Project title
胺類與初級胺氧化脢在妊娠糖尿病的角色
Internal ID
MOST105-2314-B002-148
Principal Investigator
Start Date
August 1, 2016
End Date
July 12, 2017
Investigators
Organizations
Partner Organizations
Project Web Site
The Role of Amines and Primary Amine Oxidase in Gestational Diabetes Mellitus = 胺類與初級胺氧化脢在妊娠糖尿病的角色
Keywords
初級胺氧化脢
妊娠糖尿病
醣類代謝
primary amine oxidase
gestational diabetes mellitus
glucose homeostasis
Description
Background and objectives: Primary amine oxidase (PAO), also called vascular adhesion protein-1 (not vascular cellular adhesion molecule-1, nor ICAM-1) or semicarbazide-sensitive amine oxidase, can catalyze the breakdown of bioactive amines, to produce H2O2、aldehydes, and NH3. In adipocytes, amines can induce the translocation of glucose transporters (GLUT) and enhance glucose uptake into adipocytes, through the activity of adipose PAO. Besides, PAO exists a soluble form, which has been shown to enhance glucose uptake in liver tissues in a recent report. In our preliminary results, we found that human placenta expressed PAO. We hypothesize that PAO in placenta can regulate glucose transport across placenta and affect the growth of the fetus. Besides, we think that soluble PAO from placenta can affect glucose homeostasis in pregnant women. Therefore, this project will investigate the relationships between maternal blood concentrations of amines, maternal blood PAO concentrations, placental PAO expressions, placental expressions of GLUT 1, 3, 4, 12, insulin secretion index, insulin resistance index, and birth weight. We will also compare the differences in maternal blood concentrations of amines, maternal blood PAO concentrations, placental PAO expressions, placental expressions of GLUT 1, 3, 4, 12 between women with and without gestational diabetes mellitus. (specific aim A) In cell models, we will study the effect of placental PAO on the expression of GLUTs and glucose uptake (specific aim B), and the effect of soluble PAO on the function and proliferation of pancreatic β cells, on gluconeogesis in hepatic cells, and on glucose uptake in skeletal muscle cells and adipocytes (specific aim D). We will also investigate the regulators of both cellular PAO and soluble PAO (specific aim C). Study Design and Methods: In this 3-year project, we planned to do 4 specific aims A-D: Specific aim A is to recruit a cohort of pregnant women. We will measure blood amines by targeted metabolomics approach. Their blood PAO concentrations, placental PAO expressions, and placental expressions of GLUT 1, 3, 4, 12 will be measured. The relationship between maternal blood concentrations of amines, maternal blood PAO concentrations, placental PAO expressions, placental expressions of GLUT 1, 3, 4, 12, insulin secretion index, insulin resistance index, and birth weight will be analyzed by Pearson's correlation coefficients. Confounders will be adjusted in multiple linear regression models. We will use Student's t test and multiple linear regression models to assess the differences in maternal blood concentrations of amines, maternal blood PAO concentrations, placental PAO expressions, placental expressions of GLUT 1, 3, 4, 12 between women with and without gestational diabetes mellitus. Specific aim B uses 3A-sub E cell line from placenta (ATCC CRL-1584) and primary human trophoblasts to investigate if substrates of PAO can regulate the expression of GLUT 1, 3, 4, 12 and glucose uptake through the activity of PAO, generation of H2O2, and Akt pathway. Specific aim C is to compare maternal blood PAO concentrations before and after delivery. In cell models, we will study if estrogen, progesterone, prolactin, human placenta lactogen, insulin, and metalloprotease inhibitors can regulate the expression of cellular and soluble PAO. Specific aim D is to study the effect of soluble PAO on insulin secretion and cell proliferation using pancreatic β cell line INS1, and if the effect acts through the generation of H2O2. We will also investigate the effect of soluble PAO on glucose uptake in skeletal muscle cell line L6 and 3T3-L1 adipocytes, and if the effects act through the generation of H2O2 and Akt pathway. In hepatic cell line HepG2, we will study if soluble PAO can regulate gluconeogenesis, and if the effect acts through the generation of H2O2 and Akt pathway.