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.

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.

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.