Long-term oral L-arginine administration improves peripheral and hepatic insulin sensitivity in type 2 diabetic patients

WSTĘP. Celem badania była ocena wpływu przewlekłego doustnego stosowania L-argininy, działającej przez normalizację szlaku NO/cykliczny 3’,5’-guanozyno monofosforan (cGMP), na poprawę insulinowrażliwości obwodowej i wątrobowej u 12 szczupłych osób chorych na cukrzycę typu 2. MATERIAŁ I METODY. Badanie, przeprowadzone metodą podwójnie ślepej próby, trwało 3 miesiące. W pierwszym miesiącu chorych leczono typową dietą cukrzycową. Następnie losowo przydzielono ich do dwóch grup. W grupie 1 przez 2 miesiące stosowano typową dietę i placebo (doustnie 3 × d.). W grupie 2 pacjentów leczono przez miesiąc dietą i placebo (doustnie 3 × d.) i następnie przez miesiąc dietą i L-argininą (3 g 3 × d.). Po pierwszymi i drugim miesiącu wykonano badanie za pomocą klamry euglikemiczno-hiperinsulinemicznej z jednoczesnym wlewem dożylnym znakowanej izotopowo glukozy (glukoza 6,6- 2H2). Grupą kontrolną stanowiło 10 zdrowych osób, u których również wykonano badanie za pomocą klamry. WYNIKI. W grupie 1 w czasie badania nie zaobserwowano zmian podstawowego stężenia cGMP, skurczowego ciśnienia tętniczego, przepływu krwi w przedramieniu, wykorzystania glukozy i endogennej produkcji glukozy. W grupie 2 przyjmowanie L-argininy spowodowało normalizację podstawowego stężenia cGMP, poprawę przepływu w przedramieniu o 36%, oraz wykorzystania glukozy w badaniu metodą klamry metabolicznej o 34%, jak również obniżenie skurczowego ciśnienia tętniczego i endogennej produkcji glukozy odpowiednio o 14 i 29%. Pomimo tego w porównaniu z grupą kontrolną podawanie L-argininy nie normalizuje całkowicie metabolizmu glukozy. WNIOSKI. Podawanie L-argininy u chorych na cukrzycę typu 2 znacznie poprawia insulinowrażliwość obwodową i wątrobową, lecz nie normalizuje jej całkowicie.INTRODUCTION. The aim of this study was to evaluate whether long-term administration of L-arginine acting through a normalization of NO/cyclic-guanosine- 3’,5’-cyclic monophosphate (cGMP) pathway was able to ameliorate peripheral and hepatic insulin sensitivity in 12 lean type 2 diabetic patients. MATERIAL AND METHODS. A double-blind study was performed for 3 months. In the first month, patients were treated with their usual diet. Then they were randomly allocated into two groups. In group 1, patients were treated with diet plus placebo (orally three times per day) for 2 months. In group 2 patients were treated for 1 month with diet plus placebo (orally, three times per day) and then for 1 month with diet plus L-arginine (3 g three times per day). At the end of the first and the second month of therapy, patients underwent a euglycemic-hyperinsulinemic clamp combined with [6,6-2H2] glucose infusion. A total of 10 normal subjects underwent the same test as control subjects. RESULTS. In group 1, no changes in basal cGMP levels, systolic blood pressure, forearm blood flow, glucose disposal, and endogenous glucose production were observed throughout. In group 2, L-arginine normalized basal cGMP levels and significantly increased forearm blood flow by 36% and glucose disposal during the clamp by 34%, whereas it decreased systolic blood pressure, and endogenous glucose production by 14 and 29%, respectively. However, compared with normal subjects, L-arginine treatment was not able to completely overcome the defect in glucose disposal. CONCLUSIONS. L-arginine treatment significantly improves but does not completely normalize peripheral and hepatic insulin sensitivity in type 2 diabetic patients

Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome

Endothelial nitric oxide synthase (eNOS) variants were previously demonstrated in cardiovascular disease. To evaluate whether eNOS gene variants are associated with insulin resistance and type 2 diabetes, we evaluated polymorphisms in Exon7 (E298D), intron 18 (IVS18 + 27A-->C), and intron 23 (IVS23 + 10G-->T) in 159 type 2 diabetic patients without macrovascular complications and in 207 healthy control subjects. Samples for all hormonal and metabolic variables were obtained after an overnight fast. The D298 and IVS18 + 27C alleles, but not the IVS23 + 10G-->T variant, were significantly more frequent in type 2 diabetic patients than in control subjects. The two- and three-loci haplotype analysis showed that there is a statistically significant association between the eNOS variants and type 2 diabetes. No significant differences were observed in the clinical characteristics of type 2 diabetic patients according to genotypes (except for visceral obesity [waist-to-hip ratio], which was significantly more present in D298 homozygotes). Healthy control subjects homozygous for both D298 and IVS18 + 27C presented higher insulin, C-peptide, and nitric oxide levels, as well as higher HOMA (homeostasis model assessment) values than the double wild-type homozygotes, with values superimposable on those found in type 2 diabetic patients. In conclusion, we described a significant association between eNOS gene polymorphisms and type 2 diabetes, suggesting a new genetic susceptibility factor for hyperinsulinemia, insulin resistance, and type 2 diabetes

High Dose Ifosfamide in Relapsed and Unresectable High-Grade Osteosarcoma Patients: A Retrospective Series

Background: The evidence on high-dose ifosfamide (HD-IFO) use in patients with relapsed osteosarcoma is limited. We performed a retrospective study to analyze HD-IFO activity. Methods: Patients with osteosarcoma relapsed after standard treatment [methotrexate, doxorubicin, cisplatin +/- ifosfamide (MAP+/-I)] with measurable disease according to RECIST1.1 were eligible to ifosfamide (3 g/m2/day) continuous infusion (c.i.) days 1-5 q21d. RECIST1.1 overall response rate (ORR) (complete response (CR) + partial response (PR)), progression-free survival at 6-month (6m-PFS), duration of response (DOR), and 2-year overall survival (2y-OS) were assessed. PARP1 expression and gene mutations were tested by immunohistochemistry and next-generation sequencing. Results: 51 patients were included. ORR was 20% (1 CR + 9 PR). Median DOR was 5 months (95%CI 2-7). Median PFS, 6m-PFS, OS, and 2y-OS were 6 months (95%CI 4-9), 51%, 15 months (10-19), and 30%, respectively. A second surgical complete remission (CR2) was achieved in 26 (51%) patients. After multivariate analysis, previous use of ifosfamide (HR 2.007, p = 0.034) and CR2 (HR 0.126, p < 0.001) showed a significant correlation with PFS and OS, respectively. No significant correlation was found between outcomes and PARP1 or gene mutations. Conclusions: HD-IFO should be considered as the standard first-line treatment option in relapsed osteosarcoma and control arm of future trial in this setting