Sphingosine 1-phosphate (S1P) is known to regulate insulin resistance in hepatocytes, skeletal muscle cells, and pancreatic β-cells. Among its 5 cognate receptors (S1pr1-S1pr5), S1P seems to counteract insulin signaling and confer insulin resistance via S1pr2 in these cells. S1P may also regulate insulin resistance in adipocytes, but the S1pr subtype(s) involved remains unknown. Here, we investigated systemic glucose/insulin tolerance and phenotypes of epididymal adipocytes in high-fat diet (HFD)-fed wild-type and S1pr2-deficient (S1pr2(-/-)) mice. Adult S1pr2(-/-) mice displayed smaller body/epididymal fat tissue weights, but the differences became negligible after 4 weeks with HFD. However, HFD-fed S1pr2(-/-) mice displayed better scores in glucose/insulin tolerance tests and had smaller epididymal adipocytes that expressed higher levels of proliferating cell nuclear antigen than wild-type mice. Next, proliferation/differentiation of 3T3-L1 and 3T3-F442A preadipocytes were examined in the presence of various S1pr antagonists: JTE-013 (S1pr2 antagonist), VPC-23019 (S1pr1/S1pr3 antagonist), and CYM-50358 (S1pr4 antagonist). S1P or JTE-013 treatment of 3T3-L1 preadipocytes potently activated their proliferation and Erk phosphorylation, whereas VPC-23019 inhibited both of these processes, and CYM-50358 had no effects. In contrast, S1P or JTE-013 treatment inhibited adipogenic differentiation of 3T3-F442A preadipocytes, whereas VPC-23019 activated it. The small interfering RNA knockdown of S1pr2 promoted proliferation and inhibited differentiation of 3T3-F442A preadipocytes, whereas that of S1pr1 acted oppositely. Moreover, oral JTE-013 administration improved glucose tolerance/insulin sensitivity in ob/ob mice. Taken together, S1pr2 blockade induced proliferation but suppressed differentiation of (pre)adipocytes both in vivo and in vitro, highlighting a novel therapeutic approach for obesity/type 2 diabetes.
Recently, more than ten cases of thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome or Castleman-Kojima disease exhibiting such symptoms as thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly have been reported in Japan. We have found two cases of TAFRO syndrome and have reviewed another eighteen previously reported cases. Histological findings of the lymph nodes and levels of interleukin 6 (IL-6) and vascular endothelial growth factor in both serum/plasma and effusions are important characteristics for diagnosing this syndrome.
Insulin is often administered for glucocorticoid (GC) -induced hyperglycemia. We have developed and validated a scoring system to predict insulin requirement for optimal control of hyperglycemia during GC treatment through retrospective studies. The Developing set: 303 adults out of 2718 patients, undergoing their first treatment of prednisolone (PSL) with a dosage of 5 mg/day or more for 4 weeks at least, were divided into 2 groups depending on with or without administration of insulin during GC treatment. Risk factors for insulin requirement were identified by a stepwise logistic regression analysis after univariate analyses of clinical parameters before GC treatment between the 2 groups. We constructed a point-addition scoring system, consisting of several categories and their coefficients in each risk factor, derived from another multivariate analysis. We validated it to validation sets A (n=44) and B (n=77) in another two facilities, respectively. Male, FPG, HbA1c, serum CRE, and an initial dose of PSL were identified as the risk factors. The AUC by ROC analysis of the total scores when the Developing set was scored, showed 0.94. The sensitivity, specificity, and accuracy were 90%, 88%, and 88%; 88%, 67%, and 71%; 83%, 76%, and 77% in the Developing set, Validation set A, and B, respectively if the cut off value of the total scores was defined as 19 points. The scoring system: Table is useful.
Disclosure
M. Kawashima: None. Y. Kitada: None. K. Kajita: None. I. Mori: None. T. Ishizuka: None. D. Murakami: None. H. Okada: None. H. Morita: None.
Funding
Sanofi; Eli Lilly Japan K.K.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.