Anti-inflammatory effect of SGLT-2 inhibitors via uric acid and insulin.

Sodium-glucose cotransporter 2 (SGLT-2) inhibitors (i) reduce cardiovascular and renal events in patients with and without type 2 diabetes (T2D). However, the underlying mechanisms are debated. Low-grade inflammation (LGI) is a key driver of vascular complications, suggested to be attenuated by SGLT-2i in animal models. Based on a specific working hypothesis, here we investigated the net effect of SGLT-2i on LGI in patients with T2D and the possible underlying mechanism. We enrolled patients with T2D treated either with a stable therapy with SGLT-2i or with other glucose-lowering drugs (GLD) (n = 43 per group after matching for a range of pro-inflammatory variables), and tested hs-CRP and interleukin (IL)-6 as primary variables of interest. Patients treated with SGLT-2i had lower circulating levels of IL-6, a prototypical marker of LGI, but also of uric acid and fasting insulin, compared with patients treated with other GLD. Then, to explore whether uric acid and insulin might mediate the effect of SGLT-2i on IL-6, we tested physiologically pertinent doses of these two molecules (i.e. 0.5 mM uric acid and 1 nM insulin) in two in vitro models of LGI, i.e. monocytes (THP-1) treated with LPS and endothelial cells (HUVEC) exposed to hyperglycaemia. Results from in vitro models supported a pro-inflammatory role for uric acid and its combination with insulin in monocytes and for uric acid alone in hyperglycaemia-stimulated endothelial cells. On the contrary, we observed no drug-intrinsic, anti-inflammatory effect for dapagliflozin, empagliflozin, and canagliflozin in the same models. Overall, these results suggest that SGLT-2i possess a tangible activity against LGI, an effect possibly mediated by their ability to lower uric acid and insulin concentrations and that juxtaposes other proposed mechanisms in explaining the observed benefit of this class on cardiovascular and renal endpoints.

Molecular markers of breast cancer cells identified in fine needle aspiration samples from resected sentinel lymph nodes.

OBJECTIVE: To analyze a procedure for breast cancer that requires performance of a molecular test before extensive intraoperative examination, fine needle aspiration cytology (FNAC) of surgically removed sentinel lymph nodes (SLNs). STUDY DESIGN: The diagnostic accuracy of extensive histologic examination and immunohistochemistry (IHC) of 101 SLNs from 98 breast carcinoma patients were compared with that of the evaluation of 2 specific mRNA markers by reverse transcriptase polymerase change reaction (mammaglobin and MUC-1). Cell specimens were obtained by FNAC of the SLNs immediately before freezing. RESULTS: Metastases were detected on frozen sections in 19 cases (18.81%). IHC on serial sections confirmed the metastases and showed micrometastases or isolated tumor cells in 24 SLNs (23.76%). Mammaglobin was expressed in 20 FNAC specimens (19.80%). MUC-1 assay was positive in 11 cases only (10.89%). CONCLUSION: This technique allows a complete histologic examination without sacrifice of part of the SLN and at the same time is a valuable diagnostic adjunct to the detection of occult tumor cells. Moreover, it is less expensive and time consuming than extensive IHC.