L-Arginine supplementation improves insulin sensitivity and beta cell function in the offspring of diabetic rats through AKT and PDX-1 activation
L-Arginine supplementation improves insulin sensitivity and beta cell function in the offspring of diabetic rats through AKT and PDX-1 activation
复制标题
DOI：
10.1016/j.ejphar.2016.10.001
复制
发表时间：
2016-11-15
影响因子：
5
通讯作者：
Hirata, Aparecida Emiko
中科院分区：
文献类型：
--
作者：
Carvalho, Diego Soares;Diniz, Marilia Melo;Hirata, Aparecida Emiko
母体高血糖可导致后代葡萄糖代谢和胰腺β细胞功能缺陷。本研究的目的是评估母体糖尿病对后代胰岛、肌肉和脂肪组织的影响，有或没有口服L-精氨酸补充。使用链脲佐菌素（60 mg/kg）诱导糖尿病。在3月龄时对动物进行研究，并从断奶时开始给药（蔗糖或L-精氨酸）。我们观察到，L-Arg改善了糖尿病母亲（DA）后代的胰岛素敏感性，这反映在肌肉和脂肪组织中胰岛素诱导的Akt磷酸化水平较高。胰岛素抵抗与氧化应激增加有关，NADPH氧化酶起着重要作用。我们的研究结果表明，增强相互作用的p47（PHOX）与gp 91（PHOX）在骨骼肌组织中的糖尿病大鼠（DV）的后代酶的亚基在DA大鼠L-Arg治疗后被取消。母体糖尿病引起后代胰岛功能的改变，导致在低（2.8 mM）和高（16.7 mM）葡萄糖浓度下胰岛素分泌增加。L-Arg可逆转这种作用，提示其可能是胰岛素分泌过程中的重要调节剂。此外，L-Arg可能直接对胰岛维持和存活的必需分子发挥作用，降低p47（PHOX）的蛋白表达，同时增加Akt磷酸化和PDX-1表达。L-Arg发挥其有益作用的机制可能涉及一氧化氮的生物利用度，因为治疗恢复了胰腺中的NO水平。
Maternal hyperglycemia can result in defects in glucose metabolism and pancreatic beta-cell function in offspring. The purpose of this study was to evaluate the impact of maternal diabetes mellitus on pancreatic islets, muscle and adipose tissue of the offspring, with or without oral L-Arginine supplementation. The induction of diabetes was performed using streptozotocin (60 mg/kg). Animals were studied at 3 months of age and treatment (sucrose or L-Arginine) was administered from weaning. We observed that L-Arg improved insulin sensitivity in the offspring of diabetic mothers (DA), reflected by higher insulin-induced phosphorylation of Akt in muscle and adipose tissue. Insulin resistance is associated with increased oxidative stress and the NADPH oxidase enzyme plays an important role. Our results showed that the augmented interaction of p47(PHOX) with gp91(PHOX) subunits of the enzyme in skeletal muscle tissue in the offspring of diabetic rats (DV) was abolished after L-Arg treatment in DA rats. Maternal diabetes caused alterations in the islet functionality of the offspring leading to increased insulin secretion at both low (2.8 mM) and high (16.7 mM) concentrations of glucose. L-Arg reverses this effect, suggesting that it may be an important modulator in the insulin secretory process. In addition it is possible that L-Arg exerts its effects directly onto essential molecules for the maintenance and survival of pancreatic islets, decreasing protein expression of p47(PHOX) while increasing Akt phosphorylation and PDX-1 expression. The mechanism by which L-Arg exerts its beneficial effects may involve nitric oxide bioavailability since treatment restored NO levels in the pancreas.