Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

G protein-coupled receptors (GPCRs) form a superfamily of plasma membrane receptors that couple to four major families of heterotrimeric G proteins, Gs, Gi, Gq, and G12. GPCRs represent excellent targets for drug therapy. Since the individual GPCRs are expressed by many different cell types, the in vivo metabolic roles of a specific GPCR expressed by a distinct cell type are not well understood. The development of designer GPCRs known as DREADDs (designer receptors exclusively activated by a designer drug) that selectively couple to distinct classes of heterotrimeric G proteins has greatly facilitated studies in this area. This review focuses on the use of DREADD technology to explore the physiological and pathophysiological roles of distinct GPCR/G protein cascades in several metabolically important cell types. The novel insights gained from these studies should stimulate the development of GPCR-based treatments for major metabolic diseases such as type 2 diabetes and obesity. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 61 is January 8, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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PMID:Use of DREADD Technology to Identify Novel Targets for Antidiabetic Drugs. 3274 68

The free fatty acid receptor 1 (FFAR1, formerly GPR40), is a potential G protein-coupled receptor (GPCR) target for the treatment of type 2 diabetes mellitus (T2DM), as it enhances glucose-dependent insulin secretion upon activation by endogenous long-chain free fatty acids. The presence of two allosterically communicating binding sites and the lack of the conserved GPCR structural motifs challenge the general knowledge of its activation mechanism. To date, four X-ray crystal structures are available for computer-aided drug design. In this study, we employed molecular dynamics (MD) and supervised molecular dynamics (SuMD) to deliver insights into the (un)binding mechanism of the agonist MK-8666, and the allosteric communications between the two experimentally determined FFAR1 binding sites. We found that FFAR1 extracellular loop 2 (ECL2) mediates the binding of the partial agonist MK-8666. Moreover, simulations showed that the agonists MK-8666 and AP8 are reciprocally stabilized and that AP8 influences MK-8666 unbinding from FFAR1.
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PMID:Addressing free fatty acid receptor 1 (FFAR1) activation using supervised molecular dynamics. 3285 80

Bariatric and metabolic surgery (BMS) is the most effective treatment for obesity, type 2 diabetes and co-morbidities, including nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. The beneficial effects of BMS are beyond the primary goal of gastric restriction and nutrients malabsorption. Roux-en-Y gastric bypass and vertical sleeve gastrectomy are the 2 most commonly performed procedures of BMS. Both surgeries lead to physiologic changes in gastrointestinal tract; subsequently alter bile acids pool and composition, gut microbial activities, gut hormones, and circulating exosomes; and ultimately contribute to the improved glycemic control, insulin sensitivity, lipid metabolism, energy expenditure, and weight loss. The mechanisms underlying the benefits of BMS likely involve the bile acid-signaling pathway mediated mainly by nuclear farnesoid X receptor and the membrane Takeda G protein-coupled receptor, bile acids-gut microbiota interaction, and exosomes. In this review, we focus on recent advances in potential mechanisms and aim to learn novel insights into the molecular mechanisms underlying metabolic disorders.
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PMID:Recent advances in the mechanisms underlying the beneficial effects of bariatric and metabolic surgery. 3303 39


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