Pax6 Haploinsufficiency Causes Abnormal Metabolic Homeostasis by Down-Regulating Glucagon-Like Peptide 1 in Mice

Ding, Jun; Gao, Yan; Zhao, Jing; Yan, Hong; Guo, Suhan; Zhang, Qinxian; Li, Lingsong; Gao, Xiang

doi:10.1210/en.2008-1006

Cited by 28 publications

(40 citation statements)

References 41 publications

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“…Taken together, these studies provide evidence that increased local production of GLP-1 in the pancreas may occur as a result of impaired b-cell function. The mechanism is unclear but could be because of a loss of tonic inhibition of insulin on GLP-1 production (Ding et al 2009). Given that b-cells are interspersed with a-cells in the human pancreas (Unger & Orci 2010) this locally produced GLP-1 may have direct paracrine effects on the remaining b-cells to promote regeneration and proliferation.…”

Section: Discussionmentioning

confidence: 99%

Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells?

Whalley¹,

Pritchard²,

Smith³

et al. 2011

Journal of Endocrinology

153

131

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Proglucagon is cleaved to glucagon by prohormone convertase 2 (PC2) in pancreatic a-cells, but is cleaved to glucagon-like peptide-1 (GLP-1) by PC1 in intestinal L-cells. The aim of this study was to identify mechanisms which switch processing of proglucagon to generate GLP-1 in the pancreas, given that GLP-1 can increase insulin secretion and b-cell mass. The a-cell line, aTC1-6, expressed PC1 at low levels and GLP-1 was detected in cells and in culture media. GLP-1 was also found in isolated human islets and in rat islets cultured for 7 days. High glucose concentrations increased Pc1 gene expression and PC1 protein in rat islets. High glucose (25 mM) also increased GLP-1 but decreased glucagon secretion from aTC1-6 cells suggesting a switch in processing to favour GLP-1. Three G protein-coupled receptors, GPR120, TGR5 and GPR119, implicated in the release of GLP-1 from L-cells are expressed in aTC1-6 cells. Incubation of these cells with an agonist of TGR5 increased PC1 promoter activity and GLP-1 secretion suggesting that this is a mechanism for switching processing to GLP-1 in the pancreas. Treatment of isolated rat islets with streptozotocin caused b-cell toxicity as evidenced by decreased glucosestimulated insulin secretion. This increased GLP-1 but not glucagon in the islets. In summary, proglucagon can be processed to GLP-1 in pancreatic cells. This process is upregulated by elevated glucose, activation of TGR5 and b-cell destruction. Understanding this phenomenon may lead to advances in therapies to protect b-cell mass, and thereby slow progression from insulin resistance to type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells?

Whalley¹,

Pritchard²,

Smith³

et al. 2011

Journal of Endocrinology

153

131

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“…This approach provided a wealth of potential interactions; however, Pax6 was the only miR-7 predicted target. As Pax6 expression is known to be tightly regulated in many organs (van Raamsdonk and Tilghman, 2000;Baulmann et al, 2002;Yasuda et al, 2002;Ding et al, 2009), we hypothesized that miR-7 may be a new endocrine regulatory gene upstream of Pax6.…”

Section: Pax6 Is a Mir-7 Targetmentioning

confidence: 99%

“…In both humans and mice, two Pax6 alleles are required in order to maintain proper glucose homeostasis, i.e. loss of only one allele results in glucose intolerance (Yasuda et al, 2002;Ding et al, 2009). Similarly, the development of other organs is sensitive to Pax6 haplo-insufficiency, including the iris and the lens (van Raamsdonk and Tilghman, 2000;Collinson et al, 2001;Baulmann et al, 2002;Kroeber et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Pancreas-enriched miRNA refines endocrine cell differentiation

et al. 2012

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SUMMARYGenome-encoded microRNAs (miRNAs) provide a post-transcriptional regulatory layer that is important for pancreas development. However, how specific miRNAs are intertwined into the transcriptional network, which controls endocrine differentiation, is not well understood. Here, we show that microRNA-7 (miR-7) is specifically expressed in endocrine precursors and in mature endocrine cells. We further demonstrate that Pax6 is an important target of miR-7. miR-7 overexpression in developing pancreas explants or in transgenic mice led to Pax6 downregulation and inhibition of -and -cell differentiation, resembling the molecular changes caused by haploinsufficient expression of Pax6. Accordingly, miR-7 knockdown resulted in Pax6 upregulation and promoted -and -cell differentiation. Furthermore, Pax6 downregulation reversed the effect of miR-7 knockdown on insulin promoter activity. These data suggest a novel miR-7-based circuit that ensures precise control of endocrine cell differentiation.

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“…Although heterozygous Pax6 mutants display eye malformations (reduced lens size, iris and corneal anomalies) and some forebrain patterning defects (10,11), no obvious morphological abnormalities have been detected in the pancreas. Yet mice and human patients heterozygous for a Pax6 mutation often display impaired glucose tolerance at the adult stage (12,13). Rodents homozygous for a Pax6 null mutation lack eye and olfactory bulbs, have severe brain anomalies, and display severe defects in the differentiation of pancreatic endocrine cells (7, 9, 14 -18).…”

mentioning

confidence: 99%

The Pax6b Homeodomain Is Dispensable for Pancreatic Endocrine Cell Differentiation in Zebrafish

Verbruggen

Georlette

et al. 2010

Journal of Biological Chemistry

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Pax6 is a well conserved transcription factor that contains two DNA-binding domains, a paired domain and a homeodomain, and plays a key role in the development of eye, brain, and pancreas in vertebrates. The recent identification of the zebrafish sunrise mutant, harboring a mutation in the pax6b homeobox and presenting eye abnormalities but no obvious pancreatic defects, raised a question about the role of pax6b in zebrafish pancreas. We show here that pax6b does play an essential role in pancreatic endocrine cell differentiation, as revealed by the phenotype of a novel zebrafish pax6b null mutant and of embryos injected with pax6b morpholinos. Pax6b-depleted embryos have almost no ␤ cells, a strongly reduced number of ␦ cells, and a significant increase of ⑀ cells. Through the use of various morpholinos targeting intron-exon junctions, pax6b RNA splicing was perturbed at several sites, leading either to retention of intronic sequences or to deletion of exonic sequences in the pax6b transcript. By this strategy, we show that deletion of the Pax6b homeodomain in zebrafish embryos does not disturb pancreas development, whereas lens formation is strongly affected. These data thus provide the explanation for the lack of pancreatic defects in the sunrise pax6b mutants. In addition, partial reduction of Pax6b function in zebrafish embryos performed by injection of small amounts of pax6b morpholinos caused a clear rise in ␣ cell number and in glucagon expression, emphasizing the importance of the fine tuning of the Pax6b level to its biological activity.

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Pax6 Haploinsufficiency Causes Abnormal Metabolic Homeostasis by Down-Regulating Glucagon-Like Peptide 1 in Mice

Cited by 28 publications

References 41 publications

Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells?

Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells?

Pancreas-enriched miRNA refines endocrine cell differentiation

The Pax6b Homeodomain Is Dispensable for Pancreatic Endocrine Cell Differentiation in Zebrafish

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