BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is very frequent in type 2 diabetes with increased risk of further development of liver fibrosis. Animal studies have shown that GLP-1 receptor agonists may reduce liver lipogenesis. However, data in humans are scarce. OBJECTIVE: To study the effect of liraglutide 1.2 mg/d on liver fat content (LFC) in patients with uncontrolled type 2 diabetes and to evaluate the factors potentially associated with liraglutide-induced modification of LFC. METHODS: LFC was measured by 1H-MR spectroscopy before and after 6 months of liraglutide treatment in 68 patients with uncontrolled type 2 diabetes mellitus. RESULTS: Treatment with liraglutide was associated with a significant decrease in body weight, HbA1C and a marked relative reduction in LFC of 31% (p<0.0001). No significant modification of LFC was observed in a parallel group of patients 6 months after intensification of the antidiabetic treatment with insulin. The reduction in LFC and body weight were highly correlated (r= 0.490, p<0.0001). In multivariate analysis, the reduction in LFC was independently associated with baseline LFC (p<0.0001), age (p=0.010) and with reduction in body weight, (p<0.0001), triglycerides (p=0.019) and HbA1c (p=0.034). In the patients who had no significant decrease in body weight, no significant reduction in LFC was observed. CONCLUSIONS: Six months of treatment with liraglutide 1.2 mg/d significantly reduced LFC in patients with inadequately controlled type 2 diabetes and this effect was mainly driven by body weight reduction. Further studies are needed to confirm that this reduction in LFC may significantly reduce fibrosis progression.
Petit, J. M.
Cercueil, J. P.
The objectives of this review are to summarize the experimental data obtained using apoptotic cell-based therapies, and then to discuss future clinical developments. Indeed, apoptotic cells exhibit immunomodulatory properties that are reviewed here by focusing on more recent mechanisms. These immunomodulatory mechanisms are in particular linked to the clearance of apoptotic cells (called also efferocytosis) by phagocytes, such as macrophages, and the induction of regulatory T cells. Thus, apoptotic cell-based therapies have been used to prevent or treat experimental inflammatory diseases. Based on these studies, we have identified critical steps to design future clinical trials. This includes: the administration route, the number and schedule of administration, the appropriate apoptotic cell type to be used, as well as the apoptotic signal. We also have analyzed the clinical relevancy of apoptotic-cell-based therapies in experimental models. Additional experimental data are required concerning the treatment of inflammatory diseases (excepted for sepsis) before considering future clinical trials. In contrast, apoptotic cells have been shown to favor engraftment and to reduce acute graft-versus-host disease (GvHD) in different relevant models of transplantation. This has led to the conduct of a phase 1/2a clinical trial to alleviate GvHD. The absence of toxic effects obtained in this trial may support the development of other clinical studies based on this new cell therapy. Stem Cells 2016;34:1464-1473.
Haas, M. E.
Graham, M. J.
Crooke, R. M.
Pais de Barros, J. P.
Wang, J. G.
Biddinger, S. B.
Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxralpha in mice with hepatocyte-specific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxralpha produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxralpha, and LXRalpha was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXRalpha to modulate the phospholipid profile, or to suppress genes in the ER stress or inflammation pathways. These data show that insulin is required specifically for the lipogenic effects of LXRalpha and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER stress from the negative effects on lipogenesis.
Th17 cells contribute to the development of some autoimmune and allergic diseases by driving tissue inflammation. However, the function of Th17 cells during cancer progression remains controversial. Here, we show that human memory CD25high Th17 cells suppress T cell immunity in breast cancer. Ectonucleotidase-expressing Th17 cells accumulated in breast cancer tumors and suppressed CD4+ and CD8+ T cell activation. These cells expressed both Rorgammat and Foxp3 genes and secreted Th17 related cytokines. We further found that CD39 ectonucleotisase expression on tumor-infiltrating Th17 cells was driven by TGF-betaand IL-6. Finally, immunohistochemical analysis of localized breast cancer revealed that high-tumor infiltration by IL-17+ cells was associated with a poor clinical outcome and impeded the favorable effect of high CD8+ infiltration. Altogether, these findings suggest that intratumoral Th17 cells compromise anticancer immune responses in breast cancer patients.
A major limitation in the current topical treatment of inflammatory skin diseases is the inability to selectively deliver the drug to the inflammation site. Recently, smart drug delivery systems such as nanocarriers are being investigated to enhance the selective deposition of anti-inflammatory drugs in inflamed areas of the skin to achieve higher therapeutic efficacy with minimal side effects. Of such systems, polymeric nanoparticles are considered very efficient carriers for the topical drug delivery. In the current work, poly(l-lactide-co-glycolide) nanoparticles of nominal sizes of 70nm (NP70) and 300nm (NP300) were studied for their intra-epidermal distribution in murine and pig atopic dermatitis models over time against the respective healthy controls. Confocal laser scanning microscopical examination of skin biopsies was utilized for the qualitative and semi-quantitative analyses of nanoparticles skin deposition and penetration depth. While no skin penetration was found for any of the particles in healthy skin, the accumulation of NP70 was significantly higher than NP300 in inflamed skin (15-fold in mice, 5-fold in pigs). Penetration depth of NP70 decreased over time in mice from 55+/-3mum to 20+/-2mum and similar tendencies were observed for the other formulations. In inflamed pig skin, a similar trend was found for the penetration depth (NP70: 46+/-12mum versus NP300: 23+/-3mum); however, the NP amount remained constant for the whole analyzed period. Their ability to penetrate specifically into inflamed skin combined with minimal effects on healthy skin underlines small polymeric nanoparticles' potential as selective drug carriers in future treatment of chronic inflammatory skin diseases such as atopic dermatitis.
Barrett, P. H.
Watts, G. F.
Taskinen, M. R.
We study the associations between apoA-II fractional catabolic rate (FCR) and the kinetics of VLDL subspecies and apoA-I and show that, in abdominally obese individuals, apoA-II FCR is positively and independently associated with both apoA-I FCR and VLDL1-TG indirect FCR.
de Lazzer, A.
Bron, A. M.
Research Support, Non-U.S. Gov't
Nat Immunol. 2015 Aug;16(8):859-70. doi: 10.1038/ni.3202. Epub 2015 Jun 22.