![]() ![]() We report herein the identification of a small molecule inhibitor of Class 1 histone deacetylases (HDACs) that significantly enhances the GLP-1R signaling. If so, the metabolic and body weight benefits of GLP-1 therapy would be sizably enhanced. These results led to our hypothesis to assess whether the increase in the expression of the auxiliary proteins that supports GPCR-mediated sustained cAMP generation could enhance GLP-1R function. Previous observations from our laboratory have shown that prolonged association of the Gα s subunit with the activated and internalized GLP-1R at Rab5 endosomes sustains cAMP generation to support GSIS in pancreatic beta cells ( Girada et al., 2017). More recent reports, however, demonstrate sustained cAMP generation for several GPCRs following internalization and the formation of a multi-protein complex at endosomes where activated receptor-ligand complex, the Gα s subunit of the heterotrimeric G-protein and beta arrestin-1 contribute as key components ( Thomsen et al., 2016). The canonical pathway of GPCR activation postulates increases in the second messenger cAMP following the receptor activation that rapidly attenuates with the receptor internalization and desensitization. The activation of the receptor propels a cellular signaling cascade that eventually potentiates glucose-stimulated insulin secretion (GSIS) ( Drucker, 2006). In each instance, the receptor stabilizes in an active conformation suitable for the association with heterotrimeric G-protein subunit Gα s and subsequent activation of the adenylate cyclase. Incretin receptors can be activated by orthosteric peptide-based agonists ( Drucker et al., 2010), dual agonists ( Finan et al., 2013), and small-molecule allosteric modulators ( Knudsen et al., 2007 Bueno et al., 2016). The unmet medical need warrants additional complementary mechanisms to incretin action ( Tschöp and DiMarchi, 2017) or a novel approach to supplement incretin pharmacology. Unfortunately, not all patients achieve normal glucose control, and even fewer show reversal of obesity ( Amori et al., 2007). Incretin-based therapy and specifically glucagon-like peptide 1 receptor (GLP-1R) agonists provide sizable glycemic benefit and modest improvement in the body weight ( Astrup et al., 2009). Distilling a decade of Suber's influential writing and thinking about open access, this is the indispensable book on the subject for researchers, librarians, administrators, funders, publishers, and policy makers.Type 2 diabetes (T2D) and obesity have reached global epidemic levels and required a therapeutic intervention to reduce the burden of the disease. ![]() In this concise introduction, Peter Suber tells us what open access is and isn't, how it benefits authors and readers of research, how we pay for it, how it avoids copyright problems, how it has moved from the periphery to the mainstream, and what its future may hold. Lkrb 001 link it free#But for 350 years, scholars have written peer-reviewed journal articles for impact, not for money, and are free to consent to open access without losing revenue. Open access is made possible by the Internet and copyright-holder consent, and many authors, musicians, filmmakers, and other creators who depend on royalties are understandably unwilling to give their consent. We take advantage of this revolutionary opportunity when we make our work “open access”: digital, online, free of charge, and free of most copyright and licensing restrictions. The Internet lets us share perfect copies of our work with a worldwide audience at virtually no cost. A concise introduction to the basics of open access, describing what it is (and isn't) and showing that it is easy, fast, inexpensive, legal, and beneficial. ![]()
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