Background: Patients with type 2 diabetes (T2D) develop vascular complications due to arginine deficiency-induced microvascular endothelial dysfunction, which is related to the loss of muscle strength (MS) associated with aging. Thus, increased nitric oxide (NO)-mediated vasodilation may improve MS. We investigated the impact of the NO precursor citrulline on microvascular function (endothelial and muscle reactivity) and MS in T2D patients. Methods: Sixteen participants with T2D (53–72 years, nine females) were randomized to citrulline supplementation (CITS, 6 g/day) or placebo for 4 weeks prior to an 8-week washout period, followed by the opposite supplement for 4 weeks in a crossover trial. Endothelial function (log-transformed reactive hyperemia index, LnRHI), forearm muscle reactivity (near-infrared spectroscopy-derived tissue oxygen index (TOI) reperfusion indices), plasma arginine levels (ARG), and handgrip strength (HGS_rel) and calf MS (CMS_rel) adjusted for body weight were measured at baseline and 4 weeks for each condition. Results: CITS increased the LnRHI (∆0.11 ± 0.16 vs. ∆−0.08 ± 0.24, p < 0.05), TOI range (∆2.6 ± 3.3 vs. ∆−1.5 ± 4.8%, p < 0.01), TOI hyperemic response (∆1.2 ± 1.4 vs. ∆−0.6 ± 2.8%, p < 0.05), TOI 2 min area under the curve (∆154 ± 187 vs. ∆−41 ± 194%/s, p < 0.01), ARG (∆43 ± 28 vs. ∆1 ± 16μM/L, p < 0.001), CMS (∆1.5 ± 2.8 vs. ∆−0.3 ± 1.2 kg, p < 0.05), and CMS_rel (∆0.02 ± 0.03 vs. ∆−0.01 ± 0.02 kg/kg, p < 0.01) compared to placebo. The improvements in LnRHI and CMS_rel were correlated (r = 0.37, p < 0.05). Conclusions: This study showed that CITS improves microvascular endothelial function, muscle microvascular reactivity, and calf muscle strength in middle-aged and older patients with T2D.

Background: Acute and chronic hyperglycemia in patients with type 2 diabetes mellitus (T2DM) causes endothelial dysfunction and arterial stiffness, contributing to early mortality from cardiovascular disease (CVD). Although L-citrulline (CIT) supplementation improves endothelial function in older women and decreases fasting glucose in those with T2DM, whether it improves vascular function and blood glucose during acute hyperglycemic states in T2DM is unknown. Methods: We randomized 16 patients with T2DM (age 62 ± 6 years) to consume either CIT (6 g/day) or placebo for 4 weeks. Brachial artery flow-mediated dilation (FMD), brachial and aortic blood pressure, aortic and leg arterial stiffness (pulse wave velocity, PWV), and blood glucose concentration were assessed in the fasted state and 60 min following glucose ingestion (during acute hyperglycemia). Results: Four weeks of L-citrulline supplementation improved FMD, femoral-ankle PWV, aortic systolic blood pressure, and blood glucose concentration in the fasted state compared to placebo (all p < 0.05). During acute hyperglycemia, CIT supplementation increased FMD and reduced femoral-ankle PWV, aortic systolic BP, and glucose levels compared to placebo (all p < 0.05). Conclusions: CIT supplementation is beneficial to improve vascular function and glucose levels during chronic and acute hyperglycemia in middle-aged and older adults with T2DM.