The long term goals of this proposal are to determine the role of and optimal requirements for vitamin A in fetal islet cell development, growth, differentiation and secretion, and if vitamin A deficiency in the fetus leads to glucose intolerance or type 2 diabetes in adult life. These studies take on particular relevance since marginal vitamin A status may occur in socioeconomically disadvantaged pregnant women. Marginal vitamin A deficiency could cause defects in fetal metabolism, nutrition and growth which persist in the adult. This proposal addresses the requirement for vitamin A during pregnancy and weaning and tests whether marginal deficiency of vitamin A leads to defects in fetal islet replication, neogenesis, apoptosis, and secretion. Using a rat model of low marginal vitamin A deficiency, the specific aims are to determine whether vitamin A deficiency during fetal life and weaning affect: 1) The mass of beta- and alpha-cells by altering replication, neogenesis or apoptosis. 2) The topographical arrangement of beta- and alpha-cells within the islet. 3) Fetal and neonatal islet cell maturation and secretion of insulin or glucagon. 4) Subsequent development of glucose intolerance and diabetes. Stereological methods will be used to measure cell mass, immunochemical methods to identify beta- and alpha-cells, and BrdU incorporation to determine replication, and the TUNEL technique to measure apoptosis. Fetal islets, adult islets and pancreases of rats subjected to vitamin A deficiency during pregnancy and in later life will be tested for defects in secretion. Adult rats previously subjected to vitamin A deficiency will be tested for glucose intolerance and diabetes. These findings should show a function of vitamin A in islet development and in prevention of diabetes in later life.
NIH ExPorter
NIH ExPorter