Glucagon receptor blockage inhibits β-cell dedifferentiation through FoxO1

Abstract

Glucagon-secreting pancreatic α-cells play pivotal roles in the development of diabetes. Glucagon promotes insulin secretion from β-cells. However, the long-term effect of glucagon on the function and phenotype of β-cells had remained elusive. In this study, we found long-term intervention of glucagon or glucagon intervention with the presence of palmitic acid downregulated the β-cell specific markers, and inhibited insulin secretion in cultured β-cells. These results suggested that glucagon induced β-cell dedifferentiation under pathological conditions. Glucagon blockage by a glucagon receptor (GCGR) monoclonal antibody (mAb) attenuated glucagon-induced β-cell dedifferentiation. In primary islets, GCGR mAb treatment upregulated β-cell specific markers and increased insulin content, suggesting that blockage of endogenous glucagon inhibited β-cell dedifferentiation. To investigate the possible mechanism, we found glucagon decreased FoxO1 expression. FoxO1 inhibitor mimicked the effect of glucagon, while FoxO1 overexpression reversed the glucagon-induced β-cell dedifferentiation. In db/db mice and β-cell lineage-tracing diabetic mice, GCGR mAb lowered glucose level, upregulated plasma insulin level, increased β-cell area and inhibited β-cell dedifferentiation. In the aged β-cell specific FoxO1 knockout mice (with the blood glucose level elevated as a diabetic model), the glucose-lowering effect of GCGR mAb was attenuated, and the plasma insulin level, β-cell area and β-cell dedifferentiation was not affected by GCGR mAb. Our results proved that glucagon induced β-cell dedifferentiation under pathological conditions, and the effect was partially mediated by FoxO1. Our study reveals a novel crosstalk between α- and β-cells, and is helpful to understand the pathophysiology of diabetes and discover new targets for the diabetes treatment.

Glucagon Acting at the GLP-1 Receptor Contributes to β-Cell Regeneration Induced by Glucagon Receptor Antagonism in Diabetic Mice

“…GCGR antagonism displays an efficacious glucose control in T1D or T2D animals and humans ( 4 – 8 ). Our series of studies showed that GCGR antagonism promoted β-cell regeneration in T1D and T2D mice ( 14 – 16 , 32 ), with GLP-1R activation as one of underlying mechanisms identified in this study. Thirteen-week treatment of GCGR mAb increased β-cell mass and the number of Nkx6.1 + /Pdx1 + α-cells in cynomolgus monkeys ( 17 ), suggestive of β-cell regeneration in nonhuman primates.…”

“…Although liver is the main target of glucagon action, glucagon also acts on β-cells and is responsible for insulin secretion ( 9 – 13 ). GCGR antagonism promotes β-cell regeneration (characterized by the increased β-cell mass through β-cell proliferation, β-cell redifferentiation, conversion of α- to β-cells, and β-cell neogenesis from progenitors) in T1D and T2D mice ( 7 , 14 – 16 ) and in euglycemic nonhuman primates ( 17 ). The beneficial effect might be mediated via glucagon-like peptide 1 (GLP-1), because plasma GLP-1 level and intestinal GLP-1 content were greatly elevated by GCGR antagonism ( 18 ).…”

Pancreatic islet cell plasticity: Pathogenic or therapeutically exploitable?

“…84 Accordingly, treatment with a glucagon receptor monoclonal antibody can prevent β-cell dedifferentiation in mice. 84 That said, one aspect that needs to be borne in mind when interpreting data from these studies is the impact of ambient glucose concentrations on islet cell plasticity. Thus, such agents are primarily employed as glucoselowering drugs, yet alterations in blood glucose levels may independently affect islet cell lineage events.…”

“…Wang et al 82 Mouse Gastrin stimulates ductal precursor cell transdifferentiation Wang et al 83 Mouse: K ATP gain-of-function β-cell dedifferentiation and subsequent rescue following insulin therapy Wang et al 84 Mouse: Foxo1 KO, db/db Chronic glucagon induces β-cell dedifferentiation Glucagon receptor blockade inhibits β-cell dedifferentiation Weinberg et al 29 Mouse islets β-cell dedifferentiation Xiao et al 85 Mouse: STZ, NOD Viral gene reprogramming of α-cells into β-cells Zhang et al 86 Rat: chronic oscillating glucose Glutathione prevents β-cell dedifferentiation Pardo et al 87 and Singh et al 88 Zebrafish: β-cell ablation δto β-cell transdifferentiation Li et al 63 Zebrafish Artemisinins repress Arx to stimulate αto β-cell transdifferentiation, via GABA A receptor Ye et al 89 Zebrafish: β-cell ablation Glucagon is essential for αto β-cell transdifferentiation Fiori et al 90 Non-human primates: high-fat/highsugar diet β-cell dedifferentiation was reduced by resveratrol Spijker et al 14 Non-human primates βto α-cell dedifferentiation Abbreviations: AVP, arginine vasopressin; DPP-4, dipeptidyl peptidase-4; GABA, γ-aminobutyric acid; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1; HC, hydrocortisone; HFF, high fat fed; KO, knockout; IL, interleukin; NOD, non-obese diabetic; PP, pancreatic polypeptide; SGLT2, sodium-glucose co-transporter-2; STZ, streptozotocin.…”

“…65,77,78 Interestingly, glucagon has also been shown to modulate β-cell dedifferentiation, marked by loss of β-cell specific marker Foxo1 following prolonged glucagon exposure. 84 Accordingly, treatment with a glucagon receptor monoclonal antibody can prevent β-cell dedifferentiation in mice. 84 That said, one aspect that needs to be borne in mind when interpreting data from these studies is the impact of ambient glucose concentrations on islet cell plasticity.…”