Summary:
In middle-aged and older adults with type 2 diabetes mellitus (T2DM), L-citrulline supplementation significantly improved endothelial function and reduced arterial stiffness, as well as lowered fasting glucose levels in both fasted and acute hyperglycemic states compared to placebo administration,
though it was associated with minor gastrointestinal side effects.
| PICO | Description |
|---|---|
| Population | Middle-aged and older adults diagnosed with type 2 diabetes mellitus experiencing endothelial dysfunction and arterial stiffness. |
| Intervention | Oral L-citrulline supplementation administered at a dose sufficient to evaluate effects on vascular function in fasted and acute hyperglycemic states. |
| Comparison | Placebo treatment under identical testing conditions during fasted and acute hyperglycemic statuses. |
| Outcome | L-citrulline significantly improved endothelial function and reduced arterial stiffness markers compared to placebo; additionally, it lowered fasting and postprandial blood glucose levels. The intervention was well tolerated, with only mild gastrointestinal complaints reported. |
Clinical Context
Cardiovascular disease represents the leading cause of mortality in type 2 diabetes, driven substantially by endothelial dysfunction and arterial stiffness that accelerate atherosclerosis progression. Endothelial dysfunction, characterized by impaired nitric oxide bioavailability, represents an early and reversible stage of vascular disease. In diabetes, chronic hyperglycemia induces oxidative stress and advanced glycation end products that damage endothelial function, while acute hyperglycemic excursions cause transient but repeated vascular insults. L-citrulline is a non-essential amino acid that serves as a precursor to L-arginine, the substrate for endothelial nitric oxide synthase. Unlike direct arginine supplementation, citrulline bypasses hepatic metabolism and may more effectively increase plasma arginine levels and downstream nitric oxide production. This study evaluated whether L-citrulline supplementation could improve vascular function and glucose parameters in middle-aged and older adults with type 2 diabetes under both fasting conditions and during acute hyperglycemic challenge.
Clinical Pearls
- L-citrulline supplementation significantly improved endothelial function compared to placebo in adults with type 2 diabetes, suggesting enhanced nitric oxide bioavailability.
- Arterial stiffness markers decreased with L-citrulline treatment, indicating improvements in large vessel function that influence blood pressure and cardiovascular risk.
- Glucose-lowering effects occurred in both fasting and postprandial states, suggesting L-citrulline may provide metabolic benefits alongside vascular improvements.
- The intervention was well tolerated with only mild gastrointestinal complaints, supporting its safety profile for clinical consideration.
Practical Application
Clinicians may consider L-citrulline supplementation as an adjunctive approach for patients with type 2 diabetes at elevated cardiovascular risk, particularly those with documented endothelial dysfunction or arterial stiffness. The dual benefits on vascular function and glucose metabolism make citrulline an attractive nutritional intervention that complements standard pharmacotherapy. Dosing recommendations should follow the study protocol, and patients should be counseled about potential mild gastrointestinal effects. L-citrulline is available as an over-the-counter supplement, but clinicians should guide appropriate product selection and verify quality. This intervention may be particularly relevant for patients who are not achieving adequate cardiovascular risk reduction with standard medications or who prefer complementary approaches to pharmaceutical intensification.
Broader Evidence Context
L-citrulline has been studied in various populations for cardiovascular and metabolic benefits, with this research extending the evidence specifically to type 2 diabetes. Prior studies demonstrated citrulline’s ability to increase plasma arginine and improve endothelial function in hypertensive patients and heart failure populations. The glucose-lowering effects observed in this study are particularly novel and may relate to improved insulin sensitivity through enhanced nitric oxide-mediated glucose uptake or reduced oxidative stress. The finding that benefits occurred during both fasting and acute hyperglycemic conditions suggests robust effects that persist across metabolic states. These results support citrulline as a cardiovascular nutrition intervention with potential diabetes-specific benefits.
Study Limitations
- The specific L-citrulline dose and duration of supplementation were not detailed in the summary, limiting reproducibility of findings.
- Sample size was not specified, affecting assessment of statistical power and generalizability.
- Long-term cardiovascular outcome data cannot be extrapolated from surrogate endpoint improvements in vascular function.
- The acute hyperglycemic challenge protocol may not reflect real-world postprandial glycemic patterns.
- Interactions with diabetes medications and potential effects on medication requirements were not addressed.
Bottom Line
L-citrulline supplementation improves endothelial function, reduces arterial stiffness, and lowers glucose levels in both fasting and postprandial states in middle-aged and older adults with type 2 diabetes. Clinicians may consider L-citrulline as an adjunctive cardiovascular and metabolic intervention for diabetic patients at elevated vascular risk.
Source: Yejin Kang, et al. “Effects of L-Citrulline Supplementation on Endothelial Function, Arterial Stiffness, and Blood Glucose Level in the Fasted and Acute Hyperglycemic States in Middle-Aged and Older Adults with Type 2 Diabetes.” Read article here.
