Department of Biological Sciences, Michigan Technological University, Houghton, MI, USA.
Department of Pharmacology, Brehm Center for Diabetes, University of Michigan, Ann Arbor, MI, USA.
Endocrinology. 2021 May 1;162(5). doi: 10.1210/endocr/bqab031.
Pancreatic β-cell dysfunction is central to the development and progression of type 2 diabetes. Dysregulation of microRNAs (miRNAs) has been associated with pancreatic islet dysfunction in type 2 diabetes. Previous study has shown that miR-483 is expressed relatively higher in β-cells than in α-cells. To explore the physiological function of miR-483, we generated a β-cell-specific knockout mouse model of miR-483. Loss of miR-483 enhances high-fat diet-induced hyperglycemia and glucose intolerance by the attenuation of diet-induced insulin release. Intriguingly, mice with miR-483 deletion exhibited loss of β-cell features, as indicated by elevated expression of aldehyde dehydrogenase family 1, subfamily A3 (Aldh1a3), a marker of β-cell dedifferentiation. Moreover, Aldh1a3 was validated as a direct target of miR-483 and overexpression of miR-483 repressed Aldh1a3 expression. Genetic ablation of miR-483 also induced alterations in blood lipid profile. Collectively, these data suggest that miR-483 is critical in protecting β-cell function by repressing the β-cell disallowed gene Aldh1a3. The dysregulated miR-483 may impair insulin secretion and initiate β-cell dedifferentiation during the development of type 2 diabetes.
胰岛β细胞功能障碍是 2 型糖尿病发生和进展的核心。miRNAs（miRNA）的失调与 2 型糖尿病胰岛功能障碍有关。先前的研究表明，miR-483 在β细胞中的表达相对高于α细胞。为了探索 miR-483 的生理功能，我们生成了 miR-483 特异性敲除的β细胞小鼠模型。miR-483 的缺失通过减弱饮食诱导的胰岛素释放，加剧了高脂肪饮食诱导的高血糖和葡萄糖不耐受。有趣的是，miR-483 缺失的小鼠表现出β细胞特征的丧失，其特征是醛脱氢酶家族 1，亚家族 A3（Aldh1a3）的表达升高，这是β细胞去分化的标志。此外，Aldh1a3 被验证为 miR-483 的直接靶标，miR-483 的过表达抑制 Aldh1a3 的表达。miR-483 的遗传缺失也诱导了血脂谱的改变。总之，这些数据表明，miR-483 通过抑制β细胞不允许的基因 Aldh1a3 来保护β细胞功能至关重要。失调的 miR-483 可能在 2 型糖尿病的发展过程中损害胰岛素分泌并引发β细胞去分化。
