Fat-Soluble Vitamin Deficiencies Drive Oxidative Stress, Dyslipidaemia, and Insulin Resistance in Paediatric Type 1 Diabetes: Evidence From a North African Cohort

INTRODUCTION

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the immune-mediated destruction of pancreatic β-cells, culminating in absolute insulin deficiency and dependence on exogenous insulin for survival.^[1] Although historically defined as a disorder of glycaemic dysregulation, it is increasingly recognized as a systemic disease that profoundly affects multiple metabolic pathways.^[2] Children and adolescents with T1DM face not only the acute consequences of hyperglycaemia and diabetic ketoacidosis but also long-term risks of cardiovascular complications, impaired growth, and oxidative damage that begin early in the disease trajectory.^[3] While glycaemic control, typically assessed by glycated haemoglobin (HbA1c), remains the cornerstone of monitoring, it is now clear that broader biochemical disturbances, particularly those involving lipid metabolism, oxidative stress, and micronutrient status, play equally critical roles in shaping disease outcomes.^[4,5] Among the early metabolic derangements in T1DM, dyslipidaemia represents a central concern.^[6] Even in the absence of obesity, children with T1DM frequently present with elevated triglycerides, increased low-density lipoprotein cholesterol (LDL-C), and reduced high-density lipoprotein cholesterol (HDL-C).^[7-9] Parallel to lipid derangements, oxidative stress is increasingly acknowledged as a central driver of diabetic complications.^[4] Hyperglycaemia accelerates the production of reactive oxygen species (ROS) through multiple biochemical pathways, including glucose auto-oxidation, protein glycation, and mitochondrial dysfunction.^[10,11] Excess ROS burden overwhelms endogenous antioxidant defences, resulting in lipid peroxidation, DNA damage, and protein modification.^[12] In paediatric T1DM, oxidative stress has been implicated in the early onset of endothelial dysfunction and microvascular complications, with elevated levels of malondialdehyde serving as a reliable biomarker of lipid peroxidation.^[13] Conversely, enzymatic and non-enzymatic antioxidant systems, including superoxide dismutase and total antioxidant capacity, play a protective role in counterbalancing ROS. However, evidence suggests that these antioxidant defences are diminished in children with T1DM, further amplifying oxidative damage.^[14,15]

In addition to oxidative stress and dyslipidaemia, emerging evidence points to the relevance of insulin resistance in T1DM, a phenomenon often termed “double diabetes”.^[16] Although traditionally associated with type 2 diabetes, insulin resistance can co-exist with autoimmune diabetes, particularly in poorly controlled cases or in patients exposed to chronic inflammation and metabolic stress.^[17] Subclinical insulin resistance in T1DM has been associated with accelerated atherosclerosis, increased cardiovascular risk, and poor glycaemic stability.^[18] Indices such as the homeostatic model assessment of insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) have been applied as surrogate markers of insulin sensitivity in clinical and epidemiological studies involving children and adolescents with T1DM, primarily for comparative assessment rather than absolute quantification of insulin resistance.^[19,20] Although the assessment of insulin resistance in individuals with T1DM remains challenging, surrogate indices such as HOMA-IR and QUICKI have been widely used in clinical and epidemiological studies of T1DM.^[21] These indices are derived from fasting insulin and glucose levels and have shown reasonable correlation with insulin sensitivity measured by the hyperinsulinemic euglycemic clamp in both adults and adolescents with T1DM, particularly when applied for comparative analyses rather than absolute quantification of insulin resistance.^[22] Previous studies have demonstrated that HOMA-IR and QUICKI reflect peripheral insulin sensitivity influenced by metabolic control, insulin dosing, and glycemic variability, even in populations with suboptimal glycemic control. Notably, micronutrient status may influence these indices, as vitamins A and D are implicated in modulating insulin receptor signalling, glucose transport, and inflammatory cascades that impair insulin action.^[23] Understanding this interaction in paediatric cohorts may provide critical insights into the metabolic vulnerabilities of young diabetic patients. The existing literature on vitamins, oxidative stress, and insulin resistance in T1DM is fragmented and inconclusive. Some studies report strong associations between vitamin D deficiency and impaired insulin sensitivity,^[24] while others fail to find consistent correlations. Similarly, while vitamin A has been linked to antioxidant protection and immune regulation, its role in modulating oxidative stress markers such as MDA and antioxidant defences like SOD and TAC remains underexplored in paediatric diabetes.^[25,26] Moreover, most available studies are derived from Western or Asian populations, with limited representation from North Africa and the Middle East, where differences in genetics, diet, sunlight exposure, and healthcare systems may influence both vitamin status and disease outcomes. Despite recognition of the multifactorial nature of T1DM, few studies have comprehensively integrated fat-soluble vitamin status with atherogenic lipid indices, oxidative stress biomarkers, antioxidant defence mechanisms, and insulin sensitivity in a single paediatric cohort. This study provides a multidimensional view of the metabolic landscape in Libyan children with T1DM. Such an approach may identify vitamins as potential biomarkers and therapeutic targets for mitigating cardiovascular risk, oxidative imbalance, and insulin resistance in paediatric diabetes domains that remain under-investigated in this region.

MATERIAL AND METHODS

RESULTS

Table 1 summarizes the clinical and anthropometric characteristics of the study participants. The two groups were well matched in age and height, with no significant differences observed. However, children with T1DM exhibited significantly lower body weight and BMI compared to healthy controls, suggesting a degree of impaired growth or altered metabolic status, which aligns with the results of the previous study^[27,28] and disagrees with the study,^[28] which found no significant difference in the patient and control groups’ BMI. As expected, HbA1c levels were markedly elevated in the diabetic group (9.2 ± 1.1%) relative to controls (5.1 ± 0.4%, p <0.001), confirming poor glycaemic control in the patient cohort. The mean disease duration among T1DM patients was 3.6 ± 2.1 years, and nearly one-third had a history of diabetic ketoacidosis, reflecting the clinical burden of acute complications in this population.

The correlations of vitamins A, D, and E with lipid parameters, oxidative stress, and antioxidant defence markers in children with T1DM are presented in Table 2. Across all three vitamins, consistent trends were observed: higher vitamin concentrations were associated with a more favourable lipid and oxidative profile, whereas deficiencies correlated with atherogenic and pro-oxidant states. These results align with the previous study,^[29] which concluded that vitamin E supplementation may improve lipid profiles in diabetic patients, particularly by significantly reducing total cholesterol and LDL-C.^[29] Although the effects on triglycerides and HDL-C were not statistically significant, they demonstrated potential clinical relevance. Vitamin A in this study exhibited significant inverse correlations with LDL-C (r = −0.61, p = 0.004), TG/HDL ratio (r = −0.68, p = 0.001), and MDA levels (r = −0.71, p = 0.0006), indicating that lower vitamin A concentrations are linked to dyslipidaemia and enhanced lipid peroxidation. This may be attributed to vitamin A deficiency, which disrupts lipid regulation and weakens antioxidant defences, thereby promoting dyslipidaemia, enhancing lipid peroxidation, and increasing oxidized LDL formation that elevates cardiovascular risk.^[30] In contrast, positive correlations were found with antioxidant defences, including SOD (r = +0.73, p = 0.0003) and TAC (r = +0.67, p = 0.0012). These findings suggest that vitamin A deficiency may aggravate oxidative stress through impaired antioxidant activity, consistent with its role as a retinoid antioxidant and immune regulator.^[31]

Vitamin D displayed even stronger associations, with inverse correlations to LDL-C (r = −0.59, p = 0.006), TG/HDL ratio (r = −0.74, p = 0.0002), and MDA (r = −0.76, p = 0.0001). Positive correlations with SOD (r = +0.78, p = 0.00005) and TAC (r = +0.75, p = 0.0002) further highlight its role in modulating oxidative balance, supporting the results of the previous study.^[32,33] The scatter plots presented in Figure 1 provide a visual demonstration of the strong associations between the status of studied vitamins and oxidative stress/antioxidant defence in children with T1DM. Consistent with the correlation analyses summarized in Table 2, serum levels of vitamins A, D, and E were inversely associated with malondialdehyde, a well-established biomarker of lipid peroxidation, and positively correlated with TAC, which reflects the systemic ability to neutralize reactive oxygen species. A previous study reported that vitamin D does not significantly mediate oxidative stress in children with obesity and/or metabolic syndrome. Instead, the observed alterations in inflammatory and oxidative stress biomarkers appear to be primarily driven by obesity itself, rather than vitamin D status.^[34] In this study, lower serum levels of vitamins A, D, and E are linked to higher oxidative stress, as indicated by elevated MDA, while higher levels correlate with improved antioxidant defence. This reinforces the critical role of these vitamins in modulating redox balance in children with T1DM.

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Figure 1:

Scatter plots between the status of vitamins A, D, and E and oxidative stress/antioxidant defence in children with T1DM. T1DM: Type of diabetes mellitus. MDA: Malondialdehyde, TAC: Total antioxidant capacity, SOD: Superoxide dismutase.

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Figure 2 demonstrates a robust and biologically coherent relationship between fat-soluble vitamins and SOD activity in paediatric T1DM, underscoring the interdependence between micronutrient status and enzymatic antioxidant capacity. Retinol or vitamin A displayed a moderate but consistent association, suggesting its contribution extends beyond direct radical scavenging to the regulation of redox-sensitive transcription factors and retinoid-responsive genes that fine-tune antioxidant enzyme expression.^[25] Vitamin D emerged as the most potent correlate, consistent with accumulating evidence that it transcriptionally regulates key antioxidant enzymes through vitamin D response elements, thereby exerting dual actions as both an immunomodulator and a modulator of oxidative stress. These results support those obtained in.^[35] In parallel, α-tocopherol (vitamin E) showed positive associations with SOD, reinforcing its canonical role as the first line of defence against lipid peroxidation while simultaneously cooperating with enzymatic antioxidants to quench reactive oxygen species.^[36] The convergence of these trends highlights a critical pathophysiological insight: in T1DM, deficiencies in fat-soluble vitamins are not passive markers of poor nutritional status but active drivers of impaired antioxidant defence.^[37] This compounded deficit micronutrient depletion, coupled with diminished SOD activity, creates a permissive environment for oxidative injury, which may accelerate vascular and microvascular complications early in the disease trajectory.

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Figure 2:

Positive associations between vitamins A, D, and E and SOD activity in children with T1DM, highlighting the supportive role of fat-soluble vitamins in strengthening enzymatic antioxidant defences.T1DM: Type 1 diabetes mellitus, SOD: Superoxide dismutase.

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Table 3 reveals a consistent pattern whereby higher serum concentrations of vitamins A, D, and E were associated with reduced insulin resistance (lower HOMA-IR) and enhanced insulin sensitivity (higher HOMA-%S and QUICKI) in children with T1DM. Among these, vitamin D showed the strongest correlations (HOMA-IR: r = −0.75, QUICKI: r = +0.79), reinforcing its central role in modulating insulin signalling through enhanced receptor expression, improved β-cell function, and attenuation of inflammation mechanisms that may underlie the emergence of the “double diabetes” phenotype.^[38] Vitamin A also demonstrated significant associations, suggesting that retinol deficiency may contribute to insulin resistance by impairing retinoid-mediated transcription and promoting oxidative and inflammatory stress, while vitamin E, although exhibiting comparatively weaker correlations, maintained significant inverse relationships with HOMA-IR and positive links with sensitivity indices, likely reflecting its antioxidant protection of insulin signalling pathways.

Retinol also exhibited a moderate but significant association with HOMA-IR and QUICKI scores, as shown in Figure 3, suggesting that inadequate retinoid availability may aggravate subclinical insulin resistance through impaired antioxidant function, disruption of retinoid-mediated transcriptional regulation, and altered lipid metabolism.^[39] Although less extensively investigated than vitamin D in this context, vitamin A’s potential to influence β-cell survival and insulin receptor signalling provides a biologically plausible mechanism.^[40]

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Figure 3:

Higher levels of vitamins A, D, and E were associated with lower HOMA-IR and higher QUICKI, indicating improved insulin sensitivity in children with T1DM. T1DM: Type 1 diabetes mellitus, HOMA-IR, Homeostasis Model Assessment of Insulin Resistance, QUICKI: Quantitative Insulin Sensitivity Check Index.

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Critically, these findings delineate a broader pathophysiological framework in which fat-soluble vitamin deficiencies act in concert with oxidative stress and dyslipidaemia to undermine insulin sensitivity in paediatric T1DM. Unlike type 2 diabetes, where insulin resistance is largely obesity-driven, the mechanisms in T1DM appear to arise from the convergence of autoimmune β-cell failure, chronic low-grade inflammation, and impaired antioxidant defences secondary to micronutrient depletion. This interplay suggests that deficiencies in vitamins A, D, and E do not merely reflect poor nutritional status but actively contribute to metabolic fragility by amplifying oxidative injury, disrupting insulin signalling, and accelerating vascular vulnerability. The novelty of this analysis lies in its integrative approach: by simultaneously mapping vitamin status against validated indices of insulin resistance (HOMA-IR) and sensitivity (QUICKI), the study provides compelling evidence that micronutrient availability is not just a passive correlate but a critical determinant of metabolic resilience in young patients with autoimmune diabetes.

DISCUSSION

The consistent inverse relationships observed between these vitamins and lipid peroxidation markers, alongside positive correlations with antioxidant enzymes, delineate a pathophysiological triad in which micronutrient depletion, oxidative stress, and dyslipidaemia act in concert to impair insulin sensitivity and accelerate vascular risk as early reported.^[41] Our results emphasize the dual role of vitamin D as both an immunomodulator and a metabolic regulator, reinforcing its involvement in cardiovascular protection in the diabetic state. Similarly, vitamin E, the principal lipid-soluble antioxidant in plasma, demonstrated inverse associations with LDL-C (r = −0.55, p = 0.010), TG/HDL ratio (r = −0.62, p = 0.005), and MDA (r = −0.69, p = 0.0008). Positive correlations were observed with SOD (r = +0.71, p = 0.0004) and TAC (r = +0.66, p = 0.0015), indicating that diminished vitamin E levels coincide with weaker endogenous antioxidant defences. Given its role in neutralizing free radicals and preventing lipid peroxidation, the reduction of vitamin E in T1DM children may exacerbate oxidative stress and contribute to early vascular dysfunction.^[25] Vitamin E depletion further amplifies lipid peroxidation, promoting cellular injury through accumulation of reactive aldehydes such as 4-hydroxynonenal, while vitamin A deficiency reduces superoxide dismutase and total antioxidant capacity.^[42,43] Lower serum concentrations of vitamin A coincided with markedly higher MDA values, supporting its protective role in limiting lipid peroxidation. Although a previous study reported a similar trend for vitamin D.^[44]

Our results align with prior studies showing that retinol deficiency compromises membrane stability and increases susceptibility to oxidative damage in diabetes.^[25,45] In parallel, vitamin A showed a clear positive trend with TAC, indicating that higher retinol availability enhances the endogenous antioxidant pool, either directly through its radical-scavenging properties or indirectly via modulation of retinol-binding proteins and antioxidant enzymes. Vitamin D exhibited the strongest associations among the three vitamins, with a steeper inverse slope against MDA and a more pronounced positive correlation with TAC.^[44] This is particularly notable, as vitamin D has traditionally been studied for its immunomodulatory and skeletal roles rather than as an antioxidant. However, accumulating evidence suggests that vitamin D deficiency exacerbates oxidative imbalance through increased mitochondrial ROS production and impaired regulation of antioxidant enzymes. Vitamin E, the major lipid-soluble antioxidant, showed clear inverse associations with MDA and positive correlations with TAC, underscoring its key role in halting lipid peroxidation and preserving systemic redox balance.^[46] Even modest reductions in α-tocopherol are linked to impaired antioxidant capacity, reinforcing its clinical relevance in children with T1DM. Moreover, when considered alongside vitamins A and D, the data reveal a consistent pattern in which deficiencies cluster as part of a broader oxidative stress phenotype. This convergence suggests that fat-soluble vitamin depletion contributes to heightened lipid peroxidation, early endothelial dysfunction, and potentially premature cardiovascular risk in paediatric T1DM.^[25]

Vitamin D displayed the most pronounced associations, with children deficient in vitamin D showing markedly higher HOMA-IR and lower QUICKI. These findings align with mounting evidence that vitamin D enhances insulin receptor expression, improves glucose uptake in peripheral tissues, and attenuates chronic inflammation, thereby bridging autoimmune pathology with metabolic dysregulation.^[47] Notably, this supports the concept of a “double diabetes” phenotype, wherein autoimmune insulin deficiency co-exists with insulin resistance, compounding cardiometabolic risk even in non-obese children. Vitamin E, while showing comparatively weaker associations, nonetheless demonstrated consistent inverse correlations with HOMA-IR and positive associations with QUICKI. Its role appears predominantly indirect, acting through the attenuation of oxidative stress and preservation of insulin signalling integrity. Our data align with recent reports demonstrating that vitamin D supplementation enhances insulin receptor function and lowers cardiovascular risk in diabetes,^[48] yet extend the field by illustrating that concurrent deficiencies in vitamins A and E magnify oxidative injury and metabolic impairment. Taken together, these findings reposition fat-soluble vitamins as active determinants of oxidative and metabolic equilibrium, underscoring their therapeutic potential to enhance metabolic resilience and reduce the long-term cardiometabolic burden in children with T1DM.

CONCLUSION

This study provides compelling evidence that fat-soluble vitamin deficiencies in paediatric T1DM are not passive reflections of poor nutritional status but active contributors to metabolic vulnerability. Deficits in vitamins A, D, and E were consistently linked to dyslipidaemia, heightened oxidative stress, and impaired insulin sensitivity, underscoring their integrative role in shaping disease progression. The strong inverse associations with LDL, TG/HDL ratio, and MDA, together with positive correlations with SOD, TAC, and insulin sensitivity indices, highlight the dual impact of deficiency: amplification of oxidative injury and weakening of protective antioxidant defences. Subgroup analyses confirmed that poor glycaemic control magnifies these deficiencies, while the clustering of multiple deficits produced the most adverse oxidative and metabolic profiles, revealing a clear dose-response relationship. Importantly, multivariate models identified vitamins D and E as independent predictors of insulin resistance, reinforcing their mechanistic roles vitamin D as a regulator of insulin receptor signalling and inflammation, and vitamin E as the primary lipid-soluble antioxidant, mitigating ROS-induced metabolic dysfunction. These findings establish micronutrient status as a determinant of metabolic resilience rather than a secondary biomarker, and point to fat-soluble vitamins as both diagnostic indicators and therapeutic targets in paediatric T1DM. Taken together, this integrative analysis from a North African cohort expands current understanding of the interplay between micronutrient deficiency, oxidative imbalance, and insulin resistance in autoimmune diabetes.