Vitamin D deficiency is associated with apolipoprotein A1 levels in patients with young-onset type 2 diabetes mellitus

Abstract

BACKGROUND

Young-onset type 2 diabetes mellitus (T2DM) is associated with adverse health outcomes and increased mortality. Vitamin D (VitD) deficiency is likewise linked to various adverse health outcomes and is significantly associated with lipid metabolism in patients with T2DM. However, little is known regarding the mechanisms of interaction between VitD and apolipoprotein A1 (apoA1) in young-onset T2DM.

AIM

To evaluate the relationship between VitD and apoA1 levels in patients with young-onset T2DM.

METHODS

This cross-sectional study was conducted at Zhejiang Provincial People’s Hospital between January 2019 and December 2023. A total of 642 patients with T2DM who aged 18-40 years were included and matched with 642 individuals without diabetes (controls) based on age and sex. No specific intervention was applied, and data were collected from medical records and laboratory tests. The relationship between VitD and apoA1 levels was examined using Spearman’s correlation and logistic regression models.

RESULTS

We found that VitD levels were significantly lower in patients with T2DM compared to controls (15.9 ng/mL vs 17.4 ng/mL, P < 0.001), with a notable positive correlation between VitD deficiency and reduced apoA1 levels. Multifactor logistic regression analysis identified that severe VitD deficiency was an independent risk factor for apoA1 in young-onset T2DM patients (odds ratio = 3.43, 95% confidence interval: 1.16-10.20, β = 1.23, P = 0.026).

CONCLUSION

Our findings reveal an association between VitD and apoA1 in young-onset T2DM, suggesting that VitD may play a crucial role in metabolic regulation and cardiovascular risk management.

Key Words: Young-onset type 2 diabetes mellitus; Vitamin D; Apolipoprotein A1; Lipid metabolism; Cardiovascular risk management

Core Tip: Vitamin D (VitD) deficiency is associated with various adverse health outcomes and is significantly associated with lipid metabolism. This study is the first to explore the relationship between VitD and apolipoprotein A1 in young-onset type 2 diabetes mellitus (T2DM) patients, emphasizing their potential effects and mechanisms, and underscore the necessity for further investigation into the impact of targeted interventions, such as VitD supplementation, on metabolic parameters especially in patients with young-onset T2DM.

INTRODUCTION

The increasing prevalence of young-onset type 2 diabetes mellitus (T2DM) has become a significant public health concern, with the rates of young-onset T2DM rising two- to three-fold in recent years[1,2]. This form of diabetes is associated with higher risks of adverse cardiovascular outcomes, microvascular complications, and increased mortality compared to later-onset T2DM[1,3,4]. Furthermore, these patients face unique challenges in self-management owing to social determinants that can exacerbate diabetes distress and complicate treatment adherence[1]. The clinical importance of addressing these metabolic abnormalities is underscored by the need for tailored prevention strategies and interventions to mitigate the long-term health impacts of young-onset T2DM[5,6]. Therefore, attention must be paid to the metabolic indicators and related influencing factors in such patients.

Present evidence highlights the intricate interplay between glucose and lipid metabolism in the pathogenesis of T2DM[7,8]. Insulin resistance, a hallmark of T2DM, not only impairs glucose homeostasis but also disrupts lipid metabolism through multiple pathways[9]. Especially hepatic insulin resistance is a key factor in the occurrence and development of T2DM, lipid metabolism disorders, atherosclerosis and other diseases. In addition, insulin resistance leads to increased free fatty acid flux from adipose tissue, promoting liver synthesis of triglycerides (TG) and cholesterol and contributing to dyslipidemia[8]. This metabolic crosstalk is particularly relevant in young-onset T2DM, where the prolonged exposure to metabolic disturbances may accelerate the development of cardiovascular complications.

As we all know, dyslipidemia is a very important risk factor for diabetic cardiovascular disease (CVD) in patients with T2DM, and the apolipoprotein family has been identified and included in lipid metabolism-related indexes[10,11]. Apolipoprotein A1 (apoA1) is primarily located on the surface of high-density lipoprotein cholesterol (HDL-C), while apolipoprotein B (apoB) serves as the major structural protein for other lipoproteins[12]. Previous studies have shown that vitamin D (VitD) deficiency is associated with various adverse health outcomes and is significantly associated with higher apoB/apoA1 ratios in patients with T2DM, suggesting a potential link between VitD levels and lipid metabolism[13-15]. Additionally, genetic studies have identified correlations between apoA1 and VitD levels, indicating a complex interaction that may influence cardiovascular risk in patients with T2DM[10]. Therefore, the interplay between VitD and apoA1 may be crucial for understanding dyslipidemia and its contribution to CVD in patients with T2DM, potentially guiding future therapeutic interventions[16]. Furthermore, the association between VitD levels and insulin resistance in patients with T2DM highlights the importance of VitD in metabolic regulation[17]. Based on these previous evidence linking vitamin D to lipid metabolism, we hypothesized that VitD deficiency would be associated with lower apoA1 levels, particularly in young-onset T2DM where early metabolic derangements may have prolonged cardiovascular consequences. The prolonged exposure to metabolic abnormalities in these younger patients makes understanding and addressing modifiable risk factors like VitD deficiency particularly crucial for preventing long-term complications. Furthermore, the mechanisms linking VitD status to lipid metabolism may differ in young-onset disease due to differences in disease pathophysiology and duration. To our knowledge, our study is the first to explore the relationship between VitD and apoA1, emphasizing their potential effects and mechanisms in young-onset T2DM patients.

This study conducted a cross-sectional analysis to evaluate the association between VitD and apoA1 in patients with young-onset T2DM. The findings aim to aid in creating personalized treatment strategies and improving clinical outcomes for young-onset T2DM patients.

MATERIALS AND METHODS

Study design and participants

This cross-sectional study analyzed the data of patients with young-onset T2DM who received medical treatment at Zhejiang Provincial People’s Hospital between January 2019 and December 2023 and who met the following inclusion criteria: Patients who aged 18-40 years old, with a previous diagnosis of T2DM, and with complete medical history and examination data.

The exclusion criteria comprised patients with acute diabetes complications, such as ketoacidosis and hyperosmolar hyperglycemia; those with a history of parathyroid disorders or malignant tumors; those with severe dysfunction of the heart, liver, or kidneys; those taking medications that affect VitD and blood lipid levels within 12 weeks of the examination; and patients during pregnancy or lactation.

Additionally, we used R software to select patients without diabetes who were matched 1:1 according to age and sex. The inclusion criteria required patients to be 18-40 years old, have no prior T2DM diagnosis, and possess comprehensive medical history and examination data. The exclusion criteria were the same as those for T2DM patients. The patient’s screening process is shown in Figure 1.

Figure 1 Flow chart of study. T2DM: Type 2 diabetes mellitus; VitD: Vitamin D.

Ethical approval

This study was conducted according to the principles of the Declaration of Helsinki and was approved by the Ethics Committee of Zhejiang Provincial People’s Hospital (No. QT2024293). Because this study was retrospective, the ethical review allows for an exemption from knowing, without the need to obtain informed consent from the survey subjects again.

Data collection

We collected the baseline data of the patients through the medical records system, including age, sex, smoking habits, drinking habits, and histories of CVD, hypertension, hyperlipidemia, fatty liver, hyperuricemia, obesity, osteopenia, and chronic kidney disease (CKD). Among them, CVD histories included coronary atherosclerotic heart disease, myocardial infarction, heart failure and stroke. Screening was performed in CKD patients to exclude those with estimated glomerular filtration rate (eGFR) ≤ 60 mL/minute/1.73 m². After fasting for at least 8 hours, blood tests were conducted to assess albumin (ALB), aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), serum creatinine (Scr), uric acid (UA), fasting blood glucose (Glu), blood calcium, blood phosphorus, parathyroid hormone, TG, low- and high-density lipoprotein cholesterol (LDL-C and HDL-C, respectively), apoA1, apoB, free fatty acid, lipoprotein, and VitD levels. The eGFR was calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration formula[18].

VitD levels were assessed by determining the blood concentration of the total 25-hydroxyvitamin D (25[OH]D), which included 25[OH]D2 and 25[OH]D3, that were measured using liquid chromatography-tandem mass spectrometry. Serum 25(OH)D levels were categorized as follows: Normal (> 30 ng/mL), insufficient (20-30 ng/mL, excluding 20 ng/mL), deficient (10-20 ng/mL, excluding 10 ng/mL), and severely deficient (≤ 10 ng/mL). ApoA1 levels were measured using the immunoturbidimetric method. We defined apoA1 as high when the concentration was ≥ 1.0 g/L and low when it was < 1.0 g/L.

Statistical analysis

The index distribution was evaluated using the Kolmogorov-Smirnov test. Data with normal distribution were summarized using means and standard deviations, while data with non-normal distribution were summarized using medians and quartiles. Differences between the two groups were compared using either a Student’s t-test or a Mann-Whitney U test. Categorical variables were analyzed using χ² tests. Variable relationships were evaluated using Spearman’s correlation analysis. The relationship between VitD and apoA1 was analyzed using univariate and multivariate logistic regression. The association was described using odds ratio (OR) with 95% confidence interval (CI).

Statistical analyses were conducted using SPSS software (version 26.0; IBM Corp., Armonk, NY, United States) and R software (version 4.1.0; R Foundation for Statistical Computing, Auckland, New Zealand). R packages, including ggplot2, mice, survival, missForest, VIM, Hmisc, rms, regplot, tableone, glmnet and matchit, were used for data analysis and visualization. Statistical significance was set at P < 0.05 for all tests.

RESULTS

Comparison of baseline characteristics and laboratory-related indicators between patients with and without T2DM

Our study included 642 patients with T2DM who met the enrollment criteria and 642 patients without diabetes (controls) matched in a 1:1 ratio according to age and sex. Table 1 details the clinical characteristics of the study participants. There were no significant differences in age or sex between the two groups. Compared with the non-diabetic group, smoking and drinking habit incidence was significantly higher in the T2DM group (25.5% vs 13.9% P < 0.001 and 19.6% vs 8.7% P < 0.001, respectively). In terms of comorbidities, hypertension, hyperlipidemia, fatty liver disease, hyperuricemia, obesity, CKD, and osteoporosis were significantly more common in the T2DM group than in the non-diabetic group (P < 0.001). The indices of HDL-C and apoA1 were lower and those of ALT, AST, UA, Glu, TG, free fatty acids, LDL-C, and apoB were higher than those in the non-diabetic group, and the difference was statistically significant (P < 0.05). There were no significant differences in the levels of lipoproteins, ALP, and parathyroid hormone.

Table 1 Comparison of the clinical and laboratory data between the type 2 diabetes mellitus patients and no-diabetes mellitus patients, n (%).

	Overall (n = 1284)	No-DM (n = 642)	T2DM (n = 642)	P value
Age (years)	33.00 (29.00, 36.00)	33.00 (30.00, 36.00)	33.00 (29.00, 36.00)	0.499
Female	465 (36.2)	237 (36.9)	228 (35.5)	0.642
Smoking	253 (19.7)	89 (13.9)	164 (25.5)	< 0.001
Alcohol	182 (14.2)	56 (8.7)	126 (19.6)	< 0.001
CVD	6 (0.5)	1 (0.2)	5 (0.8)	0.22
HBP	137 (10.7)	28 (4.4)	109 (17.0)	< 0.001
Hyperlipemia	291 (22.7)	19 (3.0)	272 (42.4)	< 0.001
Fatty liver	440 (34.3)	51 (7.9)	389 (60.6)	< 0.001
Hyperuricemia	155 (12.1)	41 (6.4)	114 (17.8)	< 0.001
Obesity	133 (10.4)	21 (3.3)	112 (17.4)	< 0.001
Osteopenia	17 (1.3)	0 (0.0)	17 (2.6)	< 0.001
CKD	158 (12.3)	30 (4.7)	128 (19.9)	< 0.001
25VitD, ng/mL	16.63 (12.57, 22.63)	17.41 (13.16, 23.96)	15.90 (11.77, 21.21)	< 0.001
25VitD class				< 0.001
Normal	114 (8.9)	63 (9.8)	51 (7.9)
Insufficient	328 (25.5)	194 (30.2)	134 (20.9)
Deficient	679 (52.9)	321 (50.0)	358 (55.8)
Severely deficient	163 (12.7)	64 (10.0)	99 (15.4)
25VitD2, ng/mL	0.48 (0.19, 0.85)	0.50 (0.22, 0.88)	0.46 (0.18, 0.84)	0.344
25VitD3, ng/mL	16.10 (12.00, 21.60)	16.70 (12.61, 23.08)	15.30 (11.20, 20.40)	< 0.001
LDL-C, mmol/L	2.78 (2.19, 3.45)	2.71 (2.17, 3.34)	2.88 (2.23, 3.54)	0.01
HDL-C, mmol/L	1.04 (0.87, 1.28)	1.15 (0.98, 1.41)	0.94 (0.78, 1.13)	< 0.001
TG, mmol/L	1.52 (0.98, 2.45)	1.31 (0.81, 1.97)	1.78 (1.18, 2.94)	< 0.001
No HDL-C, mmol/L	3.68 (2.95, 4.51)	3.47 (2.77, 4.21)	3.95 (3.13, 4.84)	< 0.001
Apolipoprotein A1, g/L	1.19 (1.04, 1.42)	1.27 (1.13, 1.52)	1.11 (0.98, 1.28)	< 0.001
Apolipoprotein B, g/L	0.89 (0.72, 1.09)	0.83 (0.67, 1.01)	0.96 (0.77, 1.18)	< 0.001
ApoB/ApoA1	0.70 (0.54, 0.94)	0.62 (0.47, 0.78)	0.83 (0.62, 1.06)	< 0.001
Free fatty acids, μmol/L	503.50 (374.00, 662.00)	488.00 (355.00, 633.50)	530.00 (397.75, 693.75)	0.001
lipoprotein, mg/L	103.00 (48.75, 207.25)	102.00 (51.00, 215.50)	108.00 (47.00, 202.75)	0.489
UA, μmol/L	363.00 (284.00, 432.00)	358.00 (276.00, 422.75)	369.00 (291.00, 438.75)	0.012
Glu, mmol/L	5.20 (4.64, 7.18)	4.80 (4.46, 5.15)	7.08 (5.34, 9.79)	< 0.001
ALB, g/L	41.60 (38.10, 44.80)	43.60 (40.02, 45.90)	40.00 (37.30, 42.80)	< 0.001
ALT, U/L	24.00 (14.00, 48.00)	21.00 (13.00, 34.75)	30.00 (17.00, 62.00)	< 0.001
AST, U/L	22.00 (17.00, 32.00)	21.00 (17.00, 26.00)	24.00 (16.25, 41.75)	< 0.001
ALP, U/L	78.00 (63.00, 95.00)	76.00 (61.00, 92.75)	79.00 (65.00, 97.00)	0.087
Scr, μmol/L	69.10 (56.60, 79.50)	71.50 (58.28, 81.22)	67.10 (55.47, 76.60)	< 0.001
eGFR, mL/minute/1.73 m²	118.51 (106.40, 130.59)	114.67 (103.85, 128.66)	121.81 (110.17, 132.13)	< 0.001
Ca, mmol/L	2.32 (2.23, 2.39)	2.34 (2.27, 2.41)	2.28 (2.20, 2.36)	< 0.001
P, mmol/L	1.25 (1.11, 1.40)	1.22 (1.09, 1.36)	1.27 (1.14, 1.44)	< 0.001
iPTH, pg/mL	33.40 (24.20, 45.32)	33.50 (24.00, 45.60)	33.10 (24.40, 44.92)	0.605
Hemoglobin, g/L	147.00 (130.00, 158.00)	146.00 (129.00, 157.00)	147.00 (131.00, 159.00)	0.024
White blood cell, × 109/L	7.02 (5.80, 8.53)	6.81 (5.62, 8.24)	7.23 (6.09, 8.71)	< 0.001
PLT, × 109/L	238.00 (199.00, 280.00)	240.00 (201.25, 280.00)	237.00 (196.25, 280.00)	0.344

CVD: Cardiovascular disease; HBP: Hypertension; CKD: Chronic kidney disease; 25VitD: 25-hydroxy vitamin D; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; TG: Triglycerides; ApoB: Apolipoprotein B; ApoA1: Apolipoprotein A1; UA: Uric acid; Glu: Glucose; ALB: Albumin; ALT: Alanine transaminase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; Scr: Serum creatinine; eGFR: Estimated glomerular filtration rate (calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration formula); Ca: Blood calcium; P: Blood phosphorus; iPTH: Parathyroid hormone; PLT: Platelets.

Comparison of VitD between patients with T2DM and controls

Patients with T2DM had a significantly lower average 25(OH)D level of 15.9 ng/mL compared to 17.4 ng/mL in controls (P < 0.001) (Figure 2A and Table 1). Of the patients with T2DM, 55.8% had VitD deficiency, and 15.4% had severe VitD deficiency, which was significantly higher than the level of VitD deficiency in the corresponding controls (50% and 10%, respectively, P < 0.001) (Figure 2B and C; Table 1).

Figure 2 The distribution of vitamin D status in type 2 diabetes mellitus patients and non-diabetic control subjects. A: The average levels of vitamin D levels between patients with type 2 diabetes mellitus (T2DM) and non-diabetic controls; B: The distribution of vitamin D status in T2DM patients: Majority of T2DM patients (55.8%) were classified as vitamin D deficient, with 15.4% having severe vitamin D deficiency; C: The distribution of vitamin D status in non-diabetic control subjects: majority of T2DM patients (50%) were classified as vitamin D deficient, with 10% having severe vitamin D deficiency. ^dP < 0.001. T2DM: Type 2 diabetes mellitus; DM: Diabetes mellitus.

Comparison of baseline characteristics and laboratory-related indicators between four groups according to their VitD levels in patients with T2DM

The 642 T2DM patients were categorized into four groups according to their 25(OH)D levels: Normal, insufficient, deficient, and severely deficient. Table 2 outlines the clinical characteristics of the four groups. We found significant differences in related indices such as sex, drinking habits, fatty liver disease, Glu, TG, HDL-C, and apoA1 among the groups with different VitD levels (P < 0.05). Patients with severe VitD deficiency exhibited significantly lower HDL-C and apoA1 levels compared to those in the normal group (P < 0.001).

Table 2 Comparison of the clinical and laboratory data between the four groups, n (%).

	Overall (n = 642)	VitD normal (n = 51)	VitD insufficient (n = 134)	VitD deficient (n = 358)	VitD severely deficient (n = 99)	P value
Age (years)	33.0 (29.0, 36.0)	33.0 (29.5, 35.5)	35.0 (31.0, 38.0)	33.0 (28.0, 36.0)	31.0 (27.0, 35.0)	< 0.001
Female	228 (35.5)	31 (60.8)	33 (24.6)	118 (33.0)	46 (46.5)	< 0.001
Smoking	164 (25.5)	11 (21.6)	40 (29.9)	91 (25.4)	22 (22.2)	0.511
Alcohol	126 (19.6)	10 (19.6)	39 (29.1)	60 (16.8)	17 (17.2)	0.02
CVD	5 (0.8)	2 (3.9)	1 (0.7)	2 (0.6)	0 (0.0)	0.057
HBP	109 (17.0)	4 (7.8)	22 (16.4)	67 (18.7)	16 (16.2)	0.277
Hyperlipemia	272 (42.4)	13 (25.5)	65 (48.5)	155 (43.3)	39 (39.4)	0.037
Fatty liver	389 (60.6)	17 (33.3)	83 (61.9)	225 (62.8)	64 (64.6)	0.001
Hyperuricemia	114 (17.8)	7 (13.7)	23 (17.2)	64 (17.9)	20 (20.2)	0.799
Obesity	112 (17.4)	7 (13.7)	23 (17.2)	64 (17.9)	18 (18.2)	0.901
Osteopenia	17 (2.6)	2 (3.9)	3 (2.2)	12 (3.4)	0 (0.0)	0.285
CKD	128 (19.9)	9 (17.6)	28 (20.9)	73 (20.4)	18 (18.2)	0.923
25VitD, ng/mL	15.90 (11.77, 21.21)	35.46 (32.13, 41.36)	23.51 (21.51, 26.17)	15.08 (12.71, 17.31)	7.82 (6.11, 9.05)	< 0.001
25VitD2, ng/mL	0.46 (0.18, 0.84)	0.53 (0.26, 0.69)	0.52 (0.21, 0.90)	0.47 (0.19, 0.90)	0.33 (0.04, 0.63)	0.006
25VitD3, ng/mL	15.30 (11.20, 20.40)	34.20 (31.10, 40.55)	22.70 (20.90, 25.30)	14.18 (11.83, 16.50)	7.29 (5.92, 8.41)	< 0.001
LDL-C, mmol/L	2.88 (2.23, 3.54)	2.95 (2.42, 3.33)	2.88 (2.18, 3.53)	2.87 (2.22, 3.52)	2.92 (2.37, 3.64)	0.909
HDL-C, mmol/L	0.94 (0.78, 1.13)	1.34 (0.90, 1.86)	0.94 (0.76, 1.14)	0.93 (0.79, 1.09)	0.92 (0.79, 1.09)	< 0.001
TG, mmol/L	1.78 (1.18, 2.94)	2.54 (1.40, 3.23)	1.97 (1.33, 3.39)	1.70 (1.15, 2.92)	1.50 (1.04, 2.33)	0.007
No HDL-C, mmol/L	3.95 (3.13, 4.84)	3.95 (3.33, 4.56)	4.09 (3.42, 4.86)	3.92 (3.08, 4.86)	3.86 (3.04, 4.69)	0.331
Apolipoprotein A1, g/L	1.11 (0.98, 1.28)	1.58 (1.12, 2.36)	1.11 (0.98, 1.41)	1.10 (0.98, 1.24)	1.08 (0.92, 1.19)	< 0.001
Apolipoprotein B, g/L	0.96 (0.77, 1.18)	1.00 (0.84, 1.15)	0.99 (0.82, 1.20)	0.95 (0.77, 1.18)	0.90 (0.74, 1.17)	0.322
ApoB/ApoA1	0.83 (0.62, 1.06)	0.61 (0.46, 0.84)	0.83 (0.61, 1.05)	0.86 (0.65, 1.08)	0.82 (0.65, 1.10)	< 0.001
Free fatty acids, μmol/L	530 (398, 694)	512 (433, 608)	526 (372, 682)	525 (393,685)	571 (411, 758)	0.302
Lipoproteina, mg/L	108 (47, 203)	116 (44, 188)	92 (35, 232)	117 (47, 201)	101 (61, 201)	0.885
UA, μmol/L	369 (291, 439)	316 (272, 386)	368 (292, 424)	373 (295, 440)	373 (284, 475)	0.089
Glu, mmol/L	7.08 (5.34, 9.79)	5.46 (4.40, 7.34)	6.81 (5.26, 9.34)	7.32 (5.52, 9.92)	7.71 (5.66, 10.30)	< 0.001
ALB, g/L	40.0 (37.3, 42.8)	38.1 (35.1, 41.8)	40.7 (38.0, 43.8)	40.1 (37.8, 42.7)	39.1 (35.7, 42.2)	0.019
ALT, U/L	30.0 (17.0, 62.0)	22.0 (11.5, 59.0)	28.0 (18.0, 60.8)	31.0 (18.0, 62.0)	34.0 (16.0, 65.5)	0.211
AST, U/L	24.0 (16.3, 41.8)	23.0 (15.0, 33.0)	23.0 (17.0, 33.8)	24.0 (17.0, 42.8)	27.0 (16.0, 46.0)	0.329
ALP, U/L	79.0 (65.0, 97.0)	80.0 (65.5, 96.0)	82.0 (65.0, 101.8)	78.0 (64.0, 96.0)	76.0 (64.0, 97.5)	0.528
Scr, μmol/L	67.1 (55.5, 76.6)	57.7 (48.1, 70.3)	70.1 (60.6, 80.0)	68.1 (56.5, 76.7)	61.0 (52.0, 73.9)	< 0.001
eGFR, mL/minute/1.73 m²	121.81 (110.17, 132.13)	125.11 (119.47, 132.95)	117.11 (108.36, 128.38)	121.09 (109.86, 132.74)	124.97 (116.59, 132.42)	0.015
Ca, mmol/L	2.28 (2.20, 2.36)	2.29 (2.21, 2.36)	2.29 (2.22, 2.36)	2.28 (2.20, 2.36)	2.27 (2.17, 2.34)	0.147
P, mmol/L	1.27 (1.14, 1.44)	1.27 (1.18, 1.44)	1.28 (1.14, 1.42)	1.28 (1.15, 1.44)	1.25 (1.10, 1.44)	0.613
iPTH, pg/mL	33.1 (24.4, 44.9)	25.4 (17.4, 31.8)	30.2 (23.4, 40.6)	34.5 (26.4, 46.0)	38.1 (26.7, 46.1)	< 0.001
Hemoglobin, g/L	147 (131, 159)	132 (119, 152)	151 (139, 160)	148 (133, 160)	144 (130, 156)	0.001
White blood cell, × 109/L	7.23 (6.09, 8.71)	8.54 (6.43, 9.68)	7.00 (6.09, 8.46)	7.14 (6.02, 8.48)	7.99 (6.30, 9.04)	0.004
PLT, × 109/L	237 (196, 280)	224 (192, 258)	233 (192, 277)	237 (198, 276)	256 (207, 318)	0.011

CVD: Cardiovascular disease; HBP: Hypertension; CKD: Chronic kidney disease; 25VitD: 25-hydroxy vitamin D; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; TG: Triglycerides; ApoB: Apolipoprotein B; ApoA1: Apolipoprotein A1; UA: Uric acid; Glu: Glucose; ALB: Albumin; ALT: Alanine transaminase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; Scr: Serum creatinine; eGFR: Estimated glomerular filtration rate (calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration formula); Ca: Blood calcium; P: Blood phosphorus; iPTH: Parathyroid hormone; PLT: Platelets.

Correlations between VitD and various indicators

Spearman correlation analysis indicated a significant negative correlation (P < 0.05) between 25(OH)D levels and UA (r = -0.11), Glu (r = -0.16), parathyroid hormone (r = -0.17), apoB/apoA1 (r = -0.19), and free fatty acids (r = -0.091). Furthermore, VitD levels showed a significant positive correlation (P < 0.05) with age (r = 0.12), blood calcium (r = 0.12), blood phosphorus (r = 0.07), HDL-C (r = 0.31), and apoA1 (r = 0.41) (shown in Figure 3).

Figure 3 Correlations between vitamin D and various indicators. A and B: Correlations between vitamin D (VitD) and lipid-related indicators: A significant positive correlation between VitD levels and high-density lipoprotein cholesterol (r = 0.31), apolipoprotein A1 (apoA1) (r = 0.41), and a significant negative correlation with apolipoprotein B/apoA1 (r = -0.19), free fatty acids (r = -0.091); C and D: Correlations between VitD and other indicators: A significant positive correlation between VitD levels and blood calcium (r = 0.12), blood phosphorus (r = 0.07), and a significant negative correlation with uric acid (r = -0.11), glucose (r = -0.16), parathyroid hormone (r = -0.17). ^aP < 0.05. ^bP < 0.01. ^cP < 0.001. VitD: Vitamin D; UA: Uric acid; Glu: Glucose; ALB: Albumin; eGFR: Estimated glomerular filtration rate; ALP: Alkaline phosphatase; Hb: Haemoglobin; Ca: Blood calcium; P: Blood phosphorus; IPTH: Parathyroid hormone; HDL-C: High-density lipoprotein cholesterol; TG: Triglycerides; LDL-C: Low-density lipoprotein cholesterol.

Comparison of baseline characteristics and laboratory-related indicators between high-apoA1 and low-apoA1 levels in patients with T2DM

The 642 T2DM patients were divided into two groups based on their apoA1 levels. We defined apoA1 ≥ 1.0 g/L as high and < 1.0 g/L as low. Compared to the low-apoA1 group, the high-apoA1 group had significantly higher levels of 25(OH)D, HDL-C, and blood calcium, significantly reduced smoking and drinking habits, and lower levels of TG, UA, Glu, ALT, AST, ALP, and Scr (P < 0.05). No significant differences were observed between the two groups in terms of age, hypertension, obesity, LDL-C, apoB, blood phosphorus, and ALB. Compared to the low-apoA1 group, the percentage of patients with normal VitD levels was significantly higher in the high-apoA1 group than in the low-apoA1 group (10.23% vs 2.97%, respectively; P < 0.05), and the percentage of patients with severe VitD deficiency was significantly lower in the high-apoA1 group than in the low-apoA1 group (13.18% vs 20.30%, respectively; P < 0.05) (shown in Table 3).

Table 3 Comparison of the clinical and laboratory data between high- and low-apolipoprotein A1 groups, n (%).

	Overall (n = 642)	ApoA1 ≥ 1 g/L (n = 440)	ApoA1 < 1 g/L (n = 202)	P value
Age (years)	33.00 (29.00, 36.00)	33.00 (29.00, 37.00)	33.00 (28.00, 36.00)	0.436
Female	228 (35.51)	194 (44.09)	34 (16.83)	< 0.001
Smoking	164 (25.55)	88 (20.00)	76 (37.62)	< 0.001
Alcohol	126 (19.63)	70 (15.91)	56 (27.72)	< 0.001
CVD	5 (0.78)	2 (0.45)	3 (1.49)	0.370
HBP	109 (16.98)	74 (16.82)	35 (17.33)	0.873
Fatty liver	389 (60.59)	235 (53.41)	154 (76.24)	< 0.001
Obesity	112 (17.45)	74 (16.82)	38 (18.81)	0.536
Hyperuricemia	114 (17.76)	78 (17.73)	36 (17.82)	0.977
25VitD, ng/mL	15.90 (11.77, 21.21)	16.54 (12.54, 21.51)	15.07 (11.01, 19.96)	0.001
25VitD class				0.003
Normal	51 (7.94)	45 (10.23)	6 (2.97)
Insufficient	134 (20.87)	89 (20.23)	45 (22.28)
Deficient	358 (55.76)	248 (56.36)	110 (54.46)
Severely deficient	99 (15.42)	58 (13.18)	41 (20.30)
LDL-C, mmol/L	2.88 (2.23, 3.54)	2.89 (2.27, 3.54)	2.83 (2.12, 3.53)	0.239
HDL-C, mmol/L	0.94 (0.78, 1.13)	1.04 (0.90, 1.26)	0.76 (0.67, 0.84)	< 0.001
TG, mmol/L	1.78 (1.18, 2.94)	1.73 (1.11, 2.82)	1.86 (1.29, 3.60)	0.009
No HDL-C, mmol/L	3.95 (3.13, 4.84)	3.91 (3.15, 4.72)	4.11 (3.11, 5.01)	0.152
Apolipoprotein B, g/L	0.96 (0.77, 1.18)	0.94 (0.77, 1.18)	0.98 (0.75, 1.17)	0.780
Free fatty acids, μmol/L	530.00 (397.75, 693.75)	530.00 (389.00, 680.50)	526.00 (416.25, 710.50)	0.118
Lipoproteina, mg/L	108.00 (47.00, 202.75)	116.00 (50.75, 209.25)	88.00 (37.75, 194.25)	0.104
UA, μmol/L	369.00 (291.00, 438.75)	361.50 (279.50, 432.00)	377.00 (314.25, 453.75)	0.003
Glu, mmol/L	7.08 (5.34, 9.79)	6.72 (5.15, 9.56)	7.66 (5.93, 10.24)	0.001
ALB, g/L	40.00 (37.30, 42.80)	40.30 (37.30, 43.00)	39.60 (37.32, 42.00)	0.138
ALT, U/L	30.00 (17.00, 62.00)	28.00 (15.00, 56.00)	39.50 (21.00, 74.50)	< 0.001
AST, U/L	24.00 (16.25, 41.75)	23.00 (16.00, 38.00)	27.50 (18.00, 46.75)	0.002
ALP, U/L	79.00 (65.00, 97.00)	77.00 (63.00, 96.00)	82.50 (68.25, 99.75)	0.015
Scr, μmol/L	67.10 (55.47, 76.60)	64.75 (53.30, 75.60)	70.50 (63.47, 77.77)	< 0.001
eGFR, mL/minute/1.73 m²	121.81 (110.17, 132.13)	122.26 (110.72, 132.44)	120.67 (109.75, 130.25)	0.442
Ca, mmol/L	2.28 (2.20, 2.36)	2.29 (2.21, 2.37)	2.27 (2.19, 2.33)	0.002
P, mmol/L	1.27 (1.14, 1.44)	1.28 (1.16, 1.44)	1.25 (1.09, 1.42)	0.051
iPTH, pg/mL	33.10 (24.40, 44.92)	32.70 (24.20, 45.02)	34.45 (24.92, 44.70)	0.542
Hemoglobin, g/L	147.00 (131.00, 159.00)	145.00 (129.00, 158.00)	151.50 (140.00, 160.00)	< 0.001
White blood cell, × 109/L	7.23 (6.09, 8.71)	7.28 (6.06, 8.76)	7.16 (6.14, 8.68)	0.958
PLT, × 109/L	237.00 (196.25, 280.00)	239.50 (196.75, 285.25)	230.50 (196.50, 271.00)	0.313

CVD: Cardiovascular disease; HBP: Hypertension; 25VitD: 25-hydroxy vitamin D; LDL-C: Low-density lipoprotein cholesterol; HDL-C: High-density lipoprotein cholesterol; TG: Triglycerides; ApoA1: Apolipoprotein A1; UA: Uric acid; Glu: Glucose; ALB: Albumin; ALT: Alanine transaminase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; Scr: Serum creatinine; eGFR: Estimated glomerular filtration rate (calculated using the 2009 Chronic Kidney Disease Epidemiology Collaboration formula); Ca: Blood calcium; P: Blood phosphorus; iPTH: Parathyroid hormone; PLT: Platelets.

Factors associated with apoA1 levels in patients with T2DM

Using apoA1 as the dependent variable, the independent variables were sequentially screened. Variables with P < 0.05, including sex, smoking and drinking habits, history of hyperlipidemia and fatty liver disease, and levels of UA, Glu, ALT, AST, Scr, blood calcium, hemoglobin, TG, HDL-C and 25(OH)D, were included in the multivariate logistic regression analysis. Regression analysis identified sex (OR = 0.38, 95%CI: 0.19-0.76, β = -0.98), blood calcium (OR = 0.06, 95%CI: 0.01-0.38, β = -2.78), HDL-C (OR = 22.0, 95%CI: 7.67-63.13, β = 3.09), and severe VitD deficiency (OR = 3.43, 95%CI: 1.16-10.20, β = 1.23) as independent risk factors for apoA1 in young-onset T2DM patients (shown in Table 4).

Table 4 Univariate and multivariate logistic regression analyses for independent factors associated with apolipoprotein A1 in type 2 diabetes mellitus patients.

Variables	Univariate logistic regression analyses					multivariate logistic regression analyses
	β value	SE	Z value	P value	OR (95%CI)	β value	SE	Z value	P value	OR (95%CI)
Sex
Male					1.00 (Reference)					1.00 (Reference)
Female	-1.36	0.21	-6.44	< 0.001	0.26 (0.17-0.39)	-0.98	0.36	-2.73	0.006	0.38 (0.19-0.76)
Smoking
0					1.00 (Reference)					1.00 (Reference)
1	0.88	0.19	4.69	< 0.001	2.41 (1.67-3.49)	0.43	0.24	1.78	0.075	1.54 (0.96-2.47)
Alcohol
0					1.00 (Reference)					1.00 (Reference)
1	0.71	0.20	3.46	< 0.001	2.03 (1.36-3.03)	0.03	0.26	0.11	0.916	1.03 (0.62-1.72)
Hyperlipemia
0					1.00 (Reference)					1.00 (Reference)
1	0.54	0.17	3.15	0.002	1.72 (1.23-2.41)	0.04	0.20	0.18	0.856	1.04 (0.70-1.54)
Fatty liver
0					1.00 (Reference)					1.00 (Reference)
1	1.03	0.19	5.39	< 0.001	2.80 (1.93-4.07)	0.19	0.24	0.79	0.432	1.21 (0.76-1.92)
25VitD class
Normal					1.00 (Reference)					1.00 (Reference)
Insufficient	1.33	0.47	2.83	0.005	3.79 (1.50-9.56)	0.79	0.54	1.46	0.144	2.20 (0.77-6.30)
Deficient	1.20	0.45	2.67	0.007	3.33 (1.38-8.03)	0.57	0.52	1.11	0.266	1.78 (0.65-4.88)
Severely deficient	1.67	0.48	3.47	< 0.001	5.30 (2.07-13.59)	1.23	0.56	2.22	0.026	3.43 (1.16-10.20)
UA, μmol/L	0.01	0.00	3.26	0.001	1.01 (1.01-1.01)	-0.00	0.00	-0.31	0.754	1.00 (1.00-1.00)
Glu, mmol/L	0.04	0.02	1.98	0.048	1.04 (1.01-1.08)	-0.01	0.02	-0.57	0.570	0.99 (0.94-1.03)
ALT, U/L	0.01	0.00	2.95	0.003	1.01 (1.01-1.01)	-0.01	0.00	-0.12	0.901	1.00 (0.99-1.01)
AST, U/L	0.01	0.00	2.85	0.004	1.01 (1.01-1.01)	0.01	0.01	1.00	0.319	1.01 (1.00-1.02)
Scr, μmol/L	0.02	0.01	3.23	0.001	1.02 (1.01-1.03)	-0.00	0.01	-0.55	0.581	1.00 (0.98-1.01)
Ca, mmol/L	-2.02	0.70	-2.87	0.004	0.13 (0.03-0.53)	-2.78	0.92	-3.03	0.002	0.06 (0.01-0.38)
Hemoglobin, g/L	0.02	0.00	4.00	< 0.001	1.02 (1.01-1.03)	-0.01	0.01	-1.34	0.179	0.99 (0.98-1.00)
HDL-C class
0					1.00 (Reference)					1.00 (Reference)
1	3.46	0.51	6.72	< 0.001	31.77 (11.59-87.06)	3.09	0.54	5.75	< .001	22.00 (7.67-63.13)
TG, mmol/L	0.12	0.03	3.97	< 0.001	1.13 (1.06-1.19)	0.06	0.03	1.74	0.082	1.06 (0.99-1.12)

25VitD: 25-hydroxy vitamin D; UA: Uric acid; Glu: Glucose; ALT: Alanine transaminase; AST: Aspartate aminotransferase; Scr: Serum creatinine; Ca: Blood calcium; HDL-C: High-density lipoprotein cholesterol; TG: Triglycerides; OR: Odds ratio; CI: Confidence interval.

DISCUSSION

VitD is an indispensable fat-soluble vitamin in the human body. The main active form of VitD is 25(OH)D, which acts through VitD receptors (VDR) distributed in different tissues[19]. VitD deficiency is now recognized as a pandemic, and recent studies have shown that the binding of VitD to its receptor can participate in immune regulation, endocrine function, inflammation, insulin resistance, obesity, and other pathophysiological processes[20-23]. Our research demonstrated significantly lower VitD levels in young-onset T2DM patients compared to those in non-diabetic individuals, underscoring the important link between VitD deficiency and T2DM progression. In line with this finding, previous studies have emphasized the role of VitD in insulin sensitivity and β-cell function, which are crucial in the pathogenesis of young-onset T2DM[3,24].

Diabetic macrovascular disease includes atherosclerosis, intima thickening, and plaque formation caused by diabetes; this condition can lead to thrombosis, lumen stenosis, and occlusion, which are the main causes of death in patients with T2DM. Young-onset T2DM has been linked to elevated risks of adverse cardiovascular events and higher mortality rates[3,4]. Hyperlipidemia is a prevalent metabolic disorder marked by imbalances in LDL-C, HDL-C, TG, and total cholesterol levels. Long-term lipid metabolism disorders are associated with atherosclerotic CVDs, especially in patients with T2DM[25]. Our study reveals a positive correlation between VitD and apoA1 levels, identifying severe VitD deficiency as an independent risk factor for lower apoA1 levels, which may worsen metabolic dysregulation in this population. This result aligns with prior research findings. Faridi et al[26] identified a prospective association between low 25(OH)D levels and reduced total cholesterol and HDL-C levels. Yarparvar et al[27] conducted a randomized controlled trial demonstrating that VitD supplementation improved serum VitD levels, lipid profiles, and inflammatory biomarkers in healthy adolescent boys with high rates of vitamin deficiency. Md Isa et al[28] performed a systematic review and found that VitD deficiency or insufficiency was associated with micro- and macrovascular complications of T2DM and an increased risk of obesity, dyslipidemia, glycemic control, and other metabolic indicators. Our study provides several novel insights that distinguish it from previous research in this field. First, unlike most prior studies that focused on older populations or mixed-age cohorts, we specifically targeted young-onset T2DM patients, a demographic that is increasingly prevalent yet remains understudied in the context of VitD and lipid metabolism. This focus is particularly important given the unique metabolic challenges and long-term cardiovascular risks associated with young-onset T2DM. Second, while previous studies have primarily examined the relationship between VitD and traditional lipid parameters (e.g., HDL-C, LDL-C), our study is among the first to focus on the association between VitD and apoA1, a more specific and functionally relevant marker of lipid metabolism. Furthermore, our study design allowed us to identify severe VitD deficiency as an independent risk factor for low apoA1 levels, a finding that has not been previously reported in the context of young-onset T2DM.

The observed association between VitD and apoA1 levels in young-onset T2DM patients may be mediated through several potential biological mechanisms. VDR are expressed in various tissues involved in lipid metabolism, including hepatocytes and adipocytes[29]. Activation of VDR has been shown to modulate the expression of genes involved in HDL metabolism, such as adenosine triphosphate-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type 1, which may upregulate ABCA1 expression in macrophages, promoting cholesterol efflux and HDL biogenesis[30,31]. Additionally, VitD may influence apoA1 levels through its anti-inflammatory properties. Chronic inflammation, a common feature of T2DM, can impair HDL function and reduce apoA1 levels. VitD has been shown to suppress pro-inflammatory cytokines such as tumor necrosis factor-α and interleukin-6, which are known to downregulate apoA1 gene expression[32-34]. These mechanisms provide a plausible explanation for our findings and suggest that VitD supplementation could potentially improve apoA1 metabolism in young-onset T2DM patients. The higher incidence of complications in young-onset T2DM patients also highlights the necessity for targeted interventions to address VitD deficiency within a comprehensive diabetes management strategy[6,35]. Overall, our findings support the hypothesis that optimizing VitD levels may be vital in improving health outcomes in young individuals with T2DM.

This study’s main innovation is its systematic examination of the association between VitD and apoA1 levels in young-onset T2DM patients, addressing a crucial knowledge gap. Previous research has established the individual roles of VitD and apoA1 in metabolic disorders[10,13]; however, this study uniquely correlates their interaction specifically in a younger demographic, which is often overlooked in the existing literature. This contrasts with earlier studies that did not focus on the young-onset population, thereby providing new insights into the metabolic implications of VitD deficiency in this group.

In summary, our study provides novel insights into the relationship between VitD status and apoA1 levels in young-onset T2DM patients. The key findings include: (1) Significantly lower VitD levels in young-onset T2DM patients compared to non-diabetic controls; (2) A positive correlation between VitD and apoA1 levels; and (3) Identification of severe VitD deficiency as an independent risk factor for reduced apoA1 levels. These findings underscore the importance of VitD in maintaining lipid homeostasis. The clinical implications of this study are profound, maintaining adequate VitD levels could be crucial for optimizing apoA1 metabolism, thereby potentially reducing the incidence of CVD, as supported by evidence linking VitD deficiency to adverse cardiovascular outcomes[14,36,37]. Furthermore, the observed association between low VitD levels and increased cardiovascular risk factors underscores the need for routine screening and potential supplementation in at-risk populations[37-39].

Nonetheless, the study faced certain limitations. First, as a retrospective study, the observational nature and potential confounding factors could have affected the robustness of the conclusions. However, we tried our best to ensure the stability of the results by setting strict inclusion and exclusion criteria, adjusting multiple potential confounding factors, and adopting standardized measurement. Second, the limited sample size might have impacted the generalizability of the results. Third, the cross-sectional design inherently limits the ability to infer causal relationships, a concern highlighted in studies that advocate longitudinal approaches to better understand temporal dynamics. Fourth, data collection was restricted to a single center, which may not capture the variability present in broader populations, potentially affecting the external validity of the results. Future research should focus on larger multicenter studies with longitudinal designs to enhance the robustness of the findings and facilitate a more comprehensive understanding of the studied phenomena. Implementing these improvements would significantly strengthen the evidence and applicability of the results across diverse populations.

CONCLUSION

Our study underscores the important link between VitD levels and apoA1 in T2DM patients, indicating VitD’s vital role in influencing metabolic states in this group. Previous research has indicated that VitD deficiency is prevalent among individuals with T2DM and is linked to adverse metabolic outcomes, emphasizing the need for effective supplementation to improve metabolic health[40-42]. However, our findings underscore the necessity for further investigation into the impact of targeted interventions, such as VitD supplementation, on metabolic parameters in patients with T2DM. Future studies should prioritize multicenter, randomized controlled trials with larger cohorts to validate these associations and explore the mechanisms underlying the relationship between VitD and apoA1. Long-term follow-up is essential to assess the sustained effects of VitD intervention on the metabolic health of patients with T2DM.

ACKNOWLEDGEMENTS

We thank all patients for their participation and cooperation in this study, as well as the Department of Endocrinology of Zhejiang Provincial People’s Hospital and the Key Laboratory of Endocrine Gland Diseases of Zhejiang Province for their support.