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Aims/hypothesis: The mechanisms by which transcription factor 7-like 2 (TCF7L2) regulates the pathways that are important in the pathogenesis of type 2 diabetes are unknown. We therefore examined the role of TCF7L2 in hepatic glucose production (HGP) in vitro and characterised the whole-genome chromatin occupancy of TCF7L2 in hepatocytes. Methods: We investigated the effect of TCF7L2 silencing and overexpression on HGP from gluconeogenic precursors and used chromatin-immunoprecipitation (ChIP) combined with massively parallel DNA sequencing (ChIP-Seq) to investigate the DNA binding patterns of TCF7L2 across the whole genome. Results: Silencing of TCF7L2 induced a marked increase in basal HGP, which was accompanied by significant increases in the expression of the gluconeogenic genes Fbp1, Pck1 and G6pc. Overexpression of Tcf7l2 reversed this phenotype and significantly reduced HGP. TCF7L2 silencing did not affect the half-maximal inhibitory concentration of insulin or metformin, but HGP remained elevated in TCF7L2-silenced cells due to the increased baseline HGP. Using ChIP-Seq, we detected 2,119 binding events across the genome. Pathway analysis demonstrated that diabetes genes were significantly over-represented in the dataset. Our results indicate that TCF7L2 binds directly to multiple genes that are important in regulation of glucose metabolism in the liver, including Pck1, Fbp1, Irs1, Irs2, Akt2, Adipor1, Pdk4 and Cpt1a. Conclusions/interpretation: TCF7L2 is an important regulator of HGP in vitro and binds directly to genes that are important in pathways of glucose metabolism in the liver. These data highlight the possibility that TCF7L2 may affect fasting and postprandial hyperglycaemia in carriers of at-risk TCF7L2 genetic polymorphisms. [ABSTRACT FROM AUTHOR]

This paper aims at determining of inorganic leachate contamination for a capped unsanitary landfill in the absence of hydrogeological data. The 2D geoelectrical resistivity imaging, soil physicochemical characterization, and surface water analysis were used to determine contamination load and extent of selective heavy metal contamination underneath the landfill. The positions of the contaminated subsoil and groundwater were successfully delineated in terms of low resistivity leachate plumes of <10 Ωm. Leachate migration towards the reach of Kelang River could be clearly identified from the resistivity results and elevated concentrations of Fe in the river downslope toe of the site. Concentration of Fe, Mn, Ca, Na, K, Mg, Cu, Cr, Co, Ni, Zn, and Pb was measured for the subsoil samples collected at the downslope (BKD), upslope (BKU), and the soil-waste interface (BKI), of the landfill. The concentration levels obtained for most of the analyzed heavy metals significantly exceed the normal range in typical municipal solid waste landfill sites. The measured heavy metal contamination load in the subsoil is in the following order Fe ≫ Mn > Zn > Pb > Cr > Cu. Taking into consideration poor physical and chemical characteristics of the local soil, these metals first seem to be attenuated naturally at near surface then remobilize unavoidably due to the soil acidic environment (pH 4.2-6.18) which in turn, may allow an easy washing of these metals in contact with the shallow groundwater table during the periodic fluctuation of the Kelang River. These heavy metals are believed to have originated from hazardous industrial waste that might have been illegally dumped at the site. [ABSTRACT FROM AUTHOR]

The aim of this study was to measure mitochondrial reactive oxygen species (ROS) production directly from skeletal muscle biopsies obtained from obese insulin-resistant non-diabetic and type 2 diabetic participants. Ten lean healthy, ten obese non-diabetic and ten type 2 diabetic participants received a euglycaemic–hyperinsulinaemic clamp to measure whole body insulin sensitivity. Mitochondria were isolated from skeletal muscle biopsies, and mitochondrial ATP synthesis and hydrogen peroxide production were measured ex vivo under conditions that maximally stimulate ATP synthesis and ROS production using chemiluminescent and fluorescent techniques, respectively. Compared with lean controls, both obese non-diabetic and type 2 diabetic participants were resistant to insulin, and had a reduced rate of mitochondrial ATP production. Obese insulin-resistant participants had a decreased rate of mitochondrial ROS production, while ROS production rate in participants with type 2 diabetes was similar to that in lean healthy participants. In non-diabetic participants, the rate of ROS production was strongly correlated with the rate of ATP synthesis and the glucose disposal rate measured with the euglycaemic–hyperinsulinaemic clamp. The ROS/ATP ratio in obese insulin-resistant participants was similar to that in lean insulin-sensitive participants, while the ratio was significantly elevated in type 2 diabetes participants. Since, in absolute terms, the maximal capacity for mitochondrial ROS production was not increased in either obese insulin-resistant participants or in type 2 diabetic participants, these results do not favour a role for increased mitochondrial ROS production in the pathogenesis of insulin resistance in human skeletal muscle. However, care should be taken in extrapolating these ex vivo observations to the in vivo situation. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor regarding the loss of beta cell function as fasting glucose increases in the non-diabetic range.