Inhibition of kidney glucose transport improves hyperglycemia but increases glucose production
Treatment of patients with type 2 diabetes (T2D) with the drug metformin greatly reduces diabetic complications and mortality. Unfortunately, many patients on metformin therapy become hyperglycemic, which exacerbates insulin resistance and reduces β cell function. Dugs that target the sodium-glucose cotransporter-2 (SGLT2), which promotes glucose absorption in the kidney have been attractive for use a add-ons to metformin treatment. In this issue of the Journal of Clinical Investigation, two research groups led by Ralph DeFronzo of the University of Texas and Ele Ferrannini of the University of Pisa independently report on clinical studies testing the ability SGLT2 inhibitors to reduce plasma glucose levels in T2D patients. SGLT2 inhibition increased glucose excretion in the urine (glycosuria), lowered fasting plasma glucose, and improved tissue insulin sensitivity. Surprisingly, the use of SLGT2 inhibitors resulted in an increase in endogenous glucose production and decreased insulin secretion, though overall pancreatic β cell function was improved. In a companion Commentary, William Cefalu of the Pennington Biomedical Research Center discusses the implications of these clinical studies for the future of T2D treatment.
TITLE: Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production
AUTHOR CONTACT:
Ralph A. DeFronzo
Chief, Diabetes Div., Dept. Of Medicine, San Antonio, TX, USA
Phone: 210/567-6691; Fax: 210-567-6554; E-mail: Albarado@uthscsa.edu
View this article at: http://www.jci.org/articles/view/70704?key=4cb8772cbcd3d5a389b5
ACCOMPANYING ARTICLE
TITLE: Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients
AUTHOR CONTACT:
Ele Ferrannini
Department of Internal Medicine, University of Pisa School of Medicine, 56126 Pisa, , ITA
Phone: +39 050 553272; Fax: +39 050 553 235; E-mail: ferranni@ifc.cnr.it
View this article at: http://www.jci.org/articles/view/72227?key=fff41c6571e7ee8eb46d
ACCOMPANYING COMMENTARY
TITLE: Paradoxical insights into whole body metabolic adaptations following SGLT2 inhibition
AUTHOR CONTACT:
William Cefalu
Pennington Biomedical Research Center, Baton Rouge, LA, USA
Phone: 225-763-2658; Fax: ; E-mail: William.Cefalu@pbrc.edu
View this article at: http://www.jci.org/articles/view/74297?key=d3f2caffd22eecd27819
Targetting lipid metabolism restores function in T cells from lupus patients
Patients with the autoimmune disorder lupus erythematosus (SLE) exhibit multiple immune system defects. In this issue of the Journal of Clinical Investigation, Elizabeth Jury and colleagues at University College London reveal that T cells isolated from SLE patients have altered membrane-associated lipid profiles and exhibit increased lipid trafficking to the membrane and dysfunctional immune responses. Furthermore, normalization of lipid metabolism in isolated SLE T cells restored membrane lipid levels and immune function. In an accompanying Commentary, Steven Bensinger and Yoko Kidani of the University of California, Los Angeles discuss how targeting lipid metabolism in SLE patients may help attenuate autoimmunity.
TITLE: Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients
AUTHOR CONTACT:
Elizabeth C Jury
University College London, London, , GBR
Phone: 44 (0)20 3108 2154; E-mail: e.jury@ucl.ac.uk
View this article at: http://www.jci.org/articles/view/69571?key=7f81a1daa45935ffc584
ACCOMPANYING COMMENTARY
TITLE: Lipids rule: resetting lipid metabolism restores T cell function in systemic lupus erythematosus
AUTHOR CONTACT:
Steven Bensinger
UCLA, LA, CA, USA
Phone: 310-825-9885; Fax: ; E-mail: sbensinger@mednet.ucla.edu
View this article at: http://www.jci.org/articles/view/74141?key=d34d9451cd0706526acd
Clinical evaluation of teriparatid treatment for osteogenesis imperfecta
Patients with osteogenesis imperfecta (OI) are prone to bone fracture and skeletal deformity, and treatment options for these patients are severely limited. In this issue of the Journal of Clinical Investigation, Eric Orwoll and colleagues at Oregon Health and Sciences University evaluated the use of the teriparatide, a recombinant human parathyroid hormone, for patients with OI. Compared with patients taking placebo, OI patients taking tripartite exhibited increased bone density; however, this effect was limited to patients with a mild form of disease. In an accompanying Attending Physician article, Nick Bishop of the University of Sheffield and Jennifer Walsh of the Metabolic Bone Centre caution that despite the apparent improvement observed with teriparatide treatment, the best course of action for OI patients is supportive care to limit damage.
TITLE: Evaluation of teriparatide treatment in adults with osteogenesis imperfecta
AUTHOR CONTACT:
Denise Duncan
OHSU, Portland, , USA
Phone: 503-494-1385; Fax: ; E-mail: duncande@ohsu.edu
View this article at: http://www.jci.org/articles/view/71101?key=bb72d8308d073f4272c7
ACCOMPANYING THE ATTENDING PHYSICIAN
TITLE: Osteogenesis imperfecta in adults
AUTHOR CONTACT:
Jennifer Walsh
University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Tru, Sheffield, , GBR
Phone: +44 114 2714705; Fax: +44 114 2618775; E-mail: Jennifer.walsh2@sth.nhs.uk
View this article at: http://www.jci.org/articles/view/74230?key=5e67c9ca13b4914bf509
New classification system for breast cancers
Breast cancer tumors have long been classified according to their expression of three surface proteins: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2). These classifications are used to determine best treatments and prognoses, but are not adequate to describe tumor characteristics or compare them to normal breast tissue. In this issue of the Journal of Clinical Investigation, Tan Ince and colleagues of the University of Miami devised a method to categorize normal breast tissue cells as a reference point to classify tumor cells. By analyzing sections of normal breast tissue from 36 donors, the group delineated 13 previously undescribed cell types within the lobular structures of the tissue. These cell types fit four patterns of hormone receptor expression, which could then be used to classify breast tumor samples, and correlated with distinct survival outcomes. In an accompanying commentary, Robert Cardiff and Alexander Borowsky of University of California, Davis indicate that this new classification scheme be used to refine patient treatment plans and expand our understanding of breast cancer development.
TITLE: Taxonomy of breast cancer based on normal cell phenotype predicts outcome
AUTHOR CONTACT:
Sandro Santagata
Brigham and Women's Hospital & Harvard Medical School, Boston, MA, USA
Phone: 617-525-5686; E-mail: ssantagata@partners.org
View this article at: http://www.jci.org/articles/view/70941?key=19aa6c8206b37ab99f37
ACCOMPANYING COMMENTARY
TITLE: At last: classification of human mammary cells elucidates breast cancer origins
AUTHOR CONTACT:
Robert Cardiff
UC Davis, Davis, CA, USA
Phone: 530-752-2726; E-mail: rdcardiff@ucdavis.edu
View this article at: http://www.jci.org/articles/view/73910?key=7cf098b68edbd317f990
Timing of protein depletion influences spinal muscular atrophy development in mice
Spinal muscle atrophy (SMA) is a devastating disease that is characterized by loss of motor neuron function and subsequent muscle weakness and atrophy. The disease results from deletion of survival of motor neuron 1 (SMN1) and SMN protein deficiency. In humans, a duplication SMN1, SMN2 results in a truncated SMN protein; however, the number of SMN2 copies inversely correlates to disease severity. Disease onset occurs shortly after birth following a short period of normal muscle function. In this issue of the Journal of Clinical Investigation , Umrao Monani and colleagues at Columbia University demonstrate in a mouse model that the timing of SMN depletion during development is critical to the pathogenesis of disease.Depletion of SMN in the early neonatal period resulted in an SMA-like phenotype, while depletion of SMN in mature mice had no effect. In an accompanying Commentary, Kathryn Swoboda of the University of Utah discusses the implications of a temporal requirement of SMN for optimization of SMN repletion-based therapy.
TITLE: Requirement of enhanced Survival Motoneuron protein imposed during neuromuscular junction maturation
AUTHOR CONTACT:
Umrao Monani
Columbia University, New York, , USA
Phone: 212 342 5132; Fax: ; E-mail: um2105@columbia.edu
View this article at: http://www.jci.org/articles/view/72017?key=5ea8275e74ec48c0226a
ACCOMPANYING COMMENTARY
TITLE: SMN-targeted therapeutics for spinal muscular atrophy: are we SMArt enough yet?
AUTHOR CONTACT:
Kathryn J Swoboda
University of Utah School of Medicine, Salt Lake City, UT, USA
Phone: 801-585-9717; Fax: 801-587-9346; E-mail: swoboda@genetics.utah.edu
View this article at: http://www.jci.org/articles/view/74142?key=7515c3c11652c2f56c58
A platelet-derived factor limits murine cardiac graft rejection
Acute rejection of a transplanted organ by the recipient is mediated by an inflammatory immune response. Despite current immunosuppressive therapies, organ rejection remains problematic. In this issue of the Journal of Clinical Investigation, Craig Morrell and colleagues of the University of Rochester discovered that mice lacking the chemokine, platelet factor 4 (PF4), had an enhanced immune response to heart transplant that was associated with an increase in Th17 cells. The authors found that PF4 was essential for limiting the differentiation of naive T cells into the Th17 subtype. In a companion Commentary, Ronjon Chakraverty of University College London discusses this exciting new role for platelets in limiting transplant rejection.
TITLE: Platelet factor 4 limits Th17 differentiation and cardiac allograft rejection
AUTHOR CONTACT:
Craig Morrell
University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
Phone: 585-276-9921; E-mail: Craig_Morrell@URMC.Rochester.edu
View this article at: http://www.jci.org/articles/view/71858?key=d4602aa546acae627c89
ACCOMPANYING COMMENTARY
TITLE: An unexpected role for platelets in blocking Th17 differentiation
AUTHOR CONTACT:
Ronjon Chakraverty
University College London, London, UNK, GBR
Phone: 0207 317 7513; E-mail: r.chakraverty@medsch.ucl.ac.uk
View this article at: http://www.jci.org/articles/view/74231?key=d7f0c6a0304489c78274
ALSO IN THIS ISSUE
NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation |
TITLE: NRF2-mediated Notch pathway activation enhances hematopoietic reconstitution following myelosuppressive radiation
AUTHOR CONTACT:
Shyam Biswal
Johns Hopkins University, Baltimore, MD, USA
Phone: 410-955-4728; E-mail: sbiswal@jhsph.edu
View this article at: http://www.jci.org/articles/view/70812?key=48cfbc745cdea1906838
Journal
Journal of Clinical Investigation