The Plasticity of Pancreatic β-Cells

Abstract

Type 2 diabetes is caused by impaired insulin secretion and/or insulin resistance. Loss of pancreatic β-cell mass detected in human diabetic patients has been considered to be a major cause of impaired insulin secretion. Additionally, apoptosis is found in pancreatic β-cells; β-cell mass loss is induced when cell death exceeds proliferation. Recently, however, β-cell dedifferentiation to pancreatic endocrine progenitor cells and β-cell transdifferentiation to α-cell was reported in human islets, which led to a new underlying molecular mechanism. Hyperglycemia inhibits nuclear translocation and expression of forkhead box-O1 (FoxO1) and induces the expression of neurogenin-3(Ngn3), which is required for the development and maintenance of pancreatic endocrine progenitor cells. This new hypothesis (Foxology) is attracting attention because it explains molecular mechanism(s) underlying β-cell plasticity. The lineage tracing technique revealed that the contribution of dedifferentiation is higher than that of β-cell apoptosis retaining to β-cell mass loss. In addition, islet cells transdifferentiate each other, such as transdifferentiation of pancreatic β-cell to α-cell and vice versa. Islet cells can exhibit plasticity, and they may have the ability to redifferentiate into any cell type. This review describes recent findings in the dedifferentiation and transdifferentiation of β-cells. We outline novel treatment(s) for diabetes targeting islet cell plasticity.

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus

“…Reduced pancreatic β-cell mass is the ultimate cause of impaired insulin synthesis and secretion in DM [ 31 , 32 ]. Apoptosis of β-cells explains in part the insufficient insulin production and secretion in DM [ 32 , 33 , 34 ]. Autoimmune-isletitis-associated cell damage in type 1 DM and hyperglycemia-associated oxidative stress and endoplasmic reticulum stress in type 2 DM are involved in pancreatic β-cell apoptosis [ 35 ].…”

CD36 regulates β cell differentiation and influences type 2 diabetic sepsis

“…β-cell dedifferentiation is divided into differentiation into pancreatic endocrine progenitor cells and transdifferentiation into α-cell, both of which lead to reduction in β-cell mass and impairment of insulin secretion and/or insulin resistance in T2DM. PDX1, MAFA and insulin are the biomarkers of mature β-cells, and Neurog3, OCT4, NAGOG, and SOX9 molecules are the biomarkers of endocrine progenitor β-cells [30]. CD36 reduces insulin release by inhibiting PDX1 [11,12] and induces βcell glucotoxicity by increasing FOXO1 nuclear translocation to suppress MAFA expression [9,31].…”

“…MAFA also induces Neurog3 positive endocrine precursors to β-cells by enhancing PDX1 and producing β-cells from α-cells [32]. Insulin therapy or PDX1 or MAFA expression promotes the conversion of α-cells to pancreatic β-cells [33]. However, FOXO1 knockdown promotes β-cell dedifferentiation to progenitor-like cell expressing Neurog3, OCT4 and NAGOG [4].…”

“…Neurog3 protein is speci cally expressed in pancreatic progenitor cell and silenced after birth; thus, interfering Neurog3 prevents the generation of new insulinpositive cells [34]. Hyperglycaemia inhibits nuclear translocation and expression of FOXO1 and induces Neurog3 expression, which is necessary for the development and maintenance of pancreatic endocrine progenitor cells [33]. OCT4 and NAGOG are the characteristics of stem cells.…”

“…Targeting lipid metabolism such as CD36, lipogenic transcription factor SREBP1c and fatty acid synthase may inhibit the stemness of stem cells [35]. Hyperglycaemia, in ammatory cytokines (IL-1, IL-6 and TNF-α) and oxidative stress enhance β-cell dedifferentiation [33]. CD36 may participate in the regulation of β-cell dedifferentiation by inducing oxidative stress and up-regulating cytokines.…”