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Journal articleFine NHF, Doig CL, Elhassan YS, et al., 2017,
Glucocorticoids reprogram beta cell signaling to preserve insulin secretion
, Diabetes, Vol: 67, Pages: 278-290, ISSN: 0012-1797Excessive glucocorticoid exposure has been shown to be deleterious for pancreatic beta cell function and insulin release. However, glucocorticoids at physiological levels are essential for many homeostatic processes, including glycemic control. Here, we show that corticosterone and cortisol and their less active precursors, 11-dehydrocorticosterone (11-DHC) and cortisone, suppress voltage-dependent Ca2+ channel function and Ca2+ fluxes in rodent as well as human beta cells. However, insulin secretion, maximal ATP/ADP responses to glucose and beta cell identity were all unaffected. Further examination revealed the upregulation of parallel amplifying cAMP signals, and an increase in the number of membrane-docked insulin secretory granules. Effects of 11-DHC could be prevented by lipotoxicity and were associated with paracrine regulation of glucocorticoid activity, since global deletion of 11β-hydroxysteroid dehydrogenase type 1 normalized Ca2+ and cAMP responses. Thus, we have identified an enzymatically-amplified feedback loop whereby glucocorticoids boost cAMP to maintain insulin secretion in the face of perturbed ionic signals. Failure of this protective mechanism may contribute to diabetes in states of glucocorticoid excess such as Cushing's syndrome, which are associated with frank dyslipidemia.
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Journal articleSolimena M, Schulte AM, Marselli L, et al., 2017,
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.
, Diabetologia, Vol: 61, Pages: 641-657, ISSN: 0012-186XAIMS/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 multicentre biobank of human islets and pancreas tissues from organ donors and metabolically phenotyped pancreatectomised patients (PPP). METHODS: Affymetrix microarrays were used to assess the islet transcriptome of islets isolated either by enzymatic digestion from 103 organ donors (OD), including 84 non-diabetic and 19 type 2 diabetic individuals, or by laser capture microdissection (LCM) from surgical specimens of 103 PPP, including 32 non-diabetic, 36 with type 2 diabetes, 15 with impaired glucose tolerance (IGT) and 20 with recent-onset diabetes (<1 year), conceivably secondary to the pancreatic disorder leading to surgery (type 3c diabetes). Bioinformatics tools were used to (1) compare the islet transcriptome of type 2 diabetic vs non-diabetic OD and PPP as well as vs IGT and type 3c diabetes within the PPP group; and (2) identify transcription factors driving gene co-expression modules correlated with insulin secretion ex vivo and glucose tolerance in vivo. Selected genes of interest were validated for their expression and function in beta cells. RESULTS: Comparative transcriptomic analysis identified 19 genes differentially expressed (false discovery rate ≤0.05, fold change ≥1.5) in type 2 diabetic vs non-diabetic islets from OD and PPP. Nine out of these 19 dysregulated genes were not previously reported to be dysregulated in type 2 diabetic islets. Signature genes included TMEM37, which inhibited Ca2+-influx and insulin secretion in beta cells, and ARG2 and PPP1R1A, which promoted insulin secretion. Systems biology approaches identified HNF1A, PDX1 and REST as drivers o
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Conference paperGharavy SNM, Li X, Martinez-Sanchez A, et al., 2017,
Putative roles of the Type 2 diabetes-associated genes <i>C2CD4A</i> and <i>C2CD4B</i> in the control of insulin secretion
, Publisher: WILEY, Pages: 79-79, ISSN: 0742-3071 -
Journal articleRutter GA, 2017,
GABA signaling: A route to new pancreatic beta cells
, CELL RESEARCH, Vol: 27, Pages: 309-310, ISSN: 1001-0602An ability to convert between pancreatic islet cell types may provide a new approach to replace insulin-secreting β cells destroyed by autoimmune attack in Type 1 diabetes. Two papers, which have recently appeared in Cell, describe how this might be achieved.
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Journal articleMartinez-Sanchez A, Rutter GA, Latreille M, 2017,
MiRNAs in β-Cell development, identity, and disease.
, Frontiers in Genetics, Vol: 7, ISSN: 1664-8021Pancreatic β-cells regulate glucose metabolism by secreting insulin, which in turn stimulates the utilization or storage of the sugar by peripheral tissues. Insulin insufficiency and a prolonged period of insulin resistance are usually the core components of type 2 diabetes (T2D). Although, decreased insulin levels in T2D have long been attributed to a decrease in β-cell function and/or mass, this model has recently been refined with the recognition that a loss of β-cell "identity" and dedifferentiation also contribute to the decline in insulin production. MicroRNAs (miRNAs) are key regulatory molecules that display tissue-specific expression patterns and maintain the differentiated state of somatic cells. During the past few years, great strides have been made in understanding how miRNA circuits impact β-cell identity. Here, we review current knowledge on the role of miRNAs in regulating the acquisition of the β-cell fate during development and in maintaining mature β-cell identity and function during stress situations such as obesity, pregnancy, aging, or diabetes. We also discuss how miRNA function could be harnessed to improve our ability to generate β-cells for replacement therapy for T2D.
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