? Diabetes is a world-wide major cause of morbidity and mortality associated with impaired glucose tolerance, obesity, hyperlipidemia, hypertension, and atherosclerosis. The absorption, production, uptake, and metabolism of glucose are regulated by insulin. Normal glucose homeostasis requires that insulin is properly synthesized and secreted from the (cell upon periodic increases in blood glucose. Diabetes is associated with disturbances in pancreatic (cell function that result in the loss of glucose-stimulated insulin secretion. Recent studies demonstrated an association between (cell function, proliferation, and/or survival with an intracellular signaling pathway termed the unfolded protein response (UPR). Upon accumulation of unfolded proteins in the lumen of the endoplasmic reticulum, signal transduction pathways are activated to increase the protein folding capacity and increase the protein degradative machinery. In addition, protein synthesis is transiently attenuated through PERK-mediated phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2(). Recently, we discovered that these signaling pathways also play a role in the ability for the (cell to respond to elevated blood glucose by upregulation of insulin production and secretion. We propose that (cells utilize the UPR to detect blood glucose and regulate insulin production so that defects and/or allelic polymorphisms in this signaling pathway may contribute to the progression of diabetes. The experiments proposed will test the hypothesis that glucose homeostasis is maintained by UPR-mediated regulation of insulin production in (cells, gluconeogenesis by the liver, and/or glucose utilization in peripheral tissues. Modern molecular genetics has provided new tools for the identification and analysis of disease genes previously inaccessible to study. In this proposal we will use mouse genetics to ask fundamental questions about the regulation of glucose homeostasis in vivo that previously were not possible. These in vivo models have the potential for providing novel biologic insights into human disease and may also facilitate testing of new therapies. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
9R01DK042394-06
Application #
6690147
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Haft, Carol R
Project Start
1998-01-01
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2003
Total Cost
$343,526
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Zhang, Shuping; Macias-Garcia, Alejandra; Velazquez, Jason et al. (2018) HRI coordinates translation by eIF2?P and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency. Blood 131:450-461
Chandrahas, Vishwanatha K; Han, Jaeseok; Kaufman, Randal J (2018) Coordinating Organismal Metabolism During Protein Misfolding in the ER Through the Unfolded Protein Response. Curr Top Microbiol Immunol 414:103-130
Wang, Jie-Mei; Qiu, Yining; Yang, Zhao et al. (2018) IRE1? prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 11:
Chiang, Wei-Chieh; Chan, Priscilla; Wissinger, Bernd et al. (2017) Achromatopsia mutations target sequential steps of ATF6 activation. Proc Natl Acad Sci U S A 114:400-405
Choi, Woo-Gyun; Han, Jaeseok; Kim, Ji-Hyeon et al. (2017) eIF2? phosphorylation is required to prevent hepatocyte death and liver fibrosis in mice challenged with a high fructose diet. Nutr Metab (Lond) 14:48
DeZwaan-McCabe, Diane; Sheldon, Ryan D; Gorecki, Michelle C et al. (2017) ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis. Cell Rep 19:1794-1806
Poothong, Juthakorn; Sopha, Pattarawut; Kaufman, Randal J et al. (2017) IRE1? nucleotide sequence cleavage specificity in the unfolded protein response. FEBS Lett 591:406-414
Grootjans, Joep; Kaser, Arthur; Kaufman, Randal J et al. (2016) The unfolded protein response in immunity and inflammation. Nat Rev Immunol 16:469-84
Han, Jaeseok; Kaufman, Randal J (2016) The role of ER stress in lipid metabolism and lipotoxicity. J Lipid Res 57:1329-38
Bai, Yongsheng; Kinne, Jeff; Donham, Brandon et al. (2016) Read-Split-Run: an improved bioinformatics pipeline for identification of genome-wide non-canonical spliced regions using RNA-Seq data. BMC Genomics 17 Suppl 7:503

Showing the most recent 10 out of 85 publications