Although the atherogenic role of dietary cholesterol has been well established, its diabetogenic potential and associated metabolic disturbances have not been reported. Diet-induced hamster models of insulin resistance and dyslipidemia were employed to determine lipogenic and diabetogenic effects of dietary cholesterol. Metabolic studies were conducted in hamsters fed diets rich in fructose (40%), fat (30%), and cholesterol (0.05-0.25%) (FFC) and other test diets. Short-term feeding of the FFC diet induced insulin resistance, glucose intolerance, hypertriglyceridemia, and hypercholesterolemia. Prolonged feeding (6-22 wk) of the FFC diet led to severe hepatic steatosis, glucose intolerance, and mild increases in fasting blood glucose, suggesting progression toward type 2 diabetes, but did not induce beta-cell dysfunction. Metabolic changes induced by the diet, including dyslipidemia and insulin resistance, were cholesterol concentration dependent and were only markedly induced on a high-fructose and high-fat dietary background. There were significant increases in hepatic and plasma triglyceride with FFC feeding, likely due to a 10- to 15-fold induction of hepatic stearoyl-CoA desaturase compared with chow levels (P < 0.03). Hepatic insulin resistance was evident based on reduced tyrosine phosphorylation of the insulin receptor-beta, IRS-1, and IRS-2 as well as increased protein mass of protein tyrosine phosphatase 1B. Interestingly, nuclear liver X receptor (LXR) target genes such as ABCA1 were upregulated on the FFC diet, and dietary supplementation with an LXR agonist (instead of dietary cholesterol) worsened dyslipidemia, glucose intolerance, and upregulation of target mRNA and proteins similar to that of dietary cholesterol. In summary, these data clearly implicate dietary cholesterol, synergistically acting with dietary fat and fructose, as a major determinant of the severity of metabolic disturbances in the hamster model. Dietary cholesterol appears to induce hepatic cholesterol ester and triglyceride accumulation, and diet-induced LXR activation (via cholesterol-derived oxysterols) may possibly be one key underlying mechanism.
Modulation of mitochondrial function through inhibiting respiratory complex I activates a key sensor of cellular energy status, the 5'-AMP-activated protein kinase (AMPK). Activation of AMPK results in the mobilization of nutrient uptake and catabolism for mitochondrial ATP generation to restore energy homeostasis. How these nutrient pathways are affected in the presence of a potent modulator of mitochondrial function and the role of AMPK activation in these effects remain unclear. We have identified a molecule, named R419, that activates AMPK in vitro via complex I inhibition at much lower concentrations than metformin (IC50 100 nM vs 27 mM, respectively). R419 potently increased myocyte glucose uptake that was dependent on AMPK activation, while its ability to suppress hepatic glucose production in vitro was not. In addition, R419 treatment of mouse primary hepatocytes increased fatty acid oxidation and inhibited lipogenesis in an AMPK-dependent fashion. We have performed an extensive metabolic characterization of its effects in the db/db mouse diabetes model. In vivo metabolite profiling of R419-treated db/db mice showed a clear upregulation of fatty acid oxidation and catabolism of branched chain amino acids. Additionally, analyses performed using both 13C-palmitate and 13C-glucose tracers revealed that R419 induces complete oxidation of both glucose and palmitate to CO2 in skeletal muscle, liver, and adipose tissue, confirming that the compound increases mitochondrial function in vivo. Taken together, our results show that R419 is a potent inhibitor of complex I and modulates mitochondrial function in vitro and in diabetic animals in vivo. R419 may serve as a valuable molecular tool for investigating the impact of modulating mitochondrial function on nutrient metabolism in multiple tissues and on glucose and lipid homeostasis in diabetic animal models.
Understanding shared decision making may motivate patients to be more active in understanding the relevant information for treatment selection, as it is related to their level of satisfaction, anxiety and adherence to treatment. This relationship should encourage physicians to promote shared decision making.
Background Inflammatory Bowel Disease (IBD) with its high incidence and prevalence rates in Canada generates a heavy burden of tests and procedures. The purpose of this study is to gain a better understanding of the transfer of information from physician to patient, as well as the patient understanding and perceptions about the tests and procedures that are ordered to them in the context of IBD diagnosis and monitoring. Methods An online questionnaire was completed by 210 IBD patients in Canada. Information on the five most-often used tests or procedures in IBD diagnosis/monitoring was collected. These include: general blood test, colonoscopy, colon biopsy, medical imaging and stool testing. Results The general blood test is both the most ordered and most refused tool. It is also the one with which patients are the least comfortable, the one that generates the least concern and the one about which physicians provide the least information. The stool test is the test/procedure with which patients are the most comfortable. Procedures raise more concerns among patients and physicians provide more information about why they are needed, their impact and the risks they present. Very little information is provided to patients about the risks of having false positives or negative tests. Conclusions This study provides an initial understanding of patient perceptions, the transfer of information from a physician to a patient and a patient’s understanding of the tests and procedures that will be required to treat IBD throughout what is a lifelong disease. The present study takes a first step in better understanding the acceptance of the test or procedure by IBD patients, which is essential for them to adhere to the monitoring process. Electronic supplementary material The online version of this article (10.1186/s12876-019-0946-8) contains supplementary material, which is available to authorized users.
Background A significant proportion of patients do not respond to therapy for moderate to severe ulcerative colitis (UC), including thiopurines, glucocorticoids, and antagonists to tumour necrosis factor-a and integrin. Tofacitinib, a Janus Kinase inhibitor, has emerged as an efficacious and safe treatment for moderate to severe ulcerative colitis. However, data on its real-life efficacy remains sparse. Methods We aimed to assess the rate of clinical response and clinical remission at 3 and 6 months after tofacitinib initiation. Secondary endpoints included the rate of biomarker normalisation, corticosteroids-free clinical remission and severe infections. We conducted a multi-centre retrospective observational study of adult patients with active UC started on tofacitinib from January 1, 2015 to October 1, 2019 at the McGill University Health Center and Hotel-Dieu de Lévis. A positive clinical response was defined as a decrease of ≥3 in the partial Mayo score. Clinical remission was defined as partial Mayo score of ≤2. Biomarker normalisation was defined as faecal calprotectin ≤250 μg/g. Severe infection was defined as an infection requiring hospitalisation. Results During the study period, 40 patients with UC were started on tofacitinib at 10 mg/kg twice a day. Amongst the patients, 85% (n = 34) had failed ≥1 biologic and 50% (n = 20) had failed ≥3 biologics. At the time of this preliminary analysis, 38 patients had undergone 3 months of treatment; 30 patients had undergone 6 months of treatment. At 3 months, a clinical response was seen in 89.5% of patients (n = 34) and clinical remission occurred in 63.2%(n = 24). At 6 months, clinical response occurred in 73.3% of patients (n = 22) and clinical remission was sustained in 53.33% (n = 16). Biochemical normalisation occurred in 29.0% (n = 11) and 30.0% (n = 9) at 3 and 6 months respectively. Additionally, 63.2% (n = 24) of patients and 43.3% (n = 13) of patients achieved steroid-free clinical remission at 3 and 6 months respectively. In the interim, one patient developed a serious infection requiring discontinuation of the drug. Conclusion Our preliminary analysis demonstrates that in a real-life setting, tofacitinib is an effective treatment for inducing clinical remission in refractory UC patients. Further data will be complied to better assess the efficacy over a longer follow-up.
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