EDITOR'S PICK: Is there such a thing as too much sugar?
Treatment with insulin revolutionized the life of individuals with diabetes. However, because insulin acts to lower blood glucose levels, it can cause hypoglycemia (low levels of glucose in the blood), which, if prolonged, can lead to brain injury and coma. Although most brain defects can be corrected by restoring blood glucose levels to normal, extremely prolonged hypoglycemia can cause the death of neurons and irreversible brain damage. Surprisingly, in a study appearing in the April issue of the Journal of Clinical Investigation, researchers from the University of California at San Francisco found that in mice, hypoglycemic neuronal death is triggered when the mice are treated with a large amount of glucose and not by the hypoglycemia itself.
Raymond Swanson and colleagues showed that although hypoglycemia induced some neuronal death, the rapid infusion of glucose into hypoglycemic mice triggered more extensive neuronal death. The extent of neuronal death correlated with the production of superoxide by a molecule known as NADPH oxidase. Importantly, the amount of superoxide produced and the extent of neuronal death increased as the amount of glucose infused into the hypoglycemic mice was increased. This suggests that it might be best to treat individuals in hypoglycemic coma by gradually increasing their blood glucose levels rather than by restoring glucose levels rapidly. However, in an accompanying commentary, Philip Cryer from Washington University School of Medicine, St. Louis, cautions that "The appropriate clinical extrapolation of these data is not entirely clear."
TITLE: Hypoglycemic neuronal death is triggered by glucose reperfusion and activation of neuronal NADPH oxidase
AUTHOR CONTACT:
Raymond A. Swanson
University of California at San Francisco and Veterans Affairs Medical Center, San Francisco, California, USA.
Phone: (415) 750-2011; Fax: (415) 750-2273; E-mail: raymond.swanson@ucsf.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30077
ACCOMPANYING COMMENTARY
TITLE: Hypoglycemia, functional brain failure, and brain death
AUTHOR CONTACT:
Philip E. Cryer
Washington University School of Medicine, St. Louis, Missouri, USA.
Phone: (314) 362-7635; Fax: (314) 362-7989; E-mail: pcryer@wustl.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31669
TRANSPLANTATION: Heart grafts avoid rejection
Rats treated with a drug known as CD40Ig have been shown to accept heart grafts from rats that are not genetically identical. Although it is known that CD40Ig disrupts the interaction between CD40 and CD40L on different immune cells, exactly how this prevents heart graft rejection in rats had not been determined.
In a study that appears in the April issue of the Journal of Clinical Investigation, Ignacio Anegon and colleagues from Centre Hopitalier Universitaire de Nantes, France, identified in rats treated with CD40Ig a population of regulatory immune cells that express CD8 and low levels of CD45RC. These cells were essential for the heart graft to survive and when transferred to normal mice they prevented the rejection of a subsequent heart graft in the absence of CD40Ig treatment. In vitro, these cells produced a soluble factor known as IFN-gamma that induced endothelial cells in the heart graft to express a protein known as IDO. Importantly, neutralizing either IFN-gamma or IDO in vivo caused heart graft rejection in rats treated with CD40Ig. This study therefore describes a mechanism by which treatment with CD40Ig can result in the prevention of heart graft rejection.
As discussed in an accompanying commentary, the importance of IFN-gamma for preventing the rejection of heart grafts is likely to surprise many as it has long been considered a soluble factor that enhances inflammation. However, as Jingwu Zhang from the Institute of Health Sciences in China notes, "the paradoxical actions of IFN-gamma appear to follow the principle of yin and yang, as do many of nature's paradoxes. That is, the roles of IFN-gamma only exist in a well-defined, integrated system in which the two elements of a proinflammatory process (yang) and an antiinflammatory/regulatory process (yin) interact to achieve and maintain balance."
TITLE: CD40Ig treatment results in allograft acceptance mediated by CD8+CD45RClow T cells, IFN-gamma, and indoleamine 2,3-dioxygenase
AUTHOR CONTACT:
Ignacio Anegon
Centre Hopitalier Universitaire de Nantes, Nantes, France.
Phone: +33-240-08-74-15; Fax: +33-240-08-74-11; E-mail: Ignacio.Anegon@univ-nantes.fr.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28801
ACCOMPANYING COMMENTARY
TITLE: Yin and yang interplay of IFN-gamma in inflammation and autoimmune disease
AUTHOR CONTACT:
Jingwu Zhang,
Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Shanghai, China.
Phone: +86-21-63848329; Fax: +86-21-63852822; E-mail: jzang@bcm.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31860
BONE BIOLOGY: New gene defect causes heavy bones
Osteopetrosis is an inherited disorder whereby bones harden and become denser. There are several different types of osteopetrosis caused by distinct genetic mutations, but not all the causative genetic mutations have been identified. In a study that appears in the April issue of the Journal of Clinical Investigation, researchers from the University of Antwerp, Belgium, identify PLEKHM1 as a new gene in which loss-of-function mutations cause osteopetrosis in humans and rats.
Wim Van Hul and colleagues showed that a genetic mutation in PLEKHM1 caused the bone and tooth defects observed in incisors absent rats. A mutation in the same gene was associated with disease in a human patient with osteopetrosis. Bone cells known as osteoclasts from both this patient and incisors absent rats were impaired in their ability to destroy bone (which is essential for maintaining healthy bones). Further analysis suggested that PLEKHM1 was important for the transport of vesicles inside the osteoclasts, but further studies will be required before the precise molecular mechanism(s) by which PLEKHM1 loss-of-function mutations causes osteopetrosis is determined.
TITLE: Involvement of PLEKHM1 in osteoclastic vesicular transport and osteopetrosis in incisors absent rats and humans
AUTHOR CONTACT:
Wim Van Hul
University of Antwerp, Antwerp, Belgium.
Phone: +32-3-820-25-85; Fax: +32-3-820-25-66; E-mail: Wim.VanHul@ua.ac.be.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30328
ENDOCRINOLOGY: Pancreatic cells show variable plasticity
The pancreas contains cells that produce a number of different hormones that control the amount of glucose that is in our blood, including beta cells, which produce insulin, and alpha cells, which produce glucagon. Type I diabetes is caused by a loss of, or relative deficiency of, beta cells. Therefore, determining ways in which to renew the number of beta cells in the pancreas is an area of intensive research.
Previous studies have suggested that beta cells can be generated from acinar cells in the pancreas, whose abundance makes them an ideal cell from which to generate other cell types. However, in a study that appears in the April issue of the Journal of Clinical Investigation, Doris Stoffers and colleagues from the University of Pennsylvania School of Medicine, Philadelphia, trace the lineage of beta cells and show that beta cells do not arise from acinar cells. Instead, they found that acinar cells gave rise to more acinar cells.
By contrast, in a second study appearing in the April issue of the Journal of Clinical Investigation, Ahmed Mansouri and colleagues from the Max Planck Institute for Biophysical Chemistry, Germany, show that beta cells can be reprogrammed to become alpha cells or PP cells if they are engineered to express a protein known as ARX. These distinct observations are discussed in the accompanying commentary by Jose Ferrer and colleagues.
TITLE: Preexisting pancreatic acinar cells contribute to acinar cell, but not islet beta cell, regeneration
AUTHOR CONTACT:
Doris A. Stoffers
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-5413; Fax: (215) 898-5408; E-mail: stoffers@mail.med.upenn.edu.
Karen Kreeger
Department of Communications, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 349-5658; E-mail: karen.kreeger@uphs.upenn.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29988
RELATED MANUSCRIPT
TITLE: Embryonic endocrine pancreas and mature beta cells acquire alpha and PP cell phenotypes upon Arx misexpression
AUTHOR CONTACT:
Ahmed Mansouri
Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Phone: +49-551-2011709; Fax: +49-551-2011504; E-mail: amansou@gwdg.de.
Patrick Collombat
Max Planck Institute for Biophysical Chemistry, Göttingen, Germany.
Phone: +49-551-2011709; Fax: +49-551-2011504; E-mail: pcollom@gwdg.de.
Palle Serup
Hagedorn Research Institute, Gentofte, Denmark.
Phone: 45-4443-9822; Fax: 45-4443-8000; E-mail: pas@hagedorn.dk.
View the PDF of this article at: https://www.the-jci.org/article.php?id=29115
ACCOMPANYING COMMENTARY
TITLE: Putting pancreatic cell plasticity to the test
AUTHOR CONTACT:
Jorge Ferrer
Hospital Clinic de Barcelona, Barcelona, Spain.
Phone: +34-932275400-3028; Fax: +34-934516638; E-mail: jferrer@clinic.ub.es.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31749
PHYSIOLOGY: We've got drinking water on our minds
The amount of fluid in our body, which has a major influence on blood pressure, is regulated by a combination of molecules that comprise the renin-angiotensin system (RAS). The RAS is active in both the kidney and brain, but the mechanisms that control the RAS in the brain had not well defined until researchers from the University of Iowa, Iowa City, showed that in mice the RAS is active in a region of the brain known as the subfornical organ (SFO) and that RAS activity in the SFO drives increased consumption of water and salt.
The molecule that causes most of the effects of the RAS is angiotensin II, which is generated from angiotensinogen by renin and ACE. In their study, which appears in the April issue of the Journal of Clinical Investigation, Curt Sigmund and colleagues generated mice expressing human renin and human angiotensinogen in the brain of mice. These mice consumed more water and salt than normal mice and this increased consumption could be reversed by the administration of an inhibitor of the angiotensin II receptor into the brain. Furthermore, production of angiotensin II was specifically detected in the SFO and eliminating the expression of human angiotensinogen in the SFO reversed the increased water and salt consumption. This study indicates that the production of angiotensin II in the SFO has an important role in regulating water intake, and therefore the amount of fluid in the body. As discussed in an accompanying commentary by Kelly Parsons and Thomas Coffman, these data suggest that RAS activity in the SFO and kidney are nonredundant and that "creative use of techniques allowing for cell- and tissue-specific manipulation of gene expression in vivo" are necessary to determine further the extent of functional and regulatory overlap between RAS activity in the SFO and brain.
TITLE: Local production of angiotensin II in the subfornical organ causes elevated drinking
AUTHOR CONTACT:
Curt D. Sigmund
University of Iowa, Iowa City, Iowa, USA.
Phone: (319) 335-7604; Fax: (319) 353-5350; E-mail: curt-sigmund@uiowa.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31242
ACCOMPANYING COMMENTARY
TITLE: The renin-angiotensin system: it's all in your head
AUTHOR CONTACT:
Thomas M. Coffman
Duke University School of Medicine and Durham Veterans Affairs Medical Center, Durham, North Carolina, USA.
Phone: (919) 286-6947; Fax: (919) 286-6879; E-mail: tcoffman@acpub.duke.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=31856
HEMATOLOGY: HIF-2 boosts red blood cell numbers
Erythropoietin (EPO), a naturally occurring hormone that stimulates the production of red blood cells, is used to treat some forms of anemia. In the fetus EPO is produced by the liver. By contrast, in the adult most EPO is produced by the kidneys but some is produced by liver cells known as hepatocytes, particularly when levels of oxygen in the body are low. The role of two related proteins, HIF-1 and HIF-2 in EPO production by hepatocytes had been controversial. But now, researchers from the University of Pennsylvania, Philadelphia, have shown that in mice HIF-2 regulates hepatocyte production of EPO.
In the study, which appears in the April issue of the Journal of Clinical Investigation, Volker Haase and colleagues generated mice lacking either HIF-1-alpha or HIF-2-alpha in their hepatocytes and showed that only the mice lacking HIF-2-alpha in their hepatocytes do not produce EPO from the liver. This was observed under four different situations known to be associated with increased hepatocyte production of EPO, including early postnatal life and treatment with chemicals that mimic low levels of oxygen in the body. This identification of HIF-2 as the central regulator of EPO production by hepatocytes in mice has clinical implications for the development of therapeutics targeting the HIF-regulated pathway of EPO production for the treatment of anemia.
In an accompanying commentary, Peter Ratcliffe from the University of Oxford, United Kingdom, explains why this demonstration that different forms of HIF have distinct roles is important for developing new approaches to treat individuals with anemia.
TITLE: Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo
AUTHOR CONTACT:
Volker H. Haase
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: (215) 573-1830; Fax: (215) 898-0189; E-mail: vhaase@mail.med.upenn.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=30117
ACCOMPANYING COMMENTARY
TITLE: HIF-1 and HIF-2: working alone or together in hypoxia?
AUTHOR CONTACT:
Peter J. Ratcliffe
Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
Phone : +44-18-652-22382; Fax: +44-18-652-22500; E-mail: pjr@well.ox.ac.uk
View the PDF of this article at: https://www.the-jci.org/article.php?id=31750
Journal
Journal of Clinical Investigation