People with diabetes and hypovitaminosis C fail to conserve urinary vitamin C.

Background: Hypovitaminosis C has negative health consequences. People with diabetes and hypovitaminosis C may fail to conserve vitamin C in the urine, thereby displaying evidence of inappropriate renal leak of vitamin C. This study describes the relationship between plasma and urinary vitamin C in diabetes, with a focus on the clinical characteristics of participants with renal leak. Methods: Retrospective analysis of paired, non-fasting plasma and urine vitamin C, and also clinical characteristics, from participants with either type 1 or type 2 diabetes, recruited from a secondary care diabetes clinic. Plasma vitamin C thresholds for renal leak have been defined previously as 38.1 µmol/L for men and 43.2 µmol/L for women. Results: Statistically significant differences in clinical characteristics were seen between those with; i) renal leak (N = 77) and; ii) hypovitaminosis C but no renal leak (N = 13) and; iii) normal plasma vitamin C levels (n = 34). Compared to participants with adequate plasma vitamin C levels, participants with renal leak tended to have type 2 (rather than type 1) diabetes, a lower eGFR and a higher HbA1c. Conclusion: In the diabetes population studied, renal leak of vitamin C was common. In some participants, it may have contributed to hypovitaminosis C.

Bi-allelic Loss-of-Function Mutations in the NPR-C Receptor Result in Enhanced Growth and Connective Tissue Abnormalities.

The natriuretic peptide signaling pathway has been implicated in many cellular processes, including endochondral ossification and bone growth. More precisely, different mutations in the NPR-B receptor and the CNP ligand have been identified in individuals with either short or tall stature. In this study we show that the NPR-C receptor (encoded by NPR3) is also important for the regulation of linear bone growth. We report four individuals, originating from three different families, with a phenotype characterized by tall stature, long digits, and extra epiphyses in the hands and feet. In addition, aortic dilatation was observed in two of these families. In each affected individual, we identified a bi-allelic loss-of-function mutation in NPR3. The missense mutations (c.442T>C [p.Ser148Pro] and c.1088A>T [p.Asp363Val]) resulted in intracellular retention of the NPR-C receptor and absent localization on the plasma membrane, whereas the nonsense mutation (c.1524delC [p.Tyr508∗]) resulted in nonsense-mediated mRNA decay. Biochemical analysis of plasma from two affected and unrelated individuals revealed a reduced NTproNP/NP ratio for all ligands and also high cGMP levels. These data strongly suggest a reduced clearance of natriuretic peptides by the defective NPR-C receptor and consequently increased activity of the NPR-A/B receptors. In conclusion, this study demonstrates that loss-of-function mutations in NPR3 result in increased NPR-A/B signaling activity and cause a phenotype marked by enhanced bone growth and cardiovascular abnormalities.

Supplementation of Blackcurrant Anthocyanins Increased Cyclic Glycine-Proline in the Cerebrospinal Fluid of Parkinson Patients: Potential Treatment to Improve Insulin-Like Growth Factor-1 Function.

BACKGROUND: Insulin-like growth factor-1 (IGF-1) function is impaired in Parkinson disease. Cyclic glycine-proline (cGP), a metabolite of IGF-1, is neuroprotective through improving IGF-1 function. Parkinson disease patients score lower on Hospital-associated Anxiety and Depression Scale after supplementing blackcurrant anthocyanins (BCA), which may be associated with IGF-1 function. We evaluated the changes of cGP and IGF-1 before and after the supplementation. METHODS: Plasma and cerebrospinal fluid (CSF) were collected from 11 male patients before and after 28 day supplementation of BCA. The concentrations of IGF-1, IGF binding protein (IGFBP)-3, and cGP were measured using ELISA and HPLC-MS assays. The presence of cGP in the BCA was evaluated. RESULTS: cGP presented in the BCA. BCA supplementation increased the concentration of cGP (p < 0.01), but not IGF-1 and IGFBP-3 in the CSF. CSF concentration of cGP was correlated with plasma concentration of cGP (R = 0.68, p = 0.01) and cGP/IGF-1 molar ratio (R = 0.66, p = 0.01). The CSF/plasma ratio was high in cGP and low in IGF-1 and IGFBP-3. CONCLUSION: cGP is a natural nutrient to the BCA. The increased CSF cGP in Parkinson disease patients may result from the central uptake of plasma cGP. Given neurotrophic function, oral availability, and effective central uptake of cGP, the BCA has the potential to be developed to treat neurological conditions with IGF-1 deficiency.

Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth.

Although studies in experimental animals show that blood levels of C-type natriuretic peptide (CNP) and its bioinactive aminoterminal propeptide (NTproCNP) are potential biomarkers of long bone growth, a lack of suitable assays and appropriate reference ranges has limited the application of CNP measurements in clinical practice. Plasma concentrations of the processed product of proCNP, NTproCNP - and to a lesser extent CNP itself - correlate with concurrent height velocity throughout all phases of normal skeletal growth, as well as during interventions known to affect skeletal growth in children. Since a change in levels precedes a measurable change in height velocity during interventions, measuring NTproCNP may have predictive value in clinical practice. Findings from a variety of genetic disorders affecting CNP signaling suggest that plasma concentrations of both peptides may be helpful in diagnosis, provided factors such as concurrent height velocity, feedback regulation of CNP, and differential changes in peptide clearance are considered when interpreting values. An improved understanding of factors affecting plasma levels, and the availability of commercial kits enabling accurate measurement using small volumes of plasma, can be expected to facilitate potential applications in growth disorders including genetic causes -affecting the CNP signaling pathway.

Amino-terminal pro-C-type natriuretic peptide in heart failure.

The levels and pathophysiological role of amino terminal C-type natriuretic peptide in heart failure are unknown. The potential of plasma amino-terminal C-type natriuretic peptide (N-CNP) as a marker of cardiac function was investigated in symptomatic patients. In 305 patients with recent-onset dyspnea and/or peripheral edema, presenting to primary care, assay of plasma amino-terminal C-type natriuretic peptide and other plasma vasoactive hormones was conducted together with echocardiography. Heart failure was diagnosed in 77 (of the 305) patients by rigorous application of predefined criteria. Plasma amino-terminal C-type natriuretic peptide concentrations were elevated in patients with heart failure, and by univariate analysis were related to age, renal function, and other hormones. On multivariate analysis, tertile of plasma N-CNP interacted with tertile of plasma amino-terminal B-type natriuretic peptide to predict heart failure independent of age, gender, renal function, or echocardiographic left ventricular fractional shortening. N-CNP showed significant relations to concurrent plasma CNP, atrial natriuretic peptide (ANP), N-ANP, B-type (or brain) natriuretic peptide (BNP), N-BNP, endothelin-1, and adrenomedullin but not to echocardiographic indicators of left ventricular systolic function. Plasma amino-terminal C-type natriuretic peptide is elevated in heart failure and is related to other plasma hormones in heart failure. These findings suggest a possible compensatory response from the peripheral vasculature to heart failure by an endothelium-based vasodilator peptide and mandate further exploration of the role of C-type natriuretic peptide in this condition.