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  • Interruption of glucagon signaling pathway targeting glucago

    2021-12-03

    Interruption of glucagon signaling pathway targeting glucagon receptor (GCGR) by gene knockout, antisense oligonucleotides or specific antagonists induces α-cell hyperplasia and alleviates hyperglycemia and other metabolic symptoms in diabetic animals and patients [[7], [8], [9]]. Here we used a fully humanized competitive antagonistic GCGR monoclonal antibody (mAb), REMD 2.59, which exhibits strong hypoglycemic effects in T1D rodents [10], T2D rodents and non-human primates [11,12], as well as T1D patients [13]. We showed that the GCGR mAb induced pancreatic δ-cell neogenesis via stimulating cell proliferation and duct-derived neogenesis in normoglycemic and streptozocin (STZ)-induced T1D mice. Moreover, the increased δ-cell mass might reduce β-cell burdens in normoglycemic mice, and hold the ability of conversion to β-cells in T1D mice.
    Methods and materials
    Results
    Discussion The main finding of our study was that δ-cell mass was markedly increased by the GCGR mAb treatment. Although δ-cell hyperplasia has been reported in Gcgr knockout mice or Goto-Kakizaki diabetic rats [14,15], rare study refers to possible origin of the δ-cells. In this study, we found that the BrdU+ δ-cells increased after the GCGR mAb treatment, suggesting cell proliferation might account for the enlarged δ-cell mass. On the other hand, it has been shown that δ-cells can be generated from the duct lining cells in adult mice when Pax4 is ectopic expressed in δ-cells [6]. Pancreatic ducts are normally regarded as a place where progenitor habitats and can be converted into endocrine cells following pancreatic damage in adults [16]. If newborn cells are located in the ducts, it is possible that they are derived from progenitors. In our study, most neogenic δ-cells were found in the place near ducts, some were even located in the ductal region, and several somatostatin-positive cells were co-localized with SOX9. These results suggest that the neogenic δ-cells upon the GCGR mAb treatment are reprogrammed from duct-lining progenitors. The potential factor of the boosted δ-cell mass is barely unknown. Studies of GCGR signaling interruption have indicated existence of a hepatic α-cell axis where glucagon modulates serum amino H 89 availability, and these amino acids, particularly l-glutamine, can regulate α-cell proliferation and mass [17,18]. Similar feedback loop (such as a hepatic δ-cell axis) might also play an important role in stimulating δ-cell proliferation. Besides, the embedded molecular mechanisms referring to δ-cell regeneration may originate from key factors that regulate pancreatic differentiation, such as transcription factor Nkx6.1. It has been reported that when Nkx6.1 is deleted in β-cells, β-cells convert into δ-cells [19]. Nevertheless, the molecular mechanism that stimulates δ-cell proliferation and differentiation remains a dilemma. Next, we tried to answer what was the significance of the increased δ-cell mass. In most mammals, δ-cells exhibit a neuron-like morphology with cytoplasmic processes extending from the islet capillaries to the central core of an islet, facilitating communication with many neighboring α- and β-cells [20]. Traditionally, somatostatin secreted from δ-cells is acknowledged as an inhibitor of glucagon and insulin secretion via a paracrine manner [2]. In this GCGR blocking model, the increased glucagon level might induce compensatory increase in δ-cell mass and elevation in plasma somatostatin level. Moreover, the elevated somatostatin level demonstrated a strong suppressive effect on insulin secretion from β-cells in normal C57BL/6N mice, which could reduce β-cell burden. Recently, a series of studies suggest that δ-cells are more likely to work synergistically with β-cells. Somatostatin secretion from δ-cells is stimulated by increased extracellular glucose or tolbutamide, which is similar to insulin secretion from β-cells rather than glucagon secretion from α-cells [21,22]. One study using optogenetic strategy revealed that δ-cells and β-cells are electrically coupled and regulate α-cell activity via somatostatin, and light activation of β-cells triggered a suppression of α-cell activity via gap junction-dependent activation of δ-cells [23]. Thus, the boosted δ-cells may facilitate β-cells to suppress excessive glucagon secretion in α-cells. Moreover, we showed for the first time that the increased δ-cells inhibited insulin secretion possibly by inducing FoxO1 nuclear translocation in normoglycemic mice. However, the direct evidence that the increased δ-cell mass could modulate FoxO1 function in β-cells is needed.