PCSK9 inhibition and cholesterol homeostasis in insulin producing β-cells.

Low-density lipoprotein cholesterol (LDL-C) plays a central role in the pathology of atherosclerotic cardiovascular disease. For decades, the gold standard for LDL-C lowering have been statins, although these drugs carry a moderate risk for the development of new-onset diabetes. The inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) have emerged in the last years as potential alternatives to statins due to their high efficiency and safety without indications for a diabetes risk so far.

NUPR1 preserves insulin secretion of pancreatic β-cells during inflammatory stress by multiple low-dose streptozotocin and high-fat diet.

Obesity is associated with dyslipidemia and subclinical inflammation that promotes metabolic disturbances including insulin resistance and pancreatic β-cell dysfunction. The nuclear protein, transcriptional regulator 1 (NUPR1) responds to cellular stresses and features tissue protective properties. To characterize the role of NUPR1 in endocrine pancreatic islets during inflammatory stress, we generated transgenic mice with β-cell-specific overexpression (βNUPR1).

Clinical Impact of the TCF7L2 Gene rs7903146 Type 2 Diabetes Mellitus Risk Polymorphism in Women with Gestational Diabetes Mellitus: Impaired Glycemic Control and Increased Need of Insulin Therapy.

Background: The single nucleotide polymorphism in rs7903146 is associated with an increased risk of type 2 diabetes mellitus and gestational diabetes mellitus. Mechanisms by which this mutation acts, and its impact on the clinical course of the diseases remain unclear. Here we investigated the clinical impact of the T risk allele in women with gestational diabetes mellitus.

Comparative Dose Accuracy of Durable and Patch Insulin Pumps Under Laboratory Conditions.

Recent studies demonstrate variable results of the accuracy with which patch pumps infuse insulin. Aim of this evaluation was to measure dose accuracies of the patch pump mylifeâ„¢ OmniPod (OP) in comparison with the durable insulin pump MiniMed 640G (MM) simulating real-life clinical situations under laboratory conditions. Thirty-two OP and 15 MM were tested using insulin aspart at five different boluses (0.

Stem cells in the treatment of diabetes mellitus - Focus on mesenchymal stem cells.

Diabetes mellitus type 1 and type 2 have become a global epidemic with dramatically increasing incidences. Poorly controlled diabetes is associated with severe life-threatening complications. Beside traditional treatment with insulin and oral anti-diabetic drugs, clinicians try to improve patient's care by cell therapies using embryonic stem cells (ESC), induced pluripotent stem cells (iPSC) and adult mesenchymal stem cells (MSC).

Mesenchymal stem cell (MSC)-mediated survival of insulin producing pancreatic β-cells during cellular stress involves signalling via Akt and ERK1/2.

Mesenchymal stem cells (MSC) are of interest for cell therapy since their secreted factors mediate immunomodulation and support tissue regeneration. This study investigated the direct humoral interactions between MSC and pancreatic β-cells using human telomerase-immortalized MSC (hMSC-TERT) and rat insulinoma-derived INS-1E β-cells. hMSC-TERT supported survival of cocultured INS-1E β-cells during cellular stress by alloxan (ALX) and streptozotocin (STZ), but not in response to IL-1β.

DJ-1 Protects Pancreatic Beta Cells from Cytokine- and Streptozotocin-Mediated Cell Death.

A hallmark feature of type 1 and type 2 diabetes mellitus is the progressive dysfunction and loss of insulin-producing pancreatic beta cells, and inflammatory cytokines are known to trigger beta cell death. Here we asked whether the anti-oxidant protein DJ-1 encoded by the Parkinson's disease gene PARK7 protects islet cells from cytokine- and streptozotocin-mediated cell death. Wild type and DJ-1 knockout mice (KO) were treated with multiple low doses of streptozotocin (MLDS) to induce inflammatory beta cell stress and cell death.

Human Krüppel-like factor 11 differentially regulates human insulin promoter activity in β-cells and non-β-cells via p300 and PDX1 through the regulatory sites A3 and CACCC box.

Human Krüppel-like factor 11 (hKLF11) has been characterised to both activate and inhibit human insulin promoter (hInsP) activity. Since KLF11 is capable to differentially regulate genes dependent on recruited cofactors, we investigated the effects of hKLF11 on cotransfected hInsP in both β-cells and non-β-cells. hKLF11 protein interacts with hp300 but not with hPDX1.

PDX1- and NGN3-mediated in vitro reprogramming of human bone marrow-derived mesenchymal stromal cells into pancreatic endocrine lineages.

Background Aims: Reprogramming of multipotent adult bone marrow (BM)-derived mesenchymal stromal/stem cells (MSC) (BM-MSC) represents one of several strategies for cell-based therapy of diabetes. However, reprogramming primary BM-MSC into pancreatic endocrine lineages has not yet been consistently demonstrated.

Methods: To unravel the role and interaction of key factors governing this process, we used well-characterized telomerase-immortalized human MSC (hMSC-TERT).

Protein phosphatase 1 (PP-1)-dependent inhibition of insulin secretion by leptin in INS-1 pancreatic β-cells and human pancreatic islets.

Leptin inhibits insulin secretion from pancreatic β-cells, and in turn, insulin stimulates leptin biosynthesis and secretion from adipose tissue. Dysfunction of this adipoinsular feedback loop has been proposed to be involved in the development of hyperinsulinemia and type 2 diabetes mellitus. At the molecular level, leptin acts through various pathways, which in combination confer inhibitory effects on insulin biosynthesis and secretion.

Functional signature of human islet-derived precursor cells compared to bone marrow-derived mesenchymal stem cells.

Pancreatic islet beta-cell replenishment can be driven by epithelial cells from exocrine pancreas via epithelial-mesenchymal transition (EMT) and the reverse process MET, while specified pancreatic mesenchymal cells control islet cell development and maintenance. The role of human islet-derived precursor cells (hIPCs) in regeneration and support of endocrine islets is under investigation. Here, we analyzed hIPCs as to their immunophenotype, multilineage differentiation capacity, and gene profiling, in comparison to human bone marrow-derived mesenchymal stem cells (hBM-MSCs).

Multiple, temporal-specific roles for HNF6 in pancreatic endocrine and ductal differentiation.

Within the developing pancreas Hepatic Nuclear Factor 6 (HNF6) directly activates the pro-endocrine transcription factor, Ngn3. HNF6 and Ngn3 are each essential for endocrine differentiation and HNF6 is also required for embryonic duct development. Most HNF6(-/-) animals die as neonates, making it difficult to study later aspects of HNF6 function.

Glucose-dependent expansion of pancreatic beta-cells by the protein p8 in vitro and in vivo.

p8 protein expression is known to be upregulated in the exocrine pancreas during acute pancreatitis. Own previous work revealed glucose-dependent p8 expression also in endocrine pancreatic beta-cells. Here we demonstrate that glucose-induced INS-1 beta-cell expansion is preceded by p8 protein expression.

Nuclear protein p8 is associated with glucose-induced pancreatic beta-cell growth.

On its own, glucose is a major factor for proliferation of pancreatic beta-cells and is also an essential prerequisite for IGF-I and growth hormone-induced growth of these cells. p8 was originally identified as an emergency gene product upregulated in pancreatic acinar cells in response to acute pancreatitis. p8 was further shown to be involved in a broad range of biological functions, including cell growth, growth arrest, apoptosis, and tumor development.

Alpha-melanocyte-stimulating hormone inhibits allergic airway inflammation.

Alpha-melanocyte-stimulating hormone (alpha-MSH) is a neuropeptide controlling melanogenesis in pigmentary cells. In addition, its potent immunomodulatory and immunosuppressive activity has been recently described in cutaneous inflammatory disorders. Whether alpha-MSH is also produced in the lung and might play a role in the pathogenesis of inflammatory lung conditions, including allergic bronchial asthma, is unknown.

[Current status and perspectives of stem cell therapy for the treatment of diabetes mellitus].

Due to autoimmune destruction of insulin-producing pancreatic beta-cells, type 1 diabetic patients, and also patients with type 2 diabetes suffering from defective insulin secretion rely on lifelong substitution with insulin. A clinically established alternative therapy for diabetics with exogenous insulin substitution, the transplantation of human islets of Langerhans, is limited by the lack of donor organs. The intensive search for new sources of pancreatic beta-cells now focuses on human stem cells.

Pan-neurotrophin receptor p75 contributes to neuronal hyperreactivity and airway inflammation in a murine model of experimental asthma.

Bronchial asthma represents a severe chronic inflammatory disease with increasing prevalence. The pathogenesis is characterized by complex neuroimmune dysregulation. Although the immunopathogenesis of the disease has been extensively studied, the nature of neuronal dysfunction still remains poorly understood.

Augmentation of allergic early-phase reaction by nerve growth factor.

The allergic early-phase reaction, a hallmark of allergic bronchial asthma, is caused by allergen and immunoglobulin E-dependent mediator release from mast cells. It was previously shown that nerve growth factor (NGF) contributes to acute airway inflammation. This study further investigates the role of NGF in the allergic early-phase reaction using a well-established mouse model of ovalbumin-induced allergic airway inflammation.

Role of interleukin-6 in stress response in normal and tumorous adrenal cells and during chronic inflammation.

Interleukin-6 (IL-6) is the end-product of a cytokine signaling cascade and is secreted by specialized immune cells during inflammation. It has a great influence on many functions, including differentiation, stimulation, and activation of immune cells, or other cells of neuroendocrine origin. Thus, IL-6 serves as a key messenger in its communication with the neuroendocrine system, and serves as a potent activator of the hypothalamic-pituitary-adrenal axis at all levels.