The increase of functional β cell mass is paramount to maintain glucose homeostasis in the setting of systemic insulin resistance and/or augmented metabolic load. Understanding compensatory mechanisms that allow β cell mass adaptation may allow discovery of therapeutically actionable control nodes. In this study, we report the rapid and robust β cell hyperplasic effect in a mouse model of overfeeding-induced obesity (OIO) based on direct gastric caloric infusion. By performing RNA sequencing in islets isolated from OIO mice, we identified Sin3a as a novel transcriptional regulator of β cell mass adaptation. β cell-specific Sin3a knockout animals showed profound diabetes, due to defective acquisition of postnatal β cell mass. These findings reveal a novel regulatory pathway in β cell proliferation, and validate OIO as a model for discovery of other mechanistic determinants to β cell adaptation.

中文翻译：

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过度喂养引起的肥胖小鼠模型揭示了 Sin3a 在出生后峰值 β 细胞质量获取中的必要性


在全身胰岛素抵抗和/或代谢负荷增加的情况下，功能性β细胞量的增加对于维持葡萄糖稳态至关重要。了解允许β细胞群适应的补偿机制可能有助于发现治疗上可行的控制节点。在这项研究中，我们报告了基于直接胃热量输注的过度喂养诱导肥胖（OIO）小鼠模型中快速而强大的 β 细胞增生效应。通过对 OIO 小鼠分离的胰岛进行 RNA 测序，我们发现 Sin3a 是 β 细胞质量适应的新型转录调节因子。 β 细胞特异性 Sin3a 敲除动物由于出生后 β 细胞团的获得缺陷而表现出严重的糖尿病。这些发现揭示了 β 细胞增殖的新调控途径，并验证了 OIO 作为发现 β 细胞适应的其他机制决定因素的模型。