A role and mechanism for redox sensing by SENP1 in β-cell responses to high fat feeding.

Pancreatic β-cells respond to metabolic stress by upregulating insulin secretion, however the underlying mechanisms remain unclear. Here we show, in β-cells from overweight humans without diabetes and mice fed a high-fat diet for 2 days, insulin exocytosis and secretion are enhanced without increased Ca influx. RNA-seq of sorted β-cells suggests altered metabolic pathways early following high fat diet, where we find increased basal oxygen consumption and proton leak, but a more reduced cytosolic redox state.

The loss of pancreatic islet NADPH oxidase (NOX)2 improves islet transplantation.

Islet transplantation is a promising treatment strategy for type 1 diabetes mellitus (T1DM) patients. However, oxidative stress-induced graft failure due to an insufficient revascularization is a major problem of this therapeutic approach. NADPH oxidase (NOX)2 is an important producer of reactive oxygen species (ROS) and several studies have already reported that this enzyme plays a crucial role in the endocrine function and viability of β-cells.

Targeting Pancreatic Islet NLRP3 Improves Islet Graft Revascularization.

Hypoxia-induced islet cell death, caused by an insufficient revascularization of the grafts, is a major obstacle for successful pancreatic islet transplantation. Recently, it has been reported that the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is expressed in pancreatic islets and that its loss protects against hypoxia-induced cell death. Therefore, we hypothesized that the inhibition of NLRP3 in islets improves the survival and endocrine function of the grafts.

Microvascular fragment spheroids: Three-dimensional vascularization units for tissue engineering and regeneration.

Adipose tissue-derived microvascular fragments (MVF) serve as vascularization units in tissue engineering and regenerative medicine. Because a three-dimensional cellular arrangement has been shown to improve cell function, we herein generated for the first time MVF spheroids to investigate whether this further increases their vascularization potential. These spheroids exhibited a morphology, size, and viability comparable to that of previously introduced stromal vascular fraction (SVF) spheroids.

Early Cytokine-Induced Transient NOX2 Activity Is ER Stress-Dependent and Impacts β-Cell Function and Survival.

In type 1 diabetes (T1D) development, proinflammatory cytokines (PIC) released by immune cells lead to increased reactive oxygen species (ROS) production in β-cells. Nonetheless, the temporality of the events triggered and the role of different ROS sources remain unclear. Isolated islets from C57BL/6J wild-type (WT), NOX1 KO and NOX2 KO mice were exposed to a PIC combination.

Erythropoietin exposure of isolated pancreatic islets accelerates their revascularization after transplantation.

Aims: The exposure of isolated pancreatic islets to pro-angiogenic factors prior to their transplantation represents a promising strategy to accelerate the revascularization of the grafts. It has been shown that erythropoietin (EPO), a glycoprotein regulating erythropoiesis, also induces angiogenesis. Therefore, we hypothesized that EPO exposure of isolated islets improves their posttransplant revascularization.

Linalool inhibits the angiogenic activity of endothelial cells by downregulating intracellular ATP levels and activating TRPM8.

Angiogenesis crucially contributes to various diseases, such as cancer and diabetic retinopathy. Hence, anti-angiogenic therapy is considered as a powerful strategy against these diseases. Previous studies reported that the acyclic monoterpene linalool exhibits anticancer, anti-inflammatory and anti-oxidative activity.

Transient NADPH oxidase 2-dependent HO production drives early palmitate-induced lipotoxicity in pancreatic islets.

Modern lifestyles, including lack of physical activity and poor nutritional habits, are driving the rapidly increasing prevalence of obesity and type 2 diabetes. Increased levels of free fatty acids (FFAs), particularly saturated FFAs, in obese individuals have been linked to pancreatic β-cell failure. This process, termed lipotoxicity, involves activation of several stress responses, including ER stress and oxidative stress.

Improvement of islet transplantation by the fusion of islet cells with functional blood vessels.

Pancreatic islet transplantation still represents a promising therapeutic strategy for curative treatment of type 1 diabetes mellitus. However, a limited number of organ donors and insufficient vascularization with islet engraftment failure restrict the successful transfer of this approach into clinical practice. To overcome these problems, we herein introduce a novel strategy for the generation of prevascularized islet organoids by the fusion of pancreatic islet cells with functional native microvessels.

Protein Kinase CK2 Regulates Nerve/Glial Antigen (NG)2-Mediated Angiogenic Activity of Human Pericytes.

Protein kinase CK2 is a crucial regulator of endothelial cell proliferation, migration and sprouting during angiogenesis. However, it is still unknown whether this kinase additionally affects the angiogenic activity of other vessel-associated cells. In this study, we investigated the effect of CK2 inhibition on primary human pericytes.

Protein Kinase CK2 Controls Ca2.1-Dependent Calcium Currents and Insulin Release in Pancreatic β-Cells.

The regulation of insulin biosynthesis and secretion in pancreatic β-cells is essential for glucose homeostasis in humans. Previous findings point to the highly conserved, ubiquitously expressed serine/threonine kinase CK2 as having a negative regulatory impact on this regulation. In the cell culture model of rat pancreatic β-cells INS-1, insulin secretion is enhanced after CK2 inhibition.

Regulatory Mechanisms of Somatostatin Expression.

Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e.

Chronic activation of GPR40 does not negatively impact upon BRIN-BD11 pancreatic β-cell physiology and function.

Background: Free fatty acids (FFAs) are known for their dual effects on insulin secretion and pancreatic β-cell survival. Short-term exposure to FFAs, such as palmitate, increases insulin secretion. On the contrary, long-term exposure to saturated FFAs results in decreased insulin secretion, as well as triggering oxidative stress and endoplasmic reticulum (ER) stress, culminating in cell death.

Darbepoetin-α increases the blood volume flow in transplanted pancreatic islets in mice.

Aims: The minimal-invasive transplantation of pancreatic islets is a promising approach to treat diabetes mellitus type 1. However, islet transplantation is still hampered by the insufficient process of graft revascularization, leading to a poor clinical outcome. Accordingly, the identification of novel compounds, which accelerate and improve the revascularization of transplanted islets, is of great clinical interest.

The Marine-Derived Triterpenoid Frondoside A Inhibits Thrombus Formation.

Background: The marine-derived triterpenoid frondoside A inhibits the phosphatidylinositol-3-kinase (PI3K) pathway in cancer cells. Because this pathway is also crucially involved in platelet activation, we studied the effect of frondoside A on thrombus formation.

Methods: Frondoside A effects on platelet viability, surface adhesion molecule expression, and intracellular signaling were analyzed by flow cytometry and Western blot.

Erythropoietin accelerates the revascularization of transplanted pancreatic islets.

Background And Purpose: Pancreatic islet transplantation is a promising therapeutic approach for Type 1 diabetes. A major prerequisite for the survival of grafted islets is a rapid revascularization after transplantation. Erythropoietin (EPO), the primary regulator of erythropoiesis, has been shown to promote angiogenesis.

Protein Kinase CK2-A Putative Target for the Therapy of Diabetes Mellitus?

Since diabetes is a global epidemic, the development of novel therapeutic strategies for the treatment of this disease is of major clinical interest. Diabetes is differentiated in two types: type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). T1DM arises from an autoimmune destruction of insulin-producing β-cells whereas T2DM is characterized by an insulin resistance, an impaired insulin reaction of the target cells, and/or dysregulated insulin secretion.

Nerve/glial antigen 2 is crucially involved in the revascularization of freely transplanted pancreatic islets.

Pancreatic islets are highly vascularized endocrine units. Accordingly, their adequate revascularization is of major importance for successful islet transplantation. The proteoglycan, nerve/glial antigen 2 (NG2) expressed in pericytes is a crucial regulator of angiogenesis.

Functional interplay between the transcription factors USF1 and PDX-1 and protein kinase CK2 in pancreatic β-cells.

Glucose homeostasis is regulated by insulin, which is produced in the β-cells of the pancreas. The synthesis of insulin is controlled by several transcription factors including PDX-1, USF1 and USF2. Both, PDX-1 and USF1 were identified as substrates for protein kinase CK2.

Quinalizarin inhibits adipogenesis through down-regulation of transcription factors and microRNA modulation.

Background: Protein kinase CK2 is induced early in adipogenesis whereas later on, this kinase seems to be dispensable. Here, we have analysed how CK2 might be involved in early steps of differentiation of 3T3-L1 cells.

Methods: 3T3-L1 cells were differentiated to adipocytes in the absence or presence of quinalizarin.

HACE1 deficiency causes an autosomal recessive neurodevelopmental syndrome.

Background: The genetic aetiology of neurodevelopmental defects is extremely diverse, and the lack of distinctive phenotypic features means that genetic criteria are often required for accurate diagnostic classification. We aimed to identify the causative genetic lesions in two families in which eight affected individuals displayed variable learning disability, spasticity and abnormal gait.

Methods: Autosomal recessive inheritance was suggested by consanguinity in one family and by sibling recurrences with normal parents in the second.