Role of dietary interventions on microvascular health in South-Asian Surinamese people with type 2 diabetes in the Netherlands: A randomized controlled trial

People of South-Asian Surinamese descent with type 2 diabetes in the Netherlands have a high burden of vascular complications and faster progression than other ethnic groups. Endothelial dysfunction and degradation of the endothelial glycocalyx (EG) are early hallmarks leading to microvascular damage, potentially driven by enzymes such as heparanase-1 and inflammatory mediators like MCP-1. The study aimed to test whether two dietary strategies—repeated cycles of a fasting-mimicking diet (FMD) or supplementation with a glycocalyx mimetic (Endocalyx™)—could preserve endothelial stability and microvascular health in this high-risk group. Microvascular health was assessed non-invasively in the sublingual microvasculature using SDF imaging with GlycoCheck™.

Prior work shows intermittent fasting or fasting-mimicking diets can induce anti-inflammatory and cytoprotective effects, improve metabolic risk factors, and were safe with potential renal benefits in T2DM with microalbuminuria. Experimental diabetic models suggested repeated FMD may partially preserve glomerular endothelial glycocalyx coverage but can perturb metabolic responses. Glycocalyx-preserving approaches using sulfated glycosaminoglycan mimetics (e.g., fucoidan, a key component of Endocalyx™) have shown EG preservation in vitro and in disease contexts (including models related to CKD serum and COVID-19). South-Asian populations may exhibit metabolic inflexibility and increased vulnerability to microvascular complications, underscoring the need for targeted interventions.

Design: Multi-arm, parallel-group, randomized, placebo-controlled trial with three arms: (1) fasting-mimicking diet (FMD), (2) Endocalyx™ supplementation, (3) placebo. Setting and period: General practitioners’ offices in The Hague area, Netherlands; May 2018–September 2020. Participants: 56 adults (18–75 years) with SA-T2DM (South-Asian Surinamese descent), on hypoglycemic therapy, and documented albuminuria in prior 12 months (ACR 0.3–30 mg/mmol). eGFR >45 mL/min/1.73 m². Randomization and blinding: Allocation by LUMC Pharmacy via envelopes. Supplement and placebo arms were blinded to participants, providers, and researchers; diet arm not blinded. Interventions: FMD (Prolon®) 5-day low-protein, plant-based regimen monthly for 3 consecutive months (Day 1: 1090 kcal, 34% CHO, 56% fat, 10% protein; Days 2–5: 725 kcal, 47% CHO, 44% fat, 9% protein). Endocalyx™: 4 capsules/day for 3 months; each capsule contained fucoidan (106.25 mg), glucosamine sulfate (375 mg), hyaluronic acid (17.5 mg), SOD/polyphenol blend (120 mg), plus excipients. Placebo: Microcrystalline cellulose capsules, identical schedule. No dietary counseling otherwise. Safety and compliance: During FMD, sulfonylureas and short-acting insulin were discontinued; long-acting insulin reduced 50%; fasting glucose monitored days 6–8. Compliance checked via blood/urine ketones on Day 5 of first cycle; regular contact during cycles. Outcomes: Primary endpoint—improvement of microvascular function (MVHSdynamic) within 3 months using sublingual SDF imaging with GlycoCheck™ (parameters: VRBC, perfused capillary density, static/dynamic CBV, static/dynamic PBR, MVHS). Secondary endpoints—clinical (BP, BMI, waist), laboratory (ACR, fasting glucose, HbA1c, C-peptide, IGF-1, lipids, hsCRP, creatinine/eGFR), glycocalyx-related enzymes/markers (plasma HPSE-1 activity, HYAL-1 activity, HYAL-4 activity and protein, ANG-2, sTM); urinary HPSE-1 and MCP-1 normalized to creatinine. Data collection: Baseline and monthly visits during 3-month intervention; follow-up at month 6 (3 months post-intervention). Statistical analysis: Intention-to-treat linear mixed models for repeated measures with Bonferroni post hoc; models adjusted for age, sex, baseline microvascular and macrovascular history, and baseline hypertension. Per-protocol delta changes compared by unpaired t-tests. Significance at p<0.05. Trial registration: NCT03889236. Ethics: Conducted per Declaration of Helsinki; approved by LUMC Ethics Committee.

- Cohort and control trajectory: Compared with a general Dutch cohort, SA-T2DM participants had lower perfused capillary density at baseline. In the placebo group, endothelial health (PBR; inverse of glycocalyx dimension) and MVHSdynamic worsened over the first 3 months. - FMD arm (intention-to-treat): After 3 months (3 weeks post last cycle), PBRdynamic increased by 0.32 μm (95% CI 0.18–0.50), indicating worsening endothelial glycocalyx penetration; treatment effects vs placebo significant for CBVdynamic, PBRstatic, and MVHSdynamic. BMI decreased by −1.0 kg/m² (95% CI −1.5 to −0.5) and HbA1c by −5.1 mmol/mol (95% CI −9.6 to −0.6); BP, fasting glucose, hsCRP, and lipids unchanged. No significant changes in HPSE-1, ANG2, sTM. At 6 months, BMI remained lower (−0.6 kg/m², 95% CI −1.2 to 0.0), but HbA1c reduction was lost; PBRdynamic continued to worsen. - Endocalyx arm (intention-to-treat): Significant improvement in PBRdynamic (−0.73 μm; 95% CI −0.85 to −0.61) and MVHSdynamic (+0.7 points; 95% CI −0.3 to 1.7). Treatment effects vs placebo significant for CBVdynamic, PBRstatic, PBRdynamic, and MVHSdynamic, reflecting overall improved microvascular health. Benefits persisted at 6-month follow-up. Plasma glycocalyx enzymes/markers (HPSE-1, HYAL-1, HYAL-4, ANG2, sTM) unchanged. ACR not significantly changed overall (−2.6 mg/mmol; 95% CI −7.2 to 1.9), but two participants with highest baseline ACR normalized. Urinary MCP-1 reduction vs placebo reached significance (p<0.05). - Safety/adherence: Two hypoglycemia episodes during FMD (despite medication adjustments). One serious adverse event of dehydration-related eGFR decline after FMD resolved with IV fluids. Low ketone detection in many FMD participants suggested limited ketosis or metabolic inflexibility.

This study shows that SA-T2DM patients have compromised microvascular health at baseline and that, without intervention, microvascular parameters deteriorate over time. Repeated short FMD cycles produced transient metabolic improvements (BMI, HbA1c) but did not preserve microvascular endothelial health; PBRdynamic worsened and continued to deteriorate at follow-up, suggesting potential adverse effects on the endothelial glycocalyx despite metabolic gains. Possible reasons include established cardiovascular comorbidities limiting reversibility, suboptimal induction of ketosis/compliance, and potential metabolic inflexibility among South-Asian individuals. In contrast, Endocalyx™ supplementation improved multiple GlycoCheck™-derived microvascular metrics (CBVdynamic, PBRstatic, PBRdynamic, MVHSdynamic) with effects persisting 3 months after cessation, indicating a possible legacy effect. The reduction in urinary MCP-1 suggests an anti-inflammatory impact, though measured plasma glycocalyx enzymes/markers did not change, implying benefits may be mediated through mechanisms not captured by those assays or require longer exposure. Clinically, preserving endothelial function is an attractive strategy to reduce diabetes complications; Endocalyx™ appears promising in SA-T2DM, whereas short-cycle FMD may require optimization or may be less suitable for microvascular preservation in this population. FMD can be implemented with careful medication adjustment and monitoring but warrants caution in patients with CKD or at risk of dehydration.

In South-Asian Surinamese adults with T2DM, three months of fasting-mimicking diet cycles produced temporary reductions in BMI and HbA1c but failed to preserve microvascular endothelial health and was associated with worsening PBRdynamic, persisting at follow-up. In contrast, three months of Endocalyx™ supplementation improved sublingual microvascular health metrics and reduced urinary MCP-1, with benefits sustained after discontinuation. These findings support glycocalyx mimetic supplementation as a potential strategy to preserve microvascular endothelial health in this high-risk population. Larger, longer-duration randomized trials are needed to confirm efficacy, elucidate mechanisms, define responders (e.g., by baseline inflammation or albuminuria), and assess renal and cardiovascular outcomes. For FMD, future research should address metabolic inflexibility, optimize dietary protocols to achieve ketosis safely, and evaluate suitability in SA-T2DM, especially in the presence of CKD.

- Small sample size with incomplete accrual due to COVID-19, limiting power. - High drop-out rate in the diet arm (~30%) and low overall response rate, affecting generalizability. - Blinding not feasible for the diet arm. - Limited evidence of ketosis in many FMD participants, suggesting adherence or metabolic inflexibility issues. - eGFR was not routinely monitored; one dehydration-related SAE occurred after FMD. - Heterogeneity in baseline comorbidities (micro/macrovascular disease) may have influenced outcomes. - Biomarker panels may not have captured the mechanistic pathways mediating microvascular changes within the study duration.