Increased plasma FFA reduce insulin-stimulated glucose uptake. The mechanisms responsible for this inhibition, however, remain uncertain. It was the aim of this study to determine whether the FFA effect was dose dependent and to investigate its mechanism. We have examined in healthy volunteers (13 male/1 female) the effects of three steady state plasma FFA levels ( -50, -550, -750 MuM) on rates of glucose uptake, glycolysis (both with 3-3H-glucose), glycogen synthesis (determined with two independent methods), carbohydrate (CHO) oxidation (by indirect calorimetry), hepatic glucose output, and nonoxidative glycolysis (glycolysis minus CHO oxidation) during euglycemic-hyperinsulinemic clamping. Increasing FFA concentration (from -50 to -750 gM) decreased glucose uptake in a dose-dependent fashion (from -9 to -4 mg/kg per min). The decrease was caused mainly (-2/3) by a reduction in glycogen synthesis and to a lesser extent ( 1/3) by a reduction in CHO oxidation. We have identified two independent defects in glycogen synthesis. The first consisted of an impairment of muscle glycogen synthase activity. It required high FFA concentration ( -750MM), was associated with an increase in glucose-6-phosphate, and developed after 4-6 h of fat infusion. The second defect, which preceded the glycogen synthase defect, was seen at medium ( -550MM) FFA concentration, was associated with a decrease in muscle glucose-6-phosphate concentration, and was probably due to a reduction in glucose transport/phosphorylation. In addition, FFA and/or glycerol increased insulin-suppressed hepatic glucose output by -50%. We concluded that fatty acids caused a dose-dependent inhibition of insulin-stimulated glucose uptake (by decreasing glycogen synthesis and CHO oxidation) and that FFA and/or glycerol increased insulin-suppressed hepatic glucose output and thus caused insulin resistance at the peripheral and the hepatic level. (J. Clin. Invest. 1994. 93:2438-2446

BackgroundThe coronavirus disease 2019 (COVID-19) epidemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), began in Wuhan city, Hubei province, in December, 2019, and has spread throughout China. Understanding the evolving epidemiology and transmission dynamics of the outbreak beyond Hubei would provide timely information to guide intervention policy. MethodsWe collected individual information from official public sources on laboratory-confirmed cases reported outside Hubei in mainland China for the period of Jan 19 to Feb 17, 2020. We used the date of the fourth revision of the case definition (Jan 27) to divide the epidemic into two time periods (Dec 24 to Jan 27, and Jan 28 to Feb 17) as the date of symptom onset. We estimated trends in the demographic characteristics of cases and key time-to-event intervals. We used a Bayesian approach to estimate the dynamics of the net reproduction number (R t ) at the provincial level. FindingsWe collected data on 8579 cases from 30 provinces. The median age of cases was 44 years (33-56), with an increasing proportion of cases in younger age groups and in elderly people (ie, aged >64 years) as the epidemic progressed. The mean time from symptom onset to hospital admission decreased from 4•4 days (95% CI 0•0-14•0) for the period of Dec 24 to Jan 27, to 2•6 days (0•0-9•0) for the period of Jan 28 to Feb 17. The mean incubation period for the entire period was estimated at 5•2 days (1•8-12•4) and the mean serial interval at 5•1 days (1•3-11•6). The epidemic dynamics in provinces outside Hubei were highly variable but consistently included a mixture of case importations and local transmission. We estimated that the epidemic was self-sustained for less than 3 weeks, with mean Rt reaching peaks between 1•08 (95% CI 0•74-1•54) in Shenzhen city of Guangdong province and 1•71 (1•32-2•17) in Shandong province. In all the locations for which we had sufficient data coverage of Rt, Rt was estimated to be below the epidemic threshold (ie, <1) after Jan 30. Interpretation Our estimates of the incubation period and serial interval were similar, suggesting an early peak of infectiousness, with possible transmission before the onset of symptoms. Our results also indicate that, as the epidemic progressed, infectious individuals were isolated more quickly, thus shortening the window of transmission in the community. Overall, our findings indicate that strict containment measures, movement restrictions, and increased awareness of the population might have contributed to interrupt local transmission of SARS-CoV-2 outside Hubei province.

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This study is the first to characterise gut microbiome in patients with HCC and to report the successful diagnosis model establishment and cross-region validation of microbial markers for HCC. Gut microbiota-targeted biomarkers represent potential non-invasive tools for early diagnosis of HCC.