Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI 48109, USA.
Dis Model Mech. 2021 Apr 1;14(4). doi: 10.1242/dmm.048909. Epub 2021 Apr 15.
Peripheral neuropathy (PN) is a common complication of prediabetes and diabetes and is an increasing problem worldwide. Existing PN treatments rely solely on glycemic control, which is effective in type 1 but not type 2 diabetes. Sex differences in response to anti-diabetic drugs further complicate the identification of effective PN therapies. Preclinical research has been primarily carried out in males, highlighting the need for increased sex consideration in PN models. We previously reported PN sex dimorphism in obese leptin-deficient ob/ob mice. This genetic model is inherently limited, however, owing to leptin's role in metabolism. Therefore, the current study goal was to examine PN and insulin resistance in male and female C57BL6/J mice fed a high-fat diet (HFD), an established murine model of human prediabetes lacking genetic mutations. HFD mice of both sexes underwent longitudinal phenotyping and exhibited expected metabolic and PN dysfunction compared to standard diet (SD)-fed animals. Hindpaw thermal latencies to heat were shorter in HFD females versus HFD males, as well as SD females versus males. Compared to HFD males, female HFD mice exhibited delayed insulin resistance, yet still developed the same trajectory of nerve conduction deficits and intraepidermal nerve fiber density loss. Subtle differences in adipokine levels were also noted by sex and obesity status. Collectively, our results indicate that although females retain early insulin sensitivity upon HFD challenge, this does not protect them from developing the same degree of PN as their male counterparts. This article has an associated First Person interview with the first author of the paper.
周围神经病变（PN）是糖尿病前期和糖尿病的常见并发症，也是全球日益严重的问题。现有的 PN 治疗方法仅依赖于血糖控制，这在 1 型糖尿病中有效，但在 2 型糖尿病中无效。抗糖尿病药物治疗反应的性别差异进一步使有效 PN 治疗方法的确定变得复杂。临床前研究主要在男性中进行，这突出表明需要在 PN 模型中增加对性别的考虑。我们之前曾报道过肥胖瘦素缺陷 ob/ob 小鼠存在 PN 性别二态性。然而，由于瘦素在代谢中的作用，这种遗传模型本身受到限制。因此，目前的研究目的是研究高脂饮食（HFD）喂养的雄性和雌性 C57BL6/J 小鼠中的 PN 和胰岛素抵抗，HFD 是一种缺乏基因突变的人类糖尿病前期的建立的小鼠模型。HFD 喂养的雄性和雌性小鼠均进行了纵向表型分析，与标准饮食（SD）喂养的动物相比，表现出预期的代谢和 PN 功能障碍。HFD 雌性小鼠的后爪对热的热潜伏期比 HFD 雄性和 SD 雄性短。与 HFD 雄性相比，雌性 HFD 小鼠表现出胰岛素抵抗延迟，但仍表现出相同的神经传导缺陷和表皮内神经纤维密度丧失轨迹。还注意到性别和肥胖状态对脂肪因子水平存在细微差异。总的来说，我们的结果表明，尽管女性在接受 HFD 挑战时仍保留早期胰岛素敏感性，但这并不能保护她们免受与男性相同程度的 PN 的影响。本文附有该论文第一作者的相关第一人称采访。
