http://www.jci.org/just-published en-us 2008 The American Society for Clinical Investigation http://www.jci.org/icons/banner/rss_title.gif http://content.jci.org David H. Adler, Joy D. Cogan, John A. Phillips, Nathalie Schnetz-Boutaud, Ginger L. Milne, Tina Iverson, Jeffrey A. Stein, David A. Brenner, Jason D. Morrow, Olivier Boutaud, John A. Oates http://www.jci.org/articles/view/30473 2α (cPLA_2α) hydrolyzes arachidonic acid from cellular membrane phospholipids, thereby providing enzymatic substrates for the synthesis of eicosanoids, such as prostaglandins and leukotrienes. Considerable understanding of cPLA_2α function has been derived from investigations of the enzyme and from cPLA_2α-null mice, but knowledge of discrete roles for this enzyme in humans is limited. We investigated a patient hypothesized to have an inherited prostanoid biosynthesis deficiency due to his multiple, complicated small intestinal ulcers despite no use of cyclooxygenase inhibitors. Levels of thromboxane B₂ and 12-hydroxyeicosatetraenoic acid produced by platelets and leukotriene B₄ released from calcium ionophore–activated blood were markedly reduced, indicating defective enzymatic release of the arachidonic acid substrate for the corresponding cyclooxygenase and lipoxygenases. Platelet aggregation and degranulation induced by adenosine diphosphate or collagen were diminished but were normal in response to arachidonic acid. Two heterozygous single base pair mutations and a known SNP were found in the coding regions of the patient’s cPLA_2α genes (p.[Ser111Pro]+[Arg485His; Lys651Arg]). The total PLA₂ activity in sonicated platelets was diminished, and the urinary metabolites of prostacyclin, prostaglandin E₂, prostaglandin D₂, and thromboxane A₂ were also reduced. These findings characterize what we believe is a novel inherited deficiency of cPLA₂. ]]> info:doi/10.1172/JCI30473 American Society for Clinical Investigation Linda Koch, F. Thomas Wunderlich, Jost Seibler, A. Christine Könner, Brigitte Hampel, Sigrid Irlenbusch, Georg Brabant, C. Ronald Kahn, Frieder Schwenk, Jens C. Brüning http://www.jci.org/articles/view/31073 Δwb), and 1 restricted to peripheral tissues (IR^Δper). While downregulation of IR expression resulted in severe hyperinsulinemia in both models, hyperglycemia was more pronounced in IR^Δwb mice. Both strains displayed a dramatic upregulation of hepatic leptin receptor expression, while only IR^Δper mice displayed increased hepatic Stat3 phosphorylation and Il6 expression. Despite a similar reduction in IR expression in white adipose tissue (WAT) mass in both models, IR^Δwb mice had a more pronounced reduction in WAT mass and severe hypoleptinemia. Leptin replacement restored hepatic Stat3 phosphorylation and normalized glucose metabolism in these mice, indicating that alterations in glucose metabolism occur largely as a consequence of lipoathrophy upon body-wide IR deletion. Moreover, chronic intracerebroventricular insulin treatment of control mice increased fat mass, fat cell size, and adipose tissue lipoprotein lipase expression, indicating that CNS insulin action promotes lipogenesis. These studies demonstrate that central insulin action plays an important role in regulating WAT mass and glucose metabolism via hepatic Stat3 activation. ]]> info:doi/10.1172/JCI31073 American Society for Clinical Investigation Jean-Eric Ghia, Patricia Blennerhassett, Stephen M. Collins http://www.jci.org/articles/view/32849 info:doi/10.1172/JCI32849 American Society for Clinical Investigation Sungjune Kim, Saif Lalani, Vrajesh V. Parekh, Tiffaney L. Vincent, Lan Wu, Luc Van Kaer http://www.jci.org/articles/view/33071 info:doi/10.1172/JCI33071 American Society for Clinical Investigation Carlo Colombo, Ottavia Porzio, Ming Liu, Ornella Massa, Mario Vasta, Silvana Salardi, Luciano Beccaria, Carla Monciotti, Sonia Toni, Oluf Pedersen, Torben Hansen, Luca Federici, Roberta Pesavento, Francesco Cadario, Giorgio Federici, Paolo Ghirri, Peter Arvan, Dario Iafusco, Fabrizio Barbetti http://www.jci.org/articles/view/33777 Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic β cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM. ]]> info:doi/10.1172/JCI33777 American Society for Clinical Investigation Naomasa Makita, Elijah Behr, Wataru Shimizu, Minoru Horie, Akihiko Sunami, Lia Crotti, Eric Schulze-Bahr, Shigetomo Fukuhara, Naoki Mochizuki, Takeru Makiyama, Hideki Itoh, Michael Christiansen, Pascal McKeown, Koji Miyamoto, Shiro Kamakura, Hiroyuki Tsutsui, Peter J. Schwartz, Alfred L. George, Dan M. Roden http://www.jci.org/articles/view/34057 SCN5A. While this overlap is important for patient management, the clinical features, prevalence, and mechanisms underlying such overlap have not been fully elucidated. To investigate the basis for this overlap, we genotyped a cohort of 44 LQT3 families of multiple ethnicities from 7 referral centers and found a high prevalence of the E1784K mutation in SCN5A. Of 41 E1784K carriers, 93% had LQT3, 22% had BrS, and 39% had sinus node dysfunction. Heterologously expressed E1784K channels showed a 15.0-mV negative shift in the voltage dependence of Na channel inactivation and a 7.5-fold increase in flecainide affinity for resting-state channels, properties also seen with other LQT3 mutations associated with a mixed clinical phenotype. Furthermore, these properties were absent in Na channels harboring the T1304M mutation, which is associated with LQT3 without a mixed clinical phenotype. These results suggest that a negative shift of steady-state Na channel inactivation and enhanced tonic block by class IC drugs represent common biophysical mechanisms underlying the phenotypic overlap of LQT3 and BrS and further indicate that class IC drugs should be avoided in patients with Na channels displaying these behaviors. ]]> info:doi/10.1172/JCI34057 American Society for Clinical Investigation Yvonne G. Weber, Alexander Storch, Thomas V. Wuttke, Knut Brockmann, Judith Kempfle, Snezana Maljevic, Lucia Margari, Christoph Kamm, Susanne A. Schneider, Stephan M. Huber, Arnulf Pekrun, Robert Roebling, Guiscard Seebohm, Saisudha Koka, Camelia Lang, Eduard Kraft, Dragica Blazevic, Alberto Salvo-Vargas, Michael Fauler, Felix M. Mottaghy, Alexander Münchau, Mark J. Edwards, Anna Presicci, Francesco Margari, Thomas Gasser, Florian Lang, Kailash P. Bhatia, Frank Lehmann-Horn, Holger Lerche http://www.jci.org/articles/view/34438 Xenopus oocytes and human erythrocytes revealed that this mutation decreased glucose transport and caused a cation leak that alters intracellular concentrations of sodium, potassium, and calcium. We screened 4 additional families, in which PED is combined with epilepsy, developmental delay, or migraine, but not with hemolysis or echinocytosis, and identified 2 additional GLUT1 mutations (A275T, G314S) that decreased glucose transport but did not affect cation permeability. Combining these data with brain imaging studies, we propose that the dyskinesias result from an exertion-induced energy deficit that may cause episodic dysfunction of the basal ganglia, and that the hemolysis with echinocytosis may result from alterations in intracellular electrolytes caused by a cation leak through mutant GLUT1. ]]> info:doi/10.1172/JCI34438 American Society for Clinical Investigation