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).

 

2. 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.

 

3. 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.

 

Publications

Featured publications

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. 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)
5. Quantitative assessment of cell population diversity in single-cell landscapes. Liu Q, Herring CA, Sheng Q, Ping J, Simmons AJ, Chen B, Banerjee A, Li W, Gu G, Coffey RJ, Shyr Y, Lau KS (2018) PLoS Biol 16(10): e2006687
   › Primary publication · 30346945 (PubMed) · PMC6211764 (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)

Community Leaders

• Guoqiang Gu
  Assistant Professor of Cell and Developmental Biol

Contact Information

2213 Garland Avenue
9415 MRB IV
Nashville, TN 37232
USA
615-936-3632 (p)

Guoqiang Gu
615-936-3634 (p)
Email

Keywords & MeSH Terms

MeSH terms are retrieved from PubMed records. Learn more.

Key: MeSH Term Keyword

beta cells Blotting, Western Caenorhabditis elegans Proteins CD4-Positive T-Lymphocytes cell death Cell Death cell differentiation cell division cell function cell lineage cell maintenance cell marking Cell Transdifferentiation Circadian Clocks Computer Simulation Cytoplasmic Granules Electroporation Endocrine System GTP-Binding Protein alpha Subunits Heat-Shock Proteins Integrin beta1 islets Keratin-19 Madin Darby Canine Kidney Cells Mitosis Molecular Sequence Data pancreatic progenitors regeneration tau Proteins Touch Young Adult