Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET- Universidad Austral, Av. Pte. Perón 1500 (B1629AHJ) Derqui-Pilar, Buenos Aires, Argentina.
Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
Clin Sci (Lond). 2019 Jan 30;133(2):351-365. doi: 10.1042/CS20180714. Print 2019 Jan 31.
Obesity, metabolic syndrome, and type 2 diabetes, three strongly interrelated diseases, are associated to increased morbidity and mortality worldwide. The pathogenesis of obesity-associated disorders is still under study. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein expressed in many cell types including adipocytes, parenchymal, and non-parenchymal hepatic cells and pancreatic cells. Studies have demonstrated that SPARC inhibits adipogenesis and promotes insulin resistance; in addition, circulating SPARC levels were positively correlated with body mass index in obese individuals. Therefore, SPARC is being proposed as a key factor in the pathogenesis of obesity-associated disorders. The aim of this study is to elucidate the role of SPARC in glucose homeostasis. We show here that SPARC null (SPARC) mice displayed an abnormal insulin-regulated glucose metabolism. SPARC mice presented an increased adipose tissue deposition and an impaired glucose homeostasis as animals aged. In addition, the absence of SPARC worsens high-fat diet-induced diabetes in mice. Interestingly, although SPARC mice on high-fat diet were sensitive to insulin they showed an impaired insulin secretion capacity. Of note, the expression of glucose transporter 2 in islets of SPARC mice was dramatically reduced. The present study provides the first evidence that deleted SPARC expression causes diabetes in mice. Thus, SPARC deficient mice constitute a valuable model for studies concerning obesity and its related metabolic complications, including diabetes.
肥胖症、代谢综合征和 2 型糖尿病是三种密切相关的疾病，与全球范围内的发病率和死亡率增加有关。肥胖相关疾病的发病机制仍在研究中。富含半胱氨酸的酸性分泌蛋白（SPARC）是一种基质细胞糖蛋白，在包括脂肪细胞、实质细胞和非实质细胞在内的许多细胞类型中表达。研究表明，SPARC 抑制脂肪生成并促进胰岛素抵抗；此外，肥胖个体的循环 SPARC 水平与体重指数呈正相关。因此，SPARC 被认为是肥胖相关疾病发病机制中的关键因素。本研究旨在阐明 SPARC 在葡萄糖稳态中的作用。我们在这里显示，SPARC 缺失（SPARC）小鼠表现出异常的胰岛素调节葡萄糖代谢。随着年龄的增长，SPARC 小鼠表现出脂肪组织沉积增加和葡萄糖稳态受损。此外，SPARC 的缺失会加重高脂肪饮食诱导的小鼠糖尿病。有趣的是，尽管高脂肪饮食的 SPARC 小鼠对胰岛素敏感，但它们表现出胰岛素分泌能力受损。值得注意的是，SPARC 小鼠胰岛中的葡萄糖转运蛋白 2 的表达显著降低。本研究首次提供了证据表明，缺失 SPARC 表达会导致小鼠糖尿病。因此，SPARC 缺陷小鼠构成了研究肥胖及其相关代谢并发症（包括糖尿病）的有价值模型。
