Type 2 diabetes mellitus (T2DM) is characterized by a progressive loss of b-cell function associated with obesity. There is a fundamental gap in understanding how chronic nutrient overload alters b-cell function. Elucidation of nutrient-induced changes in b-cell physiology may provide insight that leads to the development of pharmaceutical approaches to preserve b-cell function and mass in susceptible obese individuals. My research interests focus on elucidating the alterations in b-cell metabolic signaling under chronic nutrient overload and their role in b-cell defects using both isolated rat and human islets. The central hypothesis is that mammalian target of rapamycin complex 1 (mTORC1), a nutrient sensor, plays a pivotal role in two major metabolic alterations: ectopic lipid accumulation and islet cell expansion. Rapamycin, an inhibitor of mTORC1, and BN99, an inhibitor of acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), an enzyme that catalyzes the final step of triglyceride (TG) biosynthesis have been used to probe the molecular mechanisms by which nutrients cause these adaptive responses. The causal relationship between the adaptive responses and b-cell defects are currently investigated by measuring insulin secretion, insulin content, and b-cell apoptosis under the conditions of excess nutrients in the presence and absence of rapamycin and BN99. Our approaches are novel and innovative in that we have developed new microscopic methodologies for the simultaneous assessment of multi-factorial b-cell responses to metabolic perturbations in addition to traditional biochemical assays. Using fluorescent microscopy, we are able to quantitate lipid droplets, insulin content, and intra-islet cell size, and study alterations in islet architecture. Moreover, we can also perform time-lapse studies to monitor live cells undergoing metabolic alterations in response to excess nutrients (i.e. lipid droplet formation and islet cell growth/proliferation).
Xu, G., Kwon, G., Cruz, W. S., Marshall, C. A., McDaniel, M. L. (2001) Metabolic regulation by leucine of translation initiation through the mTOR-signaling pathway by pancreatic beta-cells. Diabetes 50: 353-360.
McDaniel, M. L., Marshall, C. A., Pappan, K. L., Kwon, G. (2002) Metabolic and autocrine regulation of the mammalian target of rapamycin by pancreatic ß-cells. Diabetes 51: 2877-2885.
Kwon, G., Pappan, K. L., Marshall, C. A., Schaffer, J. E., McDaniel, M. L. (2004) cAMP dose-dependently prevents palmitate-induced apoptosis by both protein kinase A- and cAMP-guanine nucleotide exchange factor-dependent pathways in ß-cells. J. Biol. Chem. 279: 8938-8945.
Kwon, G., Marshall, C. A., Pappan, K. L., Remedi, M. S., McDaniel, M. L. (2004) Signaling elements involved in the metabolic regulation of mTOR by nutrients, incretins, and growth factors in islets. Diabetes 53 Suppl 3: 5225-5232.
Pappan, K. L., Pan, Z., Kwon, G., Marshall, C. A., Coleman, T., Goldberg, I. J., McDaniel, M. L., Semenkovich, C. F. (2005) Pancreatic ß-cell lipoprotein lipase independently regulates islet glucose metabolism and normal insulin secretion. J. Biol. Chem. 280: 9023-9029.
Kwon, G., Marshall, C. A., Liu, H., Pappan, K. L., Remedi, M. S., McDaniel, M. L. (2006) Glucose-stimulated DNA synthesis through mTOR is regulated by KATP channels: Effects on cell cycle progression in rodent islets. J. Biol. Chem. 281: 3261-3267.
Liu, H., Remedi, M. S., Pappan, K. L., Kwon, G., Rohatgi, N. Marshall, C. A., and McDaniel, M. L. (2009) Both Glycogen Synthase Kinase-3 (GSK-3) and Mammalian Target of Rapamycin (mTOR) Pathways Contribute to DNA Synthesis, Cell Cycle Progression and Proliferation in Human Islets. Diabetes 58: 663-672.
Rohatgi, N., Remedi, M. S., Kwon, G., Pappan, K. L., Marshall, C. A., and McDaniel, M. L. (2010) Therapeutic Strategies to Increase Human b-Cell growth and proliferation by regulating mTOR and GSK-3/b -Catenin pathways. The Open Endo. J. 4(001), 40-549.
Vernier, S., Chiu, A., Schober, J., Weber, T., Nguyen, P., Luer, M., McPherson, T., Wanda, P. E., Marshall, C. A., Rohatgi, N., McDaniel, M. L., Greenberg, A. S., Kwon, G. (2012) b-cell metabolic alterations under chronic nutrient overload in rat and human islets. Islets 4 (6): 379-392.