To begin, I must first thank the members of the O'Brien lab, both past and present, not only for their contributions to the work but also for their continued support. Ken continually reminded us of the great places to be discovered outside the lab, and I will truly miss working with him. Then I would like to thank Karin Bosma for your listening ear, support and help over the past two years and especially during this stressful time.
Thanks to both Colette and Karen Gieg for your help throughout this process, which made planning, scheduling and paperwork so much easier. Thank you for creating a challenging environment in which to learn, but always giving me the encouragement and confidence I needed to succeed. To my parents, Mary and Kevin, and my siblings, Colleen, Brian, Megan, Kaitlyn, Jessica and Matt, thank you for your support throughout this 5-year experience.
Thank you for allowing me to pursue my goals at every stage of life. MAPK Mitogen-activated protein kinase MODY Maturity-onset diabetes of the young mTOR mammalian target of rapamycin.
INTRODUCTION
Diabetes
T1D, previously called juvenile diabetes or insulin-dependent diabetes, is caused by an autoimmune destruction of the insulin-producing beta cells. T1D, which arises due to genetic susceptibility combined with unknown environmental factors, accounts for approximately 5–10% of total DM cases in the United States [ 25 ]. The main symptoms of the disease are increased thirst, excessive urination, exhaustion and hunger, leading to chronic hyperglycemia.
Autoantibodies specific to beta-cell autoantigens appear in the blood and serve as markers of the disease to diagnose new patients [27]. In general, cytotoxic CD8+ T cells and helper CD4+ T cells are the major mediators of the destruction of beta cells [32]. Although the environmental factors that lead to the development of T1D are not well understood, it is thought that the autoimmune destruction of the beta cells begins after an undefined trigger event.
Although there is no cure for or method of preventing the development of the disease, the genetic susceptibility to T1D has been well studied. SNPs in the promoter region of the insulin gene, protein tyrosine phosphatase nonreceptor type 22 (PTPN22), interleukin 2 receptor alpha (IL2RA), SH2B adapter protein 3 (SH2B3), protein tyrosine phosphatase nonreceptor type 2 (PTPN2), C-type lectin domain family 16 member A (CLEC16 A), ubiquitin-associated and the SH3 domain containing A (UBASH3A), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) have all been associated with altered risk of T1D development [ 34 , 40 ].
Diabetes
Insulin resistance and beta cell failure are further discussed in the following sections: Mechanisms of insulin resistance and mechanisms of beta cell failure. Beta cell failure is currently thought to result from a combination of insufficient beta cell mass and a decrease in beta cell function. Total beta cell mass is determined by the number, size and insulin secretion capacity of an individual's beta cells [64].
In addition to the increased beta cell mass due to normal growth conditions, pregnancy and obesity promote a compensatory increase in maternal beta cell mass due to the increased demand for insulin to overcome insulin resistance. Maternal obesity also leads to defects in beta cell development and function in the offspring. However, in the offspring of both obese mice and sheep, there is an age-related decline in beta cell number and beta cell function, making the offspring more susceptible to glucose intolerance later in life.
Conversely, poor maternal nutrition can lead to a decrease in beta cell mass at birth in rats (reviewed in [64]). Therefore, although the mass of beta cells is relatively dynamic in the face of increased demand for insulin, the inability of the organism to meet the demand leads to T2D.
Diabetes Treatments
Tsirigos, K.D., et al., The TOPCONS web server for consensus prediction of membrane protein topology and signal peptides. Konstantynowicz-Nowicka, K., et al., New evidence for the role of ceramide in the development of hepatic insulin resistance. Inoue, H., et al., Sequence variants in the sulfonylurea receptor (SUR) gene are associated with NIDDM in Caucasians.
Nielsen, E.-M.D., et al., The E23K Variant of Kir6.2 Associates with Impaired Post-OGTT Serum Insulin Response and Increased Risk of Diabetes Type 2. Hart, L.M.t., et al., Variations in Insulin Secretion in Carriers of of the E23K variant in the KIR6.2 subunit of the ATP-sensitive K channel in the Beta cell. Minton, J.A.L., et al., Association Studies of Genetic Variation in the WFS1 Gene and Type 2 Diabetes in the U.K.
Franks, P.W., et al., Replication of the association between variants in the WFS1 gene and risk of type 2 diabetes in European populations. Shao, W., et al., The Wnt signaling pathway effector TCF7L2 controls gut and brain proglucagon gene expression and glucose homeostasis. Kelleher, S.L., et al., Zinc in specialized secretory tissues: roles in the pancreas, prostate, and mammary gland.
Smidt, K., et al., The zinc transporter ZNT3 co-localizes with insulin in INS-1E pancreatic beta cells and affects cell survival, insulin secretory capacity, and ZNT8 expression. Nica, A.C., et al., Cell-type, allelic and genetic signatures in the human pancreatic beta cell transcriptome. Pound, L.D., et al., The physiological effects of deletion of the mouse slc30a8 gene encoding zinc transporter-8 are influenced by gender and genetic background.
Eizirik, D.L., et al., The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. Leung, K.W., et al., Expression of ZnT and ZIP zinc transporters in human RPE and their regulation by neurotrophic factors. Liu, B.Y., et al., Downregulation of zinc transporter 8 in the pancreas of db/db mice is rescued by Exendin-4 administration.
Pound, L.D., et al., Pancreatic beta cell-enriched transcription factor Pdx-1 regulates transcription of the Slc30a8 gene through an intronic enhancer. Kirchhoff, K., et al., Polymorphisms in the TCF7L2, CDKAL1, and SLC30A8 genes are associated with impaired proinsulin conversion. Orban, T., et al., Pancreatic islet autoantibodies as predictors of type 1 diabetes in the Type 1 Diabetes Prevention Trial.
Adkins, B.A., et al., Importance of the route of intravenous glucose delivery to hepatic glucose balance in the conscious dog.
