Diabetic vascular complications pose a significant global health burden, particularly affecting South-Asian Surinamese individuals in the Netherlands who exhibit heightened vascular vulnerability. Early endothelial dysfunction is a key hallmark of vascular damage, progressing to structural microvascular changes and irreversible damage. This dysfunction is exacerbated by upregulation of glycocalyx-degrading enzymes and inflammatory cytokines like heparanase-1 (HPSE-1) and monocyte chemoattractant-1 (MCP-1), which impair the endothelial glycocalyx (EG). This study explored two dietary interventions—intermittent fasting mimicking diets (FMD) and glycocalyx mimetic supplementation (Endocalyx™)—to determine their impact on endothelial stability and microvascular health in SA-T2DM patients. The hypothesis was that these interventions could preserve endothelial stability and improve microvascular health, assessed using non-invasive sublingual microcirculation imaging (SDF) and GlycoCheck™ software. In addition to demographics and standard clinical markers, levels of HPSE-1, hyaluronidase 1 (HYAL-1), HYAL-4, angiopoietin-2 (ANG2), soluble thrombomodulin (sTM), and MCP-1 were measured.

Existing research highlights the disproportionate burden of diabetic vascular complications in South-Asian populations. Studies have documented higher rates of micro- and macrovascular complications in these individuals, even at the time of diagnosis, leading to significantly increased risks of end-stage renal disease and cardiovascular mortality. Previous studies have shown that FMD can induce beneficial cellular changes, affecting inflammation and cellular protection. One study showed that FMD was safe and improved albuminuria in T2DM patients. Another experimental study revealed that repeated FMD partially preserved the glomerular endothelial glycocalyx coverage. Furthermore, supplementation with GAG mimetics, like fucoidan (a major component of Endocalyx™), has shown promise in preserving the EG layer.

This was a randomized, placebo-controlled, three-arm, parallel-group study conducted between May 2018 and September 2020. Fifty-six SA-T2DM patients (aged 18-75) were recruited and randomized into three groups: FMD (Prolon®), Endocalyx™ supplementation, and placebo. The primary outcome was improvement in the microvascular health index (MVHSdynamic) after three months of intervention, with a follow-up measurement at month six. The FMD consisted of three monthly 5-day cycles of a low-protein, plant-based diet. Endocalyx™ supplementation involved four capsules daily for three months. Sublingual microcirculation was assessed using SDF imaging and GlycoCheck™ software, measuring red blood cell velocity, capillary density, perfused boundary region (PBR), and MVHS. Clinical parameters (blood pressure, BMI, waist circumference, fasting glucose), laboratory markers (HbA1c, C-peptide, IGF-1, lipids, inflammatory markers, glycocalyx degradation markers), and urinary markers (ACR, HPSE-1, MCP-1) were also assessed at baseline, three months, and six months. Linear mixed models and interaction analysis were used for statistical analysis.

Baseline capillary density in SA-T2DM patients was lower than in previous studies of the general Dutch population, indicating pre-existing microvascular impairment. In the placebo group, microvascular parameters worsened over time. Following three FMD cycles, only PBRdynamic significantly increased at three months, but this effect was reversed at the six-month follow-up. BMI and HbA1c decreased significantly at three months but only BMI remained significantly lower at six months. In contrast, Endocalyx™ supplementation resulted in significant improvements in PBRdynamic and MVHSdynamic at three months, which persisted at six months. Urinary MCP-1 was significantly reduced after three months of Endocalyx™ supplementation, but this effect did not persist. There were no significant changes in other glycocalyx or inflammatory markers in either intervention group.

The study demonstrates that SA-T2DM patients already present with compromised microvascular health at baseline, and this worsens without intervention. While FMD temporarily reduced BMI and HbA1c, it failed to improve and actually worsened some aspects of microvascular health at follow-up. The lack of sustained benefit from FMD might be related to pre-existing cardiovascular comorbidities or impaired metabolic switching from carbohydrates to lipids. In contrast, Endocalyx™ supplementation consistently improved microvascular health, suggesting a protective effect on the endothelial glycocalyx. The reduction in urinary MCP-1 suggests an anti-inflammatory effect. The absence of changes in other glycocalyx degradation markers may indicate that the mechanisms of action of Endocalyx™ are more complex than simply inhibiting these specific enzymes. The study’s findings highlight the need for therapies targeting different aspects of diabetic vascular disease.

This study demonstrates that glycocalyx mimetic supplementation with Endocalyx™ is a promising intervention to improve microvascular health in SA-T2DM. Although FMD showed temporary metabolic benefits, it did not improve and possibly worsened microvascular health. Future research should investigate the long-term effects of Endocalyx™ and explore the underlying mechanisms responsible for its beneficial effects. Further investigation is also needed to optimize FMD protocols for SA-T2DM patients, potentially including strategies to enhance ketogenesis.

The relatively small sample size and high dropout rate, partly due to the COVID-19 pandemic, limit the generalizability of the findings. The low rate of ketosis observed in the FMD group raises concerns about dietary adherence or potential metabolic differences between South-Asian and European populations. The study also lacked routine monitoring of eGFR, which could be crucial in patients undergoing dietary restrictions. Future studies with larger sample sizes and stricter adherence monitoring are necessary to confirm these findings and investigate the effects of these interventions on various diabetic complications.