Diabetes. 2022 Nov 1;71(11):2395-2401. doi: 10.2337/db22-0306.
The increase of functional β-cell mass is paramount to maintaining 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 for the 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 of β-cell adaptation.
在全身性胰岛素抵抗和/或代谢负荷增加的情况下，功能性β细胞质量的增加对于维持葡萄糖内稳态至关重要。了解允许β细胞质量适应的代偿机制可能会发现具有治疗作用的控制节点。在这项研究中，我们报告了基于直接胃热量输注的肥胖诱导过度喂养（OIO）小鼠模型中β细胞快速而强大的增生效应。通过对 OIO 小鼠分离的胰岛进行 RNA 测序，我们鉴定出 Sin3a 是β细胞质量适应的新型转录调节剂。β细胞特异性 Sin3a 敲除动物由于出生后β细胞质量的缺陷而出现严重的糖尿病。这些发现揭示了β细胞增殖的新调节途径，并验证了 OIO 作为发现β细胞适应其他机制决定因素的模型。
