Preclinical research implicates hypothalamic glial cell responses in the pathogenesis of obesity and type 2 diabetes (T2D). In the current study we sought to translate such findings to humans by testing whether radiologic markers of gliosis in the mediobasal hypothalamus (MBH) were greater in individuals with obesity and impaired glucose homeostasis or T2D.

Using cross-sectional and prospective cohort study designs, we applied a validated quantitative MRI approach to assess gliosis in 67 adults with obesity and normal glucose tolerance, impaired glucose tolerance (IGT), or T2D. Assessments of glucose homeostasis were conducted via oral glucose tolerance tests (OGTT) and β-cell modeling.

We found significantly greater T2 relaxation times (a marker of gliosis by MRI), that were independent of adiposity, in the groups with IGT and T2D as compared with the group with normal glucose tolerance. Findings were present in the MBH, but not control regions. Moreover, positive linear associations were present in the MBH but not control regions between T2 relaxation time and glucose area under the curve during an OGTT, fasting glucose concentrations, hemoglobin A_1c, and visceral adipose tissue mass, whereas negative linear relationships were present in the MBH for markers of insulin sensitivity and β-cell function. In a prospective cohort study, greater MBH T2 relaxation times predicted declining insulin sensitivity over 1 year.

Findings support a role for hypothalamic gliosis in the progression of insulin resistance in obesity and thus T2D pathogenesis in humans.

临床前研究表明下丘脑胶质细胞反应在肥胖和 2 型糖尿病 (T2D) 的发病机制中起作用。在目前的研究中，我们试图通过测试下丘脑中基底层 (MBH) 中神经胶质增生的放射学标志物在肥胖和葡萄糖稳态受损或 T2D 的个体中是否更大，将这些发现转化为人类。

使用横断面和前瞻性队列研究设计，我们应用经过验证的定量 MRI 方法来评估 67 名肥胖且葡萄糖耐量正常、葡萄糖耐量受损 (IGT) 或 T2D 的成年人的神经胶质增生。通过口服葡萄糖耐量试验 (OGTT) 和 β 细胞模型对葡萄糖稳态进行评估。

我们发现与正常葡萄糖耐量组相比，IGT 和 T2D 组的 T2 弛豫时间（MRI 的胶质增生标志物）显着增加，与肥胖无关。在 MBH 中存在发现，但在控制区域中没有发现。此外，在 OGTT、空腹血糖浓度、血红蛋白 A _1c和内脏脂肪组织质量期间，MBH 中存在 T2 弛豫时间和曲线下葡萄糖面积之间的正线性关联，但对照区域不存在负线性关系，而在 OGTT 中存在负线性关系。 MBH 用于胰岛素敏感性和 β 细胞功能的标志物。在一项前瞻性队列研究中，更大的 MBH T2 松弛时间预示着 1 年内胰岛素敏感性下降。

研究结果支持下丘脑神经胶质增生在肥胖患者胰岛素抵抗的进展以及人类 T2D 发病机制中的作用。