3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

Inhaled and oral salbutamol: How effective in the prophylaxis of asthma?

Inhaled and oral salbutamol were compared in 12 asthmatic patients for prophylaxis in antigen induced asthma. The patients were pretreated with 0.2- and 1.0-mg doses of inhaled salbutamol and with the standard oral 4- and 8-mg slow-release (SR) salbutamol preparations. Bronchodilatation was monitored over the ensuing 3 h and protection against antigen challenge at the end of the period. On each study day the degree of baseline airway hyperreactivity was determined by histamine challenge. Precautions were taken during the antigen challenge to ensure a reproducible response. Blood levels of salbutamol were monitored at hourly intervals for the 3 h after treatment and during the asthmatic reaction subsequent to challenge. Both the 0.2- and 1.0-mg inhalations caused immediate bronchodilatation as compared to a placebo (p < 0.05), but only the 1.0 mg dose protected subjects against antigen challenge (p < 0.05). In comparison to the placebo, no bronchodilatation was achieved with the standard 4-mg oral preparation in spite of measurable blood levels, nor were the patients protected against antigen challenge at 3 h after pretreatment. However, the 8-mg SR salbutamol caused significant bronchodilatation within 2 h and suppressed antigen challenge responses as compared to placebo (p < 0.05). It can be concluded that doses of inhaled salbutamol higher than the conventional 0.2- or the standard 4-mg oral preparations are required to protect asthmatics against inadvertent antigen exposure. In patients who are unable to use inhalers effectively, the SR preparation can be considered as an alternative.Articl

Regulation of karyopherin alpha1 and nuclear import by mammalian target of rapamycin

Under conditions of reduced mitogen or nutritional substrate levels, the serine/threonine kinase target of rapamycin (TOR) can augment the nuclear content of distinct transcription factors, and promote the induction of stress response genes. In its latent (i.e., unphosphorylated) form, the transcription factor signal transducer and activator of transcription-1 (STAT1) regulates a subset of genes involved in immune modulation and apoptosis. Based on previous work indicating a functional relationship between mTOR and the nuclear content of latent STAT1, we investigate the mechanism by which mTOR controls STAT1 nuclear import. By fluorescence confocal microscopy, inactivation of mTOR with rapamycin promoted the nuclear translocation of unphosphorylated STAT1, but not that of a STAT1 mutant incapable of binding its nuclear import adaptor karyopherin-alpha1 (KPNA1). By immunoprecipitation, KPNA1 was physically associated with mTOR and STAT1 in a complex that translocated to the nucleus in response to rapamycin. Although mTOR was not a kinase for KPNA1, the mTOR-associated phosphatase protein phosphatase 2A catalytic (PP2Ac) interacted directly with KPNA1, and regulated nuclear import of the mTOR/KPNA1 complex. KPNA1, or its interaction with STAT, was required for the nuclear import of latent STAT1, transcriptional induction of the STAT1 gene, and caspase-3 activation under conditions of reduced mTOR activity (i.e., rapamycin, glucose starvation, serum withdrawal). Therefore, at low mitogen or nutrient levels, mTOR and PP2Ac control the constitutive nuclear import of latent STAT1 by KPNA1, which are key modulators of STAT1 expression and apoptosis

The impact of genetic background on neurodegeneration and behavior in seizured mice

We used pilocarpine-induced seizures in mice to determine the impact of genetic background on the vulnerability of hippocampal neurons and associated changes of behavioral performance. The susceptibility of hippocampal neurons to seizure-induced cell death paralleled the severity of the seizures and depended on genetic background. Hippocampal neurons in C57BL/6 mice were most resistant to cell death, whereas they were highly vulnerable in FVB/N mice. The degree of neuronal degeneration in F1 hybrid mice obtained by crossing the two strains was at an intermediate level between the parent strains. Two weeks after the severe seizures, performance in a water-maze place navigation task showed a bimodal distribution. Seventeen of 19 (90%) F1 mice were completely unable to learn while the other two learned reasonably well. Of 28 C57BL/6 mice with similarly severe seizures, six were as strongly impaired as their F1 counterparts (22%). The remaining 22 performed normally, indicating a much lower probability of C57BL/6 mice to be affected. Treated mice showed a deficit of open-field exploration which was strongly correlated with the impairment in the place navigation task and was again more severe in F1 mice. Our results show that the vulnerability of hippocampal neurons to pilocarpine-induced seizures, as well as the associated behavioral changes, depended on genetic background. Furthermore, they confirm and extend our earlier finding that a relatively modest reduction of hippocampal cell death can be associated with dramatic changes of behavioral performance and emphasize the importance of tightly-controlled genetic backgrounds in biological studies