Department of Internal Medicine, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
Department of Pediatrics, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, Brazil.
Clin Endocrinol (Oxf). 2019 Jul;91(1):94-103. doi: 10.1111/cen.13984. Epub 2019 Apr 15.
Familial partial lipodystrophy type 2 (FPLD2) is characterized by insulin resistance, adipose atrophy of the extremities and central obesity. Due to the resemblance with Cushing's syndrome, we hypothesized a putative role of glucocorticoid in the pathogenesis of metabolic abnormalities in FPLD2.
To evaluate the phenotypic heterogeneity and glucocorticoid sensitivity in FPLD2 patients exhibiting the p.R482W or p.R644C LMNA mutations.
DESIGN, PATIENTS AND MEASUREMENTS: Prospective study with FPLD2 patients (n = 24) and controls (n = 24), who underwent anthropometric, body composition, metabolic profile and adipokines/cytokine plasma measurements. Plasma and salivary cortisol were measured in basal conditions and after 0.25, 0.5 and 1.0 mg of dexamethasone (DEX) given at 23:00 hours. Glucocorticoid receptor (GR) and 11βHSD isoforms expression were assessed by qPCR.
Familial partial lipodystrophy type 2 individuals presented increased waist and neck circumferences, decreased hip circumference, peripheral skinfold thickness and fat mass. Patients presented increased HOMA-IR, triglycerides, TNF-α, IL-1β, IL-6 and IL-10, and decreased adiponectin and leptin plasma levels. FPLD2 patients showed decreased ability to suppress the HPA axis compared with controls after 0.5 mg DEX. The phenotype was more pronounced in patients harbouring the p.R482W LMNA mutation. GRβ overexpression in PBMC was observed in female patients compared with female controls.
Familial partial lipodystrophy type 2 patients exhibited anthropometric, clinical and biochemical phenotypic heterogeneity related to LMNA mutation sites and to gender. LMNA mutations affecting both lamin A and lamin C lead to more severe phenotype. FPLD2 patients also showed blunted HPA axis response to DEX, probably due to the association of increased levels of proinflammatory cytokines with GRβ overexpression leading to a more severe phenotype in female.
家族性部分脂肪营养不良 2 型（FPLD2）的特征是胰岛素抵抗、四肢脂肪萎缩和中心性肥胖。由于与库欣综合征的相似性，我们假设糖皮质激素在 FPLD2 代谢异常的发病机制中可能起作用。
评估表现出 p.R482W 或 p.R644C LMNA 突变的 FPLD2 患者的表型异质性和糖皮质激素敏感性。
设计、患者和测量：前瞻性研究，纳入 24 例 FPLD2 患者和 24 例对照，进行人体测量、身体成分、代谢谱和脂肪因子/细胞因子血浆测量。在基础状态下测量血浆和唾液皮质醇，并在 23:00 时给予 0.25、0.5 和 1.0mg 地塞米松（DEX）后测量。通过 qPCR 评估糖皮质激素受体（GR）和 11βHSD 同工型的表达。
家族性部分脂肪营养不良 2 型个体的腰围和颈围增加，臀围、外周皮褶厚度和脂肪量减少。患者的 HOMA-IR、甘油三酯、TNF-α、IL-1β、IL-6 和 IL-10 增加，而脂联素和瘦素血浆水平降低。与对照组相比，FPLD2 患者在给予 0.5mg DEX 后抑制 HPA 轴的能力降低。携带 p.R482W LMNA 突变的患者表型更为明显。与女性对照组相比，女性患者的 PBMC 中观察到 GRβ 过表达。
家族性部分脂肪营养不良 2 型患者表现出与 LMNA 突变部位和性别相关的人体测量、临床和生化表型异质性。同时影响核纤层蛋白 A 和核纤层蛋白 C 的 LMNA 突变导致更严重的表型。FPLD2 患者对 DEX 的 HPA 轴反应也减弱，可能是由于促炎细胞因子水平升高与 GRβ 过表达相关，导致女性表型更为严重。
