All-encomPASsing regulation of β-cells: PAS domain proteins in β-cell dysfunction and diabetes

•Many Per-Arnt-Sim (PAS) proteins are present in β-cells and some are dysregulated in diabetes. •The Hif1α pathway regulates β-cell differentiation possibly through altering metabolism. •Arnt regulates insulin secretion through heterodimerization with multiple bHLH-PAS factors. •Pask may play important roles in regulating both α- and β-cell function. As a sensory micro-organ, pancreatic β-cells continually respond to nutritional signals and neuroendocrine input from other glucoregulatory organs. This sensory ability is essential for normal β-cell function and systemic glucose homeostasis. Period circadian protein (Per)–aryl hydrocarbon receptor nuclear translocator protein (Arnt)–single-minded protein (Sim) (PAS) domain proteins have a conserved role as sensory proteins, critical in adaptation to changes in voltage, oxygen potential, and xenobiotics. Within β-cells, PAS domain proteins such as hypoxia inducible factor 1α (Hif1α), Arnt, PAS kinase, Bmal1, and Clock respond to disparate stimuli, but act in concert to maintain proper β-cell function. Elucidating the function of these factors in islets offers a unique insight into the sensing capacity of β-cells, the consequences of impaired sensory function, and the potential to develop novel therapeutic targets for preserving β-cell function in diabetes. As a sensory micro-organ, pancreatic β-cells continually respond to nutritional signals and neuroendocrine input from other glucoregulatory organs. This sensory ability is essential for normal β-cell function and systemic glucose homeostasis. Period circadian protein (Per)–aryl hydrocarbon receptor nuclear translocator protein (Arnt)–single-minded protein (Sim) (PAS) domain proteins have a conserved role as sensory proteins, critical in adaptation to changes in voltage, oxygen potential, and xenobiotics. Within β-cells, PAS domain proteins such as hypoxia inducible factor 1α (Hif1α), Arnt, PAS kinase, Bmal1, and Clock respond to disparate stimuli, but act in concert to maintain proper β-cell function. Elucidating the function of these factors in islets offers a unique insight into the sensing capacity of β-cells, the consequences of impaired sensory function, and the potential to develop novel therapeutic targets for preserving β-cell function in diabetes. a mouse strain in which the insulin receptor has been specifically knocked out of the beta cell. These mice fail to mount a proper insulin response to glucose and become glucose intolerance the incretin hormones, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP), are secreted following a meal by L and K cells located in the gastrointestinal tract. These hormones have pleiotropic effects on multiple tissues, but in the beta cell, they act to enhance glucose stimulated insulin secretion. Exendin-4 is a GLP-1 receptor analog which is resistant to degradation by dipeptidyl peptidase IV (DPPIV). also called monogenic diabetes, it refers to several hereditary forms of diabetes caused by mutations in autosomal dominant genes that disrupt insulin production. The most common forms of MODY are MODY2 and MODY3. MODY2 is caused by several mutations in the gene encoding glucokinase and MODY 3, also known as HNF1α–MODY, is caused by mutations of the gene encoding HNF1α. rodent models of obesity and type 2 diabetes respectively that harbor a mutation in the leptin gene (ob/ob) or the leptin receptor (db/db) causing mice to become hyperphagic, obese, and hyperglycemic. transgenic mouse strains which express Cre recombinase under the control of the Pdx1 promoter. In the case of CreER transgenics, the Cre recombinase is fused to a portion of the estrogen receptor (ER), which sequesters Cre to the cytoplasm in the absence of an estrogen receptor ligand (tamoxifen). Upon ligand binding to the fusion protein, Cre can translocate to the nucleus and mediate recombination. a protein domain found in many signaling proteins, from bacteria to humans, which functions as a signal sensor. PAS domains have been identified in transcription factors, kinases and ion channels, and have been characterized as signal receptors, signal transducers or in some instances both. The PAS domain was named after the three proteins in which it was first discovered, period circadian protein (Per), aryl hydrocarbon receptor nuclear translocator protein (Arnt), and single-minded protein (Sim). While PAS domain amino acid conservation is relatively low, they share a conserved secondary structure: a five-stranded antiparallel β sheet (annotated Aβ, Bβ, Gβ, Hβ, and Iβ) with flanking αhelices (Cα, Dα, Eα, and Fα). a chemical which is reduced under hypoxic conditions and binds to thiol containing amino acids, such as cysteine. This protein adduct can then be detected through immunoblot or immunofluorescence with an anti-pimonidazole antibody. transgenic mouse strain which expresses Cre recombinase under the control of the rat insulin promoter.