Laboratory of Secretion Cell Biology, Department of Biotechnology, Genetics and Cell Biology, State University of Maringa, Maringá, Paraná, Brazil.
Endocrine Physiology Laboratory, Department of Physiological Sciences, State University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
Exp Physiol. 2020 Dec;105(12):2051-2060. doi: 10.1113/EP088846. Epub 2020 Nov 3.
What is the central question of this study? Studies reported the efficacy of metformin as a promising drug for preventing or treating of metabolic diseases. Nutrient stresses during neonatal life increase long-term risk for cardiometabolic diseases. Can early metformin treatment prevent the malprogramming effects of early overfeeding? What is the main finding and its importance? Neonatal metformin treatment prevented early overfeeding-induced metabolic dysfunction in adult rats. Inhibition of early hyperinsulinaemia and adult hyperphagia might be associated with decreased metabolic disease risk in these animals. Therefore, interventions during infant development offer a key area for future research to identify potential strategies to prevent the long-term metabolic diseases. We suggest that metformin is a potential tool for intervention.
Given the need for studies investigating the possible long-term effects of metformin use at crucial stages of development, and taking into account the concept of metabolic programming, the present work aimed to evaluate whether early metformin treatment might program rats to resist the development of adult metabolic dysfunctions caused by overnutrition during the neonatal suckling phase. Wistar rats raised in small litters (SLs, three pups per dam) and normal litters (NLs, nine pups per dam) were used as models of early overfeeding and normal feeding, respectively. During the first 12 days of suckling, animals from SL and NL groups received metformin, whereas the controls received saline injections. Food intake and body weight were monitored from weaning until 90 days of age, when biometric and biochemical parameters were assessed. The metformin treatment decreased insulin concentrations in pups from SL groups, and as adults, these animals showed improvements in glucose tolerance, insulin sensitivity, body weight gain, white fat pad stores and food intake. Low-glucose insulinotrophic effects were observed in pancreatic islets from both NL and SL groups. These results indicate that early postnatal treatment with metformin inhibits early overfeeding-induced metabolic dysfunctions in adult rats.
本研究的核心问题是什么？有研究报道二甲双胍作为一种有前途的药物，可预防或治疗代谢性疾病。新生儿期的营养应激会增加患心脏代谢疾病的长期风险。早期二甲双胍治疗能否预防早期过度喂养引起的编程效应？主要发现及其重要性是什么？新生大鼠的二甲双胍治疗可预防早期过度喂养引起的成年大鼠代谢功能障碍。早期高胰岛素血症和成年期过度摄食的抑制可能与这些动物代谢疾病风险降低有关。因此，在婴儿发育期间进行干预提供了一个关键领域，可用于确定潜在策略，以预防长期代谢疾病。我们建议二甲双胍是一种潜在的干预工具。
鉴于需要研究二甲双胍在发育关键阶段使用的可能长期影响，并考虑到代谢编程的概念，本研究旨在评估早期二甲双胍治疗是否可能使大鼠编程以抵抗新生儿哺乳阶段过度喂养引起的成年代谢功能障碍的发展。使用小窝（SL，每窝三只幼仔）和正常窝（NL，每窝九只幼仔）饲养的 Wistar 大鼠分别作为早期过度喂养和正常喂养的模型。在哺乳的前 12 天，SL 和 NL 组的动物接受二甲双胍治疗，而对照组接受生理盐水注射。从断奶开始监测动物的饮食摄入量和体重，直至 90 天龄，此时评估生物计量和生化参数。二甲双胍治疗降低了 SL 组幼仔的胰岛素浓度，成年后，这些动物的葡萄糖耐量、胰岛素敏感性、体重增加、白色脂肪垫储存和饮食摄入量得到改善。NL 和 SL 组的胰岛均观察到低血糖胰岛素促分泌作用。这些结果表明，早期产后用二甲双胍治疗可抑制成年大鼠由早期过度喂养引起的代谢功能障碍。
