We introduce ggbio, a new methodology to visualize and explore genomics annotations and high-throughput data. The plots provide detailed views of genomic regions, summary views of sequence alignments and splicing patterns, and genome-wide overviews with karyogram, circular and grand linear layouts. The methods leverage the statistical functionality available in R, the grammar of graphics and the data handling capabilities of the Bioconductor project. The plots are specified within a modular framework that enables users to construct plots in a systematic way, and are generated directly from Bioconductor data structures. The ggbio R package is available at http://www.bioconductor.org/packages/2.11/bioc/html/ggbio.html.

We showed previously that ERK1/2 were activated by glucose and amino acids in pancreatic ␤ cells. Here we examine and compare signaling events that are necessary for ERK1/2 activation by glucose and other stimuli in ␤ cells. We find that agents that interrupt Ca 2؉ signaling by a variety of mechanisms interfere with glucose-and glucagon-like peptide (GLP-1)-stimulated ERK1/2 activity. In particular, calmodulin antagonists, FK506, and cyclosporin, immunosuppressants that inhibit the calcium-dependent phosphatase calcineurin, suppress ERK1/2 activation by both glucose and GLP-1. Ca 2؉ signaling from intracellular stores is also essential for ERK1/2 activation, because thapsigargin blocks ERK1/2 activation by glucose or GLP-1. The glucosesensitive mechanism is distinct from that used by phorbol ester or insulin to stimulate ERK1/2 but shares common features with that used by GLP-1.

MAP kinases transduce signals that are involved in a multitude of cellular pathways and functions in response to a variety of ligands and cell stimuli. Aberrant or inappropriate functions of MAPKs have now been identified in diseases ranging from cancer to inflammatory disease to obesity and diabetes. In many cell types, the MAPKs ERK1/2 are linked to cell proliferation. ERK1/2 are thought to play a role in some cancers, because mutations in Ras and B-Raf, which can activate the ERK1/2 cascade, are found in many human tumors. Abnormal ERK1/2 signaling has also been found in polycystic kidney disease, and serious developmental disorders such as cardio-facio-cutaneous syndrome arise from mutations in components of the ERK1/2 cascade. ERK1/2 are essential in well-differentiated cells and have been linked to long-term potentiation in neurons and in maintenance of epithelial polarity. Additionally, ERK1/2 are important for insulin gene transcription in pancreatic beta cells, which produce insulin in response to increases in circulating glucose to permit efficient glucose utilization and storage in the organism. Nutrients and hormones that induce or repress insulin secretion activate and/or inhibit ERK1/2 in a manner that reflects the secretory demand on beta cells. Disturbances in this and other regulatory pathways may result in the contribution of ERK1/2 to the etiology of certain human disorders.

The insulin promoter is both positively and negatively regulated in response to conditions to which pancreatic ␤-cells are exposed. Exposure of intact rat islets and INS-1 pancreatic ␤-cells to 11 mM glucose for minutes to hours results in an enhancement in the rate of insulin gene transcription assessed with a reporter linked to the insulin gene promoter. In contrast, chronic exposure of rat islets or ␤-cells to 11 mM glucose results in loss of the glucose responsiveness of the insulin gene promoter. By 48 h, glucose inhibits insulin gene promoter activity. Here we show that not only the acute effect of elevated glucose to stimulate the insulin gene promoter but also the chronic effect of elevated glucose to inhibit the insulin gene promoter depend on ERK1/2 mitogen-activated protein kinase activity. In examining the underlying mechanism, we found that acute exposure to 11 mM glucose resulted in the binding of the transcription factors NFAT and Maf to the glucose-responsive A2C1 element of the insulin gene promoter. An NFAT and C/EBP-␤ complex was observed in cells chronically exposed to 11 mM glucose. Formation of NFAT-Maf and NFAT-C/EBP-␤ complexes was sensitive to inhibitors of ERK1/2 and calcineurin, consistent with our previous finding that activation of ERK1/2 by glucose required calcineurin activity and the well documented regulation of NFAT by calcineurin. These results indicate that the ERK1/2 pathway modulates partners of NFAT, which may either stimulate or repress insulin gene transcription during stimulatory and chronic exposure to elevated glucose.

Diabetes results from the inability of pancreatic islets to maintain blood glucose concentrations within a normal physiological range. Clinical features are usually not observed until islets begin to fail and irreversible damage has occurred. Diabetes is generally diagnosed based on elevated glucose, which does not distinguish between type 1 and 2 diabetes. Thus, new diagnostic approaches are needed to detect different modes of diabetes before manifestation of disease. During prediabetes (pre-DM), islets undergo stress and release micro (mi) RNAs. Here, we review studies that have measured and tracked miRNAs in the blood for those with recent-onset or longstanding type 1 diabetes, obesity, pre-diabetes, type 2 diabetes, and gestational diabetes. We summarize the findings on miRNA signatures with the potential to stage progression of different modes of diabetes. Advances in identifying selective biomarker signatures may aid in early detection and classification of diabetic conditions and treatments to prevent and reverse diabetes.