The incidence of type 2 diabetes mellitus is reaching epidemic proportions, becoming one of the majorcauses of morbidity and mortality across the globe. Despite periods of feeding and fasting, plasma glucosein normal individuals remains in a narow range. Several studies have demonstrated that defects in thestimulation of non-oxidative glucose metabolism by insulin may be among the primary lesions in insulinresistance. In skeletal and cardiac muscle, insulin stimulates glycogen accumulation through a coordinateincrease in glucose transport and regulation of glycogen metabolizing enzymes, while in liver insulin blocksglucose output by inhibiting gluconeogenesis, promoting glycogenesis and blocking glycogenolysis. Wehave made the important discovery of a novel signaling pathway involving ubquitination in the regulation ofglycogen metabolism. Our studies demonstrate that during glycogenolysis, several enzymes involved in itsmetabolism translocate to the nucleus and interact with the E3 ubiquitin ligase Malin for subsequentproteasomal degradation. Additional studies indicate that the dual specificity phosphatase Laforin acts as amolecular scaffold for this process. A fundamental unanswered question is: how hormones such as insulinand glucagon regulate the cellular function of these proteins, and how these novel pathways aredysregulated in metabolic diseases such as diabetes and obesity. This proposal will address thesequestions by examining the hypothesis that hormones such as insulin and glucagon regulate the formationof protein complexes involved in the degradation of glycogen-associated proteins. We have identifiedSTBD1 as a novel Laforin interacting protein (STBD1) that enhances glycogen synthesis and interacts withseveral other glycogen associated proteins. Our model suggests that STBD1 is critical for the assembly ofcomplexes targeted for Malin mediated degradation. We will test our model and reveal the mechanismsbehind these events by using a combination of biochemical, cellular and transgenic techniques to addressthree specific aims: (1) to assess how liver specific STBD1 expression in mice affects whole body glucosehomeostasis in normal and diabetogenic states; (2) to investigate the role of STBD1 in regulating theproteasomal degradation of glycogen associated proteins by Malin; and (3) to determine the hormonal andcellular signals that regulate STBD1 function. Accomplishing these aims will provide new insight into howhormones control glycogen metabolism, and how this process is dysregulated in metabolic disorders suchas diabetes and obesity. Importantly, this can ultimately identify novel therapeutic avenues in thesediseases.'
Section The regulation of glycogen metabolism by insulin and other hormones represents a key means to control the level of blood sugar in tissues such as muscle and liver. This proposal will investigate how newly identified enzymes and cellular pathways affect this process. Results of this study could lead to novel therapies for type 2 diabetes that are directed towards blocking glycogen breakdown while simultaneously enhancing its synthesis.
| Yang, Rongqiang; Zhang, Mei; Gustafson, Amber Renee et al. (2015) Loss of protein targeting to glycogen sensitizes human hepatocellular carcinoma cells towards glucose deprivation mediated oxidative stress and cell death. Biosci Rep 35: |
| Zhu, Yuanqi; Zhang, Mei; Kelly, Amber Renee et al. (2014) The carbohydrate-binding domain of overexpressed STBD1 is important for its stability and protein-protein interactions. Biosci Rep 34: |
