Gestational diabetes mellitus (GDM), a type of glucose intolerance diagnosed during pregnancy, is a major public health concern affecting up to ten percent of pregnancies in the U.S. annually. GDM poses long- and short-term adverse effects for the mother and offspring. Previous studies indicate possible roles for serotonin (5-HT), a multifunctional monoamine neurotransmitter, and its transporter (SERT) in the regulation of glucose homeostasis. In this study, the effects of 5-HT and SERT on insulin signaling via the insulin receptor (IR) in placenta is evaluated.
In SERT-knockout mice, blood glucose and insulin levels were significantly elevated, suggesting that SERT has a protective role against glucose intolerance and insulin resistance. Furthermore, IR phosphorylation was impaired in placenta but not in platelets from SERT-knockout mice. Co-immunoprecipitation (IP) and Western blot (WB) analysis showed that IR phosphorylation as well as IR interaction with SERT occur in an insulin-dependent manner in the human placental cell line, JAR, suggesting that SERT regulates insulin signaling via physical association with IR. Interestingly, treatment with 5-HT or selective serotonin reuptake inhibitor (SSRI), or activation of protein kinase C (PKC), which is a downstream effector of 5-HT signaling, altered insulin-induced IR phosphorylation. These data further support the hypothesis that 5-HT signaling regulates insulin signaling in the placenta.
The role of placental SERT on maternal glucose tolerance was also investigated using Cre-lox recombination methods in mice. Fasting blood glucose, insulin, and body weights were monitored in 12-week-old wild-type and SERTfl/fl female mice that were unmated, or mated with Cyp19-Cre male mice. Cyp19-Cre mice express Cre under the control of a placenta-specific promoter. Hyperglycemia, hyperinsulinemia, and increased body weight was observed in unmated and mated SERTfl/fl mice, suggesting that SERTfl/fl express an obese, glucose-intolerant phenotype. As a result, it was not possible to confirm whether placental SERT affects maternal glucose metabolism based on the data obtained.
In summary, the serotonergic signaling pathway affects insulin signaling at the cellular level (in placenta) and in the whole body. The results provide insight into metabolic abnormalities associated with SSRI use in diabetes-associated pregnancy.
|Advisor:||McGehee, Robert, Raney, Kevin|
|Commitee:||Barger, Steven, Lupashin, Vladimir, Wight, Patricia|
|School:||University of Arkansas for Medical Sciences|
|Department:||Biochemistry and Molecular Biology|
|School Location:||United States -- Arkansas|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Keywords:||Glucose, Insulin, Placenta, Serotonin|
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