Institute of Pharmacology, Toxicology and Clinical Pharmacy, Technische Universität Braunschweig, Braunschweig, Germany.
Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, Germany.
Physiol Rep. 2020 May;8(9):e14417. doi: 10.14814/phy2.14417.
Gestational diabetes mellitus (GDM) is a complex metabolic disease involving genetic and environmental factors. Recent studies have underlined its heterogeneity, so it is reasonable to divide patients into subpopulations depending on whether an insulin secretion or sensitivity defect is predominant. Since testing for GDM is usually performed in the second trimester, misinterpretation of prediabetes as gestational diabetes may occur. As with type 2 diabetes (T2DM), rodent models are needed for both GDM and prediabetes, but few do exist. Here, we compared the metabolic changes in pregnant normal NMRI mice with those in New Zealand obese (NZO) mice. Male animals of this strain are an established model of T2DM, whereas female mice of this strain are protected from hyperglycemia and β-cell death. We demonstrate that female NZO mice exhibited impaired glucose tolerance, preconceptional hyperinsulinemia, and hyperglucagonemia without any signs of manifest diabetes. The NZO model showed, compared with the NMRI control strain, a reduced proliferative response of the Langerhans islets during pregnancy (3.7 ± 0.4 vs. 7.2 ± 0.8% Ki-67-positive nuclei, p = .004). However, oral glucose tolerance tests revealed improved stimulation of insulin secretion in both strains. But this adaption was not sufficient to prevent impaired glucose tolerance in NZO mice compared with the NMRI control (p = .0002). Interestingly, glucose-stimulated insulin secretion was blunted in isolated primary NZO islets in perifusion experiments. In summary, the NZO mouse reflects important characteristics of human GDM and prediabetes in pregnancy and serves as a model for subpopulations with early alterations in glucose metabolism and primary insulin secretion defect.
妊娠期糖尿病（GDM）是一种涉及遗传和环境因素的复杂代谢性疾病。最近的研究强调了其异质性，因此根据胰岛素分泌或敏感性缺陷是否占主导地位，将患者分为亚群是合理的。由于 GDM 的检测通常在孕中期进行，因此可能会将糖尿病前期误诊为妊娠期糖尿病。与 2 型糖尿病（T2DM）一样，GDM 和糖尿病前期都需要啮齿动物模型，但目前很少有这样的模型。在这里，我们比较了正常 NMRI 小鼠和新西兰肥胖（NZO）小鼠的怀孕期代谢变化。该品系的雄性动物是 T2DM 的既定模型，而该品系的雌性小鼠则免受高血糖和β细胞死亡的影响。我们证明，雌性 NZO 小鼠表现出葡萄糖耐量受损、孕前高胰岛素血症和高血糖素血症，而没有明显的糖尿病迹象。与 NMRI 对照品系相比，NZO 模型在怀孕期间显示出胰岛的增殖反应降低（3.7±0.4%与 7.2±0.8%Ki-67 阳性核，p=0.004）。然而，口服葡萄糖耐量试验显示两种品系的胰岛素分泌均得到改善。但这种适应不足以防止 NZO 小鼠与 NMRI 对照相比出现葡萄糖耐量受损（p=0.0002）。有趣的是，在灌注实验中，分离的原发性 NZO 胰岛中葡萄糖刺激的胰岛素分泌减弱。总之，NZO 小鼠反映了人类妊娠期 GDM 和糖尿病前期的重要特征，并可作为葡萄糖代谢和原发性胰岛素分泌缺陷早期改变的亚群模型。
