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    • dofetilide br Conclusions Temporally controlled disruption o

    2021-12-24


    Conclusions Temporally-controlled disruption of Gcgr reveals a lack meaningful contribution to the improvement of glycemic control in insulinopenic conditions attributable to the intrinsic loss of GCGR signaling. On the other hand, these data highlight the importance of compensatory systems, including GLP-1R signaling. Given the potential adverse effects exhibited by therapies aiming to block Gcgr, including adverse lipid profile and hepatic function [51], [52], [53], emphasis on identifying and developing the most effective of those compensatory mechanisms may provide safe and efficacious therapies for the treatment of T1DM.
    Disclosure statement
    Acknowledgements This work was supported dofetilide by funds of the University of Cincinnati-College of Medicine (F102150) to DPT, and NIDDK (DK112934) to KMH.
    The glucagon receptor (GCGr) is a class B G-protein coupled receptor. In the liver, stimulation of GCGr signaling by binding of glucagon, a 29-amino dofetilide peptide hormone produced by the α-cells of the endocrine pancreas, stimulates hepatic glucose production via both glycogenolysis and gluconeogenesis. Through its action via the GCGr, glucagon plays a counter-regulatory role to insulin in the maintenance of euglycemia. In type-2 diabetes mellitus, the suppression of pancreatic glucagon secretion in response to hyperglycemia and hyperinsulinemia is inadequate, contributing to abnormally elevated hepatic glucose production in both the fasting and postprandial states., , , , Dysregulation of glucagon secretion has also been suggested to play a central role in the pathology of type-1 diabetes., Blockade of glucagon signaling by GCGr antagonists has long been proposed as a method to improve glycemic control in the diabetic state via reduction of hepatic glucose production., Clinical evaluation of a small-molecule GCGr antagonist was first reported in 2001, with the demonstration that oral administration of the GCGr antagonist Bay 27-9955 (), , to healthy male volunteers blunted the elevation in hepatic glucose production and plasma glucose concentration induced by administering exogenous glucagon. Over the last few years, a number of other small-molecule GCGr antagonists have entered the clinic ( and ). The disclosed data from these clinical experiments, most notably data reviewed below from experiments using either MK-0893 (), MK-3577 (), or LY2409021, demonstrate the ability of GCGr antagonists to improve glucose homeostasis in diabetic subjects. However, the therapeutic utility of this mechanism remains unclear as dose-responsive increases in circulating lipids, particularly low-density lipoprotein cholesterol (LDL-C), elevated liver enzymes, and increases in body weight have been reported in some of these studies (vide infra). The preclinical and early clinical development of small-molecule GCGr antagonists through late 2011 has been reviewed previously., The patent literature covering small-molecule GCGr antagonists through 2014 has also been recently reviewed. Starting in 2011, a series of clinical experiments with MK-0893 (), , were disclosed., Results of a glucagon challenge study were used to select doses of MK-0893 for use in a 4-week monotherapy study in subjects with type-2 diabetes. The 40mg q.d. and 120mg q.d. doses selected were predicted to achieve approximately 50% and 100% inhibition of glucagon-mediated excursions in blood glucose at steady state, respectively. In the ensuing 4-week study, both the 40mg q.d. and 120mg q.d. doses of MK-0893 were observed to be effective at lowering 24h-weighted mean glucose (WMG), with reported changes from baseline difference in least-squares (LS) mean versus placebo of 25.9mg/dL and 53.6mg/dL, respectively. At the 120mg q.d. dose ‘trends for increases in LDL-cholesterol, LFTs and blood pressure were noted.’ In a four-week study in type-2 diabetic subjects, administration of 40mg MK-0893 q.d. in combination with either 1g metformin b.i.d. or 100mg q.d. of the DPP-IV inhibitor sitagliptin resulted in lowered fasting plasma glucose (FPG) and 24h-WMG. Treatment with the combination of 40mg MK-0893 q.d. and metformin 1g b.i.d. resulted in greater decreases in FPG and 24h-WMG when compared to administration of 100mg q.d. sitagliptin in combination with 1g b.i.d. metformin. The coadministration of 40mg MK-0893 q.d. and 100mg sitagliptin q.d. was less effective in lowering FPG and 24h-WMG when compared to the sitagliptin/metformin cotherapy. Increases in total cholesterol and LDL-C from baseline were observed with MK-0893 and sitagliptin cotherapy.