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The bile acid sensor FXR regulates insulin transcription and secretion.

Farnesoid X Receptor plays an important role in maintaining bile acid, cholesterol homeostasis and glucose metabolism. Here we investigated whether FXR is expressed by pancreatic beta-cells and regulates insulin signaling in pancreatic beta-cell line and human islets. We found that FXR activation induces positive regulatory effects on glucose-induced insulin transcription and secretion by genomic and non-genomic activities. Genomic effects of FXR activation relay on the induction of the glucose regulated transcription factor KLF11. Indeed, results from silencing experiments of KLF11 demonstrat

Disruption of the STAT4 signaling pathway protects from autoimmune diabetes while retaining antiviral immune competence.

The role of the STAT4 signaling pathway in autoimmune diabetes was investigated using the rat insulin promoter lymphocytic choriomeningitis virus model of virally induced autoimmune diabetes. Abrogation of STAT4 signaling significantly reduced the development of CD4+-T cell-dependent but not CD4+-T cell-independent diabetes, illustrating the fine-tuned kinetics involved in the pathogenesis of autoimmunity. However, the absence of STAT4 did not prevent the generation of autoreactive Th1/Tc1 T cell responses, as well as protective antiviral immunity. Protection from insulin-dependent diabetes me

In vivo treatment with a MHC class I-restricted blocking peptide can prevent virus-induced autoimmune diabetes.

We tested the in vivo potential of a MHC class I-restricted blocking peptide to sufficiently lower an anti-viral CTL response for preventing virus-induced CTL-mediated autoimmune diabetes (insulin-dependent diabetes mellitus (IDDM)) in vivo without affecting systemic viral clearance. By designing and screening several peptides with high binding affinities to MHC class I H-2Db for best efficiency in blocking killing of target cells by lymphocytic choriomeningitis virus (LCMV) and other viral CTL, we identified the peptide for this study. In vitro, it selectively lowered CTL killing restricted t

IDX-1: a new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene.

We describe the cloning from a rat islet somatostatin-producing cell line of a 1.4 kb cDNA encoding a new homeoprotein, IDX-1 (islet/duodenum homeobox-1), with close sequence similarity to the Drosophila melanogaster homeobox protein Antennapedia (Antp) and the Xenopus laevis endoderm-specific homeoprotein XlHbox8. Analyses of IDX-1 mRNA and protein in rat tissues show that IDX-1 is expressed in pancreatic islets and ducts and in the duodenum. In electrophoretic mobility shift assays IDX-1 binds to three sites in the 5' flanking region of the rat somatostatin gene. In co-transfection experimen

Pax-QNR/Pax-6, a paired box- and homeobox-containing gene expressed in neurons, is also expressed in pancreatic endocrine cells.

After differential screening of a cDNA library constructed from quail neuroretina cells infected with the v-myc containing avian retrovirus MC29, we have isolated a cDNA clone Pax-QNR, homologous to the murine Pax6 which is mutated in the autosomal dominant mutation small eye (Sey) of the mouse and aniridia in man. Here we report the characterization of Pax-QNR/Pax-6 expression in the chicken, quail, and mouse pancreas. In situ hybridization performed with E3 chick embryos demonstrated that, in addition to the documented expression of Pax-QNR/Pax-6 in the neural tube, this gene is also express

Direct Endoplasmic Reticulum Targeting by the Selective Alkylphospholipid Analog and Antitumor Ether Lipid Edelfosine as a Therapeutic Approach in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC), the most common malignancy of the pancreas, shows a dismal and grim overall prognosis and survival rate, which have remained virtually unchanged for over half a century. PDAC is the most lethal of all cancers, with the highest mortality-to-incidence ratio. PDAC responds poorly to current therapies and remains an incurable malignancy. Therefore, novel therapeutic targets and drugs are urgently needed for pancreatic cancer treatment. Selective induction of apoptosis in cancer cells is an appealing approach in cancer therapy. Apoptotic cell death is highly

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… The pancreas consists of 85–95% exocrine tissue (acinar and duct tissue), which secretes digestive enzymes into the duodenum, and less than 5% endocrine tissue (islets of Langerhans), which secretes hormones into the bloodstream [ 4 , 5 ] ( Figure 1 b). … The endocrine pancreas consists of small islands containing endocrine cells (islets of Langerhans), which produce and release hormones (e.g., insulin and glucagon) into the bloodstream [ 6 ], thus controlling blood glucose levels ( Figure 1 b). …

Advanced Diagnostic Techniques

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Exploiting Expression of Hippo Effector, Yap, for Expansion of Functional Islet Mass.

Loss of pancreas β-cell function is the precipitating factor in all forms of diabetes. Cell replacement therapies, such as islet transplantation, remain the best hope for a cure; however, widespread implementation of this method is hampered by availability of donor tissue. Thus, strategies that expand functional β-cell mass are crucial for widespread usage in diabetes cell replacement therapy. Here, we investigate the regulation of the Hippo-target protein, Yes-associated protein (Yap), during development of the endocrine pancreas and its function after reactivation in human cadaveric islets.

Epigenetic mechanisms in cardiovascular complications of diabetes: towards future therapies.

The pathophysiological mechanisms of cardiovascular disease and microvascular complications in diabetes have been extensively studied, but effective methods of prevention and treatment are still lacking. In recent years, DNA methylation, histone modifications, and non-coding RNAs have arisen as possible mechanisms involved in the development, maintenance, and progression of micro- and macro-vascular complications of diabetes. Epigenetic changes have the characteristic of being heritable or deletable. For this reason, they are now being studied as a therapeutic target for the treatment of diabe

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… Moreover, it has been recently demonstrated that within the islet of Langerhans epigenetic modifications occur and can be detected years before the onset of the disease (Ouni et al. 2020 ). … Several studies demonstrated an altered DNA methylation profile in both atherosclerotic plaque, islets of Langerhans and in T2D human tissues (Avrahami and Kaestner 2019 ; Zaina et al. 2014 ; Ling and Ronn 2019 ). …

The insulin secretory granule is the major site of K(ATP) channels of the endocrine pancreas.

With ATP sites on K(ir)6.2 that inhibit activity and ADP sites on SUR1 that antagonize the inhibition, ATP-sensitive potassium channels (K(ATP) channels) are designed as exquisite sensors of adenine nucleotide levels that signal changes in glucose metabolism. If pancreatic K(ATP) channels localize to the insulin secretory granule, they would be well positioned to transduce changes in glucose metabolism into changes in granule transport and exocytosis. Tests for pancreatic K(ATP) channels localized to insulin secretory granules led to the following observations: fluorescent sulfonylureas that b

Nonmitogenic CD3 antibody reverses virally induced (rat insulin promoter-lymphocytic choriomeningitis virus) autoimmune diabetes without impeding viral clearance.

Treatment with nonmitogenic CD3 Ab reverses established autoimmune diabetes in nonobese diabetic mice by restoring self-tolerance, and is currently under clinical evaluation in patients presenting recent onset type I diabetes. Due to the immunosuppressive potential of this strategy, it was relevant to explore how this treatment would influence the outcome of concomitant viral infections. In this study, we used a transgenic model of virally induced autoimmune diabetes (rat insulin promoter-lymphocytic choriomeningitis virus) that allows for more precise tracking of the autoaggressive response a

Pharmacological and molecular characterization of glutamate receptors in the MIN6 pancreatic beta-cell line.

The MIN6 pancreatic beta-cell line responds to glutamate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate, but not N-methyl-D-aspartate (NMDA) or 1S,3R-trans-ACPD, with increases in [Ca2+]i. This correlates with MIN6 expression of AMPA receptor subunits (GluR1-4) but only weak expression of NMDA NR2 receptor subunits, as determined by reverse transcriptase polymerase chain reaction (RT-PCR). Pharmacological characterization of the MIN6 AMPA receptors showed that AMPA-triggered [Ca2+]i responses were blocked by GYKI 52466, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX)

Adaptive changes in insulin secretion by islets from neonatal rats raised on a high-carbohydrate formula.

Artificial rearing of neonatal rats on a high-carbohydrate (HC) milk formula resulted in the immediate onset of hyperinsulinemia. This study examines, in islets of 12-day-old HC rats, adaptive changes that support the hyperinsulinemic state. Increases in plasma glucagon-like peptide-1 (GLP-1) levels and islet GLP-1 receptor mRNA supported increased insulin secretion by HC islets. Isolated HC islets, but not mother-fed (MF) islets, secreted moderate amounts of insulin in a glucose- and Ca(2+)-independent manner. Under stringent Ca(2+)-free conditions and in the presence of glucose, GLP-1 plus a

Advanced Diagnostic Techniques

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Amyloid Proteins and Peripheral Neuropathy.

Painful peripheral neuropathy affects millions of people worldwide. Peripheral neuropathy develops in patients with various diseases, including rare familial or acquired amyloid polyneuropathies, as well as some common diseases, including type 2 diabetes mellitus and several chronic inflammatory diseases. Intriguingly, these diseases share a histopathological feature-deposits of amyloid-forming proteins in tissues. Amyloid-forming proteins may cause tissue dysregulation and damage, including damage to nerves, and may be a common cause of neuropathy in these, and potentially other, diseases. He

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… Amyloid in the pancreatic islets of Langerhans is a characteristic feature of T2DM [ 24 ]. Diabetic peripheral neuropathy (DPN) is one of the most common complications of T2DM and affects nearly 50% of adults with DM during their lifetime [ 25 ]. … Type 1 DM is characterized by autoimmune-mediated loss of the insulin-producing β-cells in the pancreatic islets of Langerhans, causing insulin insufficiency and hyperglycemia [ 118 ]. T2DM is the most common type of DM, accounting for approximately 90% of all DM patients [ 55 ]. …

Can type 1 diabetes be an unexpected complication of obesity?

Type 1 diabetes (T1D) is one of the most common chronic autoimmune diseases, characterized by absolute insulin deficiency caused via inflammatory destruction of the pancreatic β-cell. Genetic, epigenetic, and environmental factors play a role in the development of diseases. Almost ⅕ of cases involve people under the age of 20. In recent years, the incidence of both T1D and obesity has been increasing, especially among children, adolescents, and young people. In addition, according to the latest study, the prevalence of overweight or obesity in people with T1D has increased significantly. The r

Isolated Lesser Trochanter Fractures in Adults: A Systematic Review of Malignant, Infectious, and Benign Etiologies.

Isolated lesser trochanter (LT) fractures are uncommon in adults and may be the first clue to an underlying pathologic process. In contrast to adolescent apophyseal avulsions, the same finding in a skeletally mature patient has been linked to metastatic disease, primary bone tumors, hematologic malignancy, infection, and, less often, benign traumatic, stress-related, osteoporotic, or metabolic causes. This review examined the malignant, infectious, and benign etiologies, diagnostic pathways, treatments, and outcomes that have been reported in adults aged 18 years or older presenting with a rad

A pancreatic beta -cell-specific enhancer in the human PDX-1 gene is regulated by hepatocyte nuclear factor 3beta (HNF-3beta ), HNF-1alpha, and SPs transcription factors.

The PDX-1 transcription factor plays a key role in pancreas development. Although expressed in all cells at the early stages, in the adult it is mainly restricted to the beta-cell. To characterize the regulatory elements and potential transcription factors necessary for human PDX-1 gene expression in beta-cells, we constructed a series of 5' and 3' deletion fragments of the 5'-flanking region of the gene, fused to the luciferase reporter gene. In this report, we identify by transient transfections in beta- and non-beta-cells a novel beta-cell-specific distal enhancer element located between -3

Telmisartan ameliorates insulin sensitivity by activating the AMPK/SIRT1 pathway in skeletal muscle of obese db/db mice.

BACKGROUND: Telmisartan is a well-established angiotensin II type 1 receptor blocker that improves insulin sensitivity in animal models of obesity and insulin resistance, as well as in humans. Telmisartan has been reported to function as a partial agonist of the peroxisome proliferator-activated receptor (PPAR) γ, which is also targeted by the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase (SIRT1). Here, we investigated the pathways through which telmisartan acts on skeletal muscle, in vitro as well as in vivo. METHODS: Nine-week-old male db/db mice were fed a 60% high-fat diet

Control of pancreas and liver gene expression by HNF transcription factors.

The transcriptional regulatory networks that specify and maintain human tissue diversity are largely uncharted. To gain insight into this circuitry, we used chromatin immunoprecipitation combined with promoter microarrays to identify systematically the genes occupied by the transcriptional regulators HNF1alpha, HNF4alpha, and HNF6, together with RNA polymerase II, in human liver and pancreatic islets. We identified tissue-specific regulatory circuits formed by HNF1alpha, HNF4alpha, and HNF6 with other transcription factors, revealing how these factors function as master regulators of hepatocyt