A New Way for Beta Cell Neogenesis: Transdifferentiation from Alpha Cells Induced by Glucagon-Like Peptide 1

Abstract

Recent studies showed that alpha cells, especially immature cells and proalpha cells, might be the precursors of beta cells. Exposure to glucagon-like peptide 1 (GLP1) can ameliorate hyperglycemia in diabetic mice and restore the beta cell mass. In the present study, we adopted single high-dose (60 mg/kg, i.p.) streptozotocin (STZ) to model diabetes mellitus (DM) and randomly assigned short-tail (SD) rats to a normal group, a diabetic group, GLP1 groups (50 μg/kg, 100 μg/kg, and 200 μg/kg), a GLP1 (200 μg/kg) with exendin (9-39) group, and a GLP1 with LY294002 group. We found that the pancreatic insulin-glucagon-positive cell populations increased according to the increase in GLP1 exposure. By contrast, no insulin-amylase-positive cell populations or insulin/pan-cytokeratin cells were observed in the pancreatic sections. The GLP1 receptor antagonist exendin (9-39) and the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) family inhibitor LY294002 not only suppressed protein kinase B (Akt), pancreatic and duodenal homeobox 1 (Pdx1), forkhead box O 1 (FoxO1), and mast cell function-associated antigen A (MafA) mRNA expression but also increased MAFB expression. We concluded that treatment with GLP1 might result in beta cell neogenesis by promoting the transdifferentiation of alpha cells but not by pancreatic acinar cells, ductal cells, or the self-replication of beta cells. The regulation on the GLP1 receptor and its downstream transcription factor PI3K/AKT/FOXO1 pathway, which causes increased pancreatic and duodenal homeobox 1 (Pdx1) and MafA mRNA expression but causes decreased MAFB expression, may be the mechanism involved in this process.

Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes

“…Due to its simplicity, high incidence of diabetes and predictable time course of disease progression, STZ treatment of rodents 8 has become the perhaps most extensively used animal model for diabetes research (≈60,000 articles in relation to "Streptozotocin diabetes" listed in PubMed as of June 2020). Models of STZ-induced diabetes have been used in a variety of research undertakings including e.g., studies of β-cell preservation, endocrine cell transdifferentiation, development of noninvasive β-cell imaging techniques, and immune cell infiltration [9][10][11][12] . Although the frequent use of STZ-treated mice as models of diabetes has led to numerous stereological 2D sampling assessments of BCM, studies describing (i) the effect of STZ treatment over time on individual islets in vivo or (ii) the BCM distribution in the entire pancreas subject to STZ treatment are essentially lacking.…”

The Powdered Root of Eurycoma longifolia Jack Improves Beta-Cell Number and Pancreatic Islet Performance through PDX1 Induction and Shows Antihyperglycemic Activity in db/db Mice

“…Recent studies supported that alpha-cells may be a potential reservoir for beta-cell regeneration. The overexpression of PDX1 and MafA successfully reprogrammed alpha-cells into beta-cells in vitro and in vivo, providing a significant restoration of islet function and delaying the onset of diabetes [ 46 , 47 , 48 ].…”

Antidiabetic drug therapy alleviates type 1 diabetes in mice by promoting pancreatic α-cell transdifferentiation

“…The latter renders GLP-1 inactive (9-36) by cleaving the peptide bond between Ala 8 and Glu 9 . Notably, the active form of GLP-1 that has been previously linked to the transdifferentiation between α-and β-cells [7,22].…”