Sexual dysfunction in patients with diabetes: association between remnant cholesterol and erectile dysfunction

Background Erectile dysfunction (ED) is closely associated with dyslipidemia; however, it is yet unknown how ED and remnant cholesterol (RC) are related. As such, this research sought to explore the correlation between RC and ED among individuals with diagnosed with diabetes. Methods This cross-sectional study used information from 215 males from National Health and Nutrition Examination Survey (NHANES) from 2001 to 2004. RC was calculated as follows: the values of high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) were subtracted from the total cholesterol (TC) value, while ED diagnoses were based on self-reports. Weighted logistic regression analyses using both univariate and multivariate approaches were conducted to assess the correlation between RC and ED. Results After comprehensive adjustment, multivariable logistic regression models revealed a strong correlation between RC and ED in subjects with diabetes (with an odds ratio (OR) of 7.49 and a 95% confidence interval (CI) of 1.98–28.37; P = 0.004). On categorizing RC into 3 grades (T1-T3), the OR corresponding to higher RC grade increased. Despite the results not reaching statistical significance upon categorization, a consistent and statistically significant trend (P for trend < 0.05) was observed. Conclusion This study indicated a correlation between increased RC levels and a higher prevalence of ED in diabetic males. RC may serve as a promising predictor of ED in individuals with diabetes. However, additional studies are required to confirm these findings. Supplementary Information The online version contains supplementary material available at 10.1186/s12944-024-02046-8.

higher prevalence of ED in diabetic males.RC may serve as a promising predictor of ED in individuals with diabetes.However, additional studies are required to confirm these findings.

Background
Erectile dysfunction (ED) has been observed to have an increasing incidence with advancing age [1].ED is currently acknowledged as a serious health concern among the growing population, leading to diminished quality of life for individuals affected, as well as for their partners and families [2].The National Institutes of Health's commonly used definition of ED is the inability to develop or maintain an erection firm enough for sexual intercourse [3].There are many risk factors, including systemic disease(s), and diabetes may increase the incidence of ED [4,5], with some clinical and epidemiological research supporting a link between ED and metabolic syndrome (MS) [6,7].MS is a multifaceted disease that imposes considerable socioeconomic burdens, and mainly includes hypertension, dyslipidemia, and impaired blood glucose regulation.In addition, it is increasingly acknowledged that insulin resistance (IR) and abdominal obesity are the main signs of MS [8].Thus, it is crucial and beneficial that further research be done on the risk factors related to ED. and its associated outcomes [22].Therefore, there may be a close correlation between RC and the development of ED among individuals with DM.
To the best of current knowledge, there is limited research investigating the relationship between RC and ED in males with DM.For the first time, a novel correlation between RC and ED may be identified, particularly within the diabetic population, which may help provide different approaches to ED intervention or prevention.Therefore, to explore the question, this cross-sectional investigation used extensive information from the National Health and Nutrition Examination Survey (NHANES) (2001)(2002)(2003)(2004).

Study population
The  2001-2002 and 2003-2004) were used.Of 31,473 samples, only 7261 remained for analysis due to the absence of cholesterol data for 24,482 samples.Further exclusion of 5455 samples with missing ED data resulted in the inclusion of 1806 samples.Individuals without DM or with incomplete information were excluded (n=1591).Ultimately, a cohort comprising 215 individuals was included in this study (Figure 1 ).

Assessment of ED
The subsequent inquiry, taken from the Massachusetts Male Aging Study, was used to evaluate erectile function, "Many men have difficulties during sexual activity.
What would you say about your capacity to achieve and maintain an erection strong enough for fulfilling sexual activity?"."Usually able", "always or almost always able", "sometimes able", and "never able" were the options for the responses."The inability to sustain an erection sufficient to satisfy sexual relations was defined as ED [25,26].

Assessment of RC
7 12 In the mobile examination center (MEC), the samples of blood are prepared, kept, and then sent to the Lipoprotein Analytical Laboratory at Johns Hopkins University for analysis.The RC value was derived by subtracting the combined levels of LDL-c and HDL-c from the TC level, which was determined based on the patient's standard fasting lipid profile [27,28].

Assessment of DM
Subjects in this study were diagnosed with DM.Subjects were considered to have DM if physicians had informed them of their condition, current usage of glucose-lowering medication, or glycated hemoglobin (HbA1c) levels ≥ 6.5%.

Covariates
Based on previous research, potential factors considered in the study encompassed age, race/ethnicity, body mass index (BMI), level of education, smoking and alcohol consumption status, hypertension, and CVD.Five separate groups were created based on self-reported racial/ethnic identity: Mexican Americans; Other Hispanic; Non-Hispanic White; Non-Hispanic Black; and Other Race-Including Multi-Racial.Educational levels were categorized into five groups: < 9th grade; 9-11th grade, high-school graduate/GED or equivalent; college or AA degree; and college graduate or above.Individuals who acknowledged consuming a minimum of 12 alcoholic beverages throughout their lifetime were categorized as having a drinking habit.Those who had ever smoked ≥ 100 cigarettes were classified as smokers for the purposes of the survey.Individuals who were surveyed and found to have hypertension had been previously diagnosed with the condition.Additionally, participants identified with myocardial infarction, angina, coronary artery disease, or heart failure were categorized as having CVD.

Statistical analysis
All statistical analyses were conducted using EmpowerStats (X&Y Solutions, association between ED and RC remained strongly positive despite adjustment for more variables.In addition, on categorizing RC into 3 grades (T1-T3), an increase in OR values corresponding to higher RC grade was observed.Although the outcome did not achieve statistical significance following categorization, a consistent and statistically significant trend was observed (P for trend < 0.05).

Discussion
The purpose of this study was to evaluate the connection between RC and ED in subjects diagnosed with DM.Data from two NHANES cycles (2001)(2002)(2003)(2004)   Surprisingly, a strong correlation has been found between increased RC levels and a five-fold rise in the likelihood of peripheral artery disease in the general population [42].Hence, there is a potentially close relationship between RC and ED.The key to future treatments may rely on switching to a different strategy that considers the unique constituents of non-HDL-c, which could lead to more targeted and effective interventions; clinical trials are already assessing reducing treatments that target RC [43].Therefore, based on results of this study and extensive existing researches, it is possible that the involvement of RC could potentially impact the subsequent development and advancement of ED, and this study may contribute to providing new directions for the management and prevention of ED.However, further investigation is crucial to determine the mechanism(s) and significance.
Moreover, DM is associated with higher RC levels, which are likely attributable to dietary and lifestyle variables, as well as IR and high blood glucose levels, which lead to greater retention of triglyceride-rich lipoproteins in the plasma, impairing the activity of lipoprotein lipases [44,45].Reactive oxygen species (ROS) may accumulate up in pancreatic β-cells due to stress in the endoplasmic reticulum and malfunction in the mitochondria caused by an excess of cholesterol.Consequently, this process may lead to structural modifications in particles containing insulin [46].

Strengths and limitations
This study boasts several advantages.Notably, A sizable sample taken from the NHANES was used in this thorough analysis of diabetes patients in the United States.
Second, little research has investigated the relationship between RC and ED, especially among individuals with DM.Third, the pathogenesis of ED is complex, and the identification of new risk factors is advantageous for its early detection and management; consequently, prospects for clinical application(s) are promising.
However, the study also had some limitations, the first of which was its crosssectional design, which pose limitations when assessing the association between fluctuations in RC levels and the onset of ED.Therefore, a direct causal relationship between RC and ED could not be inferred from the findings.As such, further high-18 quality prospective studies are required to obtain more conclusive results.
Additionally, ED assessment is based on patient self-reports, which, while convenient and noninvasive, introduce the potential for recall bias.Standardized assessment tools or medical records are options to mitigate the effects of recall bias; however, the cost involved in such research is high.Therefore, additional studies to establish a causal link between RC and the prevalence of ED in diabetic individuals are warranted.

Conclusion
This study found that among males with DM, there was a positive connection between elevated RC levels and a higher prevalence of ED.RC could potentially act as a valuable predictor for ED in individuals with DM, thus enabling clinicians to implement more targeted screening and intervention strategies for ED.However, the causal connection between RC and ED necessitates additional research.
and ED[9].Furthermore, several epidemiological investigations have indicated that serum markers of dyslipidemia, such as the ratio of 6 high-density lipoprotein cholesterol (HDL-c) to total cholesterol (TC) and levels of HDL-c and low-density lipoprotein cholesterol (LDL-c) serve as predictors of ED[10][11][12].Therefore, the influence of cholesterol levels, other than HDL-c and LDL-c, on the occurrence of ED merits further investigation.Most of the remaining cholesterol is primarily composed of intermediate-density lipoproteins, very lowdensity lipoproteins, and remnants of chylomicrons, which are also known as remnant cholesterol (RC)[13].It circulates within the plasma and accumulates in the subendothelial region[14, 15], leading to endothelial dysfunction, inflammation, and eventually the onset of atherosclerosis[15, 16].Diabetes poses a significant and escalating global health burden, with an estimated 592 million individuals worldwide projected to be affected by the condition by 2035[17, 18].Complications of diabetes mellitus (DM) present a substantial healthcare challenge, encompassing macroangiopathy, microangiopathy, and sexual dysfunction in both sexes.In males with DM, the incidence of ED is roughly 3.5 times higher than in those without the disease[19].Patients with DM frequently have hyperlipidemia, which leads to the greater risk of vascular disease in this population[20].Individuals with DM exhibit elevated RC levels compared to those without DM.It has been found that elevated RC levels and low-grade inflammation have been linked to a higher likelihood of atherosclerotic cardiovascular disease in participants diagnosed withDM[21].According to a prior study, ED could serve as a standalone predictor for cardiovascular disease (CVD) arteries are more prone to have blood flow obstruction at the same degree of endothelial dysfunction and atherosclerosis[37].Glass CK et al. reported that elevated plasma cholesterol levels may independently drive the development of atherosclerosis[39].It is considered that RC may be a major contributor in the development of atherosclerosis through its pro-inflammatory effects, which include the induction of low-grade inflammation and the activation of endothelial cells in a manner that promotes inflammation[40].One hypothesis proposed a potential connection between heightened RC levels and increased triglyceride content of LDL-c particles, particularly the small dense LDL-c particles that tend to promote atherosclerosis and have a prolonged residence time in the bloodstream[41].