Diabetes mellitus is a chronic metabolic disease, the prevalence of which is constantly increasing worldwide. It is often burdened by disabling comorbidities that reduce the quality and expectancy of ...life of the affected individuals. The traditional complications of diabetes are generally described as macrovascular complications (e.g., coronary heart disease, peripheral arterial disease, and stroke), and microvascular complications (e.g., diabetic kidney disease, retinopathy, and neuropathy). Recently, due to advances in diabetes management and the increased life expectancy of diabetic patients, a strong correlation between diabetes and other pathological conditions (such as liver diseases, cancer, neurodegenerative diseases, cognitive impairments, and sleep disorders) has emerged. Therefore, these comorbidities have been proposed as emerging complications of diabetes. P66
is a redox protein that plays a role in oxidative stress, apoptosis, glucose metabolism, and cellular aging. It can be regulated by various stressful stimuli typical of the diabetic milieu and is involved in various types of organ and tissue damage under diabetic conditions. Although its role in the pathogenesis of diabetes remains controversial, there is strong evidence regarding the involvement of p66
in the traditional complications of diabetes. In this review, we will summarize the evidence supporting the role of p66
in the pathogenesis of diabetes and its complications, focusing for the first time on the emerging complications of diabetes.
Sommario
Il diabete è ormai riconosciuto come un fattore di rischio per lo sviluppo di diversi tipi di tumore. La coesistenza tra cancro e diabete aumenta del 30–50% la mortalità dei pazienti ...oncologici per tutte le cause di morte. Ad oggi esistono pochissime evidenze circa la possibilità che il trattamento dell’iperglicemia e un buon controllo glicemico, nei pazienti oncologici con diabete, possano migliorare gli outcome del tumore. Tali argomenti sono affrontati in questa rassegna.
The effects of prolonged exposure of pancreatic beta-cells to high saturated fatty acids on glucagon-like peptide-1 (GLP-1) action were investigated. Murine islets, human pancreatic 1.1B4 cells, and ...rat INS-1E cells were exposed to palmitate for 24 hours. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting, respectively. Specific short interfering RNAs were used to knockdown expression of the GLP-1 receptor (Glp1r) and Srebf1. Insulin release was assessed with a specific ELISA. Exposure of murine islets, as well as of human and INS-1E beta-cells, to palmitate reduced the ability of exendin-4 to augment insulin mRNA levels, protein content, and release. In addition, palmitate blocked exendin-4-stimulated cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, whereas phosphorylation of MAPK-ERK kinase-1/2 and ERK-1/2 was not altered. Similarly, RNA interference-mediated suppression of Glp1r expression prevented exendin-4-induced cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, but did not impair exendin-4 stimulation of MAPK-ERK kinase-1/2 and ERK-1/2. Both islets from mice fed a high fat diet and human and INS-1E beta-cells exposed to palmitate showed reduced GLP-1 receptor and pancreatic duodenal homeobox-1 (PDX-1) and increased sterol regulatory element-binding protein (SREBP-1C) mRNA and protein levels. Furthermore, suppression of SREBP-1C protein expression prevented the reduction of PDX-1 and GLP-1 receptor levels and restored exendin-4 signaling and action. Finally, treatment of INS-1E cells with metformin for 24 h resulted in inhibition of SREBP-1C expression, increased PDX-1 and GLP-1 receptor levels, consequently, enhancement of exendin-4-induced insulin release. Palmitate impairs exendin-4 effects on beta-cells by reducing PDX-1 and GLP-1 receptor expression and signaling in a SREBP-1C-dependent manner. Metformin counteracts the impairment of GLP-1 receptor signaling induced by palmitate.
Abstract We hypothesized that (1) in healthy humans subjected to intermittent positive pressure non-invasive ventilation, changes in the ventilator trigger sensitivity would be associated with ...increased scalene activity, (2) if properly processed – through inspiratory phase-locked averaging – surface electromyograms (EMG) of the scalenes would reliably detect and quantify this, (3) there would be a correlation between dyspnea and scalene EMG. Surface and intramuscular EMG activity of scalene muscles were measured in 10 subjects. They breathed quietly through a face mask for 10 min and then were connected to a mechanical ventilator. Recordings were performed during three 15-min epochs where the subjects breathed against an increasingly negative pressure trigger (−5%, −10% and −15% of maximal inspiratory pressure). With increasing values of the inspiratory trigger, inspiratory efforts, dyspnea and the scalene activity increased significantly. The scalene EMG activity level was correlated with the esophageal pressure time product and with dyspnea intensity. Inspiration-adjusted surface EMG averaging could be useful to detect small increases of the scalene muscles activity during mechanical ventilation.
Neurofibromatosis type I (NF1) is a rare genetic disease caused by mutations in the NF1 gene, which codes for tumor suppressor neurofibromin. NF1 is transmitted as an autosomal dominant and fully ...penetrant trait with no sex predominance. Precapillary pulmonary hypertension (PH) is a severe complication of NF1, initially described in patients with advanced parenchymal lung disease, which may complicate the course of NF1. We conducted this study to describe clinical, functional, radiologic, and hemodynamic characteristics and outcome of patients with NF1-associated PH. We identified 8 new cases of NF1-associated PH in patients carrying a NF1 gene mutation. No bone morphogenic protein receptor 2 (BMPR2) point mutation or large size rearrangements were identified. Seven female patients and 1 male patient were reported, suggesting a possible female predominance. PH occurred late in the course of the disease (median age, 62 yr; range, 53-68 yr). Dyspnea and signs of right heart failure were the major symptoms leading to the diagnosis of PH. At diagnosis, patients had severe hemodynamic impairment with low cardiac index (median, 2.3 L/min per m2; range, 1.9-4.7) and elevated indexed pulmonary vascular resistance (median, 15.1 mm Hg/L/min per m2; range, 4.5-25.9). All patients were in New York Heart Association functional class III with severe exercise limitation (median 6-min walk distance, 180 m; range, 60-375 m). Most patients had associated parenchymal lung disease, but some had no or mild lung involvement with disproportionate pulmonary vascular disease. Overall, the impact of PH therapy was limited and outcomes were poor. In conclusion, PH represents a rare but severe complication of NF1, characterized by female predominance, late onset in the course of NF1, and severe functional and hemodynamic impairment. Because of poor outcome and limited impact of specific PH therapy, eligible patients require early referral for lung transplantation. Further studies are needed to better understand the pathophysiology and the role, if any, of neurofibromin in NF1-associated PH.
To evaluate the efficacy of a simple mechanical device to maintain constant endotracheal cuff pressure (Pcuff) during mechanical ventilation (large encased inflatable cuff connected to the ...endotracheal cuff and receiving constant pressure from a heavy mass attached to an articulated arm).
Single-center, prospective, randomized, crossover, pilot study in a medical intensive care unit.
Nine consecutive mechanically ventilated patients (age 62+/-20 years, SAPS II score 39+/-15).
Control day: Pcuff monitored and adjusted with a manometer (Hi-Lo, Tyco Healthcare) according to current recommendations (twice a day and after each intervention on the tracheal tube); initial target Pcuff 22-28 cmH20. Prototype day: test device connected to the endotracheal cuff; same initial target. Continuous Pcuff recording during both days. Control and prototype days in random order.
Pcuff values over 50 cmH20 were recorded in six patients during the control day (178+/-159min), never during the prototype day. During the control day, Pcuff was between 30 and 50 cmH20 for 29+/-25% of the time, vs 0.3+/-0.3% during the prototype day (p<0.01). Pcuff was between 15 and 30 cmH20 for 56+/-36% of the time during the control day, vs 95+/-14% during the prototype day p<0.01). During the control day, Pcuff was below 15 cmH20 for 15+/-17% of the time, vs 4.7+/-15% during the prototype day (p<0.05).
The tested device successfully controlled Pcuff with minimal human resource consumption. Prospective studies are required to assess its clinical impact.
The role of the redox adaptor protein p66^sup Shc^ as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated. The effects of the FA palmitate on p66^sup Shc^ ...expression were evaluated in human and murine islets and in rat insulin-secreting INS-1E cells. p66^sup Shc^ expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66^sup Shc^ was investigated using pancreatic islets from p66 ^sup Shc-/-^ mice and in INS-1E cells with knockdown of p66^sup Shc^ or overexpression of wild-type and phosphorylation-defective p66^sup Shc^. Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method. Palmitate induced a selective increase in p66^sup Shc^ protein expression and phosphorylation on Ser^sup 36^ and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66^sup Shc^ expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 ^sup Shc-/-^ mice and following p66 ^sup Shc^ knockdown in INS-1E cells; by contrast, overexpression of p66^sup Shc^, but not that of the phosphorylation-defective p66^sup Shc^ mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66^sup Shc^ were dependent upon its c-Jun N-terminal kinase-mediated phosphorylation on Ser^sup 36^ and associated with generation of ROS. p66^sup Shc^ protein expression and function were also elevated in islets from HFD-fed mice and from obese/overweight cadaveric human donors. p53-dependent augmentation of p66^sup Shc^ expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.
Aims/hypothesis
The role of the redox adaptor protein p66
Shc
as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated.
Methods
The effects of the FA palmitate on ...p66
Shc
expression were evaluated in human and murine islets and in rat insulin-secreting INS-1E cells. p66
Shc
expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66
Shc
was investigated using pancreatic islets from
p66
Shc
−/−
mice and in INS-1E cells with knockdown of p66
Shc
or overexpression of wild-type and phosphorylation-defective p66
Shc
. Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method.
Results
Palmitate induced a selective increase in p66
Shc
protein expression and phosphorylation on Ser
36
and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66
Shc
expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from
p66
Shc
−/−
mice and following
p66
Shc
knockdown in INS-1E cells; by contrast, overexpression of p66
Shc
, but not that of the phosphorylation-defective p66
Shc
mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66
Shc
were dependent upon its c-Jun N-terminal kinase-mediated phosphorylation on Ser
36
and associated with generation of ROS. p66
Shc
protein expression and function were also elevated in islets from HFD-fed mice and from obese/overweight cadaveric human donors.
Conclusions/interpretation
p53-dependent augmentation of p66
Shc
expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.
PDF
