Pancreatic ß-cell failure, clinical implications, and therapeutic strategies in type 2 diabetes.

ABSTRACT: Pancreatic ß-cell failure due to a reduction in function and mass has been defined as a primary contributor to the progression of type 2 diabetes (T2D). Reserving insulin-producing ß-cells and hence restoring insulin production are gaining attention in translational diabetes research, and ß-cell replenishment has been the main focus for diabetes treatment. Significant findings in ß-cell proliferation, transdifferentiation, pluripotent stem cell differentiation, and associated small molecules have served as promising strategies to regenerate ß-cells. In this review, we summarize current knowledge on the mechanisms implicated in ß-cell dynamic processes under physiological and diabetic conditions, in which genetic factors, age-related alterations, metabolic stresses, and compromised identity are critical factors contributing to ß-cell failure in T2D. The article also focuses on recent advances in therapeutic strategies for diabetes treatment by promoting ß-cell proliferation, inducing non-ß-cell transdifferentiation, and reprograming stem cell differentiation. Although a significant challenge remains for each of these strategies, the recognition of the mechanisms responsible for ß-cell development and mature endocrine cell plasticity and remarkable advances in the generation of exogenous ß-cells from stem cells and single-cell studies pave the way for developing potential approaches to cure diabetes.

Abalign: a comprehensive multiple sequence alignment platform for B-cell receptor immune repertoires.

The utilization of high-throughput sequencing (HTS) for B-cell receptor (BCR) immune repertoire analysis has become widespread in the fields of adaptive immunity and antibody drug development. However, the sheer volume of sequences generated by these experiments presents a challenge in data processing. Specifically, multiple sequence alignment (MSA), a critical aspect of BCR analysis, remains inadequate for handling massive BCR sequencing data and lacks the ability to provide immunoglobulin-specific information. To address this gap, we introduce Abalign, a standalone program specifically designed for ultrafast MSA of BCR/antibody sequences. Benchmark tests demonstrate that Abalign achieves comparable or even better accuracy than state-of-the-art MSA tools, and shows remarkable advantages in terms of speed and memory consumption, reducing the time required for high-throughput analysis from weeks to hours. In addition to its alignment capabilities, Abalign offers a broad range of BCR analysis features, including extracting BCRs, constructing lineage trees, assigning VJ genes, analyzing clonotypes, profiling mutations, and comparing BCR immune repertoires. With its user-friendly graphic interface, Abalign can be easily run on personal computers instead of computing clusters. Overall, Abalign is an easy-to-use and effective tool that enables researchers to analyze massive BCR/antibody sequences, leading to new discoveries in the field of immunoinformatics. The software is freely available at http://cao.labshare.cn/abalign/.

Nuclear factor-Y mediates pancreatic ß-cell compensation by repressing reactive oxygen species-induced apoptosis under metabolic stress.

BACKGROUND: Pancreatic ß-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions. Deficits in ß-cell compensatory capacity result in hyperglycemia and type 2 diabetes (T2D). However, the mechanism in the regulation of ß-cell compensative capacity remains elusive. Nuclear factor-Y (NF-Y) is critical for pancreatic islets' homeostasis under physiological conditions, but its role in ß-cell compensatory response to insulin resistance in obesity is unclear. METHODS: In this study, using obese ( ob/ob ) mice with an absence of NF-Y subunit A (NF-YA) in ß-cells ( ob , Nf-ya ßKO) as well as rat insulinoma cell line (INS1)-based models, we determined whether NF-Y-mediated apoptosis makes an essential contribution to ß-cell compensation upon metabolic stress. RESULTS: Obese animals had markedly augmented NF-Y expression in pancreatic islets. Deletion of ß-cell Nf-ya in obese mice worsened glucose intolerance and resulted in ß-cell dysfunction, which was attributable to augmented ß-cell apoptosis and reactive oxygen species (ROS). Furthermore, primary pancreatic islets from Nf-ya ßKO mice were sensitive to palmitate-induced ß-cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response, which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase (JNK) and cleaved caspase-3. These detrimental effects were completely relieved by ROS scavenger. Ultimately, forced overexpression of NF-Y in INS1 ß-cell line could rescue palmitate-induced ß-cell apoptosis, dysfunction, and mitochondrial impairment. CONCLUSION: Pancreatic NF-Y might be an essential regulator of ß-cell compensation under metabolic stress.