Tumour necrosis factor a decreases glucose-6-phosphatase gene expression by activation of nuclear factor kB

The key insulin-regulated gluconeogenic enzyme G6Pase (glucose-6-phosphatase) has an important function in the control of hepatic glucose production. Here we examined the inhibition of G6Pase gene transcription by TNF (tumour necrosis factor) in H4IIE hepatoma cells. TNF decreased dexamethasone/dibtuyryl cAMP-induced G6Pase mRNA levels. TNFα, but not insulin, led to rapid activation of NFκB (nuclear factor κB). The adenoviral overexpression of a dominant negative mutant of IκBα (inhibitor of NFκB α) prevented the suppression of G6Pase expression by TNFα, but did not affect that by insulin. The regulation of G6Pase by TNF was not mediated by activation of the phosphoinositide 3-kinase/protein kinase B pathway, extracellular-signal-regulated protein kinase or p38 mitogen-activated protein kinase. Reporter gene assays demonstrated a concentration-dependent down-regulation of G6Pase promoter activity by the transient overexpression of NFκB. Although two binding sites for NFκB were identified within the G6Pase promoter, neither of these sites, nor the insulin response unit or binding sites for Sp proteins, was necessary for the regulation of G6Pase promoter activity by TNFα. In conclusion, the data indicate that the activation of NFκB is sufficient to suppress G6Pase gene expression, and is required for the regulation by TNFα, but not by insulin. We propose that NFκB does not act by binding directly to the G6Pase promoter

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo