The pancreatic beta cell plays a pivotal role in the pathogenesis of Type 2 diabetes mellitus (T2DM). In states of increasing peripheral insulin resistance, there is a heightened need to synthesize and secrete insulin in order to maintain euglycemia. As a result of increased metabolic demand, the beta cell undergoes both a functional (insulin secretory) and proliferative (growth and replication) adaptive response. Unfortunately, the compensatory ability of the beta cell is finite and ultimately fails at some critical juncture, resulting in T2DM. Data suggest the ability (or inability) of the pancreatic beta cell to maintain this adaptive program is a key determinant of whether an insulin resistant individual will progress to frank hyperglycemia and diabetes, yet currently there are no effective clinical treatments that specifically target beta cel health in T2DM. The long-term goal of this applicant is to define the molecular pathways that contribute to altered beta cell compensation and function in T2DM. In order to produce and release finely regulated amounts of insulin, the mammalian beta cell possesses a highly developed endoplasmic reticulum (ER). The sarco-endoplasmic reticulum calcium ATPase (SERCA) pump resides in the ER membrane and is tasked with maintaining a steep calcium concentration gradient between the cytosol and ER lumen. This gradient is important for multiple Ca2+-regulated signaling pathways within the beta cell. Our published data show that expression and activity of the predominant beta cell isoform, SERCA2b, is markedly dysregulated in long-standing T2DM leading to profound changes in insulin secretion, ER health, and ultimately beta cell survival. In contrast, our preliminary data demonstrate that SERCA2b is upregulated in early diet-induced obesity, and differences in SERCA2b expression may underlie the ability of the beta cell to successfully mount a compensatory program. This work will test the hypothesis that SERCA2b and the maintenance of a robust ER calcium pool are uniquely required for both the initiation and propagation of the beta cell adaptive response to emerging insulin resistance.
In Aim 1, the role of SERCA2b in beta cell compensation will be defined using in vivo and in vitro models of developing and advanced T2DM as well as a model of beta cell SERCA2b deletion.
In Aim 2, the specific signaling and proliferative pathways that regulate SERCA2b and plasticity of the ER calcium pool as part of this adaptive program will be identified. Here, the relationship between calcineurin and IRS-2-mediated signaling pathways and SERCA2b expression and activity will be defined. The overall impact of this proposal will be the identification of key pathways that can be targeted clinically as a means of preserving beta cell function in T2DM.
Type 2 diabetes mellitus (T2DM) is a disorder of glucose homeostasis that affects nearly 24 million Americans and is a leading cause of blindness, kidney failure, and cardiovascular disease. Nearly 1 in 5 Veterans has diabetes, and Veterans with this disease account for 25% of all VA pharmacy costs and more than 1.7 million hospital bed days annually. The incidence of T2DM continues to increase and is expected to double by 2030, suggesting that increased numbers of future Veterans will seek care for T2DM and increased expenditures will be required to provide this care. Dysfunction of the insulin producing pancreatic ? cells is a central component of the pathophysiology of T2DM, yet current therapies do little to address this facet of the disease. The goal of this proposal is to define how altered calcium regulation affects ? cel secretory function, endoplasmic reticulum health, and survival. The translational impact of this proposal will be the identification of key pathways that can be targeted clinically as a means of preserving ? cell function and survival in T2DM.
| DiMeglio, Linda A; Evans-Molina, Carmella; Oram, Richard A (2018) Type 1 diabetes. Lancet 391:2449-2462 |
| Beli, Eleni; Yan, Yuanqing; Moldovan, Leni et al. (2018) Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice. Diabetes 67:1867-1879 |
| Dong, X Charlie (2018) SCP4: A Small Nuclear Phosphatase Having a Big Effect on FoxOs in Gluconeogenesis. Diabetes 67:23-25 |
| Sosenko, Jay M; Geyer, Susan; Skyler, Jay S et al. (2018) The influence of body mass index and age on C-peptide at the diagnosis of type 1 diabetes in children who participated in the diabetes prevention trial-type 1. Pediatr Diabetes 19:403-409 |
| Nathan, Brandon M; Boulware, David; Geyer, Susan et al. (2017) Dysglycemia and Index60 as Prediagnostic End Points for Type 1 Diabetes Prevention Trials. Diabetes Care 40:1494-1499 |
| Gordon, Hannah M; Majithia, Neil; MacDonald, Patrick E et al. (2017) STEAP4 expression in human islets is associated with differences in body mass index, sex, HbA1c, and inflammation. Endocrine 56:528-537 |
| Maddatu, Judith; Anderson-Baucum, Emily; Evans-Molina, Carmella (2017) Smoking and the risk of type 2 diabetes. Transl Res 184:101-107 |
| Ferrara, Christine T; Geyer, Susan M; Evans-Molina, Carmella et al. (2017) The Role of Age and Excess Body Mass Index in Progression to Type 1 Diabetes in At-Risk Adults. J Clin Endocrinol Metab 102:4596-4603 |
| Bone, Robert N; Evans-Molina, Carmella (2017) Combination Immunotherapy for Type 1 Diabetes. Curr Diab Rep 17:50 |
| Sims, Emily K; Lakhter, Alexander J; Anderson-Baucum, Emily et al. (2017) MicroRNA 21 targets BCL2 mRNA to increase apoptosis in rat and human beta cells. Diabetologia 60:1057-1065 |
Showing the most recent 10 out of 41 publications
