Irwin N, Pathak V, Pathak N M, Gault V A, Flatt P R
Biomedical Sciences Research Institute, SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, UK.
Diabetes Obes Metab. 2015 Sep;17(9):887-95. doi: 10.1111/dom.12508. Epub 2015 Jul 24.
To assess the therapeutic benefits of regulatory peptides other than insulin, which have to date received limited consideration in the context of type 1 diabetes.
We assessed the effects of subchronic administration of the stable, oxyntomodulin (Oxm) analogue, (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL], for 28 days in streptozotocin (STZ)-induced insulin-deficient diabetic mice.
Twice-daily injection with (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL] significantly countered the excessive food and fluid intake in STZ-induced diabetic mice, and maintained normal body weight. Lean body mass was normalized, whilst fat mass was significantly increased compared with control STZ-induced diabetic mice. In addition, circulating glucose was significantly reduced by the Oxm analogue, whilst plasma and pancreatic insulin concentrations were increased and glucagon decreased by day 28. Plasma lipid profile was normalized by (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL] administration and circulating amylase was not significantly altered by induction of diabetes or Oxm analogue therapy. This was associated with significantly improved glucose tolerance and insulin secretion. Peripheral insulin sensitivity was also significantly improved by Oxm analogue treatment. Histological examination of pancreata showed beneficial elevations of total islet and β-cell area, associated with an increase in the number of smaller-sized islets. Further analysis revealed enhanced islet cell proliferation relative to apoptosis in Oxm analogue-treated mice.
These studies emphasize the potential of stable Oxm-based peptides, such as (d-Ser(2) )Oxm[Lys(38) -γ-glu-PAL], as therapeutic agents for insulin-deficient type 1 diabetes.
评估除胰岛素外的调节肽的治疗益处，迄今为止，这些调节肽在1型糖尿病背景下受到的关注有限。
我们评估了在链脲佐菌素（STZ）诱导的胰岛素缺乏型糖尿病小鼠中，稳定的胃泌酸调节素（Oxm）类似物（d-Ser(2)）Oxm[Lys(38)-γ-glu-PAL]亚慢性给药28天的效果。
每天两次注射（d-Ser(2)）Oxm[Lys(38)-γ-glu-PAL]可显著对抗STZ诱导的糖尿病小鼠过度的食物和液体摄入，并维持正常体重。瘦体重恢复正常，而与对照STZ诱导的糖尿病小鼠相比，脂肪量显著增加。此外，Oxm类似物可显著降低循环葡萄糖水平，而血浆和胰腺胰岛素浓度在第28天增加，胰高血糖素降低。给予（d-Ser(2)）Oxm[Lys(38)-γ-glu-PAL]可使血浆脂质谱恢复正常，糖尿病诱导或Oxm类似物治疗均未显著改变循环淀粉酶水平。这与葡萄糖耐量和胰岛素分泌的显著改善相关。Oxm类似物治疗还显著改善了外周胰岛素敏感性。胰腺组织学检查显示胰岛总面积和β细胞面积有益地增加，与较小尺寸胰岛数量的增加相关。进一步分析显示，在Oxm类似物治疗的小鼠中，胰岛细胞增殖相对于凋亡增强。
这些研究强调了基于稳定Oxm的肽，如（d-Ser(2)）Oxm[Lys(38)-γ-glu-PAL]，作为胰岛素缺乏型1型糖尿病治疗药物的潜力。
