Glycogen is a branctied storage polymer of glucose that serves as an energy reserve in many cell types. In absolute terms, liver and skeletal muscle house the largest glycogen deposits in mammals and are critical to whole body glucose metabolism. The overall goal of this proposal is to improve understanding of the mechanism and control of glycogen synthesis, its relevance to whole body glucose metabolism and its impairment in metabolic diseases like diabetes and and certain glycogen storage diseases. Glycogen is synthesized from UDP-glucose by the enzyme glycogen synthase.
Aim (i) Role of genethonin 1 (Stbd1) in glycogen metabolism. We have found a new protein, genethonin 1, that binds to glycogen and may function to target glycogen to lysosomes. We will investigate the role of genethonin 1 in this pathway.
Aim (ii). Glycogen in mouse models of glucose homeostasis. We will study genetically modified mice as a means to assess glycogen function and to assess its role in different tissues of the body. We will continue analysis of mice lacking liver glycogen (LGSKO) and will use Cre-Lox techniques to eliminate glycogen accumulation in muscle, heart, beta cells and brain by tissue specific disruption of the glycogen synthase gene, Gys1.
Aim (iii) UDP-glucose pyrophosphatase (UGPPase). This enzyme hydrolyzes UDP-glucose and thus may impact glycogen metabolism. Our work will combine transgenic overexpression with gene knockout in mice to evaluate its importance.
Aim (iv) Phosphoglucosylation of proteins and potential role in metabolic control. In the course of our work, we have found evidence for a novel post-translational modification of proteins whereby glucose-phosphate is transferred from UDP-glucose to acceptor proteins. We will explore this phenomenon, seeking to identify the modifying enzyme(s), to understand the effect of the modification on protein function and to establish its physiological relevance.

Public Health Relevance

Most of the proposal addresses glycogen which plays an important role in the energy metabolism of the body. Understanding how glycogen deposits in different tissues impact physiological parameters such as blood glucose homeostasis and exercise capacity is therefore of considerable significance. Numerous disease states affect or are affected by glycogen metabolism, including diabetes and glycogen storage diseases. The last aim seeks to define and evaluate a newly discovered covalent modification of proteins which, based on its occurence on a number of metabolic enzymes, may also have an influence on metabolism.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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Laughlin, Maren R
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Indiana University-Purdue University at Indianapolis
Schools of Medicine
United States
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Irimia, Jose M; Meyer, Catalina M; Segvich, Dyann M et al. (2017) Lack of liver glycogen causes hepatic insulin resistance and steatosis in mice. J Biol Chem 292:10455-10464
Mahalingan, Krishna K; Baskaran, Sulochanadevi; DePaoli-Roach, Anna A et al. (2017) Redox Switch for the Inhibited State of Yeast Glycogen Synthase Mimics Regulation by Phosphorylation. Biochemistry 56:179-188
Contreras, Christopher J; Segvich, Dyann M; Mahalingan, Krishna et al. (2016) Incorporation of phosphate into glycogen by glycogen synthase. Arch Biochem Biophys 597:21-9
DePaoli-Roach, Anna A; Contreras, Christopher J; Segvich, Dyann M et al. (2015) Glycogen phosphomonoester distribution in mouse models of the progressive myoclonic epilepsy, Lafora disease. J Biol Chem 290:841-50
Roach, Peter J (2015) Glycogen phosphorylation and Lafora disease. Mol Aspects Med 46:78-84
Irimia, Jose M; Tagliabracci, Vincent S; Meyer, Catalina M et al. (2015) Muscle glycogen remodeling and glycogen phosphate metabolism following exhaustive exercise of wild type and laforin knockout mice. J Biol Chem 290:22686-98
Ruiz, Rafaela; Jideonwo, Victoria; Ahn, Miwon et al. (2014) Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver. J Biol Chem 289:5510-7
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Garyali, Punitee; Segvich, Dyann M; DePaoli-Roach, Anna A et al. (2014) Protein degradation and quality control in cells from laforin and malin knockout mice. J Biol Chem 289:20606-14
Winnick, Jason J; An, Zhibo; Kraft, Guillaume et al. (2013) Liver glycogen loading dampens glycogen synthesis seen in response to either hyperinsulinemia or intraportal glucose infusion. Diabetes 62:96-101

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