Metformin strengthens uroepithelial immunity against E. coli infection

Urinary tract infection frequently caused by E. coli is one of the most common bacterial infections. Increasing antibiotic resistance jeopardizes successful treatment and alternative treatment strategies are therefore mandatory. Metformin, an oral antidiabetic drug, has been shown to activate macrophages in the protection against certain infecting microorganisms. Since epithelial cells often form the first line of defense, we here investigated the effect on uroepithelial cells during E. coli infection. Metformin upregulated the human antimicrobial peptides cathelicidin LL-37 and RNase7 via modulation of the TRPA1 channel and AMPK pathway. Interestingly, metformin stimulation enriched both LL-37 and TRPA1 in lysosomes. In addition, metformin specifically increased nitric oxide and mitochondrial, but not cytosolic ROS. Moreover, metformin also triggered mRNA expression of the proinflammatory cytokines IL1B, CXCL8 and growth factor GDF15 in human uroepithelial cells. The GDF15 peptide stimulated macrophages increased LL-37 expression, with increased bacterial killing. In conclusion, metformin stimulation strengthened the innate immunity of uroepithelial cells inducing enhanced extracellular and intracellular bacterial killing suggesting a favorable role of metformin in the host defense.

Real-world Observational Study on Patient Outcomes in Diabetes (RESPOND): study design and baseline characteristics of patients with type 2 diabetes newly initiating oral antidiabetic drug monotherapy in Japan

IntroductionTo investigate factors affecting glycemic control, oral antidiabetic drug (OAD) treatment distribution and self-care activities among patients with type 2 diabetes mellitus (T2DM) who newly initiate OAD monotherapy in a real-world setting in Japan.Research design and methodsA Real-world Observational Study on Patient Outcomes in Diabetes (RESPOND) is an ongoing, prospective, observational cohort study with follow-up at 6, 12, 18 and 24 months. Primary objectives include OAD treatment patterns (cross-sectional and longitudinal) among diabetes specialists versus non-specialists; adherence to diabetes self-care activities; quality of life; treatment satisfaction among patients and target attainment rates of parameters, including glycated hemoglobin. Here, we present the study design and baseline data.ResultsOf 1506 patients enrolled (June 2016–May 2017; 174 sites in Japan), 1485 were included in the baseline analysis (617 treated by specialists, 868 by non-specialists). Most patients were prescribed dipeptidyl peptidase-4 inhibitors (DPP-4Is) (specialist vs non-specialist, 54.1% vs 57.1%), then sodium-glucose cotransporter 2 inhibitors (13.9% vs 22.2%), metformin (20.3% vs 12.9%) and other OADs (<5% individually in both groups). Regardless of age, body mass index and glycated hemoglobin, DPP-4Is were the most commonly prescribed OADs by both specialists and non-specialists. About one-fifth and one-third of patients visiting specialists and non-specialists, respectively, received no advice on diet and exercise. The proportion of patients following self-care recommendations for diet and exercise (2/5 items on the Summary of Diabetes Self-Care Activities) was significantly higher among those visiting specialists than non-specialists.ConclusionThe use of newer OAD was common across a broad range of clinical characteristics in patients with T2DM who newly initiated monotherapy in Japan. However, patient-related and physician-related factors could affect the treatment changes during the following course of treatment. In addition, treatment outcome could vary with the observed difference in the level of patient education provided by diabetes specialists versus non-specialists.