IGF-1 and growth hormone (GH) interact with insulin to modulate its control of carbohydrate metabolism. A new study (see the related article beginning on page 96) shows that blocking the effect of GH in the presence of low serum IGF-1 concentrations enhances insulin sensitivity.
David R. Clemmons
Obesity is associated with a state of chronic, low-grade inflammation. Two manuscripts in this issue of the JCI (see the related articles beginning on pages 1796 and 1821) now report that obese adipose tissue is characterized by macrophage infiltration and that these macrophages are an important source of inflammation in this tissue. These studies prompt consideration of new models to include a major role for macrophages in the molecular changes that occur in adipose tissue in obesity.
Kathryn E. Wellen, Gökhan S. Hotamisligil
The development of type 2 diabetes requires impaired β cell function. Hyperglycemia itself causes further decreases in glucose-stimulated insulin secretion. A new study demonstrates that hyperglycemia-induced mitochondrial superoxide production activates uncoupling protein 2, which decreases the ATP/ADP ratio and thus reduces the insulin-secretory response. These data suggest that pharmacologic inhibition of mitochondrial superoxide overproduction in β cells exposed to hyperglycemia could prevent a positive feed-forward loop of glucotoxicity that drives impaired glucose tolerance toward frank type 2 diabete
Michael Brownlee
Neurofibromas are benign tumors comprised primarily of Schwann cells and fibroblasts. Mast cell infiltration is a well-known phenomenon; however, their role in tumor pathogenesis has been enigmatic. In an elegant set of experiments using cells derived from a murine model of neurofibromatosis 1 (NF1), Yang et al. dissect the molecular pathways involved in mast cell migration to neurofibromin-deficient Schwann cells. These results set the stage for rational development of therapeutics that could influence the multicellular microenvironment of neurofibromas to inhibit the development and/or progression of these tumors in human NF
David H. Viskochil
Ulcerative colitis (UC), a chronic inflammatory condition associated with a predisposition to colon cancer, is frequently characterized by DNA damage in the form of microsatellite instability (MSI). A new report links inflammation in UC with increases in the DNA repair enzymes 3-methyladenine DNA glycosylase and apurinic/apyrimidinic endonuclease, and, paradoxically, with increased MSI. These findings may represent a novel mechanism contributing to MSI in chronic inflammation.
Haiwei H. Guo, Lawrence A. Loeb
Obesity is arguably the world’s most prevalent nutritional disorder and is a substantial contributor to morbidity and early mortality. Obesity is known to have a strong genetic component, but the specific influential genes in humans are largely unknown. A new paper describes a genetic variant that appears as though it may cause some people to be fatter or thinner than others (see the related article beginning on page 1762). This commentary considers the strength of the evidence in support of this finding and discusses additional research questions that should be addressed in further evaluations of this genetic variant as a putative contributor to human obesity.
Hemant K. Tiwari, David B. Allison
Mutations in a variety of genes can cause congenital agammaglobulinemia and a failure of B cell development. The currently known genes encode components of the pre–B cell receptor or proteins that are activated by cross-linking of the pre–B cell receptor. Defects in these genes result in a block in B cell differentiation at the pro–B to pre–B cell transition. A patient with a translocation involving a previously unknown gene, LRRC8, demonstrated a block at exactly the same point in B cell differentiation (see the related article beginning on page 1707). It will be interesting to determine whether the protein encoded by this gene interacts with the pre–B cell receptor signal transduction pathway or is involved in a new pathway.
Mary Ellen Conley
The antiphospholipid syndrome is characterized clinically by fetal loss and thrombosis and serologically by the presence of autoantibodies to lipid-binding proteins. In a model of this procoagulant condition in which these antibodies are injected into pregnant mice, fetal loss was prevented by blocking of complement activation. Specifically, interaction of complement component 5a (C5a) with its receptor is necessary for thrombosis of placental vasculature (see the related article beginning on page 1644). Inhibition of complement activation may have a therapeutic role in this disease.
John P. Atkinson
Familial neurohypophyseal diabetes insipidus (FNDI) in humans is an autosomal dominant disorder caused by a variety of mutations in the arginine vasopressin (AVP) precursor. A new report demonstrates how heterozygosity for an AVP mutation causes FNDI (see the related article beginning on page 1697). Using an AVP knock-in mutation in mice, the study shows that FNDI is caused by retention of AVP precursors and progressive loss of AVP-producing neurons.
John A. Phillips III
Hematopoietic stem cell (HSC) gene therapy can potentially cure a variety of human hematopoietic diseases, such as sickle cell disease. Selection and expansion of gene-corrected HSCs has now been accomplished for the first time using HSC from large animals — dogs and humans — with a novel drug-resistance gene, MGMT, which is not expressed in normal HSCs (see the related articles beginning on pages 1561 and 1581). Highly efficient lentiviral transfer and expression of MGMT into relatively few HSCs led to repopulation of most of the hematopoietic compartment with gene-corrected cells following suitable drug treatment. This selection system may be useful in human clinical trials to permit gene therapy in autologous and allogeneic bone marrow transplantation settings.
Arthur Bank
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