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.
Highlights
Blood glucose levels in the body are regulated by hormones secreted by pancreatic endocrine cells
Pancreatic β-cells account for approximately 60% of the islets in humans, whereas in rodents, they account for about 80% [1]
Type 2 diabetes is caused by abnormal secretion of these hormones, which are related to changes in the number and mass of islet cells
Summary
Blood glucose levels in the body are regulated by hormones secreted by pancreatic endocrine cells. MafA overexpression in the β-cells of obese type 2 diabetic model mice recovered their ability to synthesize insulin, and improved glucose-stimulated insulin secretion (GSIS) as well as their blood glucose levels [21] These results indicate that c-Jun expression regulates MafA, Metabolites 2021, 11, 218 and is involved in β-cell dysfunction. Chronic ER stress induces numerous apoptotic signals including oxidative stress, IRE1α-mediated activation of apoptosis signal-regulating kinase 1/c-Jun amino-terminal kinase (ASK1/JNK), PERK-dependent C/EBP homologous protein (CHOP) expression, and activation of caspase-12, caspase-3, and endogenous mitochondria-dependent cell death pathways [4] In this manner, chronic hyperglycemia induces oxidative stress and ER stress, leading to pancreatic β-cell dysfunction and cell death (Figure 1)
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