zebrafish islet

Heterozygous variants in the hepatocyte nuclear factor 1a (HNF1a) cause MODY3 (maturity-onset diabetes of the young, type 3). In this study, we found a case of novel HNF1a p.Gln125* (HNF1a-Q125ter) variant clinically. However, the molecular mechanism linking the new HNF1a variant to impaired islet β-cell function remains unclear. Firstly, a similar HNF1a-Q125ter variant in zebrafish ( hnf1a+/- ) was generated by CRISPR/Cas9. We further crossed hnf1a+/- with several zebrafish reporter lines to investigate pancreatic β-cell function...

Microbiome dysbiosis is a feature of diabetes, but how microbial products influence insulin production is poorly understood. We report the mechanism of BefA, a microbiome-derived protein that increases proliferation of insulin-producing β cells during development in gnotobiotic zebrafish and mice. BefA disseminates systemically by multiple anatomic routes to act directly on pancreatic islets. We detail BefA's atomic structure, containing a lipid-binding SYLF domain, and demonstrate that it permeabilizes synthetic liposomes and bacterial membranes...

Mitochondria, organelles critical for energy production, modify their shape and location in response to developmental state and metabolic demands. Mitochondria are altered in diabetes, but the mechanistic basis is poorly defined, due to difficulties in assessing mitochondria within an intact organism. Here, we use in vivo imaging in transparent zebrafish larvae to demonstrate filamentous, interconnected mitochondrial networks within islet cells. Mitochondrial movements highly resemble what has been reported for human islet cells in vitro, showing conservation in behavior across species and cellular context...

Persistent endoplasmic reticulum (ER) stress induces islet inflammation and β cell loss. How islet inflammation contributes to β cell loss remains uncertain. We have reported previously that chronic overnutrition-induced ER stress in β cells causes Ripk3-mediated islet inflammation, macrophage recruitment, and a reduction of β cell numbers in a zebrafish model. We show here that β cell loss results from the intricate communications among β cells, macrophages, and neutrophils. Macrophage-derived Tnfa induces cxcl8a in β cells...

Diabetes mellitus (DM) is a complicated metabolic illness that has had a worldwide impact and placed an unsustainable load on both developed and developing countries' health care systems. According to the International Diabetes Federation, roughly 537 million individuals had diabetes in 2021, with type 2 diabetes mellitus accounting for the majority of cases (T2DM). T2DM is a chronic illness defined by insufficient insulin production from pancreatic islet cells. T2DM generates various micro and macrovascular problems, with diabetic nephropathy (DN) being one of the most serious microvascular consequences, and which can lead to end-stage renal disease...

In this study, zebrafish embryos were exposed to microplastics (MPs, 2 mg/L) and copper (Cu, 60 and 125 μg/L), alone or combined, for 14 days, and the development of motor neurons was assessed through gene expression and immunohistochemistry. DNA methyltransferases (DNMTs) genes expression was also evaluated. The results showed a downregulation of neuronal proliferation (sox2, pcna), neurogenesis (neuroD, olig2), and motor neurons development (islet) related genes, implying potential deficits in the neurogenesis of the exposed zebrafish early life stages...

The environmental pollutant 3,3'-dichlorobiphenyl (PCB-11) is a lower-chlorinated polychlorinated biphenyl (PCB) congener present in air and water samples. Both PCB-11 and its metabolite, 4-PCB-11-Sulfate, are detected in humans, including in pregnant women. Previous research in zebrafish (Danio rerio) has shown that 0.2 μM exposures to 4-PCB-11-Sulfate starting at 1 day post fertilization (dpf) increase hepatic neutral lipid accumulation in larvae at 15 dpf. Here, we explored whether nuclear factor erythroid 2-related factor 2 (Nrf2), known as the master-regulator of the adaptive response to oxidative stress, contributes to metabolic impacts of 4-PCB-11-Sulfate...

Regenerating pancreatic β-cells is a potential curative approach for diabetes. We previously identified the small molecule CID661578 as a potent inducer of β-cell regeneration, but its target and mechanism of action have remained unknown. We now screened 257 million yeast clones and determined that CID661578 targets MAP kinase-interacting serine/threonine kinase 2 (MNK2), an interaction we genetically validated in vivo. CID661578 increased β-cell neogenesis from ductal cells in zebrafish, neonatal pig islet aggregates and human pancreatic ductal organoids...

Microscopic analysis of molecules and physiology in living cells and systems is a powerful tool in life sciences. While in vivo subcellular microscopic analysis of healthy and diseased human organs remains impossible, zebrafish larvae allow studying pathophysiology of many organs using in vivo microscopy. Here, we review the potential of the larval zebrafish pancreas in the context of islets of Langerhans and Type 1 diabetes. We highlight the match of zebrafish larvae with the expanding toolbox of fluorescent probes that monitor cell identity, fate and/or physiology in real time...

The importance of pancreatic endocrine cell activity modulation by autonomic innervation has been debated. To investigate this question, we established an in vivo imaging model that also allows chronic and acute neuromodulation with genetic and optogenetic tools. Using the GCaMP6s biosensor together with endocrine cell fluorescent reporters, we imaged calcium dynamics simultaneously in multiple pancreatic islet cell types in live animals in control states and upon changes in innervation. We find that by 4 days post fertilization in zebrafish, a stage when islet architecture is reminiscent of that in adult rodents, prominent activity coupling between beta cells is present in basal glucose conditions...

Regeneration-competent species possess the ability to reverse the progression of severe diseases by restoring the function of the damaged tissue. However, the cellular dynamics underlying this capability remain unexplored. Here, we have used single-cell transcriptomics to map de novo β-cell regeneration during induction and recovery from diabetes in zebrafish. We show that the zebrafish has evolved two distinct types of somatostatin-producing δ-cells, which we term δ1- and δ2-cells. Moreover, we characterize a small population of glucose-responsive islet cells, which share the hormones and fate-determinants of both β- and δ1-cells...

Restoring damaged β-cells in diabetic patients by harnessing the plasticity of other pancreatic cells raises the questions of the efficiency of the process and of the functionality of the new Insulin -expressing cells. To overcome the weak regenerative capacity of mammals, we used regeneration-prone zebrafish to study β-cells arising following destruction. We show that most new in s ulin cells differ from the original β-cells as they coexpress Somatostatin and Insulin. These bihormonal cells are abundant, functional and able to normalize glycemia...

Visualizing the function of pancreatic β-cells in vivo has been a long-sought goal for β-cell researchers. Unlike imaging of β-cells in mammalian species with conventional positron emission tomography and single-photon emission computed tomography, which only provides limited spatial-temporal resolution, transparent zebrafish embryos are a unique model that allows high-resolution fluorescent imaging of β-cells in their native physiological microenvironment in vivo . Here, we detail a protocol for real-time visualization of individual β-cell function in vivo in a non-invasive manner, through combination of a novel transgenic zebrafish reporter line Tg ( ins:Rcamp1...

Amyloid aggregation is a ubiquitous form of protein misfolding underlying the pathologies of Alzheimer's disease (AD), Parkinson's disease (PD) and type 2 diabetes (T2D), three primary forms of human amyloid diseases. While much has been learned about the origin, diagnosis and management of these neurological and metabolic disorders, no cure is currently available due in part to the dynamic and heterogeneous nature of the toxic oligomers induced by amyloid aggregation. Here we synthesized beta casein-coated iron oxide nanoparticles (βCas IONPs) via a BPA-P(OEGA-b-DBM) block copolymer linker...

(1) Background: Many flavonoids have been reported to exhibit pharmacological activity; a preparatory study confirmed that Coreopsis lanceolata flowers (CLFs) contained high flavonoid structure content; (2) Methods: CLFs were extracted in aqueous methanol (MeOH:H2 O = 4:1) and fractionated into acetic ester (EtOAc), normal butanol ( n -BuOH), and H2 O fractions. Repeated column chromatographies for two fractions led to the isolation of two aurones and two flavonols; (3) Results: Four flavonoids were identified based on a variety of spectroscopic data analyses to be leptosidin ( 1 ), leptosin ( 2 ), isoquercetin ( 3 ), and astragalin ( 4 ), respectively...

The pancreatic β-cells sustain systemic glucose homeostasis by producing and secreting insulin according to the blood glucose levels. Defects in β-cell function are associated with hyperglycemia that can lead to diabetes. During the process of insulin secretion, β-cells experience an influx of Ca2+ . Thus, imaging the glucose-stimulated Ca2+ influx using genetically encoded calcium indicators (GECIs) provides an avenue to studying β-cell function. Previously, studies showed that isolated zebrafish islets expressing GCaMP6s exhibit significant Ca2+ activity upon stimulation with defined glucose concentrations...

OBJECTIVE: Loss of FoxO1 signaling in response to metabolic stress contributes to the etiology of type II diabetes, causing the dedifferentiation of pancreatic beta cells to a cell type reminiscent of endocrine progenitors. Lack of methods to easily model this process in vitro, however, have hindered progress into identification of key downstream targets and potential inhibitors. We therefore aimed to establish such an in vitro cellular dedifferentiation model and apply it to identify novel agents involved in the maintenance of beta cell identity...

In strong contrast to limited repair within the mammalian central nervous system, the spinal cord of adult zebrafish is capable of almost complete recovery following injury. Understanding the mechanism underlying neural repair and functional recovery in zebrafish may lead to innovative therapies for human spinal cord injury (SCI). Since neuropeptide Y (NPY) plays a protective role in the pathogenesis of several neurological diseases, in the present study, we evaluated the effects of NPY on neuronal repair and subsequent recovery of motor function in adult zebrafish following SCI...

Insulin resistance, which occurs when insulin levels are sufficiently high over a prolonged period, causing the cells to fail to respond normally to the hormone. As a system for insulin resistance and diabetes drug development, insulin-resistant rodent models have been clearly established, but there is a limitation to high-throughput drug screening. Recently, zebrafish have been identified as an excellent system for drug discovery and identification of therapeutic targets, but studies on insulin resistance models have not been extensively performed...

The development of inhibitors that can effectively mitigate the amyloidogenesis of human islet amyloid polypeptide (hIAPP), which is linked to type II diabetes, remains a great challenge. Oligotyrosines are intriguing candidates in that they can block the hIAPP aggregation through multiplex phenol-hIAPP interactions. However, oligotyrosines containing too many tyrosine units (larger than three) may fail to inhibit amyloidogenesis due to their increased hydrophobicity and strong self-aggregation propensity. In this work, we developed a strategy to hierarchically vitalize oligotyrosines in mitigating hIAPP amyloidogenesis...