Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 318 (5851): 806-809

Copyright © 2007 by the American Association for the Advancement of Science

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

Satyajit K. Karnik,1 Hainan Chen,1* Graeme W. McLean,1* Jeremy J. Heit,1* Xueying Gu,1 Andrew Y. Zhang,1 Magali Fontaine,2 Michael H. Yen,1,3 Seung K. Kim1,3{dagger}

Abstract: During pregnancy, maternal pancreatic islets grow to match dynamic physiological demands, but the mechanisms regulating adaptive islet growth in this setting are poorly understood. Here we show that menin, a protein previously characterized as an endocrine tumor suppressor and transcriptional regulator, controls islet growth in pregnant mice. Pregnancy stimulated proliferation of maternal pancreatic islet ß-cells that was accompanied by reduced islet levels of menin and its targets. Transgenic expression of menin in maternal ß-cells prevented islet expansion and led to hyperglycemia and impaired glucose tolerance, hallmark features of gestational diabetes. Prolactin, a hormonal regulator of pregnancy, repressed islet menin levels and stimulated ß-cell proliferation. These results expand our understanding of mechanisms underlying diabetes pathogenesis and reveal potential targets for therapy in diabetes.

1 Department of Developmental Biology, Stanford University, Stanford, CA 94305, USA.
2 Department of Pathology, Stanford University, Stanford, CA 94305, USA.
3 Department of Medicine (Oncology Division), Stanford University, Stanford, CA 94305, USA.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: seungkim{at}stanford.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Factors determining insulin requirements in women with type 1 diabetes mellitus during pregnancy: a review.
N. Achong, H. D. McIntyre, and L. Callaway (2014)
Obstetric Medicine
   Abstract »    Full Text »    PDF »
Soluble Factors Secreted by T Cells Promote {beta}-Cell Proliferation.
E. Dirice, S. Kahraman, W. Jiang, A. El Ouaamari, D. F. De Jesus, A. K. K. Teo, J. Hu, D. Kawamori, J. L. Gaglia, D. Mathis, et al. (2014)
Diabetes 63, 188-202
   Abstract »    Full Text »    PDF »
Advancements and challenges in generating accurate animal models of gestational diabetes mellitus.
R. C. Pasek and M. Gannon (2013)
Am J Physiol Endocrinol Metab 305, E1327-E1338
   Abstract »    Full Text »    PDF »
Serotonin regulates glucose-stimulated insulin secretion from pancreatic {beta} cells during pregnancy.
M. Ohara-Imaizumi, H. Kim, M. Yoshida, T. Fujiwara, K. Aoyagi, Y. Toyofuku, Y. Nakamichi, C. Nishiwaki, T. Okamura, T. Uchida, et al. (2013)
PNAS 110, 19420-19425
   Abstract »    Full Text »    PDF »
Defective prolactin signaling impairs pancreatic {beta}-cell development during the perinatal period.
J. Auffret, M. Freemark, N. Carre, Y. Mathieu, C. Tourrel-Cuzin, M. Lombes, J. Movassat, and N. Binart (2013)
Am J Physiol Endocrinol Metab 305, E1309-E1318
   Abstract »    Full Text »    PDF »
Altered MENIN expression disrupts the MAFA differentiation pathway in insulinoma.
Z. Hamze, C. Vercherat, A. Bernigaud-Lacheretz, W. Bazzi, R. Bonnavion, J. Lu, A. Calender, C. Pouponnot, P. Bertolino, C. Roche, et al. (2013)
Endocr. Relat. Cancer 20, 833-848
   Abstract »    Full Text »    PDF »
Menin promotes hepatocellular carcinogenesis and epigenetically up-regulates Yap1 transcription.
B. Xu, S.-H. Li, R. Zheng, S.-B. Gao, L.-H. Ding, Z.-Y. Yin, X. Lin, Z.-J. Feng, S. Zhang, X.-M. Wang, et al. (2013)
PNAS 110, 17480-17485
   Abstract »    Full Text »    PDF »
Current Understanding of the Molecular Biology of Pancreatic Neuroendocrine Tumors.
J. Zhang, R. Francois, R. Iyer, M. Seshadri, M. Zajac-Kaye, and S. N. Hochwald (2013)
J Natl Cancer Inst 105, 1005-1017
   Abstract »    Full Text »    PDF »
How to make a functional {beta}-cell.
F. W. Pagliuca and D. A. Melton (2013)
Development 140, 2472-2483
   Abstract »    Full Text »    PDF »
Characterization of {beta}-cell plasticity mechanisms induced in mice by a transient source of exogenous insulin.
M.- C. Nollevaux, J. Rahier, J. Marchandise, P. Thurion, S. Godecharles, G. Van den Steen, J. Jamart, C. Sempoux, P. Jacquemin, and Y. Guiot (2013)
Am J Physiol Endocrinol Metab 304, E711-E723
   Abstract »    Full Text »    PDF »
Relationship between lactation duration and insulin and glucose response among women with prior gestational diabetes.
S. Chouinard-Castonguay, S. J. Weisnagel, A. Tchernof, and J. Robitaille (2013)
Eur. J. Endocrinol. 168, 515-523
   Abstract »    Full Text »    PDF »
Everolimus in Advanced Pancreatic Neuroendocrine Tumors: The Clinical Experience.
J. C. Yao, A. T. Phan, V. Jehl, G. Shah, and F. Meric-Bernstam (2013)
Cancer Res. 73, 1449-1453
   Abstract »    Full Text »    PDF »
Wild-type offspring of heterozygous prolactin receptor-null female mice have maladaptive {beta}-cell responses during pregnancy.
C. Huang (2013)
J. Physiol. 591, 1325-1338
   Abstract »    Full Text »    PDF »
Interplay between Menin and K-Ras in Regulating Lung Adenocarcinoma.
Y. Wu, Z.-J. Feng, S.-B. Gao, S. Matkar, B. Xu, H.-B. Duan, X. Lin, S.-H. Li, X. Hua, and G.-H. Jin (2012)
J. Biol. Chem. 287, 40003-40011
   Abstract »    Full Text »    PDF »
Human {beta}-Cell Proliferation and Intracellular Signaling: Driving in the Dark Without a Road Map.
R. N. Kulkarni, E.-B. Mizrachi, A. G. Ocana, and A. F. Stewart (2012)
Diabetes 61, 2205-2213
   Abstract »    Full Text »    PDF »
Endoplasmic Reticulum Stress, Pancreatic {beta}-Cell Degeneration, and Diabetes.
F. R. Papa (2012)
Cold Spring Harb Perspect Med 2, a007666
   Abstract »    Full Text »    PDF »
Loss of HGF/c-Met Signaling in Pancreatic {beta}-Cells Leads to Incomplete Maternal {beta}-Cell Adaptation and Gestational Diabetes Mellitus.
C. Demirci, S. Ernst, J. C. Alvarez-Perez, T. Rosa, S. Valle, V. Shridhar, G. P. Casinelli, L. C. Alonso, R. C. Vasavada, and A. Garcia-Ocana (2012)
Diabetes 61, 1143-1152
   Abstract »    Full Text »    PDF »
A Genome-Wide Association Study of Gestational Diabetes Mellitus in Korean Women.
S. H. Kwak, S.-H. Kim, Y. M. Cho, M. J. Go, Y. S. Cho, S. H. Choi, M. K. Moon, H. S. Jung, H. D. Shin, H. M. Kang, et al. (2012)
Diabetes 61, 531-541
   Abstract »    Full Text »    PDF »
Insulin regulates menin expression, cytoplasmic localization, and interaction with FOXO1.
L. Wuescher, K. Angevine, T. Hinds, S. Ramakrishnan, S. M. Najjar, and E. J. Mensah-Osman (2011)
Am J Physiol Endocrinol Metab 301, E474-E483
   Abstract »    Full Text »    PDF »
mTOR inhibition, a potential novel approach for bronchial carcinoids.
M. Dong and J. C. Yao (2011)
Endocr. Relat. Cancer 18, C15-C18
   Abstract »    Full Text »    PDF »
Regulation of pancreatic islet gene expression in mouse islets by pregnancy.
B. T. Layden, V. Durai, M. V. Newman, A. M. Marinelarena, C. W. Ahn, G. Feng, S. Lin, X. Zhang, D. B. Kaufman, N. Jafari, et al. (2010)
J. Endocrinol. 207, 265-279
   Abstract »    Full Text »    PDF »
Reversal of preexisting hyperglycemia in diabetic mice by acute deletion of the Men1 gene.
Y. Yang, B. Gurung, T. Wu, H. Wang, D. A. Stoffers, and X. Hua (2010)
PNAS 107, 20358-20363
   Abstract »    Full Text »    PDF »
Cyclophilin B as a co-regulator of prolactin-induced gene expression and function in breast cancer cells.
F. Fang, J. Zheng, T. L. Galbaugh, A. A. Fiorillo, E. E. Hjort, X. Zeng, and C. V. Clevenger (2010)
J. Mol. Endocrinol. 44, 319-329
   Abstract »    Full Text »    PDF »
Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch.
Y. Gielchinsky, N. Laufer, E. Weitman, R. Abramovitch, Z. Granot, Y. Bergman, and E. Pikarsky (2010)
Genes & Dev. 24, 543-548
   Abstract »    Full Text »    PDF »
Prolactin Inhibits BCL6 Expression in Breast Cancer through a Stat5a-Dependent Mechanism.
T. H. Tran, F. E. Utama, J. Lin, N. Yang, A. B. Sjolund, A. Ryder, K. J. Johnson, L. M. Neilson, C. Liu, K. L. Brill, et al. (2010)
Cancer Res. 70, 1711-1721
   Abstract »    Full Text »    PDF »
Gestational Diabetes Mellitus Resulting From Impaired {beta}-Cell Compensation in the Absence of FoxM1, a Novel Downstream Effector of Placental Lactogen.
H. Zhang, J. Zhang, C. F. Pope, L. A. Crawford, R. C. Vasavada, S. M. Jagasia, and M. Gannon (2010)
Diabetes 59, 143-152
   Abstract »    Full Text »    PDF »
Quantification of pancreatic islet distribution in situ in mice.
G. Kilimnik, A. Kim, J. Jo, K. Miller, and M. Hara (2009)
Am J Physiol Endocrinol Metab 297, E1331-E1338
   Abstract »    Full Text »    PDF »
The role of oestrogens in the adaptation of islets to insulin resistance.
A. Nadal, P. Alonso-Magdalena, S. Soriano, A. B. Ropero, and I. Quesada (2009)
J. Physiol. 587, 5031-5037
   Abstract »    Full Text »    PDF »
Nuclear-Cytoplasmic Shuttling of Menin Regulates Nuclear Translocation of {beta}-Catenin.
Y. Cao, R. Liu, X. Jiang, J. Lu, J. Jiang, C. Zhang, X. Li, and G. Ning (2009)
Mol. Cell. Biol. 29, 5477-5487
   Abstract »    Full Text »    PDF »
The Multiple Endocrine Neoplasia Type 1 (MEN1) Tumor Suppressor Regulates Peroxisome Proliferator-Activated Receptor {gamma}-Dependent Adipocyte Differentiation.
K. M. A. Dreijerink, R. A. Varier, O. van Beekum, E. H. Jeninga, J. W. M. Hoppener, C. J. M. Lips, J. A. Kummer, E. Kalkhoven, and H. T. M. Timmers (2009)
Mol. Cell. Biol. 29, 5060-5069
   Abstract »    Full Text »    PDF »
Tissue Selectivity in Multiple Endocrine Neoplasia Type 1-Associated Tumorigenesis.
A. Gracanin, K. M. A. Dreijerink, R. B. van der Luijt, C. J. M. Lips, and J. W. M. Hoppener (2009)
Cancer Res. 69, 6371-6374
   Abstract »    Full Text »    PDF »
Pregnancy-Induced Rise in Serum C-Peptide Concentrations in Women With Type 1 Diabetes.
L. R. Nielsen, J. F. Rehfeld, U. Pedersen-Bjergaard, P. Damm, and E. R. Mathiesen (2009)
Diabetes Care 32, 1052-1057
   Abstract »    Full Text »    PDF »
Polycomb protein Ezh2 regulates pancreatic {beta}-cell Ink4a/Arf expression and regeneration in diabetes mellitus.
H. Chen, X. Gu, I-h. Su, R. Bottino, J. L. Contreras, A. Tarakhovsky, and S. K. Kim (2009)
Genes & Dev. 23, 975-985
   Abstract »    Full Text »    PDF »
Transcriptional Activation of the Mixed Lineage Leukemia-p27Kip1 Pathway by a Somatostatin Analogue.
K. Horiguchi, M. Yamada, T. Satoh, K. Hashimoto, J. Hirato, M. Tosaka, S. Yamada, and M. Mori (2009)
Clin. Cancer Res. 15, 2620-2629
   Abstract »    Full Text »    PDF »
Recapitulation of Pancreatic Neuroendocrine Tumors in Human Multiple Endocrine Neoplasia Type I Syndrome via Pdx1-Directed Inactivation of Men1.
H.-C. J. Shen, M. He, A. Powell, A. Adem, D. Lorang, C. Heller, A. C. Grover, K. Ylaya, S. M. Hewitt, S. J. Marx, et al. (2009)
Cancer Res. 69, 1858-1866
   Abstract »    Full Text »    PDF »
Pathways to New {beta} Cells.
Q. Zhou and D.A. Melton (2008)
Cold Spring Harb Symp Quant Biol
   Abstract »    PDF »
Tumour suppressor menin is essential for development of the pancreatic endocrine cells.
S. Fontaniere, B. Duvillie, R. Scharfmann, C. Carreira, Z.-Q. Wang, and C.-X. Zhang (2008)
J. Endocrinol. 199, 287-298
   Abstract »    Full Text »    PDF »
Adaptations in pulsatile insulin secretion, hepatic insulin clearance, and {beta}-cell mass to age-related insulin resistance in rats.
A. V. Matveyenko, J. D. Veldhuis, and P. C. Butler (2008)
Am J Physiol Endocrinol Metab 295, E832-E841
   Abstract »    Full Text »    PDF »
Beneficial effects of lipids and prolactin on insulin secretion and {beta}-cell proliferation: a role for lipids in the adaptation of islets to pregnancy.
T C. Brelje, N. V Bhagroo, L. E Stout, and R. L Sorenson (2008)
J. Endocrinol. 197, 265-276
   Abstract »    Full Text »    PDF »
{beta}-Cell Replication by Loosening the Brakes of Glucagon-Like Peptide-1 Receptor Signaling.
F. C. Schuit and D. J. Drucker (2008)
Diabetes 57, 529-531
   Full Text »    PDF »
Regeneration in Liver and Pancreas: Time to Cut the Umbilical Cord?.
Y. Dor and B. Z. Stanger (2007)
Sci. STKE 2007, pe66
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882