Context:KDT501 is an isohumulone drug that has demonstrated beneficial effects on metabolic parameters in mice.Objective:This study was intended to examine potential improvements in metabolism in humans.Design and Setting:Changes in carbohydrate and lipid metabolism, along with inflammatory markers, were evaluated in prediabetic humans in a clinical research center.Participants:Nine obese patients participated. All had prediabetes or normal glucose tolerance plus three features of metabolic syndrome.Intervention:All participants were treated with escalating doses of KDT501 to a maximum dose of 1000 mg every 12 hours for a total of 28 days.Outcome Measures:Changes in carbohydrate metabolism were measured with oral glucose tolerance, homeostatic model of insulin resistance, and euglycemic clamp; changes in plasma lipids and response to a lipid tolerance test; and changes in plasma inflammatory markers.Results:The drug was well tolerated. After KDT501 treatment, plasma triglycerides were reduced at 4 hours during a lipid tolerance test. Furthermore, plasma adiponectin and high-molecular-weight adiponectin increased significantly, and plasma tumor necrosis factor-α decreased significantly. There were no significant changes in oral glucose tolerance test results or insulin sensitivity measures.Conclusions:Despite the small sample size and the short duration of therapy, KDT501 administration reduced measures of systemic inflammation and improved postmeal plasma triglyceride levels, which may be beneficial in participants with insulin resistance or metabolic syndrome.
TCF7L2 transcription factor is a downstream effector of the canonical Wnt/β-catenin signaling, which controls cell fate and homeostasis. However, the complexity of TCF7L2 expression with numerous mRNA isoforms coding for proteins with distinct N-and C-termini allows variability in TCF7L2 functions and regulations. Here, we show that although TCF7L2 mRNA isoforms distinguish fetal, immortalized and adult differentiated endothelial cells (EC), they cannot explain the lack of significant β-catenin/TCF7 activities in ECs. Lithium, a Wnt-signaling activator, increases TCF7L2 mRNA levels and induces an RNA isoform switch favoring the expression of TCF7L2-short forms lacking the C-termini domains. Although the latter occurs in different cell types, its extent depends on the overall increase of TCF7L2 transcription, which correlates with cell-responsiveness to Wnt/β-catenin signaling. While GSK3β down-regulation increases TCF7L2 expression, there is no concomitant change in TCF7L2 mRNA isoforms, which demonstrate the dual effects of lithium on TCF7L2 expression via a GSK3β-dependent up-regulation and a GSK3β-independent modulation of RNA-splicing. TCF7L2E-long forms display a repressor activity on TCF7L2-promoter reporters and lithium induces a decrease of the endogenous TCF7L2 forms bound to native TCF7L2-promoter chromatin at two novel distal TCF7-binding sites. Altogether our data reveal a lithium-induced RNA switch favoring the expression of TCF7L2-short forms, which results in a transcriptional de-repression of lithium-target genes negatively regulated by TCF7L2-long forms, like TCF7L2, and thus to an amplification of Wnt-signaling in responsive cells.
Context The gut microbiome is a source of inflammatory factors such as lipopolysaccharide (LPS; endotoxin) that influence metabolic homeostasis. Rifaximin is a well-tolerated antibiotic that may reduce LPS. Objective We sought to develop a method to accurately assess postprandial endotoxemia and to determine whether rifaximin treatment improves metabolic homeostasis in obese humans with metabolic syndrome. Design and Setting Plasma LPS, adipose inflammation, glucose and lipid metabolism, and insulin sensitivity were evaluated in a clinical research setting. Participants Twelve obese human research participants with prediabetes or three features of metabolic syndrome participated. Intervention The research participants were randomized to placebo control or rifaximin soluble solid dispersion (80 mg/d) treatment groups and treated for 12 weeks. Outcome Measures We evaluated changes in insulin sensitivity with a euglycemic clamp; changes in lipid and glucose metabolism with oral lipid and glucose tolerance tests; changes in plasma LPS during the lipid tolerance test; and changes in adipose tissue and systemic inflammation by measuring inflammatory cytokines. Results Rifaximin treatment slightly worsened insulin sensitivity (P = 0.03), did not improve glucose or lipid homeostasis, and did not significantly improve adipose tissue inflammation. Our efforts to accurately assess plasma LPS using limulus amebocyte lysate assays revealed that the majority of LPS is masked from detection by limulus amebocyte lysate assays, but can be unmasked using a pretreatment step with protease. Unmasked LPS increases during the lipid tolerance test, but rifaximin treatment did not reduce this. Conclusions Rifaximin treatment did not lower plasma LPS or improve metabolic homeostasis in obese humans.
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