Rationale:The diabetes mellitus drug metformin is under investigation in cardiovascular disease, but the molecular mechanisms underlying possible benefits are poorly understood. Objective:Here, we have studied anti-inflammatory effects of the drug and their relationship to antihyperglycemic properties. Methods and Results:In primary hepatocytes from healthy animals, metformin and the IKKβ (inhibitor of kappa B kinase) inhibitor BI605906 both inhibited tumor necrosis factor-α–dependent IκB degradation and expression of proinflammatory mediators interleukin-6, interleukin-1β, and CXCL1/2 (C-X-C motif ligand 1/2). Metformin suppressed IKKα/β activation, an effect that could be separated from some metabolic actions, in that BI605906 did not mimic effects of metformin on lipogenic gene expression, glucose production, and AMP-activated protein kinase activation. Equally AMP-activated protein kinase was not required either for mitochondrial suppression of IκB degradation. Consistent with discrete anti-inflammato...

/pdf/anti-inflammatory-effects-of-metformin-irrespective-of-30996mj4uz.pdf

Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status

Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10'-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9',10'-double bond by carotene-9',10'-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose dependently inhibited cell growth and upregulated sirtuin 1 (SIRT1), a NAD(+)-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)-promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation [decreased inflammatory foci, TNFα, interleukin (IL)-6, NF-κB p65 protein expression, and STAT3 activation] in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene, and protein expression and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, these data indicate that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation.

https://cancerpreventionresearch.aacrjournals.org/content/canprevres/6/12/1304.full.pdf

Lycopene Metabolite, Apo-10′-Lycopenoic Acid, Inhibits Diethylnitrosamine-Initiated, High Fat Diet–Promoted Hepatic Inflammation and Tumorigenesis in Mice

Diabetes Mellitus (DM) is a chronic inflammatory disease characterized by hyperglycemia and increasing the neutrophil-lymphocyte ratio (NLR). Metformin has been widely used to treat hyperglycemia. Metformin nanoparticles can improve bioavailability and may reduce inflammation. This study aims to analyze the effectiveness of metformin nanoparticles delivery through fasting blood glucose (FGB) level and NLR in the diabetic rat model. This study used 16 white male Wistar rats, 8 weeks of age, and body weight (BW) 250-350 grams. The streptozotocin (STZ) 40 mg/kg BW were injected i.p. Rats were divided into 4 groups; K1: normal control; K2: negative control (diabetes model); K3: diabetes model treated with metformin 100mg/Kg BW; K4: diabetes model treated with nanoparticle metformin 100mg/kg BW. Blood analysis tests were conducted using the Pentra hematology analyzer. Data were analyzed using the Graphpad Prism program with the nonparametric Kruskal Wallis test. The K3 group showed a periodical decrease in FBG level from day 7 to day 28 by 122 ± 11.31 mg/dL, and the mean NLR value was 0.48 ± 0.3 x 103/uL. Group of K4 periodically decreased in FBG level, indicating that it was closer to normal than K3. The result showed that at day 28.79 ± 15.39 mg/dL, the mean NLR value slightly increased compared to the K3 group by 0.54 ± 0.3 x103/uL. The statistical tests showed a significant difference between the level of FBG (p 0.0089) but no significant difference in NLR (p 0.347). Metformin nanoparticles could decrease FBG levels and effectively reduce the NLR in the diabetic rat model.

/pdf/nanotechnology-in-metformin-delivery-fasting-blood-sugar-and-29a9xdbh.pdf

Nanotechnology in Metformin Delivery: Fasting Blood Sugar and Neutrophil-Lymphocyte Ratio of Diabetic Rat Model

T cell inflammation plays pivotal roles in obesity-associated type 2 diabetes (T2D). Multiple T cell subsets, including Th1, Th2, Th17 and regulatory T cells are critical for the development of insulin resistance in animal models of T2D. However, the relative importance of T cell subsets in human disease pathogenesis remains a critical gap in knowledge with important implications for defining the most potent inflammatory mediators of T2D. To identify T cell subsets that disproportionately contribute to T2D-associated inflammation, we broadly quantified T cell cytokine production by circulating or adipose-associated immune cells from obese subjects clinically defined as non-T2D, pre-T2D or T2D. Cytokines traditionally associated with specific T cell subsets, including IL-2 (Th1), IL-4/10/13 (Th2) and IL-17A/F (Th17), were produced at highest amounts by T2D samples. We combined cytokine outcomes with multivariate mathematical approaches to show that T cell cytokine profiles predicted T2D status with >85% accuracy. Furthermore, Th17 signature cytokines were more powerful than either Th1 or Th2 cytokines for differentiation of non-T2D from T2D samples. We conclude that Th17 cells are an underappreciated source of T cell cytokines that support inflammation and predict human T2D. Study outcomes unify contradictory claims of the importance of single cytokines and justify including Th17 cells as druggable sources of inflammation in human T2D.

An inflammatory T cell signature predicts obesity-associated type 2 diabetes (HUM3P.262)

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An inflammatory T cell signature predicts obesity-associated type 2 diabetes (HUM3P.262)