Diabetes mellitus frequently complicates cirrhosis but the pathogenic mechanisms are unknown. To assess the contribution of reduced insulin action and secretion, 24 cirrhotic‐diabetic patients ...waiting for liver transplant because of an unresectable hepatocarcinoma underwent an oral glucose tolerance test (OGTT) to assess the β‐cell function and an insulin clamp combined with 3‐3Hglucose infusion to measure whole body glucose metabolism before and 2 years after the transplant. Seven cirrhotic nondiabetic patients, 11 patients with chronic uveitis on similar immunosuppressive therapy, and 7 healthy subjects served as control groups. Cirrhotic patients showed a profound insulin resistance, and diabetics in addition also showed increased endogenous glucose production (P < .05) and insulin deficiency during the OGTT (P < .05). Liver transplantation normalized endogenous glucose production and insulin sensitivity but failed to cure diabetes in 8 of the 24 patients because a markedly low insulin response during the OGTT. Age, body mass index, family history of diabetes, immunosuppressive drugs, and pathogenesis of cirrhosis did not predict in whom liver transplant was going to cure diabetes. On the contrary, a reduced secretory response characterized the patients in whom the transplant would not be curative. In summary, insulin resistance was a primary event complicating cirrhosis but additional β‐cell secretory defects were crucial for development of diabetes. Liver transplantation, lessening insulin resistance, cured hepatogenous diabetes in 67% of cirrhotic‐diabetic patients; nevertheless 33% were still diabetics because the persistence of a reduced β‐cell function, which makes these patients eventually eligible for combined islet transplantation.
Aire's primary mechanism of action is to regulate transcription of a battery of genes in medullary thymic epithelial cells (mTECs) and, consequently, negative selection of effector T cells and ...positive selection of regulatory T cells. We found that Aire-deficient mice had expanded thymic and peripheral populations of perinatally generated IL-17A+Vγ6+Vδ1+T cells, considered to be "early responders" to tissue stress and drivers of inflammatory reactions. Aire-dependent control ofIl7expression in mTECs regulated the size of thymic IL-17A+Vγ6+Vδ1+compartments. In mice lacking Aire and γδ T cells, certain tissues typically targeted in the"Aire-less" disease, notably the retina, were only minimally infiltrated. IL-17A+Vγ6+Vδ1+cells were present in the retina of wild-type mice and expanded very early in Aire-deficient mice. A putatively parallel population of IL-17A+Vγ9+Vδ2+T cells was increased in humans lacking Aire. Thus, Aire exerts multi-faceted autoimmune control that extends to a population of innate-like T cells.
Cirrhotic patients after liver transplantation show a near-normal glucose homeostasis when in stable condition. In contrast, the basal and insulin-mediated whole-body protein metabolism remain ...altered several years after the graft. To examine whether the persisting defect of protein metabolism was due to the muscle, 7 non-diabetic liver-transplanted patients in stable condition were studied by means of the catheterization of the brachial artery and the deep forearm vein (to measure the balance across the forearm) and the infusion of labelled leucine and phenylalanine associated with indirect calorimetry. Whole-body proteolysis (as determined by endogenous leucine flux, ELF), protein synthesis (from non-oxidative leucine disposal, NOLD) and leucine oxidation (LO) were reduced in comparison to previously obtained values in a normal population. Insulin infusion (while maintaining euglycemia) induced a not significant variation of forearm phenylalanine Ra (24.4-->16.5 micromol/100 ml forearm min(-1); proteolysis) and Rd (18.5-->19.7; protein synthesis). In contrast, the whole-body insulin-dependent inhibitions of ELF (31.5-->21.8 micromol/m(2) min) and NOLD (27.3-->18.4) were impaired with respect to a normal population. On the basis of the present results, we conclude that skeletal muscle is not responsible for the alterations of leucine metabolism persisting after liver transplantation. By exclusion, this points to the liver as the major determinant of the leucine metabolism defect.
The effect of 6-diazo-5-oxo-L-norleucine (L-DON), a glutamine analog, on RSV replication was studied. At a concentration of 0.01 mM L-DON, 99% of RSV replication in treated CV-1 cells was inhibited. ...At this concentration of L-DON, the level of cellular protein synthesis was identical to untreated control cells. Trypan blue staining revealed that all the cells remained viable even at concentrations of L-DON as high as 10 mM. In addition, L-DON added as late as 24 h post infection can effectively suppress viral replication. Analysis of viral mRNA levels by Northern blot revealed that secondary transcription and subsequent steps in the virus life cycle were inhibited. Immunoprecipitation of viral proteins from drug treated or untreated cultures showed that synthesis of all viral proteins was drastically reduced by L-DON, with a slightly greater inhibition of viral glycoproteins. Furthermore, immunofluorescent staining showed that drug treated cells expressed both F and N proteins and that F was inserted into the membrane as the native F protein.
Impaired diastolic function and left ventricular hypertrophy can occur early in the natural history of essential hypertension. High circulating levels of endogenous ouabain (EO) have been described ...in essential hypertension and have also been associated with left ventricular hypertrophy. The aim of this study was to investigate whether these cardiac modifications are related to plasma EO levels in the offspring of hypertensive families.
The study involved 41 subjects with (FAM+) and 45 subjects without (FAM-) a family history of hypertension. Arterial blood pressure, left ventricular geometry and function, and plasma EO levels were measured in each subject.
Plasma EO levels were higher in the FAM+ subjects (221.5 +/- 10.95 versus 179.6 +/- 9.58 pmol/l, P = 0.004), and directly correlated with both systolic (r = 0.417, P < 0.0001) and diastolic blood pressure (r = 0.333, P = 0.002). Plasma EO was inversely related to an index of cardiac diastolic function determined as the ratio between the early and late peak flow velocity (r = -0.286, P = 0.012) and isovolumetric relaxation time (IVRT) (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, correlated with the IVRT (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, whereas the other echocardiographic parameters were similar to FAM-.
Among the offspring of families with a positive history of hypertension, circulating EO levels and blood pressure are increased. Plasma EO levels are related to alterations of some indexes of diastolic heart function in these individuals.
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