The Investigation of the Mediator Effect of C-peptide in the Relationship Between PC/HDL and MAFLD-a cross-sectional study in adult patients with type 2 diabetes

doi:10.21203/rs.3.rs-3967086/v1

Background:

This study aimed to examine the ratio of platelet counts to high-density lipoprotein‐cholesterol ratio (PC/HDL) and its association with metabolic-associated fatty liver disease (MAFLD) among type 2 diabetes mellitus (T2DM) patients. To figure out the role played by the area under the C-peptide curve (AUCCP) in the influence of PC/HDL on MAFLD.

Methods:

A total of 2687 patients with type 2 diabetes who were hospitalized in the Department of Endocrinology at Hebei General Hospital between January 2021 and January 2022 were enrolled.Demographic data was collected and all patients went through biochemical indicators and other routine blood examinations.Multivariate logistic regression model was performed to examine the association between PC/HDL, AUCCP and MAFLD with adjustments for confounders.Mediation effects were used to explore whether AUCCP mediated the association between PC/HDL and MAFLD.

Results:

The prevalence of MAFLD was 38.0% (n = 2687).The MAFLD group had a higher level of PC/HDL than the non-MAFLD group.After adjusting for confounding factors, multivariate logistic regression analysis revealed that PC/HDL was a risk factor for MAFLD.Mediational analysis showed that effect of PC/HDL on MAFLD was mediated by AUCCP.Subgroup analysis and interaction analysis suggested that the positive correlation between PC/HDL and the prevalence of MAFLD was more significant in women with T2DM, while the interaction was not significant in other subgroups.

Conclusion:

PC/HDL was positively associated with MAFLD incidence, and AUCCP partly mediated the association in T2DM patients. Moreover, the correlation between PC/HDL and MAFLD was more significant in women.

type 2 diabetes mellitus

metabolic-associated fatty liver disease

platelet counts

high-density lipoprotein‐cholesterol

C-peptide

Diabetes mellitus (DM) was a metabolic disease caused by glucose metabolism disorders.DM was one of the most common chronic diseases worldwide. he International Diabetes Federation estimated that, globally, 463 million people were living with diabetes in 2019, and this number is predicted to attain 700 million by 2045 (1). The incidence of non-alcoholic fatty liver disease (NAFLD) has clearly increased particularly in patients with type 2 diabetes mellitus (T2DM) (2). Studies have shown that about 60–70% of patients with T2DM have NAFLD (3). NAFLD has recently been proposed to rename metabolic-associated fatty liver disease (MAFLD).MAFLD was defined as the storage of lipids, in subjects who do not drink significant amounts of alcohol and in whom other known causes of steatosis, such as certain toxins and drugs, have been excluded. MAFLD was more closely related with metabolic disorder, and unhealthy lifestyle(4, 5). Patients with MAFLD were diagnosed with a definite criterion instead of exclusion conditions, which is distinguished from NAFLD(6). Recent studies have shown that the T2DM patients diagnosed with MAFLD have a greater risk of DM-related macrovascular and microvascular complications than those without MAFLD(7). MAFLD may progress to non-alcoholic steatohepatitis (NASH) and predisposes patients to cirrhosis and hepatocellular carcinoma (HCC)(8). MAFLD was associated with an increased risk of mortality(9), and cardiovascular diseases in T2DM patients(10). Considering all these aspects, coupled with the increased incidence of MAFLD and T2DM, it is possible to understand that those two diseases are critical public health issues around the world, with a significant health, social, and financial burden on society.Platelet count (PC) was also gaining attention in some research on MAFLD,which could reflect the function of platelets and was readily available in clinical practice (11). It should be emphasized that haematological indicators were often very fast and cost-effective testing methods. Platelets were the paramount element of hemostasis and also contribute to a variety of other normal and pathological processes, including thrombosis, inflammation, and immune responses. Platelet activation represented a serious risk for individuals with cardiovascular and cerebrovascular diseases (12). It was well known that PC reflected the entire activity that released cytokines and promoted thrombosis (13). Platelet activation was described as a hallmark feature in inflammatory diseases, auto-immune diseases, and a wide range of chronic diseases. Some of the main scoring systems for liver fibrosis that have been implemented in clinical practice include the NAFLD fibrosis score(14), the aspartate aminotransferase-to-platelet ratio index (APRI) (15), and fibrosis-4 (FIB-4) score(16). These blood-based noninvasive fibrosis scoring systems included PC as one of their variables, which highlights the potential role of PC in liver injury. It was reported that the population with moderate to severe NAFLD had a higher level of PC than the mild NAFLD population(17). Some studies have also shown a lower level of high-density lipoprotein cholesterol (HDL-C) in the NAFLD population(18). In addition, low HDL-C levels were caused by physical inactivity and obesity, both of which were risk factors for NAFLD. Souza et al indicated that low HDL-C level was a risk factor for NAFLD (19). Despite being closely related, no studies have elucidated the relationship between PC/HDL and MAFLD in T2DM patients. Recently, JialalI et al found that platelet counts to HDL-C ratio (PC/HDL) was an effective biomarker for predicting metabolic syndrome (MS) (20). C-peptide can be used to represent endogenous insulin secretion from pancreatic β-islet cells and insulin resistance (IR)(21). Liao et al. reported c-peptide might act not only as an independent risk factor for NAFLD but also as an important indicator for screening, monitoring, and measuring the severity of IR in NAFLD(22). Studies have demonstrated that fasting c-peptide level (FCP) concentration was particularly associated with NAFLD (23). C-peptide and the area under the curve of C-peptide (AUCCP) could reflect the secretion ability of islet βcell, while the latter is a better indicator of overall and residual islet β-cell secretion compared to FCP. Therefore, the present study was undertaken to evaluate the association of PC/HDL and MAFLD among T2DM patients, and explore the association between PC/HDL, AUCCP, and MAFLD.

Study population

This retrospective cross-sectional study enrolled T2DM patients who were hospitalized in the Department of Endocrinology of Hebei General Hospital from January 2019 to June 2022.The current study was approved by the Ethics Committee of Hebei General Hospital Ethics Committee (approval number: 2022157). Inclusion criteria were as follows: 1) Age ≥ 18 years; 2) Diagnosis of T2DM(24). The exclusion criteria were as following: patients with type 1 diabetes mellitus, gestational diabetes, other special type diabetes, active infection, severe liver and kidney insufficiency, malignant tumor, a history of myocardial infarction, a history of cerebral hemorrhage, a history of liver surgery .Patients with a recent history of major bleeding,currently receiving aspirin or another anti-platelet treatment were excluded, or hematologic disorders affecting platelet count or function.

Study Methods

A standard questionnaire was administered by trained staff to collect demographics information and previous medical history from participants,including name, age, sex, duration of diabetes, smoking and drinking habits, disease history, family history and drug history. After sitting quietly for five minutes, certified nurses measured each participant’s seated blood pressure three times using digital automatic sphygmomanometer (Omron HEM-711, Kyoto, Japan) and averaged. Participants’ body heights and weights were measured in light clothes and barefoot.Anthropometric indices were measured twice and then averaged. Venous blood was collected through the elbow vein from participants who had fasted for at least 10 h (overnight fasting).Total red and white blood cell counts, hemoglobin were analyzed using an automatic hematological analyzer (Mindray BC-5800, Shenzhen, China). A Siemens ADVIA 2400 automatic biochemical analyzer (Siemens, Germany) was used to measure all biochemical indicators, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), albumin, serum creatinine (Cr), fasting blood glucose(FBG), serum uric acid(SUA), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). Hemoglobin A1c (HbA1c) was measured by high performance liquid chromatography with HLC-723G8 automated glycohemoglobin analyzer (Tosoh, Tokyo, Japan). Subjects ingested 75 g glucose, and blood samples were collected for C-peptide at 0, 15, 30, 60, 90, and 120 min.Serum C-peptide levels were detected by a chemiluminescence method using the Adiva Centaur XP immunoassay system (Siemens, Germany). All abdominal ultrasound examinations were performed by trained physicians.All patients fasted for 8 hours before imaging.The diagnosis of hepatic steatosis was made in the presence of two or three abnormal findings on abdominal ultrasonography: diffusely increased echogenicity (“bright”) liver with liver echogenicity greater than kidney, with vascular blurring and deep attenuation of ultrasound signal.

Hypertension was defined as systolic blood pressure (SPB) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, or previous diagnosis with hypertension. Fatty liver was diagnosed based on abdominal ultrasonography. The diagnosis of MAFLD was based on the presence of hepatic steatosis (diagnosed by ultrasound) as well as the presence of one or more of the following symptoms: overweight/obesity (defined as having BMI ≥ 23 kg/m 2 ); presence of T2DM; or evidence of metabolic dysregulation(25).

The area under the curve (AUC) of C-peptide during the OGTT was calculated according to the trapezoid method.Body mass index (BMI, kg/m2) was calculated as weight (kg) divided by height (m) squared.The PC/HDL ratio was calculated as PC (×10^9/L) divided by HDL-C ratio (mmol/L).

Statistical Method

Continuous variables following normal or non-normal distribution are expressed as mean (± standard deviation) or median (interquartile range), respectively.Differences in continuous variables between the 2 groups were analyzed by Student t-test or Mann Whitney U test.Categorical variables were displayed as numbers with percentages and compared by the chisquare test or the Fisher exact test.The correlations between PC/HDL and different variables were analyzed by Pearson correlation test or Spearman rank correlation test. Multivariable logistic regression model(ModelⅠ-Ⅲ ) was built for MAFLD-risk assessment. Results of the logistic regression analysis were expressed as odds ratio (OR) and 95% confidence interval (CI) Mediation model to explore whether AUCCP mediates any associations of PC/HDL with MAFLD. We further stratified analyses according to sex, age, BMI, hypertension, family history, HbA1c,smoking and drinking status to identify the consistency of the effect of PC/HDL on MAFLD. The model used in stratified analyses was adjusted for all variables in Model Ⅲ except the corresponding stratification variable.Furthermore,the likelihood ratio test was conducted to evaluate the interaction among subgroups. SPSS Statistics Version 25.0 (SPSS, Inc., Chicago, IL, USA) was used to perform all statistical analyses.Two-tailed p values less than 0.05 were regarded as statistically significant.

1.Clinical characteristics of T2DM patients with MAFLD

Among the 2687 T2DM patients eligible for our analysis, 1463 (54.45%) patients had MADLD (Figure 1). The clinical characteristics of the T2DM patients with MAFLD, non-MAFLD are shown in Table 1 . The mean age of all participants was 62 years; 57.1% were male. The MAFLD patients were younger, had a higher proportion of smoking and drinking, had shorter T2DM duration and had more hypertension conditions compared with the patients without MAFLD.Patients with MAFLD had higher BMI, WBC, RBC, HGB, PC, ALB, ALT, AST, GGT, FPG, UA, eGFR, TC, TG, HbA1c, nonHDL-C levels and a lower level of HDL-C than patients without MAFLD(all P<0.05). It is particularly worth mentioning that T2DM patients with MAFLD had significantly higher PC/HDL levels{214.5694 (168.254, 266.6667) vs 193.8462 (146.407, 252.3587);P<0.001} and AUCCP {14.6425 (10.705, 20.0088) vs 10.6987 (7.2294, 17.3394);P<0.001)} levels than patients without MAFLD.

2.Clinical characteristics of T2DM patients by PC/HDL index

T2DM Patients were divided into high- or low-level group by the median value of PC/HDL index.Table 2 summarizes the baseline characteristics of the patients grouped by the PC/HDL index.The prevalence of MAFLD in high-PC/HDL and low-PC/HDL groups were 60.7% and 48.5%, respectively, and the difference is statistically significant.This implies a higher prevalence of MAFLD in those with a higher PC/HDL index. The patients in the high PC/HDL group were significantly younger and had higher ratio of males,shorter T2DM duration， higher BMI,WBC, RBC, GGT, FPG, UA, eGFR, TG, nonHDL-C, HbA1c, AUCCP, and lower ALB, AST, Cr, HDL-C than those in the low PC/HDL group(all P ＜0.05). Otherwise, there were no statistically significant differences between the two groups regarding prevalence of hypertension， family history ， smoking and drinking.

3. The correlation between PC/HDL and the potential risk factors of MAFLD

As shown in Figure 2, spearman correlation analysis revealed that PC/HDL was negatively correlated with age, course, AST, Cr, ALB and positively correlated with BMI, WBC, RBC, GGT, FPG, HbA1c, UA, eGFR, TG, nonHDL-C,AUCCP in all T2DM patients.

PC/HDL was positively correlated with WBC, RBC, FPG, HbA1c, UA, eGFR, TG, nonHDL-C,AUCCP, while negatively correlated with age,course and Cr in T2DM patients with MAFLD.

4. The correlation between PC/HDL and MAFLD prevalence

To explore further the association between PC/HDL and MAFLD, we built multivariate logistic regression models ( Table 3 ).A significantly positive association was found between PC/HDL and the prevalence of MAFLD in the crude model (OR:1.645,95%CI:1.405-1.927, P<0.001) and after additional adjustment for age, sex, BMI, smoking, drinking, family history,course, hypertention (model 2;OR:1.748,95% CI:11.3-2.352,P<0.001).In addition, after further adjustment for WBC, RBC, HGB, ALB, AST/ALT, GGT, TG, HbA1c, nonHDL-C, UA, Cr, FPG, eGFR (Model 3;OR:1.874，95%CI: 1.334-2.632,P<0.001), a positive association with MAFLD remained.

5. Correlation between PC/HDL and AUCCP

Table4 shows the correlation between PC/HDL and AUCCP.After adjusting for potential confounders (age, sex, BMI, smoking,drinking, family history, duration of T2DM, hypertention, WBC, RBC, HGB, ALB, AST/ALT, GGT, TG, HbA1c, nonHDL-C, UA, Cr, FPG, eGFR), PC/HDL was significantly and positively associated with AUCCP.

6. Correlation between AUCCP and MAFLD prevalence

The AUCCP was positively associated with the prevalence of MAFLD without adjustment for confounding factors(OR:2.137,95%CI:1.533-2.978, P<0.001).This association remained significant after adjustment for additional confounders (model 2 ；OR: 3.241,95%CI: 1.882-5.581, P<0.001and model 3 ；OR: 4.498,95%CI:2.126-9.518, P<0.001).

7. AUCCP-mediated effect

To analyze the role of AUCCP as a possible mediator between the PC/HDLand MAFLD, a mediational model was constructed.The mediation analysis revealed that there was a significant indirect effect of the AUCCP on the relationship between the PC/HDL and MAFLD(b =0.022,95% CI: 0.001–0.043).The results suggest that AUCCP partially mediated the relationship between PC/HDL and MAFLD，the proportion mediated was 36.36%（Figure 3）.

8. Subgroup analyses and interaction analyses evaluating MAFLDL of PC/HDL in various stratifcations

To further investigate the impact of other risk factors on the correlation between PC/HDLand MAFLD, subgroup analyses were carried out according to age，sex，hypertension，family history，smoking，drinking，duration，BMI and HbA1c.Figure 4 summarizes the results of the subgroup analysis and the interaction results.There were significant additive interactions between PC/HDL and MAFLD risk in sex(P-value for interaction =0.033).We found relatively stronger associations between PC/HDL and risk of MAFLD among women than men.We did not find a significant interaction in the other subgroup analyses.

The present study confirms the high prevalence of MAFLD as a significant comorbidity in patients diagnosed with T2DM. In this study, the prevalence of T2DM patients with MAFLD was 54.45% which was similar to the findings of Efrem IC et al (26).Here we found that PC/HDL levels were higher in MAFLD participants versus non-MAFLD participants.Even after adjustment for several confounders the significant association remained.In line with our results, Okushin et al found that PC has a positive correlation and MAFLD prevalence(27).Xu C et al. has found that subjects with higher PC level were associated with higher incidence of NAFLD(28).Prior studies have shown that a lower HDL-C level is associated with an increased risk of NAFLD(29, 30).Further elucidating the moderating role between PC/HDL and MAFLD, we found that AUCCP partially mediated the relationship between PC/HDL and MAFLD.A study has shown that FCP is a robust marker of IR-induced NAFLD(31), we used AUCCP that could more accurately fit the insulin secretion from pancreatic β-cells.Ma C et al. showed that AUCCP was higher in patients with NAFLD, it significantly correlated with HOMA-IR(32).A higher AUCCP level, an IR marker, plays an important role in the occurrence and development of NAFLD(33).Meanwhile, PC is also independently associated with IR(34).Previous studies with adults showed an association of PC levels, even within the normal range, with IR(35).Furthermore, in a previous study, Taniguchi et al (36)reported that PC was independently associated with IR in T2DM patients.Ren et al. (37)found that HDL-C levels were positively associated with IR in the newly diagnosed T2DM patients.It has been well recognized that HDL-C has anti-atherogenic, anti-inflammatory, and anti-oxidant properties.HDL-C was associated with dyslipidemia and IR(38).Thus, associations between PC/HDL and MAFLD may be partly mediated through IR indicated by AUCCP.

Other mechanisms, in addition to the mechanism involving IR, may be involved.Evidence has accrued that PC was also a marker of inflammation(39).Platelet plays a crucial role in the inflammation and immunological reaction by recognizing the surface receptors of pathogen and immune complex formation.Platelet P-selectin then binds to constitutively expressed P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes, which promotes the formation of leukocyte-platelet aggregates and forms bridges between leukocytes and the endothelial cells(40, 41).The study conducted by Park JM et al. revealed a positive correlation between the quartiles of PC and the elevation of white blood cell count, which serves as an indicator of inflammation(42).Therefore, the role of PC, a key player in inflammatory has been being paid increasing attention(43).Thrombopoietin (Tpo), a glycoprotein primarily produced in the liver, is the major regulator of both megakaryopoiesis and platelet production in human body(44).Prior research has established a positive correlation between the level of thrombopoietin (TPO) and the severity of liver fibrosis as well as the impairment of hepatocyte function(44, 45), both of which contribute to the development of MAFLD(46).The dyslipidemia observed in MAFLD is distinguished by increased levels of TG, accompanied by decreased levels of HDL-C, which aligns with the findings of our study(47).Excessive lipid accumulation in hepatocytes is a hallmark of NAFLD.The excessive accumulation of lipids in hepatocytes exhibited a positive correlation with the secretion of inflammatory cytokines, oxidative stress, and the release of multiple cytokines(48).Additionally, an accumulation of surplus free fatty acids has the potential to generate fatty acyl-CoAs, which may subsequently undergo β-oxidation.The aforementioned oxidative stress and inflammation are potentially implicated in the etiology and advancement of MAFLD(49, 50).

In addition, there were some unexpected findings in our subgroup analyses.The results of the subgroup analysis showed a significant interaction between sex (male/female) and the risk of MAFLD. The association of PC/HDL with MAFLD was stronger in women.

The association between gender and the risk of NAFLD has consistently been found to be more pronounced among women compared to men, as evidenced by previous studies(51).The findings of the studies suggest a significant increase in the level of PC with the severity of hepatic steatosis. However, upon conducting a separate analysis based on gender, this association is observed solely among women(17).Saremi and colleagues discovered that the levels of PC were significantly elevated in female patients with MAFLD compared to female control subjects, while no such association was observed among males(52).Astrid et al (53)proposed that the modification of the adiponectin–AMPK–PAI-1 signaling cascade within the liver amplified the hepatic injury observed in female mice.The impact of gender on platelet biology was demonstrated in a study conducted several years ago(54), and more recent research has indicated that women exhibit a higher quantity of fibrinogen surface receptors and a greater capacity to bind fibrinogen(55).Furthermore, it has been established that estrogens have the ability to augment platelet production(56).These differences suggest that the molecular mechanisms underlying the pathophysiology of MAFLD may differ between men and women.Similar to our outcomes,Trojak A et al noted that MAFLD patients were younger in comparison to those without(57).In a study conducted by Yamane R et al, it was observed that the prevalence of MAFLD exhibited a significant decline with the progression of patient age in individuals with T2DM(58).The present study suggested that this finding may be attributed to the poor nutritional status.In our study, age was negatively correlated to BMI(r = − 0.133, P < 0.001, data not shown).BMI increase was associated with the onset of NAFLD, whereas BMI decrease was associated with NAFLD resolution, notably, in both obese and nonobese individuals(59),low BMI was associated with malnutrition(60).

The current study has some strengths.We identified a significant association between PC/HDL in T2DM and MAFLD, and to the best of our knowledge, this is the first investigation of such an association.We employed various statistical methods to investigate the internal relationship among PC/HDL, AUCCP, and MAFLD, thereby enhancing our comprehension of their interconnections.Our study is subject to some limitations.First, the diagnosis of MAFLD was based on ultrasonography and was not confirmed by a liver biopsy to determine hepatic steatosis and its severity.Furthermore, it is imperative to conduct longitudinal research in order to establish causal relationships, as the current study is limited to a cross-sectional design.Third, only one measurement of PC levels from a baseline examination was included in the analyses.Fourth, as the present study was performed only in Chinese population, our findings need to be confirmed in other regions and ethnicities.Finally, despite adjustment for several variables, there is still potential for confounding by other unknown factors.

In the present study, a noteworthy correlation was identified between PC/HDL and MAFLD in individuals diagnosed with T2DM. Additionally, the association was found to be partially mediated by AUCCP. Furthermore, this correlation exhibited greater significance in female participants. Consequently, PC/HDL may serve as a practical and straightforward indicator for the identification of MAFLD in T2DM patients during future clinical practice.

DM Diabetes mellitus

NAFLD non-alcoholic fatty liver disease

T2DM type 2 diabetes mellitus

MAFLD metabolic-associated fatty liver disease

NASH n-alcoholic steatohepatitis

HCC hepatocellular carcinoma

PC Platelet count

HDL-C high-density lipoprotein cholesterol

PC/HDL platelet counts to HDL-C ratio

IR insulin resistance

FCP fasting c-peptide level

AST aspartate aminotransferase

ALT alanine aminotransferase

GGT gamma-glutamyl transferase

Cr albumin, serum creatinine

FBG fasting blood glucose

SUA serum uric acid

TC total cholesterol

TG triglyceride

HbA1c Hemoglobin A1c

SPB systolic blood pressure

DBP diastolic blood pressure

Ethics approval and consent to participate

The current study was approved by the Ethics Committee of Hebei General Hospital Ethics Committee (approval number: 2022157).

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the first author on reasonable request.

Competing interests

The authors have no conflicts of interest.

Funding

This study was supported by Central Committee Guides Local Science and Technology Development Project (No. 226Z7721G).

Authors’ contributions

Yuling Xing conceived the study. Yuling Xing designed the study. Yuling Xing analyzed the data and drafted the manuscript. Jing Liu,Jinhu Chen and Xiaoyu Hou assisted with the research and polished the manuscript. Xiaoyu Hou and Yu Gao evaluated the imaging results.Huijuan Ma reviewed and approved the paper. The authors read and approved the final manuscript.

Acknowledgements

Not applicable

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Table1 Baseline clinical characteristics of T2DM patients with and without MAFLD

	All patients	With NAFLD patients	Without NAFLD patients	P
	2687	1463	1224
age	62(52,69)	62(50,68)	64(56,71)	<0.001
BMI	25.87(23.46,28.07)	27.015(25,29.3)	24.22(22.055,26.455)	<0.001
course	10(3,17)	8(2,15)	10(4,20)	<0.001
Sex(men)	1534(57.10%)	846(57.8%)	688(56.2%)	0.417
Smoking	774(28.8%)	464(31.7%)	312(25.5%)	0.004
Drinking	578(21.5%)	364(24.9%)	217(17.7%)	<0.001
Family history	892(33.2%)	512(35.00%)	381(31.10%)	0.169
hypertention	1459(54.3%)	847(57.90%)	612(50.00%)	<0.001
WBC	6.31(5.31,7.65)	6.375(5.47,7.65)	6.17(5.15,7.6025)	0.023
RBC	4.61(4.21,5)	4.74(4.33,5.12)	4.475(4.05,4.8625)	<0.001
HGB	139(127,151)	142(131,154)	136(123,148)	<0.001
PLT	221(186,265)	224(188,270)	218(182,262)	0.012
ALB	40.7(37.86,43.4)	41.6(38.9,43.9)	39.9(37,43)	<0.001
ALT	17.7(13.2,25.5)	20.1(14.4,30.65)	15.8(11.9,22.1)	<0.001
AST	19.1(15.7,24)	19.7(16.2,25.1)	18.5(15.025,22.6)	<0.001
AST:ALT	1.05(0.85,1.31)	0.99(0.79,1.225)	1.15(0.935,1.41)	<0.001
GGT	23.8(16.9,36.7)	27.1(18.925,41.2)	20.45(14.9,30.125)	<0.001
FBG	8.065(6.25,10.9275)	8.24(6.315,10.88)	7.735(5.94,10.59)	0.003
Cr	70.7(61.3,82.1)	70.2(60.9,83.1)	70.3(60.8,82.1)	0.943
UA	295.6(238,359.6)	310.5(251.2,375.6)	284.33(222.15,338.95)	<0.001
eGFR	92.59(76.64,102.725)	93.9(78.505,104.33)	91.1(73.12,100.84)	<0.001
TC	4.62(3.78,5.47)	4.755(3.86,5.61)	4.4(3.675,5.225)	<0.001
TG	1.39(0.99,2.07)	1.61(1.14,2.4)	1.16(0.85,1.665)	<0.001
HDL-C	1.07(0.9,1.3)	1.03(0.88,1.23)	1.12(0.92,1.34)	<0.001
HbA1c	8.6(7.4,10.4)	8.7(7.5,10.4)	8.45(7.075,10.3)	<0.001
PC/HDL	206.4837(158.1933,259.8014)	214.5694(168.254,266.6667)	193.8462(146.407,252.3587)	<0.001
AUCCP	13.575(9.0694,19.1025)	14.6425(10.705,20.0088)	10.6987(7.2294,17.3394)	<0.001
nonHDL-C	3.5(2.66,4.29)	3.74(2.89,4.46)	3.31(2.57,4.01)	<0.001

Table 2 Baseline clinical characteristics of T2DM patients stratifed by PC/HDL

	Low PC/HDL	High PC/HDL	P
	1344	1343
age	65(59,71)	62(49,68)	<0.001
BMI	25.53(23.245,27.89)	26.13(23.88,28.4)	<0.001
course	10(4,19)	8(3,15)	<0.001
Sex	739(55.00%)	800(59.60%)	0.027
Smoking	358(26.60%)	414(30.80%)	0.068
Drinking	298(22.20%)	281(20.90%)	0.535
Family history	462(34.40%)	448(33.30%)	0.724
hypertention	738(54.90%)	740(55.10%)	0.895
WBC	5.79(4.88,6.93)	6.78(5.7375,8.24)	<0.001
RBC	4.52(4.15,4.92)	4.68(4.27,5.06)	<0.001
HGB	139(127,150)	140.5(127.75,152)	0.052
PLT	193(166,224)	257(217,295.25)	<0.001
ALB	41.1(38.5,43.6)	40.7(37.6,43.5)	0.003
ALT	17.5(13.4,24.6)	18.1(12.9,26.8)	0.448
AST	19.6(16.4,24.3)	18.5(14.9,23.45)	<0.001
AST:ALT	1.11(0.89,1.36)	1.01(0.8,1.25)	<0.001
GGT	22.2(16.2,34.9)	24.9(17.8,37.3)	<0.001
FBG	7.53(5.9075,10.22)	8.55(6.46,11.245)	<0.001
Cr	71(61.4,85.1)	69.6(60.5,80.4)	0.001
UA	281.3(223.3,343.2)	313(249.4,376.8)	<0.001
eGFR	89.17(70.4975,99.7425)	95.97(82.725,105.92)	<0.001
TC	4.62(3.69,5.6)	4.55(3.83,5.29)	0.191
TG	1.2(0.89,1.69)	1.62(1.125,2.43)	<0.001
HDL-C	1.24(1.06,1.47)	0.93(0.82,1.07)	<0.001
HbA1c	8.3(7.1,10)	8.9(7.525,10.6)	<0.001
PC/HDL	158.2524(127.1429,183.4951)	259.8039(231.1649,308.3584)	<0.001
AUCCP	12.7338(8.4288,17.4263)	14.2525(9.46,20.7313)	0.003
nonHDL-C	3.42(2.53,4.33)	3.61(2.8975,4.29)	<0.001
NAFLD	652(48.50%)	815(60.70%)	<0.001

Table 3 Logistic Regression Analysis of PC/HDL and AUCCP for MAFLD in T2DM Patients

Outcomes	Model I		Model II		Model III
	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P
PLT/HDL
low	Ref		Ref		Ref
High	1.645(1.405,1.927)	<0.001	1.748(1.3,2.352)	<0.001	1.874(1.334,2.632)	<0.001
AUCCP
low	Ref		Ref		Ref
High	2.137(1.533,2.978)	<0.001	3.241(1.882,5.581)	<0.001	4.498(2.126,9.518)	<0.001

Note：Model I Crude model；Model II : further adjusted for age, sex, BMI,smoking,drinking,family history of DM,duration of T2DM,hypertention；Model III further adjusted for WBC,RBC,HGB,ALB,AST/ALT,GGT,TG,HbA1c,nonHDL-C,UA,Cr,FBG,eGFR

Table 4 Correlation of PC/HDL with AUCCP in T2DM patients

	β (95% CI)	Std. Error	Beta	t	P
Model I	0.012(0.005,0.019)	0.003	0.142	3.437	0.001
Model II	0.008(0.001,0.016)	0.004	0.096	2.052	0.041
Model III	0.014(0.003,0.025)	0.006	0.154	2.53	0.012

Note：Model I Crude model；Model II : further adjusted for age, sex, BMI,smoking,drinking,family history of DM,duration of T2DM,hypertention；Model III further adjusted for WBC,RBC,HGB,ALB,AST/ALT,GGT,TG,HbA1c,nonHDL-C,UA,Cr,FBG,eGFR

No competing interests reported.

The Investigation of the Mediator Effect of C-peptide in the Relationship Between PC/HDL and MAFLD-a cross-sectional study in adult patients with type 2 diabetes

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