Glucagon-like peptide-1 (GLP-1) released from gut enteroendocrine cells controls meal-related glycemic excursions through augmentation of insulin and inhibition of glucagon secretion. GLP-1 also ...inhibits gastric emptying and food intake, actions maximizing nutrient absorption while limiting weight gain. Here I review the circuits engaged by endogenous versus pharmacological GLP-1 action, highlighting key GLP-1 receptor (GLP-1R)-positive cell types and pathways transducing metabolic and non-glycemic GLP-1 signals. The role(s) of GLP-1 in the benefits and side effects associated with bariatric surgery are discussed and actions of GLP-1 controlling islet function, appetite, inflammation, and cardiovascular pathophysiology are highlighted. Refinement of the risk-versus-benefit profile of GLP-1-based therapies for the treatment of diabetes and obesity has stimulated development of orally bioavailable agonists, allosteric modulators, and unimolecular multi-agonists, all targeting the GLP-1R. This review highlights established and emerging concepts, unanswered questions, and future challenges for development and optimization of GLP-1R agonists in the treatment of metabolic disease.
Glucagon-like peptide-1 (GLP-1) has emerged as a gut-derived peptide with pleiotropic actions and has demonstrated therapeutic efficacy for cardiometabolic disorders, principally diabetes and obesity. Herein, Drucker provides an updated perspective on the physiological importance, mechanisms, and pathways underlying the efficacy and safety of native GLP-1 and GLP-1R agonists.
Plastic waste poses an ecological challenge
and enzymatic degradation offers one, potentially green and scalable, route for polyesters waste recycling
. Poly(ethylene terephthalate) (PET) accounts ...for 12% of global solid waste
, and a circular carbon economy for PET is theoretically attainable through rapid enzymatic depolymerization followed by repolymerization or conversion/valorization into other products
. Application of PET hydrolases, however, has been hampered by their lack of robustness to pH and temperature ranges, slow reaction rates and inability to directly use untreated postconsumer plastics
. Here, we use a structure-based, machine learning algorithm to engineer a robust and active PET hydrolase. Our mutant and scaffold combination (FAST-PETase: functional, active, stable and tolerant PETase) contains five mutations compared to wild-type PETase (N233K/R224Q/S121E from prediction and D186H/R280A from scaffold) and shows superior PET-hydrolytic activity relative to both wild-type and engineered alternatives
between 30 and 50 °C and a range of pH levels. We demonstrate that untreated, postconsumer-PET from 51 different thermoformed products can all be almost completely degraded by FAST-PETase in 1 week. FAST-PETase can also depolymerize untreated, amorphous portions of a commercial water bottle and an entire thermally pretreated water bottle at 50 ºC. Finally, we demonstrate a closed-loop PET recycling process by using FAST-PETase and resynthesizing PET from the recovered monomers. Collectively, our results demonstrate a viable route for enzymatic plastic recycling at the industrial scale.
Immigration is perhaps the most enduring and elemental leitmotif of America. This book is the most powerful study to date of the politics and policies it has inspired, from the founders' earliest ...efforts to shape American identity to today's revealing struggles over Third World immigration, noncitizen rights, and illegal aliens. Weaving a robust new theoretical approach into a sweeping history, Daniel Tichenor ties together previous studies' idiosyncratic explanations for particular, pivotal twists and turns of immigration policy. He tells the story of lively political battles between immigration defenders and doubters over time and of the transformative policy regimes they built.
Tichenor takes us from vibrant nineteenth-century politics that propelled expansive European admissions and Chinese exclusion to the draconian restrictions that had taken hold by the 1920s, including racist quotas that later hampered the rescue of Jews from the Holocaust. American global leadership and interest group politics in the decades after World War II, he argues, led to a surprising expansion of immigration opportunities. In the 1990s, a surge of restrictionist fervor spurred the political mobilization of recent immigrants. Richly documented, this pathbreaking work shows that a small number of interlocking temporal processes, not least changing institutional opportunities and constraints, underlie the turning tides of immigration sentiments and policy regimes. Complementing a dynamic narrative with a host of helpful tables and timelines, Dividing Lines is the definitive treatment of a phenomenon that has profoundly shaped the character of American nationhood.
Protein and peptide therapeutics require parenteral administration, which can be a deterrent to medication adherence. For this reason, there have been extensive efforts to develop alternative ...delivery strategies, particularly for peptides such as insulin that are used to treat endocrine disorders. Oral delivery is especially desirable, but it faces substantial barriers related to the structural organization and physiological function of the gastrointestinal tract. This article highlights strategies designed to overcome these barriers, including permeation enhancers, inhibitors of gut enzymes, and mucus-penetrating and cell-penetrating peptides. It then focuses on the experience with oral peptides that have reached clinical trials, including insulin, calcitonin, parathyroid hormone and vasopressin, with an emphasis on the advances that have recently led to the landmark approval of an oral formulation of the glucagon-like peptide 1 receptor agonist semaglutide for the treatment of type 2 diabetes.
Glucagon-like peptide-1, produced predominantly in enteroendocrine cells, controls glucose metabolism and energy homeostasis through regulation of islet hormone secretion, gastrointestinal motility, ...and food intake, enabling development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. GLP-1 also acts on the immune system to suppress inflammation, and GLP-1R signaling in multiple tissues impacts cardiovascular function in health and disease. Here we review how GLP-1 and clinically approved GLP-1R agonists engage mechanisms that influence the risk of developing cardiovascular disease. We discuss how GLP-1R agonists modify inflammation, cardiovascular physiology, and pathophysiology in normal and diabetic animals through direct and indirect mechanisms and review human studies illustrating mechanisms linking GLP-1R signaling to modification of the cardiovascular complications of diabetes. The risks and benefits of GLP-1R agonists are updated in light of recent data suggesting that GLP-1R agonists favorably modify outcomes in diabetic subjects at high risk for cardiovascular events.
GLP-1 receptor agonists are utilized for treatment of diabetes and obesity. Herein we update mechanisms linking GLP-1R signaling to control of glucose, body weight, inflammation, heart rate, blood pressure, and atherosclerosis, integrating data from preclinical and human studies that illuminate the efficacy, safety, and biology of the GLP-1 receptor system.
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