The Gu laboratory studies how pancreatic islet beta cells are made and how they function and survive over a long life-span using mouse and human islet models. The impact of these studies is to reveal how beta cells in some individuals will lose function and viability, resulting in reduced functional beta-cell mass and subsequent diabetes in human subjects.

Four major islet cell types reside in the islets.  They are alpha, beta, delta, and PP cells that secrete glucagon, insulin, somatostatin, and pancreatic polypeptide, respectively.  Dysfunction of endocrine islets, especially the insulin secreting beta cells, results in diabetes. Paradoxically, insulin secretion per se makes beta cells vulnerable to workload-induced death and dysfunction, presumably via over-activation of stress response genes (SRGs). Our goals are to unravel the molecular and cellular mechanisms that allow the generation and maintenance of sufficient functional beta-cell mass in each individual to prevent the development of diabetes.

Our current studies focus on:

  1. Establishing how genetic and epigenetic factors pre-determine postnatal functional β-cell mass and the risk of diabetes. It is well established that several metabolic diseases, including diabetes, is greatly influenced by the maternal environments, best known as “Developmental Origin of Health and Disease – DOHaD”. We have shown that modulating the DNA enhancer methylation patterns in islet progenitors can impact the proliferation and secretion capacity of postnatal beta cells. Our follow-up studies are to define the specific epigenetic modifications that predetermine postnatal beta-cell fitness (i.e., the ability to enhance their proliferation and secretion under stimulation).


  1. Determining how β-cells selectively repress failure-causing SRGs. For sustainable function, each β cell has to synthesize millions of proinsulin molecules in the ER, with ~20% of these misfolded in the ER, which cause ER stress and dysfunction. High glucose metabolism, the trigger of insulin secretion, will induce overproduction of reactive oxygen species (ROS) that cause beta-cell dysfunction. Thus, beta cells activate stress responses to remove misfolded proteins and ROS. However, the SRGs cannot be overactivated, which would have caused cell dysfunction and/or death. We have shown that a family of transcription factors, (Myelin transcription factors or Myt TFs) guards against SRG overactivation. Our current studies is test if eliminating the Myt TF protection predisposes human β cells to workload-induced failure and diabetes.


  1. Determining the mechanisms and physiological roles of MT regulation in β cells. Microtubules (MTs) are tubulin-assembled biopolymers that act as a high way for long-range vesicular transport. Thus, the conventional view is that the β cells use MTs growing out of the centrosome to transport insulin vesicles from the cell interior to underneath the plasma membrane for docking and secretion. In contrast, we recently showed that the beta-cell MTs form a non-directional meshwork that is unsuitable for directional cargo transport, but they act as a “trap” for insulin vesicles to present over secretion. Our current studies for this topic is to examine the molecular players that can regulate MT activities and how MT-deregulation causes β-cell failure and diabetes. He and his collaborator are actively examining the roles of several motor proteins, including kinesins and dyneins, and microtubule associated proteins (MAPS) in this process.



The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Glucose Regulates Microtubule Disassembly and the Dose of Insulin Secretion via Tau Phosphorylation. Ho KH, Yang X, Osipovich AB, Cabrera O, Hayashi ML, Magnuson MA, Gu G, Kaverina I (2020) Diabetes 69(9): 1936-1947
    › Primary publication · 32540877 (PubMed) · PMC7458041 (PubMed Central)
  2. Myt Transcription Factors Prevent Stress-Response Gene Overactivation to Enable Postnatal Pancreatic β Cell Proliferation, Function, and Survival. Hu R, Walker E, Huang C, Xu Y, Weng C, Erickson GE, Coldren A, Yang X, Brissova M, Kaverina I, Balamurugan AN, Wright CVE, Li Y, Stein R, Gu G (2020) Dev Cell 53(4): 390-405.e10
    › Primary publication · 32359405 (PubMed) · PMC7278035 (PubMed Central)
  3. Coregulator Sin3a Promotes Postnatal Murine β-Cell Fitness by Regulating Genes in Ca Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism, and Stress Response. Yang X, Graff SM, Heiser CN, Ho KH, Chen B, Simmons AJ, Southard-Smith AN, David G, Jacobson DA, Kaverina I, Wright CVE, Lau KS, Gu G (2020) Diabetes 69(6): 1219-1231
    › Primary publication · 32245798 (PubMed) · PMC7243292 (PubMed Central)
  4. Regulation of Glucose-Dependent Golgi-Derived Microtubules by cAMP/EPAC2 Promotes Secretory Vesicle Biogenesis in Pancreatic β Cells. Trogden KP, Zhu X, Lee JS, Wright CVE, Gu G, Kaverina I (2019) Curr Biol 29(14): 2339-2350.e5
    › Primary publication · 31303487 (PubMed) · PMC6698911 (PubMed Central)
  5. Neurog3-Independent Methylation Is the Earliest Detectable Mark Distinguishing Pancreatic Progenitor Identity. Liu J, Banerjee A, Herring CA, Attalla J, Hu R, Xu Y, Shao Q, Simmons AJ, Dadi PK, Wang S, Jacobson DA, Liu B, Hodges E, Lau KS, Gu G (2019) Dev Cell 48(1): 49-63.e7
    › Primary publication · 30620902 (PubMed) · PMC6327977 (PubMed Central)
  6. Synaptotagmin 4 Regulates Pancreatic β Cell Maturation by Modulating the Ca Sensitivity of Insulin Secretion Vesicles. Huang C, Walker EM, Dadi PK, Hu R, Xu Y, Zhang W, Sanavia T, Mun J, Liu J, Nair GG, Tan HYA, Wang S, Magnuson MA, Stoeckert CJ, Hebrok M, Gannon M, Han W, Stein R, Jacobson DA, Gu G (2018) Dev Cell 45(3): 347-361.e5
    › Primary publication · 29656931 (PubMed) · PMC5962294 (PubMed Central)
  7. Microtubules Negatively Regulate Insulin Secretion in Pancreatic β Cells. Zhu X, Hu R, Brissova M, Stein RW, Powers AC, Gu G, Kaverina I (2015) Dev Cell 34(6): 656-68
    › Primary publication · 26418295 (PubMed) · PMC4594944 (PubMed Central)
  8. Diabetes recovery by age-dependent conversion of pancreatic δ-cells into insulin producers. Chera S, Baronnier D, Ghila L, Cigliola V, Jensen JN, Gu G, Furuyama K, Thorel F, Gribble FM, Reimann F, Herrera PL (2014) Nature 514(7523): 503-7
    › Primary publication · 25141178 (PubMed) · PMC4209186 (PubMed Central)
  9. Loss of Fbw7 reprograms adult pancreatic ductal cells into α, δ, and β cells. Sancho R, Gruber R, Gu G, Behrens A (2014) Cell Stem Cell 15(2): 139-53
    › Primary publication · 25105579 (PubMed) · PMC4136739 (PubMed Central)
  10. Generation of a tenascin-C-CreER2 knockin mouse line for conditional DNA recombination in renal medullary interstitial cells. He W, Xie Q, Wang Y, Chen J, Zhao M, Davis LS, Breyer MD, Gu G, Hao CM (2013) PLoS One 8(11): e79839
    › Primary publication · 24244568 (PubMed) · PMC3823583 (PubMed Central)
  11. Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation. Sugiyama T, Benitez CM, Ghodasara A, Liu L, McLean GW, Lee J, Blauwkamp TA, Nusse R, Wright CV, Gu G, Kim SK (2013) Proc Natl Acad Sci U S A 110(31): 12691-6
    › Primary publication · 23852729 (PubMed) · PMC3732989 (PubMed Central)
  12. Sustained Neurog3 expression in hormone-expressing islet cells is required for endocrine maturation and function. Wang S, Jensen JN, Seymour PA, Hsu W, Dor Y, Sander M, Magnuson MA, Serup P, Gu G (2009) Proc Natl Acad Sci U S A 106(24): 9715-20
    › Primary publication · 19487660 (PubMed) · PMC2701002 (PubMed Central)
  13. A CK19(CreERT) knockin mouse line allows for conditional DNA recombination in epithelial cells in multiple endodermal organs. Means AL, Xu Y, Zhao A, Ray KC, Gu G (2008) Genesis 46(6): 318-23
    › Primary publication · 18543299 (PubMed) · PMC3735352 (PubMed Central)
  14. Cre reconstitution allows for DNA recombination selectively in dual-marker-expressing cells in transgenic mice. Xu Y, Xu G, Liu B, Gu G (2007) Nucleic Acids Res 35(19): e126
    › Primary publication · 17893102 (PubMed) · PMC2095822 (PubMed Central)
  15. Temporal control of neurogenin3 activity in pancreas progenitors reveals competence windows for the generation of different endocrine cell types. Johansson KA, Dursun U, Jordan N, Gu G, Beermann F, Gradwohl G, Grapin-Botton A (2007) Dev Cell 12(3): 457-65
    › Primary publication · 17336910 (PubMed)
  16. The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation. Nikolova G, Jabs N, Konstantinova I, Domogatskaya A, Tryggvason K, Sorokin L, Fässler R, Gu G, Gerber HP, Ferrara N, Melton DA, Lammert E (2006) Dev Cell 10(3): 397-405
    › Primary publication · 16516842 (PubMed)