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Reversal of Preexisting Hyperglycemia in Diabetic Mice by Acute Deletion of the Men1 Gene

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Reversal of Preexisting Hyperglycemia in Diabetic Mice by Acute Deletion of the Men1 Gene Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene Yuqing Yanga, Buddha Gurunga, Ting Wub, Haoren Wanga, Doris A. Stoffersc,d, and Xianxin Huaa,d,1 aAbramson Family Cancer Research Institute, Department of Cancer Biology, Abramson Cancer Center, cDepartment of Medicine, and dInstitute for Diabetes, Obesity, and Metabolism, University of Pennsylvania, Philadelphia, PA 19104; and bDepartment of Basic Medical Sciences, Medical College, Xiamen University, Xiamen 361005, China Edited by Arnold J. Levine, Institute for Advanced Study, Princeton, NJ, and approved September 28, 2010 (received for review August 18, 2010) A hallmark of diabetes is an absolute or relative reduction in the Men1 excision differently from normal β cells. Thus, it is im- number of functional β cells. Therapies that could increase the num- portant to determine whether Men1 excision actually ameliorates ber of endogenous β cells under diabetic conditions would be desir- or reverses hyperglycemia in diabetic mice. able. Prevalent gene targeting mouse models for assessing β-cell How menin regulates β-cell proliferation is not well understood. proliferation and diabetes pathogenesis only address whether de- Although menin has been shown to be crucial for expression of letion of a gene prevents the development of diabetes. Models cyclin-dependent kinase inhibitor p18ink4c (p18 hereafter) and p27 testing whether acute excision of a single gene can ameliorate or in islets (10, 11) and liver cells (12), Men1 excision does not affect reverse preexisting hyperglycemia in established diabetes remain to liver cell proliferation (7). These findings raise the possibility that be explored, which could directly validate the effect of gene exci- menin may also regulate β cell proliferation through effectors sion on treating diabetes. Here, we report that acute and temporally other than p18 and p27 (12). Menin up-regulates gene transcrip- controlled excision of the Men1 gene, which encodes menin, ame- tion through histone H3 modifications, such as H3K4 methylation liorated preexisting hyperglycemia in streptozotocin-treated mice. (13, 14). However, it is unclear whether menin represses tran- Moreover, Men1 excision also improved the preexisting hypergly- scription of endogenous genes, especially proproliferative cell cy- cemia and glucose intolerance in genetic db/db diabetic mice. Fur- cle genes in β cells. thermore, acute Men1 excision reversed preexisting glucose in- In this study, we found that acute Men1 excision ameliorated tolerance in high-fat diet-fed mice. Men1 excision improved glucose preexisting hyperglycemia in streptozotocin (STZ)-treated mice. CELL BIOLOGY metabolism at least partly through increasing proliferation of en- Moreover, acute Men1 excision also corrected preexisting glu- dogenous β cells and islet size. Acute Men1 excision up-regulated cose intolerance or hyperglycemia in genetic db/db or high-fat a group of proproliferative genes in pancreatic islets. Together, diet-fed diabetic mice. Acute Men1 ablation promoted β-cell these findings demonstrate that established hyperglycemia can be proliferation and increased β-cell number partly by coordinately reversed through repression of a single gene, Men1, in diabetic up-regulating multiple proproliferative cell cycle genes. Our conditions, and suggest that menin is a vital regulator in pathogen- findings suggest that menin actively regulates the process of di- esis of diabetes. abetes and could be manipulated to treat diabetes. cell proliferation | db/db | high-fat diet | type 2 diabetes Results Insulin Secretion by Islets and Peripheral Insulin Sensitivity Are Not oth type 1 and type 2 diabetes ultimately result from an in- Affected by Men1 Ablation. Conventional mouse knockout models Bsufficient number of functional β cells in islets (1). Therefore, have been used to determine whether gene ablation can prevent approaches that promote β-cell regeneration or proliferation and development of diabetes (2). To further determine the effect of gene increase the number of endogenous β cells under diabetic con- ablation on reversing established abnormal glucose homeostasis, ditions would be desirable. Thus far, many factors including we used a conditional and inducible Men1 knockout model and de- multiple cell cycle regulators have been tested in mouse models, termined whether acute Men1 excision ameliorated preexisting hy- Men1l/l and their roles in β-cell proliferation and diabetes development perglycemia in diabetic mice. ;Cre-ER mice were generated by crossing Men1l/l mice to mice expressing the Ubc9 promoter-driven have been determined (2). For instance, cyclin D1, cyclin D2, Cre-ERT2 transgene (6, 15). Men1l/l;Cre-ER and control Men1l/l mice and cyclin-dependent kinase 4 (Cdk4) are crucial for β cell were fed tamoxifen (TAM), and Men1 excision in pancreatic islets proliferation and preventing the development of hyperglycemia cip1/kip1 was determined by quantitative real-time PCR (qRT-PCR) and (2). Deletion of p27 (p27 hereafter), a cyclin-dependent immunostaining, 30 d after TAM treatment. Menin expression was kinase inhibitor, prevents development of diabetes in db/db mice, l/l β markedly reduced in Men1 ;Cre-ER islets as compared with control partly by increasing the number of cells (3). Deletion of Lkb1, islets (Fig. 1 A–C), indicating effective Men1 excision. a tumor suppressor involved in AMP kinase activation, promotes To determine whether Men1 excision affects insulin secretion by β -cell proliferation and ameliorates glucose intolerance (4). How- pancreatic β cells in response to glucose, islet perifusion studies ever, no report has shown that acute deletion of a single gene reverses were performed by using islets isolated from mice, 30 d after TAM preexisting glucose intolerance or hyperglycemia in mouse models. feeding. Size-matched islets isolated from Men1-excised and con- Such a study would be desirable and is closely related to treating di- trol mice were perifused with glucose or potassium chloride (4). abetes, because it directly evaluates the impact of manipulating a sin- The first-phase, second-phase, or total insulin secretion was similar gle gene on treating preexisting diabetes. between the Men1-excised and control islets (Fig. 1D), suggesting Menin is a nuclear protein encoded by the Men1 gene that is mutated in patients with familial multiple endocrine neoplasia type 1 (MEN1) syndrome (5). Menin preferentially represses Author contributions: Y.Y., D.A.S., and X.H. designed research; Y.Y., B.G., T.W., and H.W. proliferation of endocrine cells including β cells (6, 7). Although performed research; Y.Y. and X.H. analyzed data; and Y.Y. and X.H. wrote the paper. Men1 excision after a long period promotes β-cell proliferation The authors declare no conflict of interest. and increases blood insulin levels under normal conditions (6, 8, 9), This article is a PNAS Direct Submission. little is known as to whether acute Men1 excision can correct pre- 1To whom correspondence should be addressed. E-mail: [email protected]. existing abnormal glucose homeostasis in diabetic mice. Stressed This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. endogenous β cells under diabetic conditions may respond to 1073/pnas.1012257107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1012257107 PNAS Early Edition | 1of6 Downloaded by guest on September 23, 2021 Menin/Insulin excision on preexisting hyperglycemia in mice that were treated A *** Men1l/l Men1∆/∆ 1.0 Men1l/l with STZ, a β-cell cytotoxic agent that preferentially damages ∆/∆ l/l )l Men1 β ANRm .8 B C cells (16). Both Men1 ;Cre-ER and control mice developed evel hyperglycemia 3 wk after STZ treatment (SI Appendix, Fig. 1A). e .6 vitaler Men1 1neM We then examined whether excision could affect the .4 preexisting hyperglycemia in the diabetic mice (Fig. 2A). No ( .2 improvement in hyperglycemia was observed in the Men1l/l 0 control mice after TAM treatment over 6 wk of observation (Fig. 2B). In contrast, blood glucose levels started to decrease in 55% of D E Men1l/l;Cre-ER mice as early as 3 wk after TAM feeding (Fig. 2C, l/l enil 100 rescued). However, 45% of the Men1 ;Cre-ER mice remained 4 l l/l l/l )n Men1 do esoculg evel Men1 esa e i ∆/∆ ∆/∆ Men1 egatnecreP fo sab 90 Men1 hyperglycemic after TAM treatment (Fig. 2C, unrescued). Further m / 3 stelsi 001/ stelsi 80 investigation showed that Men1 was effectively excised in islets in e l e Glucose ramp r ni 2 (0-25mM) 70 the rescued mice after TAM treatment (Fig. 2D, Center), whereas lu 60 Men1 excision was inefficient in the unrescued mice (Fig. 2D, Glucose (0mM) KCl (30mM) s 1 n fi g I o 50 Right). The inef cient Men1 excision might be partly attributable to lb lb n ( β 0 40 STZ-induced alkylation of genomic DNA in cells (16). These 30 60 90 120 150 (min) 03060(min) Duration of perifusion Time after insulin injection results strongly indicate that Men1 excision ameliorates hypergly- cemia in mice with preexisting diabetes. Fig. 1. Men1 excision does not affect insulin secretion by islets and pe- Moreover, BrdU incorporation by β cells and the number of l/l l/l ripheral insulin sensitivity. Men1 or Men1 ;Cre-ER mice at the age of 12 wk insulin-positive cells were higher in the rescued mice than those in were fed tamoxifen (TAM) at 200 mg/kg of body weight per day. (A) Men1 l/l l/l the unrescued and control mice (Fig. 2 E and F and SI Appendix, mRNA levels in islets isolated from Men1 and Men1 ;Cre-ER mice 30 d after fi TAM treatment (n = 10 mice). (B and C) Immunostaining for menin and in- Fig. 1 B and C). Random serum insulin levels were not signi cantly sulin in islets from Men1l/l (B) and Men1l/l;Cre-ER mice (C) 30 d after TAM different among the three groups (Fig. 2G); however, Men1 ab- treatment (n = 6 mice).
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