Department of Experimental Medical Science, Biomedical Center Floor C13, Lund University, Tornavagen 10, 221 84, Lund, Sweden.
Diabetologia. 2019 Jul;62(7):1257-1267. doi: 10.1007/s00125-019-4877-2. Epub 2019 May 8.
AIMS/HYPOTHESIS: Finding new treatment alternatives for individuals with diabetes with severe insulin resistance is highly desired. To identify novel mechanisms that improve glucose uptake in skeletal muscle, independently from insulin levels and signalling, we have explored the therapeutic potential of a short peptide sequence, RG54, derived from apolipoprotein A-I (ApoA-I).
INS-1E rat clonal beta cells, C2C12 rat muscle myotubes and J774 mouse macrophages were used to study the impact of RG54 peptide on glucose-stimulated insulin secretion, glucose uptake and cholesterol efflux, respectively. GTTs were carried out on diet-induced insulin-resistant and Lepr diabetic mouse models treated with RG54 peptide, and the impact of RG54 peptide on atherosclerosis was evaluated in Apoe mice. Control mice received ApoA-I protein, liraglutide or NaCl.
The synthetic RG54 peptide induced glucose uptake in cultured muscle myotubes by a similar amount as insulin, and also primed pancreatic beta cells for improved glucose-stimulated insulin secretion. The findings were verified in diet-induced insulin-resistant and Lepr diabetic mice, jointly confirming the physiological effect. The RG54 peptide also efficiently catalysed cholesterol efflux from macrophages and prevented the formation of atherosclerotic plaques in Apoe mice.
CONCLUSIONS/INTERPRETATION: The RG54 peptide exhibits good prospects for providing glucose control and reducing the risk of cardiovascular disease in individuals with severe insulin resistance.
目的/假设：寻找新的治疗方法来治疗严重胰岛素抵抗的糖尿病患者是非常需要的。为了寻找改善骨骼肌葡萄糖摄取的新机制，而不依赖于胰岛素水平和信号，我们探索了一种源自载脂蛋白 A-I（ApoA-I）的短肽序列 RG54 的治疗潜力。
我们使用 INS-1E 大鼠克隆β细胞、C2C12 大鼠肌肉成肌细胞和 J774 小鼠巨噬细胞，分别研究 RG54 肽对葡萄糖刺激的胰岛素分泌、葡萄糖摄取和胆固醇外排的影响。在接受 RG54 肽治疗的饮食诱导的胰岛素抵抗和 Lepr 糖尿病小鼠模型上进行 GTT，并在 Apoe 小鼠上评估 RG54 肽对动脉粥样硬化的影响。对照组小鼠接受 ApoA-I 蛋白、利拉鲁肽或 NaCl。
合成的 RG54 肽在培养的肌肉成肌细胞中诱导的葡萄糖摄取量与胰岛素相似，并且还为改善葡萄糖刺激的胰岛素分泌作用提供了预备作用。这些发现得到了饮食诱导的胰岛素抵抗和 Lepr 糖尿病小鼠的验证，共同证实了其生理作用。RG54 肽还能有效地从巨噬细胞中催化胆固醇外流，并能预防 Apoe 小鼠形成动脉粥样硬化斑块。
结论/解释：RG54 肽有望为严重胰岛素抵抗的个体提供血糖控制和降低心血管疾病风险的治疗方法。
