The role of amino acid status as a signaling event and the pathway by which it signals resulting in ? cell apoptosis has not been evaluated as a causative event. Beyond the consequences of hyperglycemia and hyperlipidemia, additional molecular mechanism (s) that cause ? cell apoptosis during development of diabetes are not well studied but will be vital for the development of novel diagnostic and therapeutic strategies. Apoptosis of ? cells in Type 2 Diabetes (T2DM) is associated with increased stress in the endoplasmic reticulum (ER). Our laboratory has contributed a body of work on the cellular responses to diverse stress conditions, including ER stress and amino acid limitation. Combined work from many labs has shown that the cellular response to ER stress involves the translation and transcriptional reprogramming of cells. We discovered a novel anabolic program that accompanies the translational recovery of late ER stress. This program promotes amino acid uptake, increased tRNA charging, and increased expression of genes involved in protein synthesis. This program which has prosurvival and growth actions under mild stress, paradoxically, promote apoptosis under conditions of chronic stress, by stimulating protein synthesis, by inducing the production of reactive oxygen species, and by exhausting the ATP supply. We propose to study the molecular mechanism of this novel 'suicide'adaptive stress response in insulinoma cells and islets from diabetic mouse models. We will study (i) the mechanisms of transcriptional and translational control, (ii) the mechanism and significance of increased amino acid uptake in the regulation of mRNA translation and (iii) the mechanism via which increased methionine and cystine uptake contribute to protection of ? cells from ER stress-induced apoptosis. Our studies will reveal novel biomarkers in ER stress-induced diabetes (a condition related to T2DM), with diagnostic and therapeutic potential.

Public Health Relevance

Anabolic cellular responses are associated with growth, proliferation and increased metabolic activity. They are usually observed in tumor cells. We made the unexpected finding that insulin-producing pancreatic ? cells induce an anabolic gene expression program in response to stress in the endoplasmic reticulum (ER). ER stress in ? cells is associated with ? cell apoptosis in Type 2 Diabetes (T2DM), an important feature of the disease. In this proposal we will study the components of this anabolic program that lead to apoptosis of ? cells. We aim to discover novel biomarkers for diagnosis and treatment of T2DM.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Maruvada, Padma
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Case Western Reserve University
Schools of Medicine
United States
Zip Code
Davuluri, Gangarao; Krokowski, Dawid; Guan, Bo-Jhih et al. (2016) Metabolic adaptation of skeletal muscle to hyperammonemia drives the beneficial effects of l-leucine in cirrhosis. J Hepatol 65:929-937
Hao, Yujun; Samuels, Yardena; Li, Qingling et al. (2016) Oncogenic PIK3CA mutations reprogram glutamine metabolism in colorectal cancer. Nat Commun 7:11971
Kenche, Harshavardhan; Ye, Zhi-Wei; Vedagiri, Kokilavani et al. (2016) Adverse Outcomes Associated with Cigarette Smoke Radicals Related to Damage to Protein-disulfide Isomerase. J Biol Chem 291:4763-78
Hsu, K-S; Guan, B-J; Cheng, X et al. (2016) Translational control of PML contributes to TNFα-induced apoptosis of MCF7 breast cancer cells and decreased angiogenesis in HUVECs. Cell Death Differ 23:469-83
Saikia, Mridusmita; Hatzoglou, Maria (2015) The Many Virtues of tRNA-derived Stress-induced RNAs (tiRNAs): Discovering Novel Mechanisms of Stress Response and Effect on Human Health. J Biol Chem 290:29761-8
Han, Dong-Yun; Guan, Bo-Jhih; Wang, Ya-Juan et al. (2015) L-type Calcium Channel Blockers Enhance Trafficking and Function of Epilepsy-associated α1(D219N) Subunits of GABA(A) Receptors. ACS Chem Biol 10:2135-48
Komar, Anton A; Hatzoglou, Maria (2015) Exploring Internal Ribosome Entry Sites as Therapeutic Targets. Front Oncol 5:233
Majumder, Mithu; Mitchell, Daniel; Merkulov, Sergei et al. (2015) Residues required for phosphorylation of translation initiation factor eIF2α under diverse stress conditions are divergent between yeast and human. Int J Biochem Cell Biol 59:135-41
Schuster, Andrew T; Homer, Craig R; Kemp, Jacqueline R et al. (2015) Chromosome-associated protein D3 promotes bacterial clearance in human intestinal epithelial cells by repressing expression of amino acid transporters. Gastroenterology 148:1405-16.e3
Gao, Xing-Huang; Krokowski, Dawid; Guan, Bo-Jhih et al. (2015) Quantitative H2S-mediated protein sulfhydration reveals metabolic reprogramming during the integrated stress response. Elife 4:e10067

Showing the most recent 10 out of 51 publications