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    • Congenital Gcgr mice exhibit increased

    2022-05-25

    Congenital Gcgr mice exhibit increased hepatic Fgf21 expression and circulating FGF21 levels. Previous studies by other investigators demonstrated that neutralization of circulating FGF21 with specific GNE-7915 impairs glucose control in these mice [6]. In addition, the FGF21 analog LY2405319 lowers blood glucose in STZ mice [44], suggesting that high FGF21 levels may contribute to the protection from hyperglycemia exhibited by the STZ-treated Gcgr mice. Tamoxifen-induced Gcgr deletion in STZ-treated mice also resulted in increased FGF21 levels, although only after long-term Gcgr deletion. Thus, FGF21 cannot account for the reduced baseline glycemia in normal and STZ mice with short-term Gcgr deletion. Like FGF21, congenital Gcgr mice also exhibit dramatically increased GLP-1 levels [2], and these can be recapitulated with treatment with antisense probes to reduce Gcgr expression [13]. In contrast to FGF21, we found significantly elevated plasma GLP-1 in mice with short-term Gcgr deletion, positioning it as a candidate to contribute to the improved glucose control exhibited by those mice. Thus, early evidence suggests that increased plasma GLP-1 makes a meaningful contribution to the improved glycemia associated with reduced GCGR signaling. Hence, mice lacking glucagon [11] or Gcgr [2], [45] exhibit a larger degree of improved glucose tolerance when compared to mice lacking proglucagon gene expression and consequently both glucagon and GLP-1 [40]. In addition, the double mutant Gcgr:Glp1r mice lack the improved glucose tolerance exhibited by normoglycemic Gcgrmice [46]. Further, STZ-treated Gcgr:Glp1r mice exhibit reduced degree of protection from baseline hyperglycemia compared to Gcgr mice [27], and treatment with the GLP-1R antagonist exendin 9 during a glucose challenge significantly increases blood glucose in Gcgr mice [6]. Consistent with these data, treatment with the GLP-1R antagonist Jant4 completely eliminated, albeit transiently, the modest protection from hyperglycemia due to acute Gcgr deletion in STZ-treated mice. The loss of efficacy of the antagonist preventing the blood glucose lowering is consistent with a steady increase in plasma GLP-1 levels that eventually overcome the fixed dose of antagonism. Alternatively, progressive development of GLP-1R-independent compensatory mechanisms may contribute to the gain of hyperglycemic protection. A genetic mouse model allowing simultaneous time-controlled deletion of both Gcgr and Glp1r should allow tracking the onset of those alternative mechanisms. Regardless, these findings position GLP-1R as one of the early compensatory mechanisms engaged following the loss of GCGR signaling that contribute to protection from hyperglycemia due to loss of Gcgr. The mechanisms whereby the increase in plasma GLP-1 levels may contribute to the blood glucose lowering are unclear but they may involve the temporary reduction in feeding observed in STZ-TMX-treated cKO mice. In addition, Jant4 prevented the body weight loss seen in STZ-mice with short-term Gcgr deletion. These results are consistent with a contribution of increased GLP-1R to the protection from obesity exhibited by Gcgr mice [3]. It is well established that loss of Gcgr leads to increased circulating glucagon that exceed increases of GLP-1 [2]. Since glucagon exhibits weak agonism on the GLP-1R [47], it is possible that increased glucagon levels may indirectly regulate glycemia and body weight by acting as a weak GLP-1 mimetic. Although there is evidence of a beneficial role of GLP-1 pharmacology in improving glycemic control in T1DM subjects [48], [49], [50], the extent to which a contribution of GLP-1R to glycemic control in insulinopenic conditions may be clinically relevant remains to be convincingly demonstrated. Given the experience with GLP-1 mimetics to treat type-2 diabetes, the translation of these therapies to the pharmacological toolbox currently available to treat Type-1 Diabetes may provide meaningful improvements in glycemic control in those patients.