Genetic lineage tracing identifies adaptive mechanisms of pancreatic islet β cells in various mouse models of diabetes with distinct age of initiation.

During the pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D), pancreatic islets, especially the β cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet (HFD) and streptozotocin (STZ) treatment are well-established models to study islet damage in T2D and T1D respectively.

β-Cell miRNA-503-5p Induced by Hypomethylation and Inflammation Promotes Insulin Resistance and β-Cell Decompensation.

Unlabelled: Chronic inflammation promotes pancreatic β-cell decompensation to insulin resistance because of local accumulation of supraphysiologic interleukin 1β (IL-1β) levels. However, the underlying molecular mechanisms remain elusive. We show that miR-503-5p is exclusively upregulated in islets from humans with type 2 diabetes and diabetic rodents because of its promoter hypomethylation and increased local IL-1β levels.

Restored UBE2C expression in islets promotes β-cell regeneration in mice by ubiquitinating PER1.

Insulin deficiency may be due to the reduced proliferation capacity of islet β-cell, contributing to the onset of diabetes. It is therefore imperative to investigate the mechanism of the β-cell regeneration in the islets. NKX6.

BRSK2 in pancreatic β cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and β-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population.

Single-cell RNA sequencing combined with single-cell proteomics identifies the metabolic adaptation of islet cell subpopulations to high-fat diet in mice.

Aims/hypothesis: Islets have complex heterogeneity and subpopulations. Cell surface markers representing alpha, beta and delta cell subpopulations are urgently needed for investigations to explore the compositional changes of each subpopulation in obesity progress and diabetes onset, and the adaptation mechanism of islet metabolism induced by a high-fat diet (HFD).

Methods: Single-cell RNA sequencing (scRNA-seq) was applied to identify alpha, beta and delta cell subpopulation markers in an HFD-induced mouse model of glucose intolerance.

Rab31, a receptor of advanced glycation end products (RAGE) interacting protein, inhibits AGE induced pancreatic β-cell apoptosis through the pAKT/BCL2 pathway.

Receptor of advanced glycation end products (RAGE) mediates diverse signal transduction following ligand stimulation and plays an important role in diabetes complications and aging associated disease. We have previously verified that advanced glycation end products (AGE) bind to RAGE to cause pancreatic β-cell apoptosis through the mitochondrial pathway. However, the direct interacting protein(s) of RAGE in β cells has never been appreciated.

Protocol for in vivo and ex vivo assessments of glucose-stimulated insulin secretion in mouse islet β cells.

Pancreatic islet β cells secrete insulin in a biphasic manner when sensing high blood glucose level. This protocol describes the evaluation of different phases of insulin secretion, as well as basal, glucose-stimulated and total insulin secretion abilities, thereby enabling precise assessment of β cell function both in vivo and ex vivo. The in vivo assay consists of intravenous tube imbedding surgery and hyperglycemic clamp.

Expression of miRNA-29 in Pancreatic β Cells Promotes Inflammation and Diabetes via TRAF3.

Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by insulin resistance and pancreatic β cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a key β cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. β cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD).

Inhibition of miR-153, an IL-1β-responsive miRNA, prevents beta cell failure and inflammation-associated diabetes.

Objective: Systemic levels of up-regulated IL-1β and IL-1 receptors promote the pathogenesis of inflammation-associated diabetes. IL-1 receptor antagonist (IL-Ra) has shown slightly elevated beta cell function in patients with type 2 diabetes without significant improvement of hyperglycaemia. We investigated whether miR-153, an IL-1β responsive miRNA, could mimic IL-1β effects and whether its interruption would improve blood glucose control then offer an assistant curative approach to inflammation-associated diabetes.

Ets1-Mediated Acetylation of FoxO1 Is Critical for Gluconeogenesis Regulation during Feed-Fast Cycles.

The homeostatic balance of hepatic glucose uptake and production is exquisitely controlled by hormonal signals during feed-fast cycles. FoxO1, a transcription factor that functions in the regulation of glucose homeostasis, undergoes posttranslational modifications, such as acetylation, in response to hormonal signals, yet the mechanism remains poorly elucidated. Through expression profiling of 324 co-factors of CBP, a well-known acetyl-transferase of FoxO1, we identify Ets1 as a modulator of FoxO1 acetylation that is highly associated with feed-fast cycles.

MicroRNA-24 promotes pancreatic beta cells toward dedifferentiation to avoid endoplasmic reticulum stress-induced apoptosis.

Current research indicates that beta cell loss in type 2 diabetes may be attributed to beta cell dedifferentiation rather than apoptosis; however, the mechanisms by which this occurs remain poorly understood. Our previous study demonstrated that elevation of microRNA-24 (miR-24) in a diabetic setting caused beta cell dysfunction and replicative deficiency. In this study, we focused on the role of miR-24 in beta cell apoptosis and dedifferentiation under endoplasmic reticulum (ER) stress conditions.

Hepatic c-Jun regulates glucose metabolism via FGF21 and modulates body temperature through the neural signals.

Objective: c-Jun, a prominent member of the activator protein 1 (AP-1) family, is involved in various physiology processes such as cell death and survival. However, a role of hepatic c-Jun in the whole-body metabolism is poorly understood.

Methods: We generated liver-specific c-Jun knock-out (c-jun) mice to investigate the effect of hepatic c-Jun on the whole-body physiology, particularly in blood glucose and body temperature.

Glucolipotoxicity-Inhibited Regulates Pancreatic β-Cell Function and Survival.

Inhibition of microRNAs (miRNAs) essential for pancreatic β-cell biology (e.g., ) results in β-cell failure and diabetes in rodent models.

A Presenilin/Notch1 pathway regulated by miR-375, miR-30a, and miR-34a mediates glucotoxicity induced-pancreatic beta cell apoptosis.

The presenilin-mediated Notch1 cleavage pathway plays a critical role in controlling pancreatic beta cell fate and survival. The aim of the present study was to investigate the role of Notch1 activation in glucotoxicity-induced beta cell impairment and the contributions of miR-375, miR-30a, and miR-34a to this pathway. We found that the protein levels of presenilins (PSEN1 and PSEN2), and NOTCH1 were decreased in INS-1 cells after treatment with increased concentrations of glucose, whereas no significant alteration of mRNA level of Notch1 was observed.