How sweet it isn't: repeat episodes of low blood sugar spell diabetic disaster
Low blood glucose (hypoglycemia) can occur when a person with diabetes has injected too much insulin, eaten too little food, or exercised without extra food. They may experience nausea, sweating, faintness, and confusion. In reaction to these symptoms the person is prompted to eat, and the body instinctively knows to take counterregulatory measures including decreasing insulin secretion, and increasing glucagon and epinephrine secretion. Single or repeated episodes of hypoglycemia can impair the body's ability to detect low blood sugar in the future. This impairment can allow an individual to develop severe hypoglycemia in which they may lose consciousness, experience convulsions, fall into a coma, and suffer brain damage. This failure to respond to hypoglycemia has become a major limitation to effective insulin therapy in type 1 diabetes.
In a study appearing in the June issue of the Journal of Clinical Investigation, Rory J. McCrimmon and colleagues from Yale University, show that administration to the brain of urocortin I suppresses the counterregulatory response to hypoglycemia for at least 24 hours in rats. They show that urocortin I, which activates corticotrophin-releasing factor receptor 2 (CRFR2), impairs the sensitivity of glucose-sensing neurons in the brain. In contrast, administration of CRF, which activates CRFR1, amplifies the response to hypoglycemia. The data suggest that the regulation of the counterregulatory response to hypoglycemia is largely determined by the interaction between CRFR2-mediated suppression and CRFR1-mediated activation in the hypothalamus.
In an accompanying commentary, Philip Cryer from Washington University School of Medicine discusses how hypoglycemia in diabetes will likely remain a problem until safe and effective methods are developed that would offer insulin replacement based on plasma glucose concentration.
TITLE: Corticotrophin-releasing factor receptors within the ventromedial hypothalamus regulate hypoglycemia-induced hormonal counterregulation
AUTHOR CONTACT:
Rory J. McCrimmon
Yale University, New Haven, Connecticut, USA.
Phone: (203) 785-4664; Fax: (203) 737-5558; E-mail: rory.mccrimmon@yale.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27775
ACCOMPANYING COMMENTARY
TITLE: Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes
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=28735
ONCOLOGY
Researchers isolate signaling pathway that spurs breast cancer spread
The spread of a tumor from one organ to another is the major cause of morbidity from cancer. However, therapeutic strategies for direct interference with the invasion process are lacking. In a study appearing in the June issue of the Journal of Clinical Investigation, Martin Jechlinger and colleagues from Memorial Sloan-Kettering Cancer Center, New York, show that the ability of cancerous epithelial cells in breast tissue to spread to another organ is dependent on a signaling pathway that involves platelet-derived growth factor (PDGF) and its receptor, PDGFR. Inhibition of PDGFR signaling caused the death of mouse and human breast cancer cells in culture. The authors also noted that the expression of two types of the PDGF receptor, PDGFR-alpha and PDGFR-beta, correlated with the invasive behavior of human breast cancer carcinomas. The authors suggest that administration of the established cancer drug ST1571 may be a useful therapeutic approach to interfere with PDGF/PDGFR signaling and therefore prevent breast cancer spread.
TITLE: Autocrine PDGFR signaling promotes mammary cancer metastasis
AUTHOR CONTACT:
Martin Jechlinger
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: (212) 639-6193; Fax: (212) 717-3125; E-mail: jechlinm@mskcc.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=24652
MICROBIOLOGY
TB or not TB: mycolic acid manipulation controls immune response to tuberculosis infection
Fine structural modification of lipids present in the cell wall of the tuberculosis-causing organism Mycobacterium tuberculosis play a central role in activating the host immune response during infection. One such alteration is the cis-cyclopropanation of mycolic acids attached to trehalose dimycolate (TDM). In a study appearing in the June issue of the Journal of Clinical Investigation, Michael S. Glickman and colleagues from Memorial Sloan-Kettering Cancer Center, New York, examined the effect of trans-cyclopropanation of oxygenated mycolic acids attached to TDM on the immune response to tuberculosis infection in mice. Surprisingly, they found that a strain of Mycobacterium tuberculosis that lacked this structural change was hypervirulent in mice, causing an enhanced immune response and larger granulomas than the wild-type M. tuberculosis strain. These results establish the trans-cyclopropanation of TDM as a suppressor of M. tuberculosis–induced inflammation and virulence.
In an accompanying commentary, Lee Riley from the University of California, Berkeley, discusses the relationship between bioactive lipids and the disease process during tuberculosis infection.
TITLE: Trans-cyclopropanation of mycolic acids on trehalose dimycolate suppresses Mycobacterium tuberculosis–induced inflammation and virulence
AUTHOR CONTACT:
Michael S. Glickman
Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Phone: (212) 639-3191; Fax: (646) 422-2124; E-mail: glickmam@mskcc.org.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27335
ACCOMPANYING COMMENTARY
TITLE: Of mice, men, and elephants: Mycobacterium tuberculosis cell envelope lipids and pathogenesis
AUTHOR CONTACT:
Lee W. Riley
University of California, Berkeley, California, USA.
Phone: (510) 642-9200; Fax: (510) 642-6350; Email: lwriley@berkeley.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28734
MICROBIOLOGY
An inside out look at Cryptococcus fungal infection
Upon inhalation, the yeast-like fungus Cryptococcus neoformans grows within the alveolar space of the lung and can cause the pulmonary infection cryptococcosis. In immunocompetent individuals the infection is usually contained within this organ. However, in immunocompromised individuals the spores can disseminate both intracellularly (inside host cells) as well as extracellularly (in the bloodstream) from the lung to the brain, causing the life-threatening disease meningoencephalitis. In a study appearing in the June issue of the Journal of Clinical Investigation, Maurizio Del Poeta and colleagues from the Medical University of South Carolina examined how intracellular versus extracellular growth of this pathogen contributes to disease development. Del Poeta et al. show that there is a critical extracellular growth phase after the organism reaches the lung, but before it is taken up by macrophages. In this phase, the organism encounters the neutral pH and physiological carbon dioxide level that is characteristic of host tissues. The authors found that a sphingolipid known as glucosylceramide, which is present on the surface of fungal cells, is critical for extracellular growth under these conditions in alveolar spaces and in the bloodstream, but not in the host intracellular environment, such an within the phagolysosome of macrophages, which is acidic.
In an accompanying commentary, Aaron P. Mitchell from Columbia University discusses how the use of anti-glucosylceramide antibodies that bind to glucosylceramide and inhibit C. neoformans growth may be a potential anti-fungal therapeutic strategy.
TITLE: Glucosylceramide synthase is an essential regulator of pathogenicity of Cryptococcus neoformans
AUTHOR CONTACT:
Maurizio Del Poeta
Medical University of South Carolina, Charleston, South Carolina, USA.
Phone: (843) 792-8381; Fax: (843) 792-8565; E-mail: delpoeta@musc.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=27890
ACCOMPANYING COMMENTARY
TITLE: Cryptococcal virulence: beyond the usual suspects
AUTHOR CONTACT:
Aaron P. Mitchell
Columbia University, New York, New York, USA.
Phone: (212) 305-8251; Fax: (212) 342-1741; Email: apm4@columbia.edu.
View the PDF of this article at: https://www.the-jci.org/article.php?id=28842
CARDIOLOGY
Under pressure: what type of stress and for how long is too much for the heart?
High-powered athletes and pregnant women often experience physiologic cardiac hypertrophy – a beneficial and necessary increase in heart size and pumping capacity that allows them to maintain necessary cardiac output under conditions of physiologic stress. However, hypertrophy has recently been recognized as a risk factor for increased mortality. As the athlete and soon-to be mother's hearts to do not progress to heart failure, researchers have long been interested in determining how the heart adapts to physiological versus pathological triggers that cause an adaptive versus maladaptive cardiac response. Since most pathological causes of cardiac hypertrophy are usually chronic (e.g. high blood pressure, cardiac valve abnormalities), while physiological stresses are intermittent by nature, it is thought likely that the duration of stress on the heart could be a critical factor. It is also possible that the heart reacts differently to different types of stress, even if applied for the same period of time.
In a study appearing in the June issue of the Journal of Clinical Investigation, Howard Rockman and colleagues from the University of North Carolina applied intermittent stress, in the form of pressure overload, to the hearts of mice and tested the roles of duration and nature of the stress on the development of heart failure. They report that it is the nature of the stress on the heart, not its duration, that is the key determinant in the heart's maladaptive response to stress. Rockman and coworkers found that the increase in heart size was a time-dependent reaction to cardiac stress that does not itself lead to cardiac maladaptation. Rather, the molecular signaling pathways active within the stressed heart (particularly altered function of the beta-adrenergic receptor expressed on the surface of heart cells), and not the growth response itself, is the trigger that leads to heart failure.
In an accompanying commentary, Jil Tardiff from Yeshiva University discusses how the results of this study will spur new approaches to the treatment of pathologic cardiac hypertrophy.
AUTHOR CONTACT:
View the PDF of this article at: https://www.the-jci.org/article.php?id=25397
ACCOMPANYING COMMENTARY
TITLE: Cardiac hypertrophy: stressing out the heart
AUTHOR CONTACT:
View the PDF of this article at: https://www.the-jci.org/article.php?id=28884
IMMUNOLOGY
Immune syndrome IPEX puts a hex on T cell function
The X-linked syndrome known as IPEX is characterized by immune dysregulation, polyendocrinopathy, and enteropathy, and is caused by mutations in the FOXP3 gene. In a study appearing in the June issue of the Journal of Clinical Investigation, Maria G. Roncarolo and colleagues from San Raffaele Telethon Institute for Gene Therapy in Milan, Italy, present the first comprehensive study of T cell biology in patients affected by IPEX. They found that the immune dysregulation in IPEX patients is due to the deficient capacity of CD34+ T cells to produce the cytokines interleukin-2 and interferon-gamma. They believe that the lack of interleukin-2 production by T cells has a critical effect on the function of regulatory T cells (a small subset of the T cell population that act to curb over-aggressive T cell responses), and that this dysfunction leads to the immune pathology characteristic of this syndrome.
In an accompanying commentary, Raif Geha from Harvard Medical School further discusses the role of FOXP3 in the generation and function of regulatory T cells and how FOXP3 mutations correlate with the clinical symptoms observed in IPEX patients.
TITLE: Defective regulatory and effector T cell functions in patients with FOXP3 mutations
AUTHOR CONTACT:
View the PDF of this article at: https://www.the-jci.org/article.php?id=25112
ACCOMPANYING COMMENTARY
TITLE: IPEX and the role of Foxp3 in the development and function of human Tregs
AUTHOR CONTACT:
View the PDF of this article at: https://www.the-jci.org/article.php?id=28880
METABOLIC DISEASE
Role of liver enzyme SCD1 in diet-induced liver insulin resistance
The metabolic syndrome – also called the insulin resistance syndrome – is a cluster of the most dangerous heart attack risk factors: diabetes, abdominal obesity, changes in cholesterol, and high blood pressure. Previous studies have shown that the enzyme stearoyl-CoA desaturase–1 (SCD1), which is highest in the liver and fatty tissue, plays an important role in these conditions. In a study appearing in the June issue of the Journal of Clinical Investigation, Luciano Rossetti and colleagues from the Albert Einstein College of Medicine studied SCD1-deficient mice and rats in order to gain insight into the role of SCD1 in liver metabolism. These authors demonstrate that short-term inhibition of the activity of the liver form of the SCD1 enzyme is sufficient to prevent diet-induced insulin resistance in the liver, signifying an important role for hepatic SCD1 in liver insulin sensitivity.
In an accompanying commentary, James Ntambi and colleagues from the University of Wisconsin-Madison discuss whether obesity and the symptoms of the metabolic syndrome might be alleviated by inhibition of SCD1.
TITLE: Critical role of stearoyl-CoA desaturase–1 (SCD1) in the onset of diet-induced hepatic insulin resistance
AUTHOR CONTACT:
View the PDF of this article at: https://www.the-jci.org/article.php?id=26991
ACCOMPANYING COMMENTARY
TITLE: Probing the role of stearoyl-CoA desaturase-1 in hepatic insulin resistance
AUTHOR CONTACT:
View the PDF of this article at: https://www.the-jci.org/article.php?id=28774
Journal of Clinical Investigation
Howard A. Rockman
Duke University Medical Center, Durham, North Carolina, USA.
Phone: (919) 668-2520; Fax: (919) 668-2524; E-mail: h.rockman@duke.edu.
Jil C. Tardiff
Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.
Phone: (718) 430-8914; Fax: (718) 430-8919; Email: tardiff@aecom.yu.edu.
Maria G. Roncarolo
San Raffaele Telethon Institute for Gene Therapy, Milan, Italy.
Phone: 39-02-26434875; Fax: 39-02-26434668; E-mail: m.roncarolo@hsr.it.
Raif S. Geha
Harvard Medical School, Boston, Massachusetts, USA.
Phone: (617) 919-2482; Fax: (617) 730-0528; E-mail: raif.geha@childrens.harvard.edu.
Luciano Rossetti
Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, USA.
Phone: (718) 430-4118; Fax: (718) 430-8557; E-mail: rossetti@aecom.yu.edu.
James M. Ntambi
University of Wisconsin-Madison, Madison, Wisconsin, USA.
Phone: (608) 265-3700; Fax: (608) 265-3272; Email: ntambi@biochem.wisc.edu.
Journal