Core circadian transcription factor Bmal1 mediates β cell response and recovery from pro-inflammatory injury.

The circadian clock plays a vital role in modulating the cellular immune response. However, its role in mediating pro-inflammatory diabetogenic β cell injury remains largely unexplored. Our studies demonstrate that the exposure of β cells to IL-1β-mediated inflammation alters genome-wide DNA binding of core circadian transcription factors BMAL1:CLOCK enriched for genomic sites important for cellular response to inflammation.

Heterogeneous enhancer states orchestrate β cell responses to metabolic stress.

Obesity-induced β cell dysfunction contributes to the onset of type 2 diabetes. Nevertheless, elucidating epigenetic mechanisms underlying islet dysfunction at single cell level remains challenging. Here we profile single-nuclei RNA along with enhancer marks H3K4me1 or H3K27ac in islets from lean or obese mice.

BMAL1 modulates senescence programming via AP-1.

Cellular senescence and circadian dysregulation are biological hallmarks of aging. Whether they are coordinately regulated has not been thoroughly studied. We hypothesize that BMAL1, a pioneer transcription factor and master regulator of the molecular circadian clock, plays a role in the senescence program.

The nuclear receptor REV-ERBα is implicated in the alteration of β-cell autophagy and survival under diabetogenic conditions.

Pancreatic β-cell failure in type 2 diabetes mellitus (T2DM) is associated with impaired regulation of autophagy which controls β-cell development, function, and survival through clearance of misfolded proteins and damaged organelles. However, the mechanisms responsible for defective autophagy in T2DM β-cells remain unknown. Since recent studies identified circadian clock transcriptional repressor REV-ERBα as a novel regulator of autophagy in cancer, in this study we set out to test whether REV-ERBα-mediated inhibition of autophagy contributes to the β-cell failure in T2DM.

It's What and When You Eat: An Overview of Transcriptional and Epigenetic Responses to Dietary Perturbations in Pancreatic Islets.

Our ever-changing modern environment is a significant contributor to the increased prevalence of many chronic diseases, and particularly, type 2 diabetes mellitus (T2DM). Although the modern era has ushered in numerous changes to our daily living conditions, changes in "what" and "when" we eat appear to disproportionately fuel the rise of T2DM. The pancreatic islet is a key biological controller of an organism's glucose homeostasis and thus plays an outsized role to coordinate the response to environmental factors to preserve euglycemia through a delicate balance of endocrine outputs.

Time-restricted feeding prevents deleterious metabolic effects of circadian disruption through epigenetic control of β cell function.

Circadian rhythm disruption (CD) is associated with impaired glucose homeostasis and type 2 diabetes mellitus (T2DM). While the link between CD and T2DM remains unclear, there is accumulating evidence that disruption of fasting/feeding cycles mediates metabolic dysfunction. Here, we used an approach encompassing analysis of behavioral, physiological, transcriptomic, and epigenomic effects of CD and consequences of restoring fasting/feeding cycles through time-restricted feeding (tRF) in mice.

Electrogenic sodium bicarbonate cotransporter NBCe1 regulates pancreatic β cell function in type 2 diabetes.

Pancreatic β cell failure in type 2 diabetes mellitus (T2DM) is attributed to perturbations of the β cell's transcriptional landscape resulting in impaired glucose-stimulated insulin secretion. Recent studies identified SLC4A4 (a gene encoding an electrogenic Na+-coupled HCO3- cotransporter and intracellular pH regulator, NBCe1) as one of the misexpressed genes in β cells of patients with T2DM. Thus, in the current study, we set out to test the hypothesis that misexpression of SLC4A4/NBCe1 in T2DM β cells contributes to β cell dysfunction and impaired glucose homeostasis.

Pro-inflammatory β cell small extracellular vesicles induce β cell failure through activation of the CXCL10/CXCR3 axis in diabetes.

Coordinated communication among pancreatic islet cells is necessary for maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β cell stress.

Live-cell imaging of glucose-induced metabolic coupling of β and α cell metabolism in health and type 2 diabetes.

Type 2 diabetes is characterized by β and α cell dysfunction. We used phasor-FLIM (Fluorescence Lifetime Imaging Microscopy) to monitor oxidative phosphorylation and glycolysis in living islet cells before and after glucose stimulation. In healthy cells, glucose enhanced oxidative phosphorylation in β cells and suppressed oxidative phosphorylation in α cells.

TBK1 regulates regeneration of pancreatic β-cells.

Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells.

Induction of Core Circadian Clock Transcription Factor Bmal1 Enhances β-Cell Function and Protects Against Obesity-Induced Glucose Intolerance.

Type 2 diabetes mellitus (T2DM) is characterized by β-cell dysfunction as a result of impaired glucose-stimulated insulin secretion (GSIS). Studies show that β-cell circadian clocks are important regulators of GSIS and glucose homeostasis. These observations raise the question about whether enhancement of the circadian clock in β-cells will confer protection against β-cell dysfunction under diabetogenic conditions.

Proinflammatory Cytokine Interleukin 1β Disrupts β-cell Circadian Clock Function and Regulation of Insulin Secretion.

Intrinsic β-cell circadian clocks are important regulators of insulin secretion and overall glucose homeostasis. Whether the circadian clock in β-cells is perturbed following exposure to prodiabetogenic stressors such as proinflammatory cytokines, and whether these perturbations are featured during the development of diabetes, remains unknown. To address this, we examined the effects of cytokine-mediated inflammation common to the pathophysiology of diabetes, on the physiological and molecular regulation of the β-cell circadian clock.

A method for the generation of human stem cell-derived alpha cells.

The generation of pancreatic cell types from renewable cell sources holds promise for cell replacement therapies for diabetes. Although most effort has focused on generating pancreatic beta cells, considerable evidence indicates that glucagon secreting alpha cells are critically involved in disease progression and proper glucose control. Here we report on the generation of stem cell-derived human pancreatic alpha (SC-alpha) cells from pluripotent stem cells via a transient pre-alpha cell intermediate.

Dietary carbohydrates modulate metabolic and β-cell adaptation to high-fat diet-induced obesity.

Obesity is associated with several chronic comorbidities, one of which is type 2 diabetes mellitus (T2DM). The pathogenesis of obesity and T2DM is influenced by alterations in diet macronutrient composition, which regulate energy expenditure, metabolic function, glucose homeostasis, and pancreatic islet cell biology. Recent studies suggest that increased intake of dietary carbohydrates plays a previously underappreciated role in the promotion of obesity and consequent metabolic dysfunction.

Accelerated osteocyte senescence and skeletal fragility in mice with type 2 diabetes.

The worldwide prevalence of type 2 diabetes (T2D) is increasing. Despite normal to higher bone density, patients with T2D paradoxically have elevated fracture risk resulting, in part, from poor bone quality. Advanced glycation endproducts (AGEs) and inflammation as a consequence of enhanced receptor for AGE (RAGE) signaling are hypothesized culprits, although the exact mechanisms underlying skeletal dysfunction in T2D are unclear.

Publisher Correction: Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Targeted Derivation of Organotypic Glucose- and GLP-1-Responsive β Cells Prior to Transplantation into Diabetic Recipients.

Generation of functional β cells from pluripotent sources would accelerate diagnostic and therapeutic applications for diabetes research and therapy. However, it has been challenging to generate competent β cells with dynamic insulin-secretory capacity to glucose and incretin stimulations. We introduced transcription factors, critical for β-cell development and function, in differentiating human induced pluripotent stem cells (PSCs) and assessed the impact on the functionality of derived β-cell (psBC) progeny.

Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells.

β-cell proliferation induction is a promising therapeutic strategy to restore β-cell mass. By screening small molecules in a transgenic zebrafish model of type 1 diabetes, we identified inhibitors of non-canonical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε), as enhancers of β-cell regeneration. The most potent β-cell regeneration enhancer was a cinnamic acid derivative (E)-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA), which, acting through the cAMP-dependent protein kinase A (PKA), stimulated β-cell-specific proliferation by increasing cyclic AMP (cAMP) levels and mechanistic target of rapamycin (mTOR) activity.

Physiological Glucocorticoid Replacement in Adrenal Insufficiency: Does It Fix the Broken Clock?

Chronotherapeutic glucocorticoid replacement modulates clock gene expression.

Impaired β-cell glucokinase as an underlying mechanism in diet-induced diabetes.

High-fat diet (HFD)-fed mouse models have been widely used to study early type 2 diabetes. Decreased β-cell glucokinase (GCK) expression has been observed in HFD-induced diabetes. However, owing to its crucial roles in glucose metabolism in the liver and in islet β-cells, the contribution of decreased GCK expression to the development of HFD-induced diabetes is unclear.

Proteasomal degradation of the histone acetyl transferase p300 contributes to beta-cell injury in a diabetes environment.

In type 2 diabetes, amyloid oligomers, chronic hyperglycemia, lipotoxicity, and pro-inflammatory cytokines are detrimental to beta-cells, causing apoptosis and impaired insulin secretion. The histone acetyl transferase p300, involved in remodeling of chromatin structure by epigenetic mechanisms, is a key ubiquitous activator of the transcriptional machinery. In this study, we report that loss of p300 acetyl transferase activity and expression leads to beta-cell apoptosis, and most importantly, that stress situations known to be associated with diabetes alter p300 levels and functional integrity.

Postnatal Ontogenesis of the Islet Circadian Clock Plays a Contributory Role in β-Cell Maturation Process.

Development of cell replacement therapies in diabetes requires understanding of the molecular underpinnings of β-cell maturation. The circadian clock regulates diverse cellular functions important for regulation of β-cell function and turnover. However, postnatal ontogenesis of the islet circadian clock and its potential role in β-cell maturation remain unknown.

Circadian Etiology of Type 2 Diabetes Mellitus.

The epidemic of Type 2 diabetes mellitus necessitates development of novel therapeutic and preventative strategies to attenuate expansion of this debilitating disease. Evidence links the circadian system to various aspects of diabetes pathophysiology and treatment. The aim of this review will be to outline the rationale for therapeutic targeting of the circadian system in the treatment and prevention of Type 2 diabetes mellitus and consequent metabolic comorbidities.