β‐Cell dysfunction in diabetes: The role of neuroplastin

Diabetes is a disease, the most important characteristic of which is chronic hyperglycemia, and is classified as either an absolute (type 1) or relative (type 2) deficiency of insulin production by β-cells. β-Cell dysfunction and/or decrease in β-cell mass is a hallmark of diabetes, both type 1 and type 2. Pancreatic β-cell mass is determined by the number and size of β-cells. Pancreatic β-cells are required for insulin production and secretion in response to changing blood glucose levels, which is indispensable for glucose homeostasis. Type 1 diabetes involves both immune-mediated and non-immune-mediated forms of hyperglycemia, and the pathogenesis of type 1 diabetes results from a complex interplay between the pancreatic β-cells and both innate and adaptive immune systems. An increase in islet-specific autoreactive CD8+ T lymphocytes and decreased regulatory immune function have been associated with type 1 diabetes, and the development of type 1 diabetes is initiated by the presentation of β-cell peptides by antigen-presenting cells (APCs), such as macrophages and dendritic cells. APCs bearing the autoantigens migrate to the pancreatic lymph nodes where they interact with autoreactive CD4+ T lymphocytes, which in turn mediate the activation of autoreactive CD8+ T cells. The activated CD8+ T cells return to the islet and lyse β-cells expressing immunogenic self-antigens on major histocompatibility complex (MHC) class I surface molecules. β-Cell destruction is further exacerbated by the release of pro-inflammatory cytokines and reactive oxygen species from innate immune cells (macrophages, natural killer cells, and neutrophils). This entire process is amplified by defects in regulatory T lymphocytes, which do not effectively suppress autoimmunity. Activated T cells within the pancreatic lymph node also stimulate B lymphocytes to produce autoantibodies against β-cell proteins, such as anti-glutamic acid decarboxylase (GAD) antibody, anti-insulin antibody, islet cell antigen (IA)-2 antibody, and anti-zinc transporter (ZnT) 8 antibody, that can be measured in the circulation and are considered as biomarkers of type 1 diabetes. Type 1 diabetes is also characterized by the presence of autoimmune inflammation in the islets (insulitis) and shows a strong association with human leukocyte antigen (HLA) haplotypes1. Insulin resistance and β-cell dysfunction are major determinants of type 2 diabetes. Beyond insulin resistance, inflammation and oxidative stress have also been critical factors of type 2 diabetes, and inflammatory intermediates produced by adipocytes and macrophages may initiate low-grade, chronic inflammation that could induce injury to the β-cells with resultant inadequate insulin production. Several pieces of evidence have been published on the malfunction of helper T cells, cytotoxic T cells, and regulatory T cells underpinning pancreatic β-cell failure in type 2 diabetes. Inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), and interleukin-1β are consistently associated with β-cell failure in preclinical models and in people with type 2 diabetes. Similarly, markers of oxidative stress, such as increased reactive oxygen species (ROS) and depleted intracellular antioxidants, are consistently associated with pancreatic β-cell damage linked to type 2 diabetes. Some parts of β-cells are known to be dedifferentiated or transdifferentiated to other cell types in type 2 diabetes2. It is very intriguing that the above discussions on the pathogenesis of diabetes shed light on the similarities between type 1 diabetes and type 2 diabetes pathogenesis, especially in terms of β-cell dysfunction. Although current treatments for diabetes mainly aim to replace insufficient insulin and to improve pancreatic β-cell function, increasing patients' β-cell mass could potentially improve or even cure diabetes. Many transcription factors and signaling pathways are involved in early pancreas development and β-cell differentiation, which affect pancreatic β-cell mass and function as molecular regulators of β-cell proliferation and apoptosis that are responsible for maintenance and expansion of β-cell mass3. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident secretory protein that has been known to reduce inflammation and promotes proliferation in pancreatic β-cells. Many studies have demonstrated the potential of MANF as a therapeutic agent for diabetes, making it essential to understand the mechanisms underlying MANF's functions4. One of the binding partners of MANF is neuroplastin (NPTN), which is localized on the cell surface; however, its roles in pancreatic β-cells remain unclear. Recently, Kitamura et al.5 generated β-cell-specific NPTN knockout mice by breeding Nptnflox/flox mice with Ins1Cre mice (Nptnf/f:Ins1Cre) and reported dual roles of NPTN in pancreatic β-cells, that is, regulating insulin secretion and promoting islet inflammation. In their research, they found roles of NPTN in pancreatic β-cells, that is, an inhibitory effect on insulin secretion and pro-inflammatory effects in β-cells. NPTN deficiency improved glucose tolerance by increasing insulin secretion and β-cell mass in the pancreas. Proliferation and mitochondrial numbers in β-cells increased in the knockout islets. They also found elevated cytosolic Ca++ levels associated with significantly decreased plasma membrane ATPase (PMCA)2 protein levels in Nptnf/f:Ins1Cre islets, which were also reproduced in NPTN KO INS-1832/13 cells in vitro, as well. NPTN induced the expression of pro-inflammatory cytokines via the TRAF6-NF-κB axis in β-cells, and NPTN deficiency conferred resistance to streptozotocin (STZ)-induced type 1 diabetes phenotypes. Exogenous MANF treatment in islets or β-cells led to similar phenotypes as those observed in NPTN-deficient models. Their study has several important implications. First of all, they were the first group that found NPTN is a binding partner of MANF, and in this study, they further extended their research to elucidate the role of NPTN in β-cells. The role of NPTN is intriguing but not simple and straightforward, however. NPTN regulates cytosolic Ca++ level by the inhibitory protein–protein interaction with PMCA2 and, at the same time, induces the gene expression of pro-inflammatory cytokines, both of which could lead to decreases in glucose-stimulated insulin secretion (GSIS) and β-cell apoptosis. Second, they found MANF effect could be mediated through antagonizing NPTN's functions. With all these criticisms, Kitamura's work, which showed novel roles of neuroplastin in association with MANF in pancreatic β-cells, provided important perspectives that could potentially lead to new insights on the pathogenesis and progression of diabetes and could also provide intriguing clues for therapeutic strategies. I, Moon-Kyu Lee, am an editorial board member of Journal of Diabetes Investigation and the author of this article. To minimize bias, I was excluded from all editorial decision-making related to the acceptance of this article for publication.