Proinflammatory cytokines are recently reported to inhibit insulin signaling causing insulin resistance. IL-1alpha is also one of the proinflammatory cytokines; however, it has not been clarified whether IL-1alpha may also cause insulin resistance. Here, we investigated the effects of IL-1alpha treatment on insulin signaling in 3T3-L1 adipocytes. IL-1alpha treatment up to 4 h did not alter insulin-stimulated insulin receptor tyrosine phosphorylation, whereas tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and the association with phosphatidylinositol 3-kinase were partially inhibited with the maximal inhibition in around 15 min. IRS-1 was transiently phosphorylated on some serine residues around 15 min after IL-1alpha stimulation, when several serine kinases, IkappaB kinase, c-Jun-N-terminal kinase, ERK, and p70S6K were activated. Chemical inhibitors for these kinases inhibited IL-1alpha-induced serine phosphorylation of IRS-1. Tyrosine phosphorylation of IRS-1 was recovered only by the IKK inhibitor or JNK inhibitor, suggesting specific involvement of these two kinases. Insulin-stimulated Akt phosphorylation and 2-deoxyglucose uptake were not inhibited only by IL-1alpha. Interestingly, Akt phosphorylation was synergistically inhibited by IL-1alpha in the presence of IL-6. Taken together, short-term IL-1alpha treatment transiently causes insulin resistance at IRS-1 level with its serine phosphorylation. IL-1alpha may suppress insulin signaling downstream of IRS-1 in the presence of other cytokines, such as IL-6.

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Serine phosphorylation of insulin receptor substrate (IRS)-1 and the induction of suppressor of cytokine signaling 3 (SOCS3) is recently well documented as the mechanisms for the insulin resistance. However, the relationship between these two mechanisms is not fully understood. In this study, we investigated the involvement of SOCS3 and IRS-1 serine phosphorylation in TNFalpha-induced insulin resistance in 3T3-L1 adipocytes. TNFalpha transiently stimulated serine phosphorylation of IRS-1 from 10 min to 1 h, whereas insulin-stimulated IRS-1 tyrosine phosphorylation was inhibited only after TNFalpha treatment longer than 4 h. These results suggest that serine phosphorylation of IRS-1 alone is not the major mechanism for the inhibited insulin signaling by TNFalpha. TNFalpha stimulation longer than 4 h enhanced the expression of SOCS3 and signal transducer and activator of transcription-3 phosphorylation, concomitantly with the production of IL-6. Anti-IL-6 neutralizing antibody ameliorated suppressed insulin signaling by 24 h TNFalpha treatment, when it partially decreased SOCS3 induction and signal transducer and activator of transcription-3 phosphorylation. These results suggest that SOCS3 induction is involved in inhibited insulin signaling by TNFalpha. However, low-level expression of SOCS3 by IL-6 or adenovirus vector did not affect insulin-stimulated IRS-1 tyrosine phosphorylation. Interestingly, when IRS-1 serine phosphorylation was enhanced by TNFalpha or anisomycin in the presence of low-level SOCS3, IRS-1 degradation was remarkably enhanced. Taken together, both IRS-1 serine phosphorylation and SOCS3 induction are necessary, but one of the pair is not sufficient for the inhibited insulin signaling. Chronic TNFalpha may inhibit insulin signaling effectively because it causes both IRS-1 serine phosphorylation and the following SOCS3 induction in 3T3-L1 adipocytes.

Progression of symptoms was a significant factor for predicting CAP and selecting patients who required CXR. Inclusion of progression of symptoms among the other recommended criteria, namely, dyspnoea, fever > 38 degrees C, heart rate > 100 beats/min and abnormal chest findings, improved prediction of the incidence of CAP in general practice.

In a previous study, a method of obtaining mean erythrocyte age ($$M_{RBC}$$ M RBC ) from HbA1c and average plasma glucose (AG) was proposed. However, the true value of the hemoglobin glycation constant ($$k_g$$ k g dL/mg/day), required for this model has yet to be well characterized. Another study also proposed a method of deriving $$M_{RBC}$$ M RBC from erythrocyte creatine (EC). Utilizing these formulae, this study aimed to determine a more accurate estimate of $$k_g$$ k g . One hundred and seven subjects including 31 patients with hemolytic anemia and 76 subjects without anemia were included in this study. EC and HbA1c data were analyzed, and $$M_{RBC}$$ M RBC using HbA1c, AG and the newly-derived constant, $$k_g$$ k g were compared to $$M_{RBC}$$ M RBC using traditional $$^{51}\hbox {Cr}$$ 51 Cr in three patients whose data were taken from previous case studies. A value of $$7.0\times 10^{-6}$$ 7.0 × 10 - 6 dL/mg/day was determined for $$k_g$$ k g . $$M_{RBC}$$ M RBC using HbA1c, AG and $$k_g$$ k g were found to no be significantly different (paired t-test, $$p=0.45$$ p = 0.45 ) to $$M_{RBC}$$ M RBC using traditional $$^{51}\hbox {Cr}$$ 51 Cr . $$k_g$$ k g enables the estimation of $$M_{RBC}$$ M RBC from HbA1c and AG.