Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
Division of Research, Kaiser Permanente Northern California, Oakland, CA.
Diabetes. 2018 May;67(5):885-897. doi: 10.2337/db17-1150. Epub 2018 Feb 7.
Specific circulating metabolites have emerged as important risk factors for the development of diabetes. The acylcarnitines (acylCs) are a family of metabolites known to be elevated in type 2 diabetes (T2D) and linked to peripheral insulin resistance. However, the effect of acylCs on pancreatic β-cell function is not well understood. Here, we profiled circulating acylCs in two diabetes cohorts: ) women with gestational diabetes mellitus (GDM) and ) women with recent GDM who later developed impaired glucose tolerance (IGT), new-onset T2D, or returned to normoglycemia within a 2-year follow-up period. We observed a specific elevation in serum medium-chain (M)-acylCs, particularly hexanoyl- and octanoylcarnitine, among women with GDM and individuals with T2D without alteration in long-chain acylCs. Mice treated with M-acylCs exhibited glucose intolerance, attributed to impaired insulin secretion. Murine and human islets exposed to elevated levels of M-acylCs developed defects in glucose-stimulated insulin secretion and this was directly linked to reduced mitochondrial respiratory capacity and subsequent ability to couple glucose metabolism to insulin secretion. In conclusion, our study reveals that an elevation in circulating M-acylCs is associated with GDM and early stages of T2D onset and that this elevation directly impairs β-cell function.
特定的循环代谢物已成为糖尿病发展的重要危险因素。酰基辅酶 A（acylC）是一类已知在 2 型糖尿病（T2D）中升高的代谢物，与外周胰岛素抵抗有关。然而，酰基辅酶 A 对胰腺β细胞功能的影响尚不清楚。在这里，我们在两个糖尿病队列中对循环酰基辅酶 A 进行了分析：）患有妊娠糖尿病（GDM）的女性和）患有 GDM 的女性，她们后来发展为糖耐量受损（IGT）、新诊断的 T2D 或在 2 年随访期间恢复正常血糖。我们观察到 GDM 女性和 T2D 患者血清中中链（M）-酰基辅酶 A 水平升高，特别是己酰肉碱和辛酰肉碱，而长链酰基辅酶 A 没有改变。用 M-酰基辅酶 A 处理的小鼠表现出葡萄糖不耐受，归因于胰岛素分泌受损。暴露于升高水平的 M-酰基辅酶 A 的鼠和人胰岛表现出葡萄糖刺激的胰岛素分泌缺陷，这与线粒体呼吸能力降低以及随后将葡萄糖代谢与胰岛素分泌偶联的能力直接相关。总之，我们的研究表明，循环 M-酰基辅酶 A 的升高与 GDM 和 T2D 发病的早期阶段有关，并且这种升高直接损害β细胞功能。
