- Type 2 diabetes (T2D) plagues nearly 10% of the US population (~30 million people); a shocking 84 million more have prediabetes and show signs of impaired glucose tolerance. Compounding this problem, certain insulin-sensitizing drugs are undergoing global market suspensions, leaving prediabetic and T2D patients with few treatment options and creating an urgent need for new therapeutics. Because multi- tissue dysfunction contributes to prediabetes and progression to T2D, prevention or reversal of these diseases requires a multi-pronged approach. Specifically, pancreatic ?-cell dysfunction and skeletal muscle (skm) insulin resistance are primary features of human prediabetes and T2D. STX4, a primary component of the SNARE exocytosis machinery, is reduced in ?-cells and skm from humans with T2D. Furthermore, STX4 is required for normal ?-cell insulin secretion and skm insulin sensitivity in mouse models and human islets. Our long-term goal is to understand how ?-cell and skm signaling can be manipulated to prevent or reverse prediabetes and halt the progression to T2D. Our central hypothesis is that STX4 enrichment supports ?-cells and/or skeletal muscle to prevent and reverse the damaging effects of diabetogenic stress. The rationale for the proposed research is that once these new mechanisms of STX4 are elucidated, STX4 signaling can be manipulated to prevent or reverse T2D. During the last funding cycle, we revealed new roles for STX4 in promoting ?-cell survival and skm function. Indeed, mice overexpressing STX4 in these tissues have a remarkable 33% extended lifespan and are protected from aging- and diet-induced metabolic dysfunction. Also, we showed that STX4 can reverse insulin resistance in obese mice. However, the tissue-specific role of STX4 was unknown. Therefore, we generated inducible ?-cell- and skm- specific STX4 overexpression and knockout mice, as well as RNA-based candidate therapeutics for tissue-specific STX4 enrichment. Our provocative new preliminary data indicate that STX4 participates in anti-inflammatory signaling in the ?-cells, and localizes to the outer mitochondrial membrane to regulate mitochondrial function in skm. Therefore, the objective of this application is to test these candidate mechanisms linking STX4 enrichment and protection of ?-cells and skm from diabetogenic stress and to evaluate candidate STX4 enrichment therapeutics. We will use our inducible mouse models and human tissues/cells for these studies.
In Aim 1, we will evaluate the mechanisms underlying the protective actions of STX4 in ?-cells and test novel ?-cell STX4 enrichment strategies;
in Aim 2, we will delineate how STX4 enrichment protects skm and how it reverses HFD-induced dysfunction. We will use innovative molecular tools to test novel hypotheses about STX4 action in the context of a translation-focused institutional environment at City of Hope. This work will positively impact diabetes research by evaluating a promising candidate strategy to reverse prediabetes and halt progression to T2D and by uncovering novel mechanisms of glycemic regulation.
Pre-diabetes and Type 2 diabetes (T2D) emanate from coordinate defects in multiple tissues; we have found a factor that can protect and reverse these defects. We are focused upon revealing the molecular mechanisms involved in the various tissue and cell-types. Understanding how this factor carries out these beneficial actions in these cell types will inform on how best to target it to prevent/treat diabetes.
|Aslamy, Arianne; Oh, Eunjin; Olson, Erika M et al. (2018) Doc2b Protects ?-Cells Against Inflammatory Damage and Enhances Function. Diabetes 67:1332-1344|
|Salunkhe, Vishal A; Veluthakal, Rajakrishnan; Kahn, Steven E et al. (2018) Novel approaches to restore beta cell function in prediabetes and type 2 diabetes. Diabetologia 61:1895-1901|
|Oh, Eunjin; Ahn, Miwon; Afelik, Solomon et al. (2018) Syntaxin 4 Expression in Pancreatic ?-Cells Promotes Islet Function and Protects Functional ?-Cell Mass. Diabetes 67:2626-2639|
|Veluthakal, Rajakrishnan; Chepurny, Oleg G; Leech, Colin A et al. (2018) Restoration of Glucose-Stimulated Cdc42-Pak1 Activation and Insulin Secretion by a Selective Epac Activator in Type 2 Diabetic Human Islets. Diabetes 67:1999-2011|
|Aslamy, Arianne; Oh, Eunjin; Ahn, Miwon et al. (2018) Exocytosis Protein DOC2B as a Biomarker of Type 1 Diabetes. J Clin Endocrinol Metab 103:1966-1976|
|Tunduguru, Ragadeepthi; Thurmond, Debbie C (2017) Promoting Glucose Transporter-4 Vesicle Trafficking along Cytoskeletal Tracks: PAK-Ing Them Out. Front Endocrinol (Lausanne) 8:329|
|Tunduguru, Ragadeepthi; Zhang, Jing; Aslamy, Arianne et al. (2017) The actin-related p41ARC subunit contributes to p21-activated kinase-1 (PAK1)-mediated glucose uptake into skeletal muscle cells. J Biol Chem 292:19034-19043|
|Aslamy, Arianne; Thurmond, Debbie C (2017) Exocytosis proteins as novel targets for diabetes prevention and/or remediation? Am J Physiol Regul Integr Comp Physiol 312:R739-R752|
|Ocaña, Gail J; Pérez, Liliana; Guindon, Lynette et al. (2017) Inflammatory stress of pancreatic beta cells drives release of extracellular heat-shock protein 90?. Immunology 151:198-210|
|Ahn, Miwon; Yoder, Stephanie M; Wang, Zhanxiang et al. (2016) The p21-activated kinase (PAK1) is involved in diet-induced beta cell mass expansion and survival in mice and human islets. Diabetologia 59:2145-55|
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