Aims

Metformin, rosiglitazone and sulfonylureas enhance either insulin action or secretion and thus have been used extensively as early stage anti-diabetic medication, independently of the aetiology of the disease. When administered to newly diagnosed diabetes patients, these drugs produce variable results. Here, we examined the effects of the three early stage oral hypoglycaemic agents in mice with diabetes induced by multiple low doses of streptozotocin, focusing specifically on the developmental biology of pancreatic islets.

Methods

Streptozotocin-treated diabetic mice expressing a fluorescent reporter specifically in pancreatic islet α-cells were administered the biguanide metformin (100 mg/kg), thiazolidinedione rosiglitazone (10 mg/kg), or sulfonylurea tolbutamide (20 mg/kg) for 10 days. We assessed the impact of the treatment on metabolic status of the animals as well as on the morphology, proliferative potential and transdifferentiation of pancreatic islet cells, using immunofluorescence.

Results

The effect of the therapy on the islet cells varied depending on the drug and included enhanced pancreatic islet β-cell proliferation, in case of metformin and rosiglitazone; de-differentiation of α-cells and β-cell apoptosis with tolbutamide; increased relative number of β-cells and bi-hormonal insulin + glucagon + cells with metformin. These effects were accompanied by normalisation of food and fluid intake with only minor effects on glycaemia at the low doses of the agents employed.

Conclusions

Our data suggest that metformin and rosiglitazone attenuate the depletion of the β-cell pool in the streptozotocin-induced diabetes, whereas tolbutamide exacerbates the β-cell apoptosis, but is likely to protect β-cells from chronic hyperglycaemia by directly elevating insulin secretion.

中文翻译：

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双胍类、磺脲类和噻唑烷二酮类药物一线治疗糖尿病对胰岛细胞群分化、增殖和凋亡的影响

目标

二甲双胍、罗格列酮和磺脲类药物可增强胰岛素作用或分泌，因此已广泛用作早期抗糖尿病药物，与疾病的病因无关。当对新诊断的糖尿病患者给药时，这些药物会产生不同的结果。在这里，我们研究了三种早期口服降糖药对多次低剂量链脲佐菌素诱导的糖尿病小鼠的影响，特别关注胰岛的发育生物学。

方法

链脲佐菌素处理的糖尿病小鼠在胰岛 α 细胞中表达特异性荧光报告基因，给予双胍二甲双胍 (100 mg/kg)、噻唑烷二酮罗格列酮 (10 mg/kg) 或磺脲类甲苯磺丁脲 (20 mg/kg) 10 天。我们使用免疫荧光评估了治疗对动物代谢状态以及胰岛细​​胞形态、增殖潜力和转分化的影响。

结果

治疗对胰岛细胞的影响因药物而异，包括增强胰岛 β 细胞增殖，如二甲双胍和罗格列酮；用甲苯磺丁脲去分化 α 细胞和 β 细胞凋亡；β细胞和双激素胰岛素+胰高血糖素+细胞与二甲双胍的相对数量增加。这些影响伴随着食物和液体摄入的正常化，在所用药物的低剂量下对血糖的影响很小。

结论

我们的数据表明，二甲双胍和罗格列酮可减轻链脲佐菌素诱导的糖尿病中 β 细胞库的消耗，而甲苯磺丁脲会加剧 β 细胞凋亡，但可能通过直接提高胰岛素分泌来保护 β 细胞免受慢性高血糖症的影响。