Ropivacaine HCl Extensive pharmacological and structural ana

Extensive pharmacological and structural analysis shows GCGR antibody REMD-477 competitively blocks GLC binding to the GCGR with 30-pM binding affinity, and can fully inhibit the receptor activity at low nanomolar concentrations in Ropivacaine HCl 14, 17, 20. Functionally identical to REMD-477, REMD2.59 is a surrogate human antibody specifically generated for chronical preclinical studies in rodents and primates. Unlike previous small-molecule approaches (30), REMD-477 does not have deleterious effects on serum lipid profiles 11, 12, 19, 21, 31 in both ongoing clinical trials in diabetes patients. In short, the anti-GCGR antibody as tested here offers a novel and powerful therapeutic tool to effectively and specifically inhibit GCGR with proven record of clinical safety and efficacy at molecular and metabolic levels. Several other diabetic therapies, including GLC-like peptide-1 agonists 37, 38, dipeptidyl peptidase 4 inhibition (39), and sodium glucose cotransporter 2 inhibitors 40, 41, have demonstrated various degrees of cardiovascular benefits along with ameliorated metabolic defects in glucose homeostasis. Yet, not all glucose-lowering therapies have such significant cardiovascular protective effects as sodium glucose cotransporter 2 inhibition 42, 43, 44, 45, 46. It is also unclear if these therapies will be efficacious for common forms of heart failure without the confounding metabolic disorders. Our current study in 2 heart failure disease models free from systemic metabolic disorders further supports that GCGR inhibition may be repurposed as an effective therapy for common forms of heart failure.
Acknowledgment
Introduction Glucagon is traditionally believed to be an alpha-cell derived hormone that increases blood glucose levels through increased hepatic glucose production [1]. The antagonism or agonism of the glucagon receptor has long been regarded as potential therapeutic strategies. Whereas agonism of the glucagon receptor (GCGr) is commonly used for treatment of hypoglycemia in patients with type 1 diabetes [2], [3] and potentially as a weight-lowering drug for obese individuals [4], antagonizing the GCGr on the other hand has been suggested a novel drug candidate for treatment of type 2 diabetes [5]. The diabetogenic role of glucagon is widely accepted [6], as demonstrated in the early 1980s using glucagon receptor antagonists in rodents [7], [8] and recently also confirmed in patients with type 2 diabetes [9]. However, a number of preclinical studies now suggest that the secretion of glucagon and alpha cell mass is controlled by amino acids whereas glucagon may contribute to hepatic amino acid turnover through ureagenesis and gluconeogenesis and thereby constituting a new endocrine feedback system [10], [11], [12], [13].
Clinical rationale for measurement of glucagon Measurement of glucagon may be clinically relevant for the diagnosis of glucagon-producing tumors (part of the group of pancreatic neuroendocrine tumors) [14], [15]. Although the incidence of glucagonomas are extremely low (∼1:1.000.000) the pathophysiology of such tumors may help us understand how differential processing of proglucagon results in heterogeneous clinical phenotypes: Hypoglycemia due to increased plasma levels of active GLP-1, and hyperglycemia due to increased plasma concentrations of glucagon [16]. That said, it may be of interest to profile the secretion of glucagon during daily life and upon metabolic challenges [17] and the majority of the current literature is actually based on the associations of glucagon with development of diabetes. From the development of the first glucagon assay in 1959 [18], the majority of research investigating hypersecretion of glucagon has applied C-terminal glucagon assays, whereas a few have used, what turned out to be unreliable, sandwich and or side-viewing glucagon assays [19], which led to falsely increased secretory rates of glucagon due to cross-reactivity with other proglucagon derived peptides (Fig. 1A), namely oxyntomodulin and glicentin. Truly C-terminal assays (C-terminal wrapping assays) may be specific and provide its user with an accurate profile of glucagon secretion [20], but on the other hand these are unable to discriminate between potential N-terminally elongated and/or truncated glucagon forms that may exist in dysmetabolic conditions [16] and their importance has yet to be decided. In addition, the C-terminal assays may, dependent of the quality of the antibody used, also cross-react with proglucagon molecules. It therefore remain important to assess the specificity of antibody based measurement methods, as described previously using mass-spectrometry based methods and assay validation guidelines.