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Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are effective therapies for type 2 diabetes (T2D) and obesity, yet patient responses are variable. Variation in the human Glp1r gene might be directly linked to therapeutic responses. A naturally occurring missense variant, A316T, protects against T2D and cardiovascular disease. Here, we have generated and characterised a human Glp1r A316T mouse model. Human Glp1r A316T/A316T mice displayed lower fasting blood glucose versus wildtype littermates, even under metabolic stress, and exhibited alterations in islet cytoarchitecture and α/β identity under a high-fat, high-sucrose diet. This was however associated with blunted responses to GLP-1RAs in vivo. Further investigations in rodent and human β-cell models demonstrated that human Glp1r A316T exhibits characteristics of constitutive activation but dampened GLP-1RA responses. Results are further supported by cryo-EM analyses and molecular dynamics simulations of GLP-1R A316T structure, collectively demonstrating that the A316T variant governs basal GLP-1R activity and pharmacological responses to GLP-1R-targeting therapies.

Introduction: Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults in Western countries, with a median age at diagnosis of 72 years. This guide, developed by the Spanish Group for Chronic Lymphocytic Leukemia (GELLC), addresses the most relevant aspects of CLL, with the objectives of facilitating and aiding the diagnostic process, establishing therapeutic recommendations for choosing the best treatment for each type of patient, as well as standardizing the management of CLL and ensuring equity across different hospitals in terms of the use of the various available treatment regimens., Methodology: The references obtained were classified according to the level of evidence and following the criteria established by the Agency for Health Research and Quality, and the recommendations were classified according to the criteria of the National Comprehensive Cancer Network (NCCN)., Diagnosis: The diagnosis of CLL requires the presence of 5 × 10 9 /l clonal B lymphocytes with the characteristic phenotype (CD19, CD5, CD20, CD23, and kappa or lambda chain restriction) demonstrated by flow cytometry in peripheral blood and maintained for at least 3 months. The presence of cytopenia caused by a typical bone marrow infiltrate establishes the diagnosis of CLL, regardless of the number of circulating lymphocytes or existing lymph node involvement. CLL and small lymphocytic lymphoma (SLL) are the same disease with different presentations, so they should be treated the same way. Current international guidelines recommend FISH with the 4 probes as a mandatory test in clinical practice to guide the prognosis of patients. They also recommend determining the mutational status of the immunoglobulin heavy chain variable region (IGHV) before the first treatment and detecting TP53 mutations before the first and subsequent relapses., Treatment: Treatment should be initiated in symptomatic patients with criteria for active disease according to iwCLL. The first aspect to highlight is the prioritization of targeted therapies over immunochemotherapy. In first-line treatment, for patients with del(17p) and/or TP53 mutation, the best therapeutic option is a second-generation covalent Bruton's tyrosine kinase inhibitor (BTKi) administered indefinitely, while in cases without del(17p) or TP53 mutation with mutated IGHV, time-limited therapy with a combination including a BCL2 inhibitor (BCL2i) should be considered as the first therapeutic option. For patients with unmutated IGHV, both continuous BTKi and finite therapy with BCL2i are valid options that should be individually evaluated considering potential toxicities, drug interactions, patient preference, and logistical aspects. In very frail patients, supportive treatment should be considered. In relapse/refractory patients, prior treatment, the biological risk of CLL, the duration of response (if prior finite treatment), or the reason for stopping BTKi (if prior continuous treatment) should be considered., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)