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43 papers found.
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Pancreatic alpha cell-selective deletion of Tcf7l2 impairs glucagon secretion and counter-regulatory responses to hypoglycaemia in mice

Aims/hypothesis Transcription factor 7-like 2 (TCF7L2) is a high mobility group (HMG) box-containing transcription factor and downstream effector of the Wnt signalling pathway. SNPs in the TCF7L2 gene have previously been associated with an increased risk of type 2 diabetes in genome-wide association studies. In animal studies, loss of Tcf7l2 function is associated with defective...

Systems biology of the IMIDIA biobank from organ donors and pancreatectomised patients defines a novel transcriptomic signature of islets from individuals with type 2 diabetes

Aims/hypothesis Pancreatic islet beta cell failure causes type 2 diabetes in humans. To identify transcriptomic changes in type 2 diabetic islets, the Innovative Medicines Initiative for Diabetes: Improving beta-cell function and identification of diagnostic biomarkers for treatment monitoring in Diabetes (IMIDIA) consortium (www.​imidia.​org) established a comprehensive, unique...

Role of microRNAs in the age-associated decline of pancreatic beta cell function in rat islets

Aims/hypothesis Ageing can lead to reduced insulin sensitivity and loss of pancreatic beta cell function, predisposing individuals to the development of diabetes. The aim of this study was to assess the contribution of microRNAs (miRNAs) to age-associated beta cell dysfunction. Methods The global mRNA and miRNA profiles of 3- and 12-month-old rat islets were collected by...

Comment on: Schuit et al. β-Cell–Specific Gene Repression: A Mechanism to Protect Against Inappropriate or Maladjusted Insulin Secretion? Diabetes 2012;61:969–975

Guy A. Rutter Timothy J. Pullen - e write in connection to the recent review article by Schuit et al. (1) on gene repression in the b-cell. Although most review articles display a natural (and

Regulating Glucagon Secretion: Somatostatin in the Spotlight

Guy A. Rutter Tis likely to involve a complex interplay between he regulation of islet hormone secretion in vivo circulating nutrients, hormones, and neurotransmitters (1). A new study by Hauge

Cell type-specific deletion in mice reveals roles for PAS kinase in insulin and glucagon production

Aims/hypothesis Per-Arnt-Sim kinase (PASK) is a nutrient-regulated domain-containing protein kinase previously implicated in the control of insulin gene expression and glucagon secretion. Here, we explore the roles of PASK in the control of islet hormone release, by generating mice with selective deletion of the Pask gene in pancreatic beta or alpha cells. Methods Floxed alleles...

Selective disruption of Tcf7l2 in the pancreatic β cell impairs secretory function and lowers β cell mass

Type 2 diabetes (T2D) is characterized by β cell dysfunction and loss. Single nucleotide polymorphisms in the T-cell factor 7-like 2 (TCF7L2) gene, associated with T2D by genome-wide association studies, lead to impaired β cell function. While deletion of the homologous murine Tcf7l2 gene throughout the developing pancreas leads to impaired glucose tolerance, deletion in the...

Sarco(endo)plasmic reticulum ATPase is a molecular partner of Wolfram syndrome 1 protein, which negatively regulates its expression

Wolfram syndrome is an autosomal recessive disorder characterized by neurodegeneration and diabetes mellitus. The gene responsible for the syndrome (WFS1) encodes an endoplasmic reticulum (ER)-resident transmembrane protein that is involved in the regulation of the unfolded protein response (UPR), intracellular ion homeostasis, cyclic adenosine monophosphate production and...

Glucose-Induced Nuclear Shuttling of ChREBP Is Mediated by Sorcin and Ca2+ Ions in Pancreatic β-Cells

Nafeesa A. Noordeen Gargi Meur Guy A. Rutter Isabelle Leclerc Carbohydrate-responsive element-binding protein (ChREBP) is a regulator of pancreatic b-cell gene expression and an important mediator

The Peutz-Jeghers kinase LKB1 suppresses polyp growth from intestinal cells of a proglucagon-expressing lineage in mice

Liver kinase B1 (LKB1; also known as STK11) is a serine/threonine kinase and tumour suppressor that is mutated in Peutz-Jeghers syndrome (PJS), a premalignant syndrome associated with the development of gastrointestinal polyps. Proglucagon-expressing enteroendocrine cells are involved in the control of glucose homeostasis and the regulation of appetite through the secretion of...

Divergent Effects of Liraglutide, Exendin-4, and Sitagliptin on Beta-Cell Mass and Indicators of Pancreatitis in a Mouse Model of Hyperglycaemia

Aims Glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP4) inhibitors improve glucose tolerance by still incompletely understood mechanisms. Each class of antihyperglycemic drugs has also been proposed to increase pancreatitis risk. Here, we compare systematically the effects of two widely-used GLP-1 analogues, liraglutide and exendin-4, and the DPP4...

Overexpression of Monocarboxylate Transporter-1 (Slc16a1) in Mouse Pancreatic β-Cells Leads to Relative Hyperinsulinism During Exercise

Timothy J. Pullen Lykke Sylow Gao Sun Andrew P. Halestrap Erik A. Richter Guy A. Rutter Exercise-induced hyperinsulinism (EIHI) is an autosomal dominant disorder characterized by inappropriate

Frequency-dependent mitochondrial Ca2+ accumulation regulates ATP synthesis in pancreatic β cells

Pancreatic β cells respond to increases in glucose concentration with enhanced metabolism, the closure of ATP-sensitive K+ channels and electrical spiking. The latter results in oscillatory Ca2+ influx through voltage-gated Ca2+ channels and the activation of insulin release. The relationship between changes in cytosolic and mitochondrial free calcium concentration ([Ca2+]cyt and...

Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells

Aims/hypothesis Hypoxic damage complicates islet isolation for transplantation and may contribute to beta cell failure in type 2 diabetes. Polymorphisms in the SLC30A8 gene, encoding the secretory granule zinc transporter 8 (ZnT8), influence type 2 diabetes risk, conceivably by modulating cytosolic Zn2+ levels. We have therefore explored the role of ZnT8 and cytosolic Zn2+ in the...

Hypothalamic Nutrient Sensing Activates a Forebrain-Hindbrain Neuronal Circuit to Regulate Glucose Production In Vivo

Carol K.L. Lam Madhu Chari Guy A. Rutter Tony K.T. Lam OBJECTIVE-Hypothalamic nutrient sensing regulates glucose production, but the neuronal circuits involved remain largely unknown. Recent studies

AMP-Activated Protein Kinase: A New Beta-Cell Glucose Sensor?: Regulation by Amino Acids and Calcium Ions

Isabelle Leclerc 1 Guy A. Rutter 1 0 /cAMP- response element binding protein; DMEM, Dulbecco's modified Eagle's medium; IBMX, isobutylmethylxanthine; KHB, Kreb's-HEPES-bicarbonate buffered medium

The Mitochondrial Na+/Ca2+ Exchanger Upregulates Glucose Dependent Ca2+ Signalling Linked to Insulin Secretion

Mitochondria mediate dual metabolic and Ca2+ shuttling activities. While the former is required for Ca2+ signalling linked to insulin secretion, the role of the latter in β cell function has not been well understood, primarily because the molecular identity of the mitochondrial Ca2+ transporters were elusive and the selectivity of their inhibitors was questionable. This study...