Association between circulating CTRP12 levels and type 2 diabetes: A meta-analysis

Abstract

BACKGROUND

C1q/TNF-related protein 12 (CTRP12) is an important adipokine that plays a critical role in the regulation of energy metabolism and is considered to have potential protective effects in the development of type 2 diabetes mellitus (T2DM).

AIM

To conduct a comprehensive systematic review and meta-analysis of published papers evaluating the association between CTRP12 levels and the risk of T2DM.

METHODS

A literature search of PubMed, Web of Science, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, VIP Chinese Science Journals Database, Wanfang, and SinoMed was conducted to identify studies published up to November 2025. Thirteen cohort studies met the inclusion criteria after stepwise screening. Given the substantial heterogeneity among studies, pooled estimates were derived using a random-effects model. Subgroup analyses were undertaken to explore potential sources of variability. Publication bias was assessed using Egger’s and Begg’s tests, along with funnel plot inspection.

RESULTS

The 13 studies included in the analysis involved 2193 participants including patients with T2DM and healthy controls. Meta-analysis demonstrated that circulating CTRP12 levels were significantly lower in patients with T2DM than those in healthy controls (Z = 6.96, P < 0.00001). Sensitivity analysis showed stable results, indicating robust pooled effects. Subgroup analysis suggested that heterogeneity primarily originated from participants’ body mass index and the homeostasis model assessment of insulin resistance. Quality assessment showed that most included studies achieved relatively high Newcastle-Ottawa Scale scores, suggesting that the overall methodological quality was generally satisfactory.

CONCLUSION

The meta-analysis demonstrated that circulating CTRP12 levels were significantly reduced in individuals with T2DM. This finding suggests that CTRP12 may exert protective effects in disorders of glucose and lipid metabolism.

Key Words: C1q/TNF-related protein 12; Type 2 diabetes; Glucose metabolism; Insulin resistance; Meta-analysis

Core Tip: C1q/TNF-related protein 12 (CTRP12) is an adipokine involved in the regulation of glucose and lipid metabolism. However, existing evidence regarding its association with type 2 diabetes mellitus (T2DM) has not yet been systematically integrated. This systematic review and meta-analysis, encompassing 13 studies with 2193 participants, evaluated circulating CTRP12 levels in patients with T2DM. Circulating CTRP12 levels were significantly reduced in individuals with T2DM. Body mass index and insulin resistance were identified as major contributors to heterogeneity. These findings suggest a potential protective role of CTRP12 in metabolic dysregulation and support its value as a biomarker in T2DM.

INTRODUCTION

Diabetes continues to pose a major global public health challenge, with an estimated 589 million adults affected worldwide by 2024. Type 2 diabetes mellitus (T2DM), accounting for more than 90% of all diabetes cases, is associated with increased all-cause mortality and a wide range of vascular complications[1]. In addition, T2DM is an independent risk factor for multiple chronic diseases, and the elevated risks persist even after adjustment for confounding factors such as age, sex, obesity, hypertension, and dyslipidemia[2]. Although a variety of antidiabetic therapies, including metformin, insulin, sodium/glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 receptor co-agonists, are currently available and primarily aim to improve glycemic control through insulin sensitization, enhanced insulin secretion, or modulation of energy metabolism[3,4], these treatments often fail to fundamentally reverse cellular injury or fully restore metabolic homeostasis in key organs such as the liver and skeletal muscle. Consequently, there is an urgent need to explore endogenous regulatory factors involved in metabolic homeostasis, as such factors may play a crucial role in the onset and progression of T2DM.

In recent years, adipose tissue has increasingly been recognized as an active endocrine organ rather than merely a passive site for energy storage. It secretes a variety of adipokines that play essential roles in regulating insulin sensitivity, glucose metabolism, inflammatory processes, and whole-body energy balance[5,6]. Beyond the well-established adipokines adiponectin and leptin, accumulating evidence indicates that newly identified adipokines may also participate in the development of T2DM[7]. Among these, the complement C1q/TNF-related protein (CTRP) family has received growing attention due to its structural resemblance to adiponectin and its emerging involvement in glucose and lipid metabolism[8]. The CTRP family consists of multiple members with distinct biological functions, several of which have been shown to exert important regulatory effects on insulin sensitivity, inflammatory responses, and energy homeostasis. These observations provide new insights into the mechanisms underlying metabolic disease pathogenesis[9].

Within this family, CTRP12, also referred to as adipolin, is a recently identified adipokine that is predominantly secreted by adipose tissue. It contributes to metabolic homeostasis by enhancing insulin signaling in the liver and adipose tissue, alleviating insulin resistance, and suppressing inflammatory responses[10,11]. Experimental studies have demonstrated that CTRP12 is closely associated with the development of T2DM and mediates its effects through both insulin-dependent and insulin-independent pathways[12]. Although several clinical studies have examined alterations in circulating CTRP12 levels among patients with T2DM, many of these investigations were retrospective or cross-sectional in design and involved relatively small sample sizes, leading to considerable heterogeneity and inconsistent findings[13]. Furthermore, study populations were often limited to specific subgroups, such as individuals with obesity, metabolic syndrome, or those receiving particular therapeutic interventions. Differences in sample sources and measurement techniques further compromised the reliability and generalizability of the results. Therefore, well-designed systematic reviews and meta-analyses are required to synthesize existing clinical evidence, quantitatively assess overall changes in circulating CTRP12 levels in patients with T2DM, and explore their relationships with insulin resistance, glycemic control, and other metabolic parameters. Such analyses would provide more robust evidence to clarify the role of CTRP12 in diabetes development and to evaluate its potential clinical utility as a biomarker or therapeutic target. The overall study design and main findings are summarized in Figure 1.

Figure 1 Graphical abstract. Overview of the study design and main findings. T2DM: Type 2 diabetes; CTRP12: C1q/TNF-related protein 12; GLUT4: Glucose transporter type 4.

MATERIALS AND METHODS

The present study is a meta-analysis of observational studies evaluating the association between circulating CTRP12 levels and T2DM. This review was conducted in accordance with the PRISMA recommendations and was prospectively registered in PROSPERO (CRD420251142618).

Search strategy

Two reviewers conducted a comprehensive search of major international and Chinese databases, including PubMed, EMBASE, the Cochrane Library, China National Knowledge Infrastructure, Wanfang, VIP Chinese Science Journals Database, and SinoMed, from database inception to November 6, 2025. The search strategy combined controlled vocabulary terms with free-text keywords and was adjusted as appropriate for each database. An example of the PubMed search strategy was as follows: (“Diabetes Mellitus, Type 2”[MeSH Terms] OR “Type 2 Diabetes” OR “T2DM” OR “Non-Insulin-Dependent Diabetes Mellitus”) AND (“CTRP12” OR “C1q TNF related protein 12” OR “C1q/TNF-related protein 12” OR “Adipolin”). No language restrictions were applied. In addition to electronic database searches, the reference lists of all included studies and relevant reviews were manually screened to identify potentially eligible articles. No additional grey literature databases were searched. All retrieved records were deduplicated before screening. Two reviewers independently screened titles and abstracts, followed by full-text assessments. Any disagreements regarding study eligibility were resolved through discussion with a third reviewer. Reasons for exclusion at the full-text stage were recorded in detail, and the study selection process is summarized in a PRISMA flowchart.

Inclusion and exclusion criteria

Inclusion criteria: (1) Studies involving adult participants diagnosed with T2DM, with or without complications; (2) Observational studies (e.g., case-control, cross-sectional, or cohort studies) evaluating the association between circulating CTRP12 levels and T2DM; (3) A control group composed of healthy adults from the same time period; and (4) Reporting circulating CTRP12 levels with sufficient data for quantitative analysis.

Exclusion criteria: (1) Duplicate data; (2) Retracted articles; and (3) Studies lacking valid data, such as an absence of healthy controls or conference abstracts.

Data collection and quality assessment

Data were extracted on study characteristics and participant information, including sample sizes of the T2DM and control groups, first author, year of publication, geographic region, age, body mass index (BMI), metabolic and biochemical indicators, presence of comorbidities, and circulating CTRP12 concentrations. The risk of bias in observational studies was assessed using the Newcastle-Ottawa Scale (NOS)[14], which assigns a maximum of nine points across the domains of selection, comparability, and outcome assessment. Data extraction and quality assessment were performed independently by two reviewers. The extracted data were then cross-checked for consistency. Any discrepancies were resolved through discussion with a third reviewer until agreement was achieved.

Statistical analysis

Descriptive data were summarized as means with SDs. Given that most included studies reported cross-sectional comparisons of circulating CTRP12 levels between T2DM patients and healthy controls, pooled standardized mean differences were calculated to estimate the magnitude of association. Prior to statistical analysis, all reported CTRP12 concentrations, originally expressed in ng/mL, were converted to pg/mL to ensure consistency. Between-study heterogeneity was assessed using Cochran’s Q test and quantified with the I² statistic. Given the presence of substantial heterogeneity (I² > 50%), pooled effect estimates were calculated using a random-effects model. Potential publication bias was evaluated using Egger’s regression test, Begg’s test, and visual inspection of funnel plot symmetry. To examine the robustness of the pooled results, a leave-one-out sensitivity analysis was conducted by sequentially excluding each study and recalculating the pooled standardized mean difference. A two-sided P value of less than 0.05 was considered statistically significant. All statistical analyses were performed using Review Manager software (version 5.3) and Stata software (version 15.1).

RESULTS

Evidence identification and study characteristics

A total of 75 records were retrieved through the database search. After de-duplication and initial screening of titles and abstracts, 62 studies were excluded because they were duplicate publications, lacked appropriate healthy control groups, were non-original research, were unrelated to the research objective, or involved animal experiments. Eighteen articles underwent full-text review, of which five were excluded because of ineligible comparator groups or overlapping datasets. Ultimately, 13 cohort studies[13,15-26] met all eligibility criteria and were included in the quantitative synthesis, as shown in Figure 2. These studies collectively enrolled 2193 participants with and without T2DM. Ten studies were conducted in Chinese populations, while three involved non-Chinese cohorts. The publication years ranged from 2017 to 2025, and participant ages ranged from 20 years to 70 years. All studies measured circulating CTRP12 concentrations using enzyme-linked immunosorbent assays. Several cohorts included participants with comorbid conditions such as obesity, hypertension, diabetic nephropathy, or carotid atherosclerosis. Detailed characteristics of the included studies are summarized in Table 1, and all available data were incorporated into the pooled analyses.

Figure 2 PRISMA flow diagram for study selection. CNKI: China National Knowledge Infrastructure; VIP: VIP Chinese Science Journals Database.

Table 1 Baseline characteristics of the included studies, mean ± SD.

Ref.	Country	Study design	Age (years) T2DM/control	CTRP12/adipolin assay	Sample size (T2DM/control)	CTRP12 concentration (T2DM)	CTRP12 concentration (control)	Unit
Ameer et al[15], 2021	Iraq	Case-control study	35-60	ELISA	72 (54/18)	1.32 ± 0.48	1.64 ± 0.73	ng/mL
Bai et al[16], 2017	China	Cross-sectional study	51 ± 11.85/49 ± 11.11	ELISA	262 (124/138)	0.446.8 ± 87.92	808.5 ± 102.66	pg/mL
Liu et al[17], 2025	China	Case-control study	65.67 ± 3.29/66.02 ± 3.34	ELISA	278 (139/139)	2.7 ± 0.79	4.03 ± 1.14	ng/mL
Du et al[13], 2020	China	Case-control study	55.79 ± 10.06/49.32 ± 8.3	ELISA	169 (115/54)	424.14 ± 211.35	555.83 ± 244.23	pg/mL
Guo et al[18], 2021	China	Cross-sectional study	54.66 ± 9.61/52.73 ± 9.94	ELISA	231 (161/70)	2.36 ± 1.2	3.97 ± 1.22	ng/mL
Han et al[19], 2020	China	Case-control study	54 ± 7.42/51 ± 8.0	ELISA	83 (56/27)	392.3 ± 150.57	660.53 ± 160.51	pg/mL
Gorgani-Firuzjaee and Khodabandehloo[20], 2020	Iran	Case-control study	55.95 ± 1.97/46.44 ± 1.25	ELISA	60 (30/30)	167.36 ± 33	391.96 ± 91	pg/mL
Ligade et al[21], 2023	India	Cross-sectional study	20-50	ELISA	30 (20/10)	5.91 ± 4.36	7.68 ± 6.5	ng/mL
Yang et al[22], 2025	China	Case-control study	54.35 ± 8.07/54.54 ± 8.27	ELISA	196 (156/40)	2.68 ± 0.89	4.18 ± 1.14	ng/mL
Zhang and Huang[23], 2025	China	Case-control study	-	ELISA	250 (200/50)	2.17 ± 0.99	4.13 ± 1.25	ng/mL
Liu et al[24], 2025	China	Case-control study	-	ELISA	174 (116/58)	0.52 ± 0.13	0.91 ± 0.13	ng/mL
Sun et al[25], 2024	China	Case-control study	66.04 ± 3.91/66.11 ± 3.82	ELISA	298 (198/100)	478.58 ± 155.45	717.89 ± 244.4	pg/mL
Liu et al[26], 2019	China	Case-control study	47.29 ± 12.82/45.23 ± 13.23	ELISA	90 (60/30)	4.12 ± 1.45	6.84 ± 1.09	ng/mL

T2DM: Type 2 diabetes mellitus; CTRP12: C1q/TNF-related protein 12; ELISA: Enzyme-linked immunosorbent assay.

Quality assessment

Methodological quality was evaluated for all included studies using the NOS, with detailed scores presented in Table 2. Among the 13 eligible studies, NOS scores ranged from 5 to 9. Most studies received relatively high NOS scores, indicating generally good methodological quality. No study was identified as having a critically low score. Overall, the included evidence demonstrated acceptable methodological rigor, supporting the reliability of the pooled results.

Table 2 Quality assessment of included studies using the Newcastle-Ottawa Scale.

Ref.	Selection (max 4)	Comparability (max 2)	Outcome (max 3)	Total score (0-9)
Ameer et al[15], 2021	2	2	1	5
Bai et al[16], 2017	3	2	2	7
Liu et al[17], 2025	2	1	3	6
Du et al[13], 2020	4	2	2	8
Guo et al[18], 2021	4	2	2	8
Han et al[19], 2020	3	2	2	7
Gorgani-Firuzjaee and Khodabandehloo[20], 2020	3	2	3	8
Ligade et al[21], 2023	4	1	3	8
Yang et al[22], 2025	4	2	3	9
Zhang and Huang[23], 2025	4	2	2	8
Liu et al[24], 2025	4	2	3	9
Sun et al[25], 2024	3	2	3	8
Liu et al[26], 2019	3	2	2	7

Circulating levels of CTRP12

Across the included studies, pooled estimates demonstrated that individuals with T2DM exhibited markedly reduced circulating CTRP12 concentrations compared with healthy controls (Z = 6.96, P < 0.00001; Figure 3). Considerable heterogeneity was observed among studies (I² = 95%, P < 0.00001), warranting the use of a random-effects model for synthesis. To assess the stability of the summary estimate, a leave-one-out analysis was performed. Sequential removal of each study produced no meaningful change in the direction or magnitude of the pooled effect, indicating that the overall findings were robust (Figure 4).

Figure 3 Meta-analysis of circulating C1q/TNF-related protein 12 levels in patients with type 2 diabetes mellitus compared with those of healthy controls. The forest plot showed the pooled standardized mean difference in circulating C1q/TNF-related protein 12 levels between patients with type 2 diabetes mellitus and healthy controls. Negative values indicated lower C1q/TNF-related protein 12 levels in patients with type 2 diabetes mellitus than those in healthy individuals. CI: Confidence interval.

Figure 4 Sensitivity analysis using standardized mean difference. Each point represents the pooled standardized mean difference after sequential exclusion of one study. Horizontal lines indicate the corresponding 95% confidence intervals. The vertical dashed line represents the overall pooled standardized mean difference including all studies. The minimal change in effect estimates across exclusions suggests that the overall result is robust and not driven by any single study. CI: Confidence interval.

Subgroup analysis

Given the presence of marked heterogeneity, relevant clinical and metabolic variables were extracted from the included studies, and subgroup analyses were conducted to explore potential sources of heterogeneity (Table 3).

Table 3 The results of subgroup analysis.

Subgroup	Number of comparisons	Participants	SMD (95%CI)	Z value	P value	Test of heterogeneity
						I2 (%)	P value
Overall	13	2193	-1.73 (-2.22 to -1.25)	-	-	-	-
FBG	10	1813				0	0.65
7.0-10.0 mmol/L	8	1640	-2.05 (-2.76 to -1.35)	5.7	< 0.00001	97	< 0.00001
> 10.0 mmol/L	2	173	-1.87 (-2.24 to 1.49)	9.74	< 0.00001	0	0.46
FINS	8	1346	-	-	-	0	0.71
≤ 10 μU/mL	4	826	-2.17 (-3.24 to -1.10)	3.99	< 0.00001	97	< 0.00001
> 10 μU/mL	4	520	-2.42 (-3.21 to -1.63)	6.01	< 0.00001	90	< 0.00001
HOMA-IR	9	1644	-	-	-	78.5	0.03
≥ 3.0	7	1330	-2.37 (-3.10 to -1.64)	6.35	< 0.00001	96	< 0.00001
< 3.0	2	314	-1.47 (-1.84 to 1.10)	7.78	< 0.00001	38	0.21
HbA1c	10	1581	-	-	-	0	0.56
< 8.0%	4	619	-1.50 (-2.18 to -0.82)	4.31	< 0.00001	90	< 0.00001
≥ 8.0%	6	962	-1.79 (-2.45 to -1.12)	5.26	< 0.00001	94	< 0.00001
Age	9	1667	-	-	-	7.2	0.3
≤ 55	5	862	-2.08 (-2.99 to -1.17)	4.48	< 0.00001	96	< 0.00001
> 55	4	805	-1.50 (-2.12 to -0.87)	4.69	< 0.00001	93	< 0.00001
BMI	10	1813	-	-	-	91.6	< 0.00001
Normal	1	298	-1.26 (-1.52 to -1.00)	9.44	< 0.00001	-	-
Overweight	8	1455	-1.98 (-2.68 to -1.27)	5.5	< 0.00001	96	< 0.00001
Obese	1	60	-3.24 (-4.02 to -2.45)	8.09	-	-	-
TG	10	1813	-	-	-	60.6	0.11
< 1.7 mmol/L	3	632	-2.77 (-4.08 to -1.47)	4.16	< 0.00001	97	< 0.00001
≥ 1.7 mmol/L	7	1181	-1.65 (-2.11 to -1.19)	7.01	< 0.00001	90	< 0.00001
TC	10	1813	-	-	-	0	0.39
< 5.2 mmol/L	7	1172	-2.20 (-2.88 to -1.51)	6.30	< 0.00001	94	< 0.00001
≥ 5.2 mmol/L	3	641	-1.60 (-2.77 to -0.43)	2.68	< 0.00001	97	< 0.00001
LDL-C	9	1723	-	-	-	0	0.69
< 3 mmol/L	5	820	-1.85 (-2.30 to -1.41)	8.17	< 0.00001	81	< 0.00001
≥ 3 mmol/L	4	903	-2.14 (-3.51 to -0.77)	3.06	< 0.00001	98	0.002
HDL-C	10	1813	-	-	-	62	0.10
< 1.0 mmol/L	2	381	-1.43 (-1.88 to -0.99)	6.30	< 0.00001	59	< 0.00001
≥ 1.0 mmol/L	8	1432	-2.15 (-2.90 to -1.41)	5.65	< 0.00001	96	< 0.00001
Year	13	2193	-	-	-	71.7	0.06
≤ 2020	6	838	-2.38 (-3.49 to -1.26)	4.18	< 0.00001	97	< 0.00001
> 2020	7	1355	-1.27 (-1.55 to -0.99)	8.95	< 0.00001	76	< 0.00001
Race	13	2193	-	-	-	0	0.61
Chinese	10	2031	-1.84 (-2.36 to -1.31)	6.82	< 0.00001	95	< 0.00001
Non-Chinese	3	162	-1.37 (-3.06 to -0.32)	1.59	0.11	94	< 0.00001

SMD: Standardized mean difference; CI: Confidence interval; FPG: Fasting plasma glucose; FINS: Fasting insulin; HOMA-IR: Homeostatic model assessment-insulin resistance; HbA1c: Hemoglobin a1c; BMI: Body mass index; TG: Triglycerides; TC: Total cholesterol; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol.

Study and population characteristics

Subgroup analyses based on publication year, BMI, age, and population ethnicity were performed. The results indicated that publication year (P = 0.06), age (P = 0.3), and ethnicity (P = 0.61) were not significant sources of heterogeneity. BMI (P < 0.00001) was identified as a potential contributor to heterogeneity. However, because only one study was included in both the normal-weight group and the obesity group, reliable assessment of within-group heterogeneity was not feasible. These results should therefore be interpreted with caution.

Glycemic parameters

Subgroup analyses were further conducted according to fasting blood glucose, fasting insulin concentration, and glycated hemoglobin levels. The findings showed that fasting blood glucose (P = 0.65), fasting insulin concentration (P = 0.71), and glycated hemoglobin (P = 0.56) were not major contributors to heterogeneity. In contrast, the homeostasis model assessment of insulin resistance (P = 0.03) was identified as a possible key source of heterogeneity.

Lipid parameters

Lipid-related parameters, including total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, were extracted and subgroup analyses conducted based on clinically abnormal values. The results showed that total cholesterol (P = 0.39), triglycerides (P = 0.11), high-density lipoprotein cholesterol (P = 0.10), and low-density lipoprotein cholesterol (P = 0.69) were not major sources of heterogeneity.

Publication bias

Potential publication bias was evaluated by visual inspection of the funnel plot, which did not show obvious asymmetry (Figure 5). This observation was supported by statistical tests, as Egger’s regression test was not significant (t = -0.95, P = 0.428), and Begg’s test also yielded a non-significant result (Z = 0.79, P = 0.364). Collectively, these findings suggest a low likelihood of publication bias affecting the pooled estimates.

Figure 5 Funnel plot for assessment of publication bias. The distribution of studies was largely symmetrical, indicating no obvious publication bias in this meta-analysis. SMD: Standardized mean difference.

DISCUSSION

This meta-analysis demonstrated that circulating CTRP12 levels were significantly reduced in patients with T2DM compared with those in healthy controls. Subgroup analyses further suggested that BMI and the insulin resistance index were the main sources of heterogeneity. These findings are generally consistent with accumulating evidence from experimental and clinical studies indicating that CTRP12 functions as an insulin-sensitizing adipokine and plays an important role in glucose homeostasis and metabolic regulation. Previous studies have reported that CTRP12 expression is decreased under obese or insulin-resistant conditions and is associated with impaired insulin signaling and chronic inflammation[12]. Although most clinical studies investigating circulating CTRP12 levels in patients with T2DM have reported a decreasing trend, the available evidence remains inconsistent because of limited sample sizes and heterogeneity in study design. By quantitatively synthesizing existing evidence, this meta-analysis provides a more robust assessment of the association between circulating CTRP12 levels and T2DM, thereby supplementing and strengthening current knowledge.

CTRP12 is an adipokine secreted predominantly by adipocytes and plays an important regulatory role in the maintenance of glucose and lipid metabolic homeostasis[27]. The results of our meta-analysis further suggest that CTRP12 may have important metabolic regulatory implications in the development and progression of T2DM. From a mechanistic perspective, accumulating experimental evidence indicates that CTRP12 exerts glucose-lowering effects through multiple insulin-sensitizing mechanisms. These mechanisms include enhancement of insulin signaling, suppression of hepatic gluconeogenesis, and attenuation of inflammatory responses, which together promote glucose uptake and utilization[28]. In adipocytes, CTRP12 has been shown to activate the phosphoinositide 3-kinase/protein kinase B signaling pathway[12], which promotes glucose transporter translocation[29,30] and thereby enhances glucose uptake. In the liver, CTRP12 is suggested to signal through adiponectin receptors[31], leading to activation of the downstream adenosine monophosphate-activated protein kinase pathway[32]. Activation of this pathway suppresses the expression of forkhead box protein O1 and its downstream gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, thereby inhibiting hepatic gluconeogenesis[33,34]. In addition, CTRP12 has been shown to improve hepatic insulin sensitivity and facilitate glucose utilization in experimental models[12]. Animal studies further demonstrate that exogenous administration of CTRP12 ameliorates inflammatory infiltration in adipose tissue and promotes glucose utilization by adipocytes in diabetic mice[35]. CTRP12 may also indirectly enhance skeletal muscle insulin responsiveness by improving systemic insulin resistance, thereby promoting glucose uptake and utilization in peripheral tissues[12].

Taken together, these findings suggest that the reduction in circulating CTRP12 levels observed clinically may reflect impaired adipose-derived insulin sensitization, which contributes to systemic insulin resistance and dysregulated glucose metabolism in T2DM. From a translational perspective, CTRP12 may serve not only as a biomarker reflecting adipose tissue dysfunction and insulin resistance, but also as a potential therapeutic target for metabolic diseases. Exogenous supplementation of CTRP12 protein may therefore represent a novel and promising therapeutic approach for patients with diabetes. The molecular mechanisms underlying these effects are summarized schematically in Figure 6.

Figure 6 Mechanisms underlying the glucose-lowering effects of C1q/TNF-related protein 12. Akt: Protein kinase B; PI3K: Phosphoinositide 3-kinase; FOXO1: Forkhead box protein O1; PEPCK: Phosphoenolpyruvate carboxykinase; G6Pase: Glucose-6-phosphatase; AMPK: Adenosine monophosphate-activated protein kinase; CTRP12: C1q/TNF-related protein 12; GLUT4: Glucose transporter type 4.

Due to the high degree of heterogeneity in the data, subgroup analyses were performed to explore the influence of different factors on CTRP12 levels. The results indicated that publication year was not a source of heterogeneity. As an adipokine, CTRP12 may be associated with obesity, and previous studies have shown that obesity disrupts the production of adipocyte-derived cytokines and promotes the progression of disorders related to dysregulated lipid metabolism[36]. The findings of the current study suggest that circulating CTRP12 levels may be independently associated with factors such as BMI. This observation supports the possibility of a link between adiposity-related adipose dysfunction and reduced CTRP12 expression. However, because of the limited number of studies within each BMI subgroup, these results should be interpreted with caution. In addition, subgroup analyses indicated that age and ethnicity were not major sources of heterogeneity. Nevertheless, age may still influence CTRP12 expression to some extent. Insulin sensitivity declines with aging, and adipose tissue function gradually deteriorates, changes that may affect the secretion of adipokines, including members of the CTRP family[37]. Older individuals often exhibit chronic low-grade inflammation[38], which may further suppress CTRP12 synthesis and secretion. Direct evidence systematically evaluating the associations of age and ethnicity with CTRP12 expression remains limited, and future multicenter studies with large sample sizes are therefore needed to verify these assumptions.

Insulin resistance and reduced insulin sensitivity are central pathological mechanisms underlying the onset and progression of T2DM. Insulin resistance refers to diminished responsiveness to insulin, resulting in impaired glucose uptake and utilization. Reduced insulin sensitivity also prevents effective regulation of glucose homeostasis, ultimately leading to persistent hyperglycemia[39]. CTRP12 has been shown to improve insulin resistance[12], and our subgroup analysis identified homeostasis model assessment of insulin resistance as a major source of heterogeneity. In contrast, fasting insulin, fasting blood glucose, and glycated hemoglobin did not significantly contribute to heterogeneity. These findings suggest that changes in circulating CTRP12 levels may more directly reflect insulin resistance rather than glycemic control or insulin secretion. Previous animal studies demonstrated that CTRP12 activates adenosine monophosphate-activated protein kinase to improve insulin signaling, thereby reducing gluconeogenesis and enhancing glucose uptake[10]. In vitro studies using cultured hepatocytes and adipocytes further showed that CTRP12 improves insulin resistance through activation of the protein kinase B signaling pathway[12]. In addition, experimentally induced hyperinsulinemia has been shown to significantly increase circulating CTRP12 levels in healthy lean individuals[40]. Collectively, these findings indicate that reduced circulating CTRP12 levels may preferentially reflect insulin resistance rather than glycemic control, highlighting its potential role as a biomarker of metabolic dysfunction.

As a key adipokine, CTRP12 participates not only in the regulation of glucose metabolism but also in lipid metabolism, particularly hepatic lipid metabolism. Early studies reported that exogenous CTRP12 improved dyslipidemia in obese mice[35]. Subsequent work by Tan et al[32] demonstrated that CTRP12-deficient mice exhibit increased hepatic lipid accumulation, reduced fatty acid oxidation, and diminished energy expenditure, particularly under high-fat diet conditions. In hepatocytes, CTRP12 suppresses triglyceride synthesis and reduces secretion of very low-density lipoprotein, thereby modulating hepatic lipid metabolism and lowering postprandial triglyceride levels[41]. These findings suggest that CTRP12 may be associated with lipid abnormalities. Accordingly, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were analyzed in subgroup analyses. The results showed that total cholesterol, triglycerides, and high-density lipoprotein cholesterol were not major sources of heterogeneity, indicating that changes in CTRP12 levels may not be directly influenced by lipid fluctuations. These findings further support the important role of CTRP12 in lipid regulation. Future large-sample, multicenter clinical studies and mechanistic investigations are therefore required to clarify the causal relationships and metabolic pathways linking CTRP12 to lipid metabolism.

Limitations

This article has several methodological constraints that should be considered when interpreting the findings. First, all included investigations were observational cohort studies, and the overall sample size was modest. These limitations may reduce the precision of the pooled estimates, as smaller datasets are inherently more sensitive to random variation and individual heterogeneity. In addition, most of the included studies were conducted in Chinese populations, which may limit the generalizability of the findings to other ethnic groups and geographic regions. Differences in genetic background, lifestyle, and environmental exposures across populations may also have influenced the observed associations. Therefore, future large-scale studies involving multi-ethnic and multi-regional populations are needed to validate and extend these results. Another limitation relates to data reporting in two studies, in which outcomes were presented as medians with interquartile ranges. Although these values were converted to means and standard deviations using established statistical methods to enable data synthesis, this transformation may introduce estimation bias. Moreover, the relatively small number of eligible studies may restrict a comprehensive evaluation of the association between CTRP12 and T2DM. Future research would benefit from larger, multicenter cohorts with prospective designs, which would help confirm the present findings and enhance their external validity.

CONCLUSION

This study demonstrates that circulating CTRP12 levels are significantly reduced in patients with T2DM compared with healthy controls. This reduction is closely associated with the degree of insulin resistance. These findings suggest that CTRP12 may play an important role in the regulation of lipid and energy metabolism by exerting protective effects during the development of glucose and lipid metabolic disorders. Future large-sample prospective clinical studies and mechanistic investigations are required to clarify the causal relationships and metabolic pathways linking CTRP12 to lipid metabolism and the pathogenesis of T2DM. Such studies may provide novel biological targets for the early identification and intervention of metabolic diseases.