Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France
Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
Diabetes. 2020 Apr;69(4):647-660. doi: 10.2337/db19-0377. Epub 2020 Jan 31.
Aging-dependent changes in tissue function are associated with the development of metabolic diseases. However, the molecular connections linking aging, obesity, and diabetes remain unclear. Lamin A, lamin C, and progerin, products of the gene, have antagonistic functions on energy metabolism and life span. Lamin C, albeit promoting obesity, increases life span, suggesting that this isoform is crucial for maintaining healthy conditions under metabolic stresses. Because β-cell loss during obesity or aging leads to diabetes, we investigated the contribution of lamin C to β-cell function in physiopathological conditions. We demonstrate that aged lamin C only-expressing mice ( ) become obese but remain glucose tolerant due to adaptive mechanisms including increased β-cell mass and insulin secretion. Triggering diabetes in young mice revealed that animals normalize their fasting glycemia by both increasing insulin secretion and regenerating β-cells. Genome-wide analyses combined to functional analyses revealed an increase of mitochondrial biogenesis and global translational rate in islets, two major processes involved in insulin secretion. Altogether, our results demonstrate for the first time that the sole expression of lamin C protects from glucose intolerance through a β-cell-adaptive transcriptional program during metabolic stresses, highlighting gene processing as a new therapeutic target for diabetes treatment.
组织功能的衰老相关变化与代谢疾病的发展有关。然而，将衰老、肥胖和糖尿病联系起来的分子联系仍不清楚。核纤层蛋白 A、核纤层蛋白 C 和早老素是 基因的产物，它们在能量代谢和寿命方面具有拮抗作用。核纤层蛋白 C 虽然促进肥胖，但能增加寿命，这表明这种异构体对于在代谢应激下维持健康状态至关重要。由于肥胖或衰老期间β细胞的丢失会导致糖尿病，我们研究了核纤层蛋白 C 在生理病理条件下对β细胞功能的贡献。我们证明，仅表达核纤层蛋白 C 的老年小鼠（ ）变得肥胖，但由于包括β细胞数量增加和胰岛素分泌在内的适应性机制，它们仍然保持葡萄糖耐量。在年轻小鼠中引发糖尿病表明， 动物通过增加胰岛素分泌和β细胞再生来使空腹血糖正常化。全基因组分析与功能分析相结合，揭示了 胰岛中涉及胰岛素分泌的两个主要过程——线粒体生物发生和整体翻译率的增加。总之，我们的研究结果首次表明，仅表达核纤层蛋白 C 通过代谢应激期间β细胞适应性转录程序来保护免受葡萄糖不耐受，突出了 基因加工作为糖尿病治疗的新治疗靶点。
