EDITOR'S PICK
OCT1 required for therapeutic effects of diabetes drug Metformin
The drug metformin is among the most widely prescribed drugs for the treatment of type 2 diabetes and results in an array of therapeutic benefits. Although it has been used for over 30 years, only recently have studies begun to reveal the molecular events responsible for its therapeutic effects. Notably, these studies have shown that metformin acts by phosphorylating the enzyme AMPK, the cellular "energy-sensor", leading to a variety of cellular responses important in diabetic therapy.
A set of mouse and human studies led by Kathleen Giacomini from the University of California, San Francisco and reported in the May 1st issue of the Journal of Clinical Investigation, show that mice lacking organic cation transporter 1 (OCT1) have reduced effects of metformin on AMPK phosphorylation and a decreased ability to control glucose levels. The authors also identified seven mutations in OCT1 in humans that reduce metformin uptake. These studies indicate that OCT1 is important in mediating the therapeutic effects of metformin and that genetic variation in OCT1 in diabetics may contribute to the varied patient responses to this drug.
In an accompanying commentary, Marc Reitman and Eric Schadt from Merck and Rosetta Inpharmatics, respectively, discuss how the identification of individuals that possess specific mutations in certain genes, which are known to affect the action of a particular drug, may eventually help clinicians devise personalized treatment regimes that ensure administration of the right drug for the right person at the right time. They conclude that "tailoring therapeutic choices to the individual should allow lower and better-tolerated doses of drugs that are simultaneously safer and more efficacious. One could eliminate trial-and-error periods of switching among the nine classes of diabetes drugs."
TITLE: Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action
AUTHOR CONTACT:
Kathleen M. Giacomini
University of California San Francisco, San Francisco, California, USA.
Phone: (415) 476-1936; Fax (415) 502-4322; E-mail: kathy.giacomini@ucsf.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=30558
ACCOMPANYING COMMENTARY
TITLE: Pharmacogenetics of metformin response: a step in the path toward personalized medicine
AUTHOR CONTACT:
Marc L. Reitman
Merck Research Laboratories, Rahway, New Jersey, USA.
Phone: (732) 594-4609; Fax: (732) 594-3337; E-mail: marc_reitman@merck.com
View the PDF of this article at: https://www.the-jci.org/article.php?id=32133
DERMATOLOGY
One genetic mutation heals another in blistering skin disease
Mutations in the laminin beta 3 (LAMB3) gene cause the blistering skin disease epidermolysis bullosa (EB). In the May 1st issue of the Journal of Clinical Investigation, Marcel Jonkman and colleagues from the University of Groningen in The Netherlands describe 2 unrelated patients with junctional EB who underwent revertant mosaicism, a spontaneously occurring process in which mutations at second sites within the LAMB3 gene in skin cells known as keratinocytes were capable of correcting the inherited mutation, restoring LAMB3 protein expression to normal, and triggered areas of previously affected skin to return to a clinically healthy state. The presence of the patients' own naturally corrected keratinocytes opens up the possibility of applying revertant cell therapy to other individuals with EB caused by LAMB3 mutations.
In an accompanying commentary, Jorge Frank and Rudolf Happle from Maastricht University and Philipp University, respectively, suggest that, in the future, skin grafts from areas of an EB patient's own normal-appearing skin could be transplanted to affected skin regions on the same patient (after first removing the affected skin). This approach would avoid triggering immune reactions that are often responsible for graft rejection. Alternatively, in LAMB3 revertant mosaic patients, the patient's own naturally corrected skin cells could be isolated and increased in number using special laboratory techniques and then used for grafting. Frank and Happle conclude that "this encouraging report is just the beginning of a new era in which laboratory researchers and clinicians will intensify their efforts to develop and improve strategies of gene therapy for potentially fatal skin diseases."
TITLE: Revertant mosaicism in junctional epidermolysis bullosa due to multiple correcting second-site mutations in LAMB3
AUTHOR CONTACT:
Marcel F. Jonkman
University Medical Center Groningen, Groningen, The Netherlands.
Phone:31-50-361-2520; Fax: 31-50-361-2624; E-mail: m.f.jonkman@derm.umcg.nl
View the PDF of this article at: https://www.the-jci.org/article.php?id=30465
ACCOMPANYING COMMENTARY
TITLE: Cutaneous mosaicism: right before our eyes
AUTHOR CONTACT:
Jorge Frank
Maastricht University Center for Molecular Dermatology, Maastricht, The Netherlands.
Phone:31-43-387-5292; Fax: 31-43-387-7293; E-mail: jfra@sder.azm.nl
View the PDF of this article at: https://www.the-jci.org/article.php?id=32111
METABOLIC DISEASE
Why wounds are slow to heal in diabetics
Individuals with diabetes often experience slow or limited wound healing. Endothelial progenitor cells (EPCs), which derive from bone marrow, normally travel to sites of injury and are essential for the formation of blood vessels and wound healing. In a study reported in the May 1st issue of the Journal of Clinical Investigation, Omaida Velazquez and colleagues from University of Pennsylvania Medical Center reveal why the numbers of these vital EPCs are decreased in the circulation and at wound sites in diabetes.
The authors examined diabetic mice and found that increased oxygen levels (hyperoxia) enhanced the mobilization of EPCs from the bone marrow to the peripheral blood circulation. The high oxygen levels increased the activation of the bone marrow enzyme eNOS, which stimulated nitric oxide production, helping to produce greater numbers of EPCs. However, local injection of the chemokine stromal cell–derived factor 1 alpha (SDF-1alpha) was required to recruit these EPCs from the circulation to the wound site. The increased presence of EPCs at the wound site resulted in accelerated wound healing. The authors concluded that impaired eNOS activation and decreased SDF-1alpha expression in diabetes are responsible for the defect in diabetic wound healing.
In an accompanying commentary, Harold Brem and Marjana Tomic-Canic from Columbia University and Cornell University, respectively, reinforce that future therapeutics for diabetic wound healing will have to correct multiple deficiencies simultaneously. Therapeutic interventions, including correcting EPC activation via hyperbaric oxygen therapy and correcting EPC homing via administration of SDF-1alpha, may significantly accelerate diabetic wound healing by correcting the deficit in EPC number that is inherent to diabetic wounds.
TITLE: Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1alpha
AUTHOR CONTACT:
Omaida C. Velazquez
University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.
Phone: (215) 662-6451; Fax: (215) 662-4871; E-mail: omaida.velazquez@uphs.upenn.edu
Marc Kaplan
Director of Communications
University of Pennsylvania Medical Center, Philadelphia, Pennsylvania, USA.
Phone: (215) 662-2560; E-mail: marc.kaplan@uphs.upenn.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=29710
ACCOMPANYING COMMENTARY
TITLE: Cellular and molecular basis of wound healing in diabetes
AUTHOR CONTACT:
Harold Brem
Columbia University, New York, New York, USA.
Phone: (212) 932-4325; Fax: (212) 658-9806; E-mail: hb2133@columbia.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=32169
IMMUNOLOGY
Researchers create 2 distinct mouse models of Omenn syndrome
Omenn syndrome (OS) is a rapidly fatal immunodeficiency disease in which a defect in the immune response against pathogens coexists with autoimmunity. Most patients have mutations in the genes RAG1 or RAG2 that affect T and B cell function. Our understanding of OS has been limited due to the absence of a suitable animal model of disease. In the May 1st issue of the Journal of Clinical Investigation, two separate studies each report a distinct mouse model of Omenn syndrome and provide insight into the genesis of this disease.
In the first of these two reports, Anna Villa and colleagues from Istituto di Tecnologie Biomediche, Milan created mice carrying an R229Q mutation in the Rag2 gene, a mutation that has been identified in several OS patients. They found that B and T lymphocyte precursors were arrested in the early stages of development, causing multiple symptoms of human OS. In an independent study, Masaaki Murakami and colleagues from Osaka University discovered a spontaneous R972Q mutation in the Rag1 gene in mice; this mutation was identical to a mutation found in an OS patient. A number of alternations in B and T cell function were also observed in these animals.
In an accompanying commentary, Serre-Yu Wong and David Roth from New York University School of Medicine use these 2 reports to discuss the mechanisms at work in the development of immunodeficiency and allergy/autoimmunity in OS. Both research groups have established their Rag mutant mice as valid murine models of OS. Future studies of these animals may clarify the source of the variation in the symptoms of OS and distinguish the contributions of environmental and genetis factors to this complex disease.
TITLE: Homeostatically proliferating CD4+ T cells are involved in the pathogenesis of an Omenn syndrome murine model
AUTHOR CONTACT:
Masaaki Murakami
Osaka University, Osaka, Japan.
Phone: 81-6-6879-3881; Fax: 81-6-6879-3889; E-mail: murakami@molonc.med.osaka-u.ac.jp
View the PDF of this article at: https://www.the-jci.org/article.php?id=30513
RELATED MANUSCRIPT
TITLE: A hypomorphic R229Q Rag2 mouse mutant recapitulates human Omenn sydnrome
AUTHOR CONTACT:
Anna Villa
Istituto di Tecnologie Biomediche, Milan, Italy.
Phone: 39-02-2642-2636; Fax: 39-02-2642-2660; E-mail: anna.villa@itb.cnr.it
View the PDF of this article at: https://www.the-jci.org/article.php?id=30928
ACCOMPANYING COMMENTARY
TITLE: Murine models of Omenn syndrome
AUTHOR CONTACT:
David B. Roth
New York University School of Medicine, New York, New York, USA.
Phone: (212) 263-0945; Fax: (212) 263-5711; E-mail: roth@saturn.med.nyu.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=32214
ONCOLOGY
Deficiency in enzyme GGTase-I delays onset and severity of lung cancer in mice
Geranylgeranyltransferase type I (GGTase-I) has been suggested as a drug target in the treatment of cancer and a host of other diseases. Several inhibitors of GGTase-I (GGTIs) have been synthesized and tested. However, different GGTIs have had very different properties, and a clear picture of the impact of GGTase-I deficiency and GGTI treatment has not yet emerged. Now, in a study appearing in the May 1st issue of the Journal of Clinical Investigation, Martin Bergo and colleagues from Sahlgrenska University Hospital in Sweden describe the impact of GGTase-I deficiency in mammalian cells.
The authors found that, in mice, loss of the gene encoding GGTase-I in cells that would normally produce lung tumors driven by the oncogene K-RAS, resulted in delayed onset and decreased severity of lung cancer in these animals. The findings suggest that, if these results hold true in humans, then inhibiting GGTase-I may be a useful strategy to treat K-RAS–induced malignancies.
In an accompanying commentary, Mark Philips and Adrienne Cox from New York University School of Medicine explore the actions of GGTAse-I and conclude that this new mouse model of disease is likely to be an invaluable tool in assessing the role of GGTase-I in oncogenesis.
TITLE: GGTase-I deficiency reduces tumor formation and improves survival in mice with K-RAS–induced lung cancer
AUTHOR CONTACT:
Martin O. Bergo
Sahlgrenska University Hospital, Goteborg, Sweden.
Phone: 46-31-342-78-58; Fax: 46-31-82-37-62; E-mail: martin.bergo@wlab.gu.se
View the PDF of this article at: https://www.the-jci.org/article.php?id=30868
ACCOMPANYING COMMENTARY
TITLE: Geranylgeranyltransferase I as a target for anti-cancer drugs
AUTHOR CONTACT:
Mark R. Philips
New York University School of Medicine, New York, New York, USA.
Phone: (212) 263-7404; Fax: (212) 263-9210; E-mail: philim01@med.nyu.edu
View the PDF of this article at: https://www.the-jci.org/article.php?id=32108
Journal
Journal of Clinical Investigation