This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Prenatal environment greatly affects fetal programming and development. Various factors lead to low birth weight (LBW) which is associated with adult disorders such as type 2 diabetes. However, the mechanism is still uncertain and controversial. We have started to establish LBW and maternal diabetic animal models to investigate how prenatal environment affects pancreatic beta cell programming and development. Methods: For LBW model, we feed pregnant animals with low protein (LP, 6%, normal is 20%) diet, and thiamine deficient diet; for diabetic model, we use Bic mice (beta cell is destroyed by overexpression of calmodulin), and more than 90% pancreatectomy or streptozotocin-induced SD female rats as type 1, and Agouti/kk mice as type 2 diabetic models. We test fetal beta cell development and offspring pancreatic beta cell function. Results: We have obtained some results from 10 week old Wister rat offspring. In LP group (fed mother and pups with LP diet during pregnancy, nursing and after nursing), body weight was only 30% of normal group; blood glucose was normal in these two groups; pancreatic islet protein and DNA contents were approximately 50% decreased; islet function, glucose utilization and glucose oxidation, were also decreased to 60% of normal. We tested thiamine deficiency in cultured the beta cell line INS-1, and found that a thiamine antagonist significantly inhibited tritium-thymidine incorporation into INS-1 cell DNA. In diabetic models, hyperglycemia would be an important factor to affect beta cell; we tested cultured islets with high glucose, and found that 3-day high glucose treatment decreased islet pyruvate dehydrogenase and pyruvate carboxylase activities, but high free fatty acid only inhibited pyruvate dehydrogenase activity. Discussion: These results suggest many factors affect offspring beta cell function by different mechanisms. We will continuously test fetal beta cell development, offspring beta cell function and specific gene expression.
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