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IGFBP1 increases β-cell regeneration by promoting α- to β-cell transdifferentiation.

ABSTRACT: There is great interest in therapeutically harnessing endogenous regenerative mechanisms to increase the number of β cells in people with diabetes. By performing whole-genome expression profiling of zebrafish islets, we identified 11 secreted proteins that are upregulated during β-cell regeneration. We then tested the proteins' ability to potentiate β-cell regeneration in zebrafish at supraphysiological levels. One protein, insulin-like growth factor (Igf) binding-protein 1 (Igfbp1), potently promoted β-cell regeneration by potentiating α- to β-cell transdifferentiation. Using various inhibitors and activators of the Igf pathway, we show that Igfbp1 exerts its regenerative effect, at least partly, by inhibiting Igf signaling. Igfbp1's effect on transdifferentiation appears conserved across species: Treating mouse and human islets with recombinant IGFBP1 in vitro increased the number of cells co-expressing insulin and glucagon threefold. Moreover, a prospective human study showed that having high IGFBP1 levels reduces the risk of developing type-2 diabetes by more than 85%. Thus, we identify IGFBP1 as an endogenous promoter of β-cell regeneration and highlight its clinical importance in diabetes.

SUBMITTER: Lu J

PROVIDER: S-EPMC5116948 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Pax4 Gene Delivery Improves Islet Transplantation Efficacy by Promoting β Cell Survival and α-to-β Cell Transdifferentiation.

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Artemisinins target GABA receptor signaling to induce alpha to beta cell transdifferentiation

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Human pancreatic α- to β-cell area ratio increases after type 2 diabetes onset.

Project description:Aims/introductionPancreatic α-cell area and the α- to β-cell area ratio (α/β) might be associated with glucose tolerance. The aim was to clarify how these histological parameters change as glucose tolerance deteriorates.Materials and methodsWe analyzed pancreatic tissues obtained from pancreatectomies of 43 patients. We evaluated the relationships between α-cell area or the α/β and various clinical parameters. Additionally, we analyzed α-cell proliferation and the expression patterns of various pancreatic transcription factors.ResultsThe α/β in individuals with longstanding (previously diagnosed) type 2 diabetes (0.36 ± 0.12) was higher than that in those with normal glucose tolerance (0.18 ± 0.10; P < 0.01), impaired glucose tolerance (0.17 ± 0.12; P < 0.05) and newly diagnosed diabetes (0.17 ± 0.12; P < 0.05). In all participants, glycated hemoglobin (HbA1c) correlated with relative α-cell area (P = 0.010). Diabetes duration (P = 0.004), HbA1c (P < 0.001) and plasma glucose levels (P = 0.008) were significantly correlated with the α/β in single regression analyses, and diabetes duration was the only independent and significant determinant in stepwise multiple regression analyses (P = 0.006). The α-cell Ki67-positive ratio in patients with HbA1c ≥6.5% was significantly higher than that in patients with HbA1c <6.5% (P = 0.022). We identified β-cells that expressed aristaless-related homeobox and α-cells that did not express aristaless-related homeobox at all glucose tolerance stages. Aristaless-related homeobox and NK homeobox 6.1 expression patterns varied in insulin and glucagon double-positive cells.ConclusionsThe pancreatic α/β increases after type 2 diabetes onset and correlates with diabetes duration. This change might occur through α-cell proliferation and phenotypic changes in pancreatic endocrine cells.

| S-EPMC6215948 | biostudies-literature

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