Human β-Cell Proliferation and Intracellular Signaling Part 2: Still Driving in the Dark Without a Road Map

  1. Adolfo Garcia-Ocaña4,6
  1. 1Division of Metabolism, Endocrinology, and Diabetes, University of Michigan, and U.S. Department of Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, MI
  2. 2Islet Cell Biology and Regenerative Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, MA
  3. 3Department of Medicine, Harvard Medical School, Boston, MA
  4. 4Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
  5. 5Division of Endocrinology and Metabolism, Tulane University School of Medicine and Health Sciences Center, New Orleans, LA
  6. 6Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
  1. Corresponding authors: Ernesto Bernal-Mizrachi, ebernal{at}, and Adolfo Garcia-Ocaña, adolfo.g.ocana{at}


Enhancing β-cell proliferation is a major goal for type 1 and type 2 diabetes research. Unraveling the network of β-cell intracellular signaling pathways that promote β-cell replication can provide the tools to address this important task. In a previous Perspectives in Diabetes article, we discussed what was known regarding several important intracellular signaling pathways in rodent β-cells, including the insulin receptor substrate/phosphatidylinositol-3 kinase/Akt (IRS-PI3K-Akt) pathways, glycogen synthase kinase-3 (GSK3) and mammalian target of rapamycin (mTOR) S6 kinase pathways, protein kinase Cζ (PKCζ) pathways, and their downstream cell-cycle molecular targets, and contrasted that ample knowledge to the small amount of complementary data on human β-cell intracellular signaling pathways. In this Perspectives, we summarize additional important information on signaling pathways activated by nutrients, such as glucose; growth factors, such as epidermal growth factor, platelet-derived growth factor, and Wnt; and hormones, such as leptin, estrogen, and progesterone, that are linked to rodent and human β-cell proliferation. With these two Perspectives, we attempt to construct a brief summary of knowledge for β-cell researchers on mitogenic signaling pathways and to emphasize how little is known regarding intracellular events linked to human β-cell replication. This is a critical aspect in the long-term goal of expanding human β-cells for the prevention and/or cure of type 1 and type 2 diabetes.

  • Received July 24, 2013.
  • Accepted November 20, 2013.

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