Manowsky J, Camargo RG, Kipp AP, Henkel J, Püschel GP. Insulininduced cytokine production in macrophages causes insulin resistance in hepatocytes. Am J Physiol Endocrinol Metab 310: E938-E946, 2016. First published April 19, 2016 doi:10.1152/ajpendo.00427.2015.-Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the ␤-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1␤, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1␤ was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-B. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKK␤, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues. metabolic syndrome; type 2 diabetes; inflammation; macrophage; insulin; cytokines DESPITE TREMENDOUS EFFORTS to raise public awareness about potential health hazards, the prevalence of overweight and obesity continues to increase (22). Concurrently, the incidence of impaired glucose tolerance, insulin resistance, and the often ensuing type 2 diabetes is rising at a stunning rate. Several molecular mechanisms have been proposed to explain the development of insulin resistance in obese patients. Thus, accrual of lipids with second-messenger properties in the course of ectopic triglyceride accumulation, namely diacylglycerol, can activate protein kinases, e.g., protein kinase C. This may result in the interruption of the intracellular insulin receptor signal chain by an inhibitory serine phosphorylation of the first relay protein in this chain, the insulin receptor sub-

Sections of fecal cylinders were analyzed using fluorescence in situ hybridization targeting 180 bacterial groups. Samples were collected from three groups of women (N=20 each) treated for bacterial vaginosis with ciprofloxacin+metronidazole. Group A only received the combined antibiotic regimen, whereas the A/Sb group received concomitant Saccharomyces boulardii CNCM I-745 treatment, and the A_Sb group received S. boulardii prophylaxis following the 14-day antibiotic course. The number of stool cylinders analyzed was 188 out of 228 in group A, 170 out of 228 in group A/Sb, and 172 out of 216 in group A_Sb. The colonic biomass was organized into a separate mucus layer with no bacteria, a 10-30μm broad unstirred transitional layer enriched with bacteria, and a patchy fermentative area that mixed digestive leftovers with bacteria. The antibiotics suppressed bacteria mainly in the fermentative area, whereas abundant bacterial clades retreated to the transitional mucus and survived. As a result, the total concentration of bacteria decreased only by one order. These effects were lasting, since the overall recovery of the microbial mass, bacterial diversity and concentrations were still below pre-antibiotic values 4 months after the end of antibiotic treatment. Sb-prophylaxis markedly reduced antibiotic effects and improved the recovery rates. Since the colon is a sophisticated bioreactor, the study indicated that the spatial anatomy of its biomass was crucial for its function.

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