The phosphoinositide 3-kinase–Akt/PKB pathway mediates the mitogenic effects various nutrients and growth factors in cultured cells. To study its effects in vivo in pancreatic islet β cells, we created transgenic mice that expressed a constitutively active Akt1/PKBα linked to an Insulin gene promoter. Transgenic mice exhibited a grossly visible increase in islet mass, largely due to proliferation of insulin-containing β cells. Morphometric analysis verified a six-fold increase in β cell mass/pancreas, a two-fold increase in 5-bromo-2′-deoxyuridine incorporation, a four-fold increase in the number of β cells per pancreas area, and a two-fold increase in cell size in transgenic compared with wild-type mice at 5 weeks. At least part of the increase in β cell number may be accounted for by neogenesis, defined by criteria that include β cells proliferating from ductular epithelium, and by a six-fold increase in the number of single and doublet β cells scattered throughout the exocrine pancreas of the transgenic mice. Glucose tolerance was improved, and fasting as well as fed insulin was greater compared with wild-type mice. Glucose-stimulated insulin secretion was maintained in transgenic mice, which were resistant to streptozotocin–induced diabetes. We conclude that activation of the Akt1/PKBα pathway affects islet β cell mass by alteration of size and number.
Ernesto Bernal-Mizrachi, Wu Wen, Sarah Stahlhut, Cris M. Welling, M. Alan Permutt
Title and authors | Publication | Year |
---|---|---|
FoxO1 Mediates Insulin-Dependent Regulation of Hepatic VLDL Production
Adama Kamagate1, Shen Qu1, German Perdomo1, Dongming Su1, Dae Hyun Kim1, Sandra Slusher1, Marcia Meseck2 and H. Henry Dong1 |
Journal of Clinical Investigation | 2008 |
S6 Kinase 1 is required for Akt1-mediated Insulinoma, but not pancreatic b cell Hypertrophy
Samira Alliouachene , Robyn L. Tuttle , Stephanie Boumard , Thomas Lapointe , Sophie Berissi , Stephane Germain , Francis Jaubert , David Tosh , Morris J. Birnbaum , Mario Pende |
Journal of Clinical Investigation | 2008 |
Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice
Y Shigeyama, T Kobayashi, Y Kido, N Hashimoto, SI Asahara, T Matsuda, A Takeda, T Inoue, Y Shibutani, M Koyanagi, T Uchida, M Inoue, O Hino, M Kasuga, T Noda |
Molecular and cellular biology | 2008 |
Regulation of pancreas plasticity and malignant transformation by Akt signaling
L Elghazi, AJ Weiss, DJ Barker, J Callaghan, L Staloch, EP Sandgren, M Gannon, VN Adsay, E Bernal-Mizrachi |
Gastroenterology | 2008 |
Decreased fetal size is associated with beta-cell hyperfunction in early life and failure with age
MV Chakravarthy, Y Zhu, MB Wice, T Coleman, KL Pappan, CA Marshall, ML McDaniel, CF Semenkovich |
Diabetes | 2008 |
Glial Cell Line-Derived Neurotrophic Factor increases beta cell mass and improves glucose tolerance
S Mwangi, M Anitha, C Mallikarjun, X Ding, M Hara, A Parsadanian, CP Larsen, P Thule, SV Sitaraman, F Anania, S Srinivasan |
Gastroenterology | 2008 |
Genetic deficiency of glycogen synthase kinase-3beta corrects diabetes in mouse models of insulin resistance
K Tanabe, Z Liu, S Patel, BW Doble, L Li, C Cras-Méneur, SC Martinez, CM Welling, MF White, E Bernal-Mizrachi, JR Woodgett, MA Permutt |
PLoS Biology | 2008 |
IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice
J Agudo, E Ayuso, V Jimenez, A Salavert, A Casellas, S Tafuro, V Haurigot, J Ruberte, JC Segovia, J Bueren, F Bosch |
Diabetologia | 2008 |
β-cell failure as a complication of diabetes
KJ Chang-Chen, R Mullur, E Bernal-Mizrachi |
Reviews in Endocrine and Metabolic Disorders | 2008 |
Genetic modelling of the PTEN/AKT pathway in cancer research
O Renner, C Blanco-Aparicio, A Carnero |
Clinical and Translational Oncology | 2008 |
Mice with beta cell overexpression of glycogen synthase kinase-3β have reduced beta cell mass and proliferation
Z Liu, K Tanabe, E Bernal-Mizrachi, MA Permutt |
Diabetologia | 2008 |
Experimental models of hepatocellular carcinoma
P Newell, A Villanueva, SL Friedman, K Koike, JM Llovet |
Journal of Hepatology | 2008 |
Disruption of Tsc2 in pancreatic beta cells induces beta cell mass expansion and improved glucose tolerance in a TORC1-dependent manner
L Rachdi, N Balcazar, F Osorio-Duque, L Elghazi, A Weiss, A Gould, KJ Chang-Chen, MJ Gambello, E Bernal-Mizrachi |
Proceedings of the National Academy of Sciences | 2008 |
Exendin-4 Stimulation of Cyclin A2 in -Cell Proliferation
WJ Song, WE Schreiber, E Zhong, FF Liu, BD Kornfeld, FE Wondisford, MA Hussain |
Diabetes | 2008 |
Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice
XD Wang, MZ Vatamaniuk, SK Wang, CA Roneker, RA Simmons, XG Lei |
Diabetologia | 2008 |
Constitutively Active Akt Induces Enhanced Myelination in the CNS
AI Flores, SP Narayanan, EN Morse, HE Shick, X Yin, G Kidd, RL Avila, DA Kirschner, WB Macklin |
The Journal of neuroscience : the official journal of the Society for Neuroscience | 2008 |
Trefoil Factor 3 Stimulates Human and Rodent Pancreatic Islet β-Cell Replication with Retention of Function
PT Fueger, JC Schisler, D Lu, DA Babu, RG Mirmira, CB Newgard, HE Hohmeier |
Molecular Endocrinology | 2008 |
Insulin Stimulates Primary β-Cell Proliferation via Raf-1 Kinase
JL Beith, EU Alejandro, JD Johnson |
Endocrinology | 2008 |
Stimulation of Human and Rat Islet β-Cell Proliferation with Retention of Function by the Homeodomain Transcription Factor Nkx6.1
JC Schisler, PT Fueger, DA Babu, HE Hohmeier, JS Tessem, D Lu, TC Becker, B Naziruddin, M Levy, RG Mirmira, CB Newgard |
Molecular and cellular biology | 2008 |