Serum fetuin-A in diabetic and nondiabetic hemodialysis patients. Minia J Med Res 2023; 34: 72–77.

82.

Zhao

Hou

Wang

, et al. Relation of serum and vitreous concentrations of fetuin-A with diabetic retinopathy. Med Sci Monit 2015; 21: 1839–1842.

83.

Yilmaz

Gunay

Elevated serum fetuin-A levels are associated with grades of retinopathy in type 2 diabetic patients. Int Ophthalmol 2018; 38: 2445–2450.

84.

Priya

Jayashree

Senthilkumar

, et al. Role of fetuin-A and vascular endothelial growth factor in type 2 diabetes mellitus patients without and with retinopathy. Diabetes Metab Syndr 2019; 13: 2699–2703.

85.

Mostafa

EAM

AlShaarawy

BAI

Abd El-Hamid

, et al. Evaluation of fetuin-A level in diabetic retinopathy. Egypt J Intern Med 2022; 34: 62.

86.

Jung

Kim

, et al. Associations of serum fetuin-A levels with insulin resistance and vascular complications in patients with type 2 diabetes. Diab Vasc Dis Res 2013; 10: 459–467.

87.

Dabrowska

Tarach

Wojtysiak-Duma

, et al. Fetuin-A (AHSG) and its usefulness in clinical practice. Review of the literature. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2015; 159: 352–359.

88.

Yin

Cai

Zhu

, et al. Association of plasma fetuin-A and clinical characteristics in patients with new-onset type 2 diabetes mellitus. Int J Clin Exp Med 2015; 8: 991–999.

89.

H-Y

F-H

H-T

, et al. Both diabetes and fetuin-A are independently associated with increased risk of arterial stiffness. Clin Chim Acta 2015; 445: 133–138.

90.

Lorant

Grujicic

Hoebaus

, et al. Fetuin-A levels are increased in patients with type 2 diabetes and peripheral arterial disease. Diabetes Care 2011; 34: 156–161.

91.

Mehrotra

Westenfeld

Christenson

, et al. Serum fetuin-A in nondialyzed patients with diabetic nephropathy: relationship with coronary artery calcification. Kidney Int 2005; 67: 1070–1077.

92.

Koluman

Mutluay

Derici

, et al. Association between osteoprotegerin, fetuin-A, carotid intima media thickness, and urinary albumin excretion in type 2 diabetes. Clin Nephrol 2013; 80: 9–16.

93.

Ozenç

Simsek

Yildirim

, et al. Association between the development of diabetic foot and serum fetuin‑A levels. Pol Arch Med Wewn 2013; 123: 513–518.

94.

Sardana

Goyal

Bedi

Molecular and pathobiological involvement of fetuin-A in the pathogenesis of NAFLD. Inflammopharmacology 2021; 29: 1061–1074.

95.

Demirbaş

Kurtipek

Tunçez

, et al. The role of cystatin-C and fetuin-A in the determination of early atherosclerotic risk in psoriasis patients. Dermatol Ther 2020; 33: e13898.

96.

Larik

MO.

Fetuin-A levels in association with calcific aortic valve disease: a meta-analysis. Atheroscler Plus 2023; 54: 27–29.

97.

Werida

Elattar

Abdelghafour

, et al. Effect of rosuvastatin on sortilin and fetuin-A in type 2 diabetic patients: a randomized controlled trial. Int J Diab Dev Ctries 2025; 45: 207–218.

98.

Filardi

Panimolle

Tiberti

, et al. Circulating levels of fetuin-A are associated with moderate-severe hepatic steatosis in young adults. J Endocrinol Invest 2021; 44: 105–110.

99.

Yamasandhi

Dharmalingam

Balekuduru

Fetuin-A in newly detected type 2 diabetes mellitus as a marker of non-alcoholic fatty liver disease. Indian J Gastroenterol 2021; 40: 556–562.

100.

Inoue

Wada

Eguchi

, et al. Urinary fetuin-A is a novel marker for diabetic nephropathy in type 2 diabetes identified by lectin microarray. PLoS One 2013; 8: e77118.

101.

Magalhães

Zürbig

Mischak

, et al. Urinary fetuin-A peptides as a new marker for impaired kidney function in patients with type 2 diabetes. Clin Kidney J 2021; 14: 269–276.

102.

Chuang

Lin

Huang

, et al. SUN-156 DNlite-IVD103, a novel urinary test, predicts progressive eGFR decline in type 2 diabetes with microalbuminuria. Kidney Int Rep 2020; 5: S264.

103.

Chuang

G-T

Kremer

Huang

C-H

, et al. Urinary fetuin-A fragments predict progressive estimated glomerular filtration rate decline in two independent type 2 diabetes cohorts of different ethnicities. Am J Nephrol 2024; 55: 106–114.

104.

Musolino

Greco

D’Agostino

, et al. Urinary post-translationally modified fetuin-A (uPTM-FetA) in chronic kidney disease patients with and without diabetic kidney disease. Medicina (Kaunas) 2024; 60: 363.

105.

Tian

Wang

, et al. Association of plasma galectin-3 and fetuin-A levels with diabetic retinopathy in type 2 diabetes mellitus patients. Endokrynol Pol 2023; 74: 536–543.

106.

Das

Rathore

Guha

A meta-analysis and systematic review on adipokines as potential biomarker for proliferative diabetic retinopathy. Int J Diab Dev Ctries 2025; 45: 751–763.

107.

Behnoush

Samavarchitehrani

Shirazi Ghaleno

, et al. Fetuin-A levels in diabetic retinopathy: a systematic review and meta-analysis. J Diabetes Metab Disord 2024; 24: 31.

108.

Odiase

Ranganathan

, et al. The role of fetuin-A in tumor cell growth, prognosis, and dissemination. Int J Mol Sci 2024; 25: 12918.

109.

Yoon

Boonpraman

Kim

, et al. Reduction of fetuin-A levels contributes to impairment of Purkinje cells in cerebella of patients with Parkinson’s disease. BMB Rep 2023; 56: 308.

110.

Langan

R-A

Harris

Sadiq

SJN

. Fetuin-A, a CSF biomarker of multiple sclerosis disease activity, is upregulated at the blood-CSF barrier (P5.329). Neurology 2016; 86: P5.329.

111.

Guo

X-L

Wang

Y-D

Liu

Y-J

, et al. Fetal hepatocytes protect the HSPC genome via fetuin-A. Nature 2025; 637: 402–411.

112.

Mancuso

Spiga

Rubino

, et al. Effects of Alpha-2-HS-glycoprotein on cognitive and emotional assessment in prediabetic and diabetic subjects. J Affect Disord 2021; 282: 700–706.

113.

Vörös

Márkus

Atzél

, et al. Serum fetuin-A is decreased in cirrhotic patients with Wilson’s disease. PLoS One 2023; 18: e0282801.

114.

Chen

Zhu

Guo

, et al. Serum fetuin-A and risk of thoracic aortic aneurysms: a two-sample mendelian randomization study. Front Endocrinol (Lausanne) 2024; 15: 1361416.

115.

Małujło-Balcerska

Kumor-Kisielewska

Śmigielski

Leptin, resistin and fetuin a concentration as the potential useful biomarkers in stable COPD—an exploratory study. Cytokine 2023; 169: 156275.

116.

Reinehr

Roth

CL.

Fetuin-A and its relation to metabolic syndrome and fatty liver disease in obese children before and after weight loss. J Clin Endocrinol Metab 2008; 93: 4479–4485.

117.

Laughlin

McEvoy

Barrett-Connor

, et al. Fetuin-A, a new vascular biomarker of cognitive decline in older adults. Clin Endocrinol 2014; 81: 134–140.

118.

Chekol Abebe

Tilahun Muche

Behaile

TMA

, et al. Role of fetuin-A in the pathogenesis of psoriasis and its potential clinical applications. Clin Cosmet Investig Dermatol 2022; 15: 595–607.

119.

Malin

del Rincon

Huang

, et al. Exercise-induced lowering of fetuin-A may increase hepatic insulin sensitivity. Med Sci Sports Exerc 2014; 46: 2085–2090.

120.

Esteghamati

Afarideh

Feyzi

, et al. Comparative effects of metformin and pioglitazone on fetuin-A and osteoprotegerin concentrations in patients with newly diagnosed diabetes: a randomized clinical trial. Diab Metab Syndr 2015; 9: 258–265.

121.

Icer

Yıldıran

Effects of nutritional status on serum fetuin-A level. Crit Rev Food Sci Nutr 2020; 60: 1938–1946.

122.

Mohammed

Taha

Muhi

SA.

A case-control study to determination FBXW7 and fetuin-A levels in patients with type 2 diabetes in Iraq. J Diabetes Metab Disord 2021; 20: 237–243.

123.

Dalamaga

Karmaniolas

Chamberland

, et al. Higher fetuin-A, lower adiponectin and free leptin levels mediate effects of excess body weight on insulin resistance and risk for myelodysplastic syndrome. Metabolism 2013; 62: 1830–1839.

124.

Kawano

Arora

The role of adiponectin in obesity, diabetes, and cardiovascular disease. J Cardiometab Syndr 2009; 4: 44–49.

125.

Lee

Lim

Yang

SJ.

Involvement of resveratrol in crosstalk between adipokine adiponectin and hepatokine fetuin-A in vivo and in vitro. J Nutr Biochem 2015; 26: 1254–1260.

126.

Erdmann

Salmhofer

Knauß

, et al. Relationship of fetuin-A levels to weight-dependent insulin resistance and type 2 diabetes mellitus. Regul Pept 2012; 178: 6–10.

127.

Hsu

M-C

Chen

C-H

Wang

M-C

, et al. Apigenin targets fetuin-A to ameliorate obesity-induced insulin resistance. Int J Biol Sci 2024; 20: 1563–1577.

128.

Heo

Choi

Jeon

, et al. Visfatin induces inflammation and insulin resistance via the NF-κB and STAT3 signaling pathways in hepatocytes. J Diabetes Res 2019; 2019: 4021623.

129.

Nada

El-Gharbawy

Abbas

, et al. Effect of adding fenofibrate versus curcumin to glimepiride in patients with type 2 diabetes: a randomized controlled trial. BMC Pharmacol Toxicol 2025; 26: 119.

130.

Kim

K-J

Yoon

Won

, et al. Assessment of the efficacy of lowering LDL cholesterol with rosuvastatin 10 mg in four Korean statin benefit groups as per ACC/AHA guidelines (NewStaR4G). J Clin Med 2020; 9: 916.

131.

Nag

Mandal

Mukherjee

, et al. Vildagliptin inhibits high fat and fetuin-A mediated DPP-4 expression, intracellular lipid accumulation and improves insulin secretory defects in pancreatic beta cells. Biochim Biophys Acta Mol Basis Dis 2024; 1870: 167047.

132.

Karimi

Abednatanzi

Soheily

, et al. Evaluating the effect of combined exercise with Broccoli consumption on fetuin A and B in men with type 2 diabetes. J Nutr Fasting Health 2025; 13: 116–124.

133.

Farsani

Faramarzi

Karaji

, et al. Resistance training and ursolic acid consumption affect hepatokines in aged diabetic rat liver. Sci Rep 2025; 15: 24326.

134.

Khadir

Kavalakatt

Madhu

, et al. Fetuin-A levels are increased in the adipose tissue of diabetic obese humans but not in circulation. Lipids Health Dis 2018; 17: 291.

135.

Keihanian

Arazi

Kargarfard

Effects of aerobic versus resistance training on serum fetuin-A, fetuin-B, and fibroblast growth factor-21 levels in male diabetic patients. Physiol Int 2019; 106: 70–80.

136.

Ramírez-Vélez

García-Hermoso

Hackney

, et al. Effects of exercise training on Fetuin-a in obese, type 2 diabetes and cardiovascular disease in adults and elderly: a systematic review and Meta-analysis. Lipids Health Dis 2019; 18: 23.

137.

Salama

El-Damarawi

MA.

Effect of two exercise varieties on fetuin-A plasma level in experimental diabetic nephropathy. Tanta Med J 2017; 45: 21.

138.

González-Ruiz

Ramírez-Vélez

Correa-Bautista

, et al. The effects of exercise on abdominal fat and liver enzymes in pediatric obesity: a systematic review and meta-analysis. Child Obes 2017; 13: 272–282.

139.

Guo

Liong

, et al. Beneficial mechanisms of aerobic exercise on hepatic lipid metabolism in non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int 2015; 14: 139–144.

140.

Valentine

Ruderman

NB.

AMP-activated protein kinase (AMPK): does this master regulator of cellular energy state distinguish insulin sensitive from insulin resistant obesity?

Curr Obes Rep 2014; 3: 248–255.

The evolving roles of fetuin-A in type 2 diabetes mellitus and its potential clinical implications: a review

Abstract

Plain language summary

Keywords

Introduction

Methodology

Structural features of fetuin-A

The relationship of fetuin-A with T2DM

The role of fetuin-A in the pathogenesis of T2DM

The relationship of fetuin-A with T2DM complications

The potential diagnostic implications of fetuin-A in T2DM

The potential therapeutic implications of fetuin-A in T2DM

Conclusion and future perspectives

Footnotes

Appendix

Acknowledgements

Declarations

ORCID iDs

References