Menin Controls Growth of Pancreatic ß-Cells in Pregnant Mice and Promotes Gestational Diabetes Mellitus

Karnik, Satyajit K.; Chen, Hainan; McLean, Graeme; Heit, Jeremy J; Gu, Xueying; Zhang, Andrew Y.; Fontaine, Magali J.; Yen, Michael H.; Kim, Seung K.

doi:10.1126/science.1146812

Cited by 330 publications

(346 citation statements)

References 29 publications

Supporting

Mentioning

324

Contrasting

Unclassified

Order By: Relevance

“…It has recently been shown that prolactin represses islet menin levels and stimulates beta cell proliferation during pregnancy in mice. It was found that the transgenic expression of the gene encoding menin in maternal beta cells inhibited islet expansion and led to the development of GDM phenotypes [35]. In human studies, inadequate compensatory insulin secretion in the face of increased insulin resistance has consistently been observed in patients with GDM [36][37][38].…”

Section: Discussionmentioning

confidence: 99%

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis New genetic variants associated with susceptibility to type 2 diabetes mellitus have been discovered in recent genome-wide association (GWA) studies. The aim of the present study was to examine the association between these diabetogenic variants and gestational diabetes mellitus (GDM). Methods The study included 869 Korean women with GDM and 345 female and 287 male Korean non-diabetic controls. We genotyped the single nucleotide polymorphisms (SNPs) rs7756992 and rs7754840 in CDKAL1; rs564398, rs1333040, rs10757278 and rs10811661 in the CDKN2A−CDKN2B region; rs8050136 in FTO; rs1111875, rs5015480 and rs7923837 in HHEX; rs4402960 in IGF2BP2; and rs13266634 in SLC30A8. In addition, rs7903146 and rs12255372 in TCF7L2; rs5215 and rs5219 in KCNJ11; and rs3856806 and rs1801282 in PPARG were genotyped. The genotype frequencies in the GDM patients were compared with those in the non-diabetic controls. Results Compared with controls (men and women combined), GDM was associated with rs7756992 and rs7754840 (OR 1.55, 95% CI 1.34-1.79, p=4.17×10 −9 ) in CDKAL1; rs10811661 (OR 1.49, 95% CI 1.29-1.72, p=1.05×10 −7 ) in the CDKN2A−CDKN2B region; rs1111875 (OR 1.27, 95% CI 1.09-1.49, p=0.003), rs5015480, and rs7923837 in HHEX; rs4402960 (OR 1.18, 95% CI 1.01-1.38, p=0.03) in IGF2BP2; rs13266634 (OR 1.24, 95% CI 1.07-1.43, p=0.005) in SLC30A8; and rs7903146 (OR 1.58, 95% CI 1.03-2.43, p=0.038) in TCF7L2. The risk alleles of the SNPs rs7756992 and rs7754840 in CDKAL1; rs10811661 in the CDKN2A-CDKN2B region; and rs1111875, rs5015480 and rs7923837 in HHEX were associated with significant decreases in the insulin AUC during a 100 g OGTT performed at the time of diagnosis of GDM. Conclusions/interpretation Some of the type 2 diabetesassociated genetic variants that were discovered in the recent GWA studies are also associated with GDM in Koreans.

show abstract

Section: Discussionmentioning

confidence: 99%

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The same is probably true in obese non-diabetic humans, although the increase in beta cell mass (about 50%) is less than that seen in mice [13]. Also, during pregnancy the maternal pancreatic beta cell mass increases both in rodents and humans to meet the increased physiological demands [6,14,15]. There is plenty of evidence for replication being the primary mechanism for beta cell mass expansion during obesity-induced insulin resistance and pregnancy in mice [7,9,[16][17][18].…”

Section: Introductionmentioning

confidence: 87%

Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation

et al. 2011

View full text Add to dashboard Cite

Aims/hypothesis Epidermal growth factor receptor (EGFR) signalling is essential for the proper fetal development of pancreatic islets and in the postnatal formation of an adequate beta cell mass. In this study we investigated the role of EGFR signalling in the physiological states of beta cell mass expansion in adults during metabolic syndrome and pregnancy, as well as in regeneration after pancreatic duct ligation. Methods Heterozygous Pdx1-EGFR-dominant-negative (E1-DN) mice, which have a kinase-negative EGFR under the Pdx1 promoter, and wild-type mice were both subjected to a high-fat diet, pregnancy and pancreatic duct ligation. Results The beta cell mass of wild-type mice fed the highfat diet increased by 70% and the mice remained normoglycaemic; the E1-DN mice became diabetic and failed to show any compensatory beta cell mass expansion. Similarly, pregnant wild-type mice had four times more proliferating beta cells and a 75% increase in beta cell mass at mid-gestation, in contrast to the pregnant E1-DN mice, which did not show any significant beta cell compensation and were hyperglycaemic in an intraperitoneal glucose tolerance test. However, after pancreatic duct ligation, both the wild-type and E1-DN mice showed similar expression of Ngn3 (also known as Neurog3) and beta cell proliferation increased to a similar level in the ligated part of pancreas. Conclusions/interpretations EGFR signalling is essential in beta cell mass expansion during a high-fat diet and pregnancy where replication is the primary mechanism for compensatory beta cell mass expansion. In contrast, EGFR signalling appears not to be crucial to increased beta cell proliferation after pancreatic duct ligation.

show abstract

“…Transgenic menin overexpression in β cells prevents islet expansion, which leads to maternal hyperglycemia (29). Therefore, transgenic menin mice exhibit features of human gestational diabetes (29). For these reasons, ZEB1, as a transcription factor, may be involved in the pathogenesis of T2D.…”

Section: Discussionmentioning

confidence: 99%

“…BCL-6 represses menin, a product of the Men1 gene, expression. Transgenic menin overexpression in β cells prevents islet expansion, which leads to maternal hyperglycemia (29). Therefore, transgenic menin mice exhibit features of human gestational diabetes (29).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of abnormal DNA methylation in muscle samples from monozygotic twins discordant for type 2 diabetes

Liu

Sun

Wang

et al. 2012

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. The present study aimed to examine the changes in DNA methylation of gene promoters associated with type 2 diabetes (T2D). The DNA methylation profile dataset GSE38291 was downloaded from the Gene Expression Omnibus database. A paired t-test was used to analyze differences in the DNA methylation of gene promoters between T2D and normal muscle samples. Gene Ontology (GO) enrichment analysis was performed using online tool, The Database for Annotation, Visualization and Integrated Discovery. Whole-Genome rVISTA was used to analyze the enriched transcription factor (TF) binding sites upstream of the transcription start site in the differentially methylated genes. A total of 38 genes, including Sirtuin 1, N-acetyltransferase 6, phospholipase A2 group XIIB and nuclear factor of activated T cells calcineurin-dependent 1, were identified to be differentially methylated between these two groups. One GO term, DNA geometric change (GO:0032392), was significantly enriched (P<0.05) by the hyper-methylated genes. In addition, the binding sites of one gene, zinc finger E-box binding homeobox 1, and three TFs, methyl CpG binding protein 2, TFEB and TFAP4, were significantly enriched in the hyper-and hypo-methylated genes, respectively. The resulting T2D-associated genes and potential TFs provided a novel insight into the molecular mechanisms underlying the pathology of T2D. These genes may become promising target genes for the development of treatments for T2D.

show abstract

Menin Controls Growth of Pancreatic ß-Cells in Pregnant Mice and Promotes Gestational Diabetes Mellitus

Cited by 330 publications

References 29 publications

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

Epidermal growth factor (EGF)-receptor signalling is needed for murine beta cell mass expansion in response to high-fat diet and pregnancy but not after pancreatic duct ligation

Bioinformatics analysis of abnormal DNA methylation in muscle samples from monozygotic twins discordant for type 2 diabetes

Contact Info

Product

Resources

About