Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides

Xu, Sai; Hayashi, Yoshitaka; Takagishi, Yoshiko; Itoh, Mariko; Murata, Yoshiharu

doi:10.1371/journal.pone.0064415

Cited by 3 publications

(3 citation statements)

References 24 publications

(40 reference statements)

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“…While Arx null mice die shortly after birth, hypomorphic Arx mutants are viable. Experiments using these hypomorphic Arx mutant and GCGKO mice showed that GFP‐positive α‐like cell hyperplasia in GCGKO mice with hypomorphic Arx was markedly attenuated. Thus, Arx clearly plays important roles in the differentiation and proliferation of α‐cells.…”

Section: Regulation Of the α‐Cell Mass In Normal Development And Arismentioning

confidence: 99%

Regulation of amino acid metabolism and α‐cell proliferation by glucagon

Hayashi¹,

Seino

2018

J of Diabetes Invest

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Both glucagon and glucagon‐like peptide‐1 (GLP‐1) are produced from proglucagon through proteolytic cleavage. Blocking glucagon action increases the circulating levels of glucagon and GLP‐1, reduces the blood glucose level, and induces the proliferation of islet α‐cells. Glucagon blockade also suppresses hepatic amino acid catabolism and increases the serum amino acid level. In animal models defective in both glucagon and GLP‐1, the blood glucose level is not reduced, indicating that GLP‐1 is required for glucagon blockade to reduce the blood glucose level. In contrast, hyperplasia of α‐cells and hyperaminoacidemia are observed in such animal models, indicating that GLP‐1 is not required for the regulation of α‐cell proliferation or amino acid metabolism. These findings suggest that the regulation of amino acid metabolism is a more important specific physiological role of glucagon than the regulation of glucose metabolism. Although the effects of glucagon deficiency on glucose metabolism are compensated by the suppression of insulin secretion, the effects on amino acid metabolism are not. Recently, data showing a feedback regulatory mechanism between the liver and islet α‐cells, which is mediated by glucagon and amino acids, are accumulating. However, a number of questions on the mechanism of this regulation remain to be addressed. The profile of glucagon as a regulator of amino acid metabolism must be carefully considered for glucagon blockade to be applied therapeutically in the treatment of patients with diabetes.

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Section: Regulation Of the α‐Cell Mass In Normal Development And Arismentioning

confidence: 99%

Regulation of amino acid metabolism and α‐cell proliferation by glucagon

Hayashi¹,

Seino

2018

J of Diabetes Invest

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“…At residue 330 of the mouse ARX gene, seven GCG-triplets were inserted to generate GCG7 mutant (Kitamura et al, 2009). Most of them survived for 3-4 months, few last till 5-6 months (Kitamura et al, 2009, Xu et al, 2013. GCG7 mutant mouse was analyzed as ARX expanded model in genetic study, and its ARX mRNA level was significantly down-regulated to approximately 30% of wild-type level in E15.5 pancreata (Wilcox et al, 2013a).…”

Section: Gcg7 Mutant Micementioning

confidence: 99%

“…Recently some studies show that several ARX mutations could lead to apoptosis of a-cells (Wilcox et al, 2013a, Xu et al, 2013 which is originally proposed in the research on hyperplasia of a-cells induced by absolute or relative deficiency of glucagon secretion in vivo (Hayashi et al, 2009). It is found that expression of ARX mRNA is extremely up-regulated in the huge pancreas of mice lacked pro-glucagon gene, and this compensatory hyperemia could be depressed when ARX gene is mutated in vivo, including GCG7 and P335L mutations (Hayashi, 2011, Hayashi et al, 2009, Xu et al, 2013. In this case the reduction of pancreatic a-cell could be due to an increasing a-cell apoptosis, while the b-cell mass remain no change and some b-cell specific transcription factors show no significantly up-regulated.…”

Section: Apoptosismentioning

confidence: 99%

Present status and expectation of aristaless-related homeobox (ARX) in endocrine pancreas

Xu²

2019

Int. J. Dev. Biol.

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The aristaless-related homeobox (ARX) gene has become one of most frequently mutated genes which is closely linked with development of the vertebrate central nervous system; however, the molecular and clinical bases of its function in the proliferation and differentiation of the endocrine pancreas have not, to date, been systematically characterized. ARX is considered as a regulator which determines endocrine cell fate and a bio-marker of the pancreatic a-cell. Disruption and mutation of ARX are found to lead to the deletion and reduction of a-cells both in mice models and in humans. Furthermore, expression of ARX is regulated by multiple transcription factors involved in development of the pancreas, such as Ngn3, Isl1, Nkx2.2 and Nkx6.1. Taken together, given the vital importance of glucagon in diabetes treatment, it is possible that ARX may down-regulate exorbitant glucagon levels by reducing the number of a-cells as a direct target; thus, the role of ARX in the maintenance of a-cell identity and quantity should be investigated and summarized. This article mainly focuses on the role of ARX in the endocrine pancreas, introduces the ARX-related animal model and transcription factors, and highlights the latest advances in our understanding in order to provide a clearer theoretical foundation for future scientific research.

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SIRT1 activation attenuates α cell hyperplasia, hyperglucagonaemia and hyperglycaemia in STZ-diabetic mice

Zhang

Thai

Jin

et al. 2018

Sci Rep

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The NAD+-dependent lysine deacetylase, Sirtuin 1 (SIRT1), plays a central role in metabolic regulation. With type 1 diabetes a disease that is characterised by metabolic dysregulation, we sought to assess the impact of SIRT1 activation in experimental, streptozotocin (STZ)-induced diabetes. CD1 mice with and without STZ-induced diabetes were randomized to receive the SIRT1 activating compound, SRT3025, or vehicle over 20 weeks. Vehicle treated STZ-CD1 mice developed severe hyperglycaemia with near-absent circulating insulin and widespread beta cell loss in association with hyperglucagonaemia and expanded islet alpha cell mass. Without affecting ß-cell mass or circulating insulin, diabetic mice that received SRT3025 had substantially improved glycaemic control with greatly reduced islet α cell mass and lower plasma glucagon concentrations. Consistent with reduced glucagon abundance, the diabetes-associated overexpression of key gluconeogenic enzymes, glucose-6-phosphatase and PEPCK were also lowered by SRT3025. Incubating cultured α cells with SRT3025 diminished their glucagon secretion and proliferative activity in association with a reduction in the α cell associated transcription factor, Aristaless Related Homeobox (Arx). By reducing the paradoxical increase in glucagon, SIRT1 activation may offer a new, α-cell centric approach to the treatment of type 1 diabetes.

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Aristaless-Related Homeobox Plays a Key Role in Hyperplasia of the Pancreas Islet α–Like Cells in Mice Deficient in Proglucagon-Derived Peptides

Cited by 3 publications

References 24 publications

Regulation of amino acid metabolism and α‐cell proliferation by glucagon

Regulation of amino acid metabolism and α‐cell proliferation by glucagon

Present status and expectation of aristaless-related homeobox (ARX) in endocrine pancreas

SIRT1 activation attenuates α cell hyperplasia, hyperglucagonaemia and hyperglycaemia in STZ-diabetic mice

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