Download or read book Exploring Novel Mechanisms of Pancreatic B-cell Development, Dysfunction and Survival written by Daniel Oropeza Herrero and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Diabetes has become a global health concern affecting more than 382 million people. It is ultimately a disease of the pancreatic [beta]-cell, as associated cell death and dysfunction is necessary for the progression towards hyperglycemia. In the work presented here we explore new mechanisms involved in [beta]-cell development, dysfunction and protection using a combination of cell culture techniques and in vivo work using frogs and mice as model organisms. Using the frog Xenopus laevis, we show that transient overexpression of Neurogenin3 (Ngn3), the main determinant of endocrine cell fate in the embryonic pancreas, at distinct developmental stages was able to promote ectopic and early development of [beta]-cells throughout the foregut. This was achieved by brief activation of Ngn3 after gastrulation and, most importantly, generated ectopic [beta]-cells, but not [alpha]-cells. Using microarray analysis of endoderm tissue following Ngn3 overexpression, we identified novel genes expressed in the embryonic pancreas required for the creation of ectopic [beta]-cells; including Tbx2, Mtg8 and Mtgr1. We propose these genes are important regulators of early [beta]-cell fate specification and warrant further investigation in mammalian systems downstream of Ngn3.Once [beta]-cells are produced, they must maintain efficient function throughout their life cycle for adequate secretion of insulin and subsequent blood glucose control. Reduced expression of Peroxisome proliferator-activated receptor [gamma] coactivators-1[alpha] and [beta] (Pgc1-[alpha]/[beta]), master regulators of mitochondrial biology, has been observed in several tissues associated with the pathogenesis of diabetes; in particular Pgc1-[alpha] was significantly reduced in islets of type II diabetics. To test whether this could contribute to [beta]-cell dysfunction, we reduced the expression of Pgc1-[alpha]/[beta] in adult [beta]-cells of mice using a tamoxifen-inducible Cre-lox system, which lead to impaired insulin secretion both in vitro and in vivo, but did not affect glucose homeostasis. Surprisingly, [beta]-cells lacking Pgc-1 showed no significant change in mitochondrial respiratory capacity, despite reduced mitochondrial density and dysregulated expression of genes involved in mitochondrial dynamics. Inhibition of palmitate-potentiated insulin secretion, along with altered expression of key enzymes involved in acyl-glycerol metabolism, suggests the defect in secretion may be the result of dysregulated lipid metabolism. During the course of our experimentation, we found that mice carrying the Mouse Insulin Promoter-CreERT (MIP-CreERT) transgene are protected against hyperglycemia caused by the [beta]-cell specific toxin Streptozotocin (STZ). While control littermates were significantly hyperglycemic shortly following STZ administration, MIP-CreERT mice remained normoglycemic up to four weeks following treatment. These mice had increased blood insulin levels following an oral glucose tolerance test, yet surprisingly, their islets did not show protection against STZ-induced [beta]-cell death. Further research into the underlying mechanism of protection in the model may reveal novel pathways to improve and protect [beta]-cell from cellular stress and could improve [beta]-cell physiology under hyperglycemic conditions. Taken together, our studies investigating mechanisms regulating [beta]-cell development, metabolism, and response to cellular stress shed light on several aspects of [beta]-cell biology that could contribute to the development of new therapies for both Type I and II diabetes." --