ORIGINAL ARTICLE
Atherogenic Lipoprotein Profile in First-Degree Relatives of Individuals with Type 2 Diabetes Mellitus Dyah Purnamasari1*.
Laila Miftakhul Jannah2.
Irsan Hasan3.
Muhadi4.
Sally Aman Nasution4.
Kaka Renaldi5.
Andri Sanityoso3.
Adityo Susilo6 Division of Endocrinology.
Metabolism and Diabetes.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia Division of Hepatobiliary.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
Division of Cardiology.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia Division of Gastroenterology.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
Division of Tropical and Infectious Diseases.
Department of Internal Medicine.
Faculty of Medicine Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jakarta.
Indonesia.
*Corresponding Author:
Prof.
Dyah Purnamasari.
MD.
PhD.
Division of Endocrinology.
Metabolism and Diabetes.
Department of Internal Medicine.
Faculty of Medicine.
Universitas Indonesia - Cipto Mangunkusumo Hospital.
Jl.
Diponegoro no.
Jakarta 10430.
Indonesia.
Email: dyah_p_irawan@yahoo.
ABSTRACT
Background: First-degree relatives (FDR) of individuals with type 2 diabetes mellitus (T2DM) are at higher risk of developing early metabolic disturbances, particularly insulin resistance and lipid metabolism These issues contribute to a greater predisposition to cardiovascular disease compared to the general population.
Despite the significant contribution, there is limited information on the relationship between atherogenic lipoproteins of normotensive and normoglycemic young FDR in Indonesia.
Therefore, this study aimed to evaluate the correlation between small dense low-density lipoprotein .
dLDL) levels and HOMA-IR in FDR with T2DM, as well as assess variation in sdLDL levels within FDR and non-FDR groups.
Methods:
This cross-sectional study analyzed secondary data from the Metabolic Endocrine and Diabetes Division of the Internal Medicine Department.
Faculty of Medicine.
Universitas Indonesia, and Cipto Mangunkusumo Hospital.
The primary study, titled AuEarly Cardio-Metabolic Disorders in the First-Degree Relative Population of Type 2 Diabetes Mellitus,Ay was expanded to include sdLDL measurements.
Bivariate analysis and correlation tests were used to explore the relationship between sdLDL and HOMA-IR.
Results: The experiment included 125 subjects consisting of 62 FDR and 63 non-FDR.
Based on the results, sdLDL levels were significantly higher in the FDR group compared to the non-FDR group .
42 (IQR 20.
05 (IQR 12.
mg/dL, p<0.
However, no significant correlation was observed between sdLDL levels and HOMA-IR in the FDR group .
=0.
059, p=0.
Conclusion: This study showed a significant difference in sdLDL levels between FDR and non-FDR of T2DM patients.
However, no correlation was found between sdLDL and HOMA-IR in the FDR group.
Keywords: atherogenic lipoprotein, first-degree relative, type 2 diabetes mellitus, sdLDL Acta Med Indones - Indones J Intern Med A Vol 57 A Number 3 A July 2025 Vol 57 A Number 3 A July 2025 Atherogenic Lipoprotein Profile in First-Degree Relatives of Individuals INTRODUCTION Diabetes Mellitus (DM) is a global health issue, posing a significant threat to health status.
Data from the World Health Organization (WHO) in 2014 showed an increasing prevalence of DM worldwide, with the Southeast and Western Asia regions estimated to have the highest number of 1 In Indonesia, the 2018 Basic Health Research (RISKESDAS) reported a 0.
increase in DM prevalence among the population aged Ou15 years between 2013 and 2018, showing a similar trend to the global scale.
Type 2 Diabetes Mellitus (T2DM) one of the most common non-communicable diseases, influenced by several risk factors, including genetic predisposition.
First-degree relatives (FDR) of T2DM patients are at higher risk of developing T2DM in the future.
Although no specific studies have assessed morbidity and mortality in this population, several reports have shown that FDR with T2DM experienced pancreatic beta-cell dysfunction and insulin resistance at a young age, even when glucose tolerance is still normal.
3Ae7 Insulin resistance is a key factor in the pathophysiology of metabolic syndrome, which includes central obesity, dyslipidemia, hypertension, and elevated fasting blood glucose 8,9 Several studies have shown a significant prevalence of insulin resistance among FDRs with T2DM.
10,11 This condition increases their risk of developing various metabolic diseases, including metabolic syndrome and cardiovascular diseases in the future, triggered by changes in atherogenic lipid profile, such as elevated small dense low-density lipoprotein .
dLDL).
Despite the significant risk, there is limited information regarding atherogenic lipoprotein profiles in FDR with T2DM patients in Indonesia.
Therefore, this study aimed to explore the atherogenic lipoprotein profiles in normoglycemic and normotensive FDR with T2DM and evaluate the relationship between insulin resistance and changes in lipid profiles in the high-risk population.
METHODS
Design.
Settings, and Respondents This cross-sectional study analyzed secondary data from the Metabolic Endocrine and Diabetes Division of the Internal Medicine Department.
Faculty of Medicine.
Universitas Indonesia, and Cipto Mangunkusumo National General Hospital.
The primary study is titled AuEarly Cardio-Metabolic Disorders in the FirstDegree Relative Population of Type 2 Diabetes Mellitus.
Ay The FDRs group was consisted of biological children of T2DM patients who regularly attended the endocrine clinic.
Meanwhile, the non-FDRs group consisted of medical and non-medical staff from the Cipto Mangunkusumo hospital who had no parental history of T2DM.
Subjects who signed the informed consent form received blood pressure, random blood glucose, and HbA1c testing using a BioHermes A1c Analyzer to screen for exclusion criteria.
Furthermore, subjects who met the inclusion criteria .
lood pressure <140/90 mmHg.
HbA1c levels between 4Ae5.
6%, and BMI <35 kg/mA) had venous blood drawn after 12 hours of fasting.
The blood samples obtained were used for assessment of fasting blood glucose, insulin.
HbA1c, total cholesterol.
LDL cholesterol.
HDL cholesterol, and triglycerides.
The remaining serum was centrifuged and stored at -80AC freezer in the Indonesian Medical Education and Research Institute (IMERI) Metabolic Disorder.
Cardiovascular, and Aging Cluster (MVA) laboratory.
In this study, additional sdLDL testing was performed on the stored serum samples using a sandwich ELISA with human sdLDL .
NBP2-82535 ELISA kit by Novus Biologicals.
Statistical Analysis Data analysis was performed with IBM SPSS Statistics 25.
0 and STATA version 17 software.
Univariate analysis was conducted to describe the characteristics of the subjects.
The difference in mean sdLDL between the FDRs and non-FDRs groups was analyzed using MannAeWhitney U Meanwhile, the correlation between sdLDL and HOMA-IR in the FDRs group was analyzed using SpearmanAos correlation, with a statistical significance level of p<0,05.
Ethical Issues This study received ethical approval from the Health Research Ethics Committee.
Faculty of Medicine Universitas Indonesia, with number KET-784/UN2.
F1/ETIK/PPM.
02/2024.
Dyah Purnamasari Acta Med Indones-Indones J Intern Med Furthermore, all patient data were kept confidential throughout the study process.
Mean Difference of SDLDL Levels between FDRs and Non-FDRs Subjects The analysis showed that the median sdLDL level in FDR subjects was 31.
42 mg/dL .
1Ae41.
39 mg/dL), while the non-FDR group 05 mg/dL .
ange: 12.
18Ae26.
13 mg/dL).
Due to the non-normal distribution of data, a non-parametric Mann-Whitney U test was conducted to compare the two groups.
The test showed a statistically significant difference in median sdLDL levels between FDR and non-FDR subjects .
<0.
, which remained consistent after stratifying by gender.
Among male subjects, median sdLDL levels were 32.
69 mg/dL .
RESULTS
Study Population A total of 125 subjects were included in the study, consisting of 62 with a parental history of T2DM and 63 without such a history.
Age- and sex-matching were conducted for FDR subjects.
The median age was 28 years, range: 26-31 years.
The distribution of subjects was 65 males .
%) and 60 females .
%).
Baseline characteristics of the study population are summarized in Table 1.
Table 1.
Baseline characteristics of the study population Variable All subjects .
FDRs .
Non-FDRs .
P-value Age .
ears ol.
, median (IQR) 28 .
Ae .
Ae 31.
Ae .
Male 65 .
Female 60 .
Father 26 .
Mother 32 .
Father and Mother 4 .
None 63 .
BMI .
g/m.
Mean (SD) 20 .
Male 3 .
Female 11 .
Waist circumference .
, mean (SD) 12 .
Male 12 .
Gender, n (%) Family history of T2DM, n (%) <0.
Female 19 .
TG .
g/dL), median (IQR) 77 .
Ae .
25 Ae 110.
Ae .
Ae .
5 Ae 205.
Ae .
5 Ae .
Ae .
Ae .
10 Ae 1.
18 Ae 3.
0 Ae 1.
Total cholesterol .
g/dL), median (IQR) LDL-C .
g/dL), mean
(SD)
HDL-C .
g/dL), median (IQR) Fasting insulin .
IU/L), median (IQR) HOMA-IR, median (RIK) Abbreviations: SD=standard deviation.
IQR=interquartile range.
BMI=body mass index.
TG= triglycerides.
LDL= Low Density Lipoprotein.
HDL= High Density Lipoprotein.
HOMA-IR= Homeostatic Model Assesment for Insulin Resistance Vol 57 A Number 3 A July 2025 Atherogenic Lipoprotein Profile in First-Degree Relatives of Individuals 46Ae75.
21 mg/dL) in the FDR group and 23.
mg/dL .
ange: 12.
38Ae41.
11 mg/dL) in the nonFDR group .
= 0.
For female subjects, the median sdLDL levels were 25.
17 mg/dL .
34Ae65.
23 mg/dL) in the FDR group and 20.
mg/dL .
ange: 0.
89Ae56.
09 mg/dL) in the nonFDR group .
= 0.
The difference in sdLDL levels FDR and non-FDR subjects is summarized in Table 2.
Correlation between sdLDL Levels and HOMA-IR in the FDR Group There was no significant correlation between sdLDL and HOMA-IR, with an r-value of 0.
and a p-value of 0.
The correlation between sdLDL levels and HOMA-IR in the FDR group is presented in Table 3 and Figure 1.
Table 2.
Mean Difference of sdLDL Levels between FDR and Non-FDR Subjects Group Variable SdLDL .
g/dL), median (IQR) Male Female FDRs Non-FDRs 42 .
1 Ae 41.
18 Ae 26.
Table 3.
Correlation between sdLDL Levels and HOMAIR in FDRs Group
HOMA IR
SdLDL Spearman correlation test P-value <0.
DISCUSSION
This study included a specific population comprising FDR subjects without a history of glucose intolerance or hypertension.
Previous reports on FDR population often included subjects who already had glucose intolerance.
Figure 1.
Scatter Plot of the Correlation between sdLDL Levels and HOMA-IR in FDRs Group Dyah Purnamasari such as prediabetes or DM.
This distinction is valuable for the early detection of metabolic disturbances in high-risk individuals.
The median age in this study was 28 years .
ange: 26Ae31 year.
, without a significant difference between the FDR and non-FDR groups .
Ae31.
27 years .
Ae .
, p = 0.
This study focused on a young FDR population under the age of 40, given that individuals above the age have a higher risk of metabolic disease, regardless of family history.
In comparison.
Sonuga et al.
conducted a study in Nigeria on atherogenic lipoproteins among the FDR population, which included younger subjects aged 18Ae25, with a mean age of 20 years in the 76 FDRs group and 21 years in the 74 non-FDR group.
The variation in results was attributed to differences in inclusion criteria.
Mean Difference of sdLDL Levels between FDRs and Non-FDRs Subjects There are no previous studies that have directly compared sdLDL levels between FDR and non-FDR groups.
However, several reports have examined sdLDL with designs similar to this study.
For example.
Fan et al.
on sdLDL levels in a non-diabetic population in China reported a significant difference in sdLDL values between individuals with and without metabolic syndrome .
95Ae1.
66Ae1.
p<0.
SdLDL levels have prognostic value for coronary heart disease (CHD).
According to the American Heart AssociationAos AuGet With The GuidelinesAy program, 75% of CHD patients admitted had relatively normal LDL cholesterol levels (<130 mg/dL), and 23% had <70 mg/dL.
This suggests that several patients remained at risk for CHD even within normal LDL cholesterol ranges.
The atherogenic properties of sdLDL have been confirmed in numerous reports, including the 2009 Malmy Heart Study, the Atherosclerosis Risk in Communities (ARIC), and the Multi-Ethnic Study of Atherosclerosis (MESA) in 2014.
15Ae17 The ARIC study found that sdLDL levels above 50 mg/dL were predictive of CHD This also included individuals with LDL levels below 100 mg/dL who were previously Acta Med Indones-Indones J Intern Med considered low risk.
18 Similarly, the MESA study reported a significant increase in cardiovascular disease risk with sdLDL levels over 46 mg/dL.
A report from Japan also found that LDL levels at 100 mg/dL did not predict CHD risk, but sdLDL levels above 35 mg/dL showed significantly increased risk in patients with stable CHD.
19 In this study, the FDR group showed significantly higher mean sdLDL levels compared with the non-FDR group.
Correlation between sdLDL Levels and HOMA-IR in the FDRs Group The formation of sdLDL is closely associated with insulin resistance and hypertriglyceridemia, with VLDL1-TG levels serving as a primary predictor of sdLDL particle size.
20,21 Studies investigating the relationship between sdLDL and insulin resistance include Krayenbuehl et 22 in Switzerland, who reported a correlation between LDL particle size and insulin resistance, measured by HOMA-IR .
= -0.
53, p = 0.
Similarly, a cohort study by Gerber et al.
23 found a consistent correlation between the proportion of sdLDL particles and insulin resistance .
easured by HOMA-IR) both at baseline and after a two-year follow-up .
= 0.
04 and p = 0.
Based on these results, 70.
6% of subjects showed worsened insulin resistance as the proportion of sdLDL increased during the follow-up period.
The differences between this study and the findings of Krayenbuehl et al.
22 and Gerber et 23 could be attributed to several factors.
Both previous studies included an older population with mean ages of 60 and 63 years.
The subjects had been diagnosed with DM .
ean duration of 2 and 7.
3 year.
, presented with an obese profile obese profile .
ean BMI of 30 and 30.
5 kg/mA), and showed higher baseline HOMA-IR values .
9 and 3.
36, respectivel.
In comparison, this study included a younger FDR population with a mean age of 28 years, a lower mean BMI of 42 kg/mA, and a reduced HOMA-IR of 1.
indicating minimal or no insulin resistance in the FDR group.
Limitations This study has several limitations.
First, samples were collected only once, which Vol 57 A Number 3 A July 2025 Atherogenic Lipoprotein Profile in First-Degree Relatives of Individuals prevented the ability to assess causal relationships.
Second, the DM history of both parents in the non-FDR group was not objectively verified through laboratory testing, which could introduce selection bias.
Additionally, factors that could influence insulin sensitivity, such as diet, physical activity, body composition, psychological stressAy .
voids repetition of AuphysicalA.
, psychological stress, and inflammatory parameters, were not Generalizability The results of this study can be applied to the young adult population in Indonesia with FDR of T2DM.
CONCLUSION
In conclusion, there was a significant difference in sdLDL levels between FDR and non-FDR of T2DM patients.
However, no correlation was found between sdLDL and HOMA-IR in the FDR group.
ACKNOWLEDGMENTS
The authors are grateful to the IMERI Metabolic Disorder.
Cardiovascular, and Aging Cluster (MVA) laboratory for providing the data in this study, and the staff of the Division of Endocrine.
Metabolic, and Diabetes Department of Internal Medicine.
Faculty of Medicine.
Universitas Indonesia, for helping administration and data management of this study.
CONFLICT OF INTEREST
The authors declare that no conflict of interest could influence the work reported in this paper.
ABBREVIATIONS
SD: standard deviation.
IQR: interquartile BMI: body mass index.
TG: triglycerides.
LDL-C: Low-Density Lipoprotein Cholesterol.
HDL-C: High-Density Lipoprotein Cholesterol.
HOMA-IR: Homeostatic Model Assessment for Insulin Resistance.
sdLDL: small, dense LowDensity Lipoprotein.
REFERENCES