S. J. Creely

Elevated endotoxin levels in non-alcoholic fatty liver disease

BackgroundEmerging data indicate that gut-derived endotoxin may contribute to low-grade systemic inflammation in insulin resistant states. This study aimed to examine the importance of serum endotoxin and inflammatory markers in non-alcoholic fatty liver disease (NAFLD) patients, with and without type 2 diabetes mellitus (T2DM), and to explore the effect of treatment with a lipase inhibitor, Orlistat, on their inflammatory status.MethodsFasted serum from 155 patients with biopsy proven NAFLD and 23 control subjects were analysed for endotoxin, soluble CD14 (sCD14), soluble tumour necrosis factor receptor II (sTNFRII) and various metabolic parameters. A subgroup of NAFLD patients were re-assessed 6 and 12 months after treatment with diet alone (n = 6) or diet plus Orlistat (n = 8).ResultsEndotoxin levels were significantly higher in patients with NAFLD compared with controls (NAFLD: 10.6(7.8, 14.8) EU/mL; controls: 3.9(3.2, 5.2) EU/mL, p < 0.001); NAFLD alone produced comparable endotoxin levels to T2DM (NAFLD: T2DM: 10.6(5.6, 14.2) EU/mL; non-diabetic: 10.6(8.5, 15.2) EU/mL), whilst a significant correlation between insulin resistance and serum endotoxin was observed (r = 0.27, p = 0.008). Both sCD14 (p < 0.01) and sTNFRII (p < 0.001) increased with severity of fibrosis. A positive correlation was also noted between sTNFRII and sCD14 in the NAFLD subjects (r = 0.29, p = 0.004).Sub-cohort treatment with Orlistat in patients with NAFLD showed significant decreases in ALT (p = 0.006), weight (p = 0.005) and endotoxin (p = 0.004) compared with the NAFLD, non-Orlistat treated control cohort at 6 and 12 months post therapy, respectively.ConclusionsEndotoxin levels were considerably increased in NAFLD patients, with marked increases noted in early stage fibrosis compared with controls. These results suggest elevated endotoxin may serve as an early indicator of potential liver damage, perhaps negating the need for invasive liver biopsy. As endotoxin may promote insulin resistance and inflammation, interventions aimed at reducing endotoxin levels in NAFLD patients may prove beneficial in reducing inflammatory burden.

Visfatin is regulated by rosiglitazone in type 2 diabetes mellitus and influenced by NFκB and JNK in human abdominal subcutaneous adipocytes.

Visfatin has been proposed as an insulin-mimicking adipocytokine, predominantly secreted from adipose tissue and correlated with obesity. However, recent studies suggest visfatin may act as a proinflammatory cytokine. Our studies sought to determine the significance of this adipocytokine and its potential role in the pathogenesis of T2DM. Firstly, we examined the effects of diabetic status on circulating visfatin levels, and several other adipocytokines, demonstrating that diabetic status increased visfatin*, TNF-α*** and IL-6*** compared with non-diabetic subjects (*p<0.05, **p<0.01, ***p<0.001, respectively). We then assessed the effects of an insulin sensitizer, rosiglitazone (RSG), in treatment naïve T2DM subjects, on circulating visfatin levels. Our findings showed that visfatin was reduced post-RSG treatment [vs. pre-treatment (*p<0.05)] accompanied by a reduction in HOMA-IR**, thus implicating a role for insulin in visfatin regulation. Further studies addressed the intracellular mechanisms by which visfatin may be regulated, and may exert pro-inflammatory effects, in human abdominal subcutaneous (Abd Sc) adipocytes. Following insulin (Ins) and RSG treatment, our in vitro findings highlighted that insulin (100 nM), alone, upregulated visfatin protein expression whereas, in combination with RSG (10 nM), it reduced visfatin*, IKKβ** and p-JNK1/2*. Furthermore, inhibition of JNK protein exacted a significant reduction in visfatin expression (**p<0.01), whilst NF-κB blockade increased visfatin (*p<0.05), thus identifying JNK as the more influential factor in visfatin regulation. Additional in vitro analysis on adipokines regulating visfatin showed that only Abd Sc adipocytes treated with recombinant human (rh)IL-6 increased visfatin protein (*p<0.05), whilst rh visfatin treatment, itself, had no influence on TNF-α, IL-6 or resistin secretion from Sc adipocytes. These data highlight visfatins regulation by insulin and RSG, potentially acting through NF-κB and JNK mechanisms, with only rh IL-6 modestly affecting visfatin regulation. Taken together, these findings suggest that visfatin may represent a pro-inflammatory cytokine that is influenced by insulin/insulin sensitivity via the NF-κB and JNK pathways.

Metabolic endotoxaemia as a mediator of mitochondrial dysfunction in human adipose tissue, alleviated by salicylate

Background and aims: The association between type 2 diabetes and different forms of cognitive impairment is well established. The mechanism behind the association is however still unrevealed. We ha ...

The effects adiposity, diabetic status and depot-specificity on the activation of NFKB on JNK in human abdominal adipose tissue

The President reported that ‘The case for a UN resolution’ had been prepared by the IDF to highlight the need for a United Nations Resolution on diabetes in order to focus attention on the need to stop the growing diabetes epidemic. Dr. Ferrannini reported that ISPAD was a small, but enthusiastic organisation which had recently held a very well-attended meeting in Cambridge, UK. Following information that pediatricians are not attending the EASD Annual Meetings, discussions to organise a pediatric track in the programme of the Annual Meeting have been put forward. Dr. DahlJørgensen has also suggested organising a joint EASD/ ISPAD Postgraduate Course on Pediatric Diabetes in Europe in 2008. The President reported that a joint statement with ADA on guidelines on the treatment of type 2 diabetes was simultaneously published in August in both Diabetologia and Diabetes Care. Drs. R.J. Heine and R. Holman lead an ad-hoc committee from the EASD which also included Dr. S. del Prato and Dr. U. Smith. More details on EASD and EFSD activities were reported in the President’s Address given before the Minkowski Lecture, which is available on the internet under: http://www.easd-lectures.org/copenhagen/index. php?menu=lectures&id=66 and in his speech before the 38th Claude Bernard Lecture, available under: http://www.easd-lectures.org/copenhagen/index. php?menu=lectures&id=72 The President welcomed everyone to the 42nd General Assembly.Type III phosphatidylinositol 4-kinases mediate plasma membrane PIP2 synthesis in insulin-secreting cells