Abstract
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.
Highlights
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with first onset or recognition during pregnancy, diagnosed between the second or third trimester and clearly differentiates from a preconceptionally existing manifest diabetes (American Diabetes Association, 2013, 2019)
New Zealand obese (NZO) mice showed impaired glucose tolerance with increased blood glucose excursions after stimulus compared with the control strain preconceptionally, on day 14.5 of gestation and postpartum
Adaptive mechanisms of Langerhans islets to an increased insulin demand during pregnancy, glucose tolerance, and insulin secretion profiles in vivo and ex vivo were evaluated in the polygenic NZO mouse model and compared with the NMRI control strain
Summary
Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with first onset or recognition during pregnancy, diagnosed between the second or third trimester and clearly differentiates from a preconceptionally existing manifest diabetes (American Diabetes Association, 2013, 2019). Insulin sensitivity is unchanged or increased in first trimester and resistance increases in the second or third trimester to supply glucose for the developing fetus (Di Cianni, Miccoli, Volpe, Lencioni, & Del Prato, 2003; Stanley, Fraser, & Bruce, 1998) This is compensated by adaptive mechanisms of the Langerhans islets, which increase both basal and glucose-stimulated insulin secretion during pregnancy (Catalano, 1994; Sorenson & Brelje, 1997). It is plausible that female NZO mice may be considered as a suitable polygenic model to study the pathophysiology of GDM, which was the aim of this study It should be shown whether the NZO mouse exhibits impaired glucose tolerance before and/or during pregnancy and to what extent insulin secretion is impaired. We wanted to investigate whether the phenotype of female NZO mice can be assigned to one of the different subtypes of human GDM or to a preconceptional metabolic disorder influenced by pregnancy
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