KLF5 Is Induced by FOXO1 and Causes Oxidative Stress and Diabetic Cardiomyopathy.

RATIONALE: Diabetic cardiomyopathy (DbCM) is a major complication in type-1 diabetes, accompanied by altered cardiac energetics, impaired mitochondrial function, and oxidative stress. Previous studies indicate that type-1 diabetes is associated with increased cardiac expression of KLF5 (Krüppel-like factor-5) and PPARα (peroxisome proliferator-activated receptor) that regulate cardiac lipid metabolism. OBJECTIVE: In this study, we investigated the involvement of KLF5 in DbCM and its transcriptional regulation. METHODS AND RESULTS: KLF5 mRNA levels were assessed in isolated cardiomyocytes from cardiovascular patients with diabetes and were higher compared with nondiabetic individuals. Analyses in human cells and diabetic mice with cardiomyocyte-specific FOXO1 (Forkhead box protein O1) deletion showed that FOXO1 bound directly on the KLF5 promoter and increased KLF5 expression. Diabetic mice with cardiomyocyte-specific FOXO1 deletion had lower cardiac KLF5 expression and were protected from DbCM. Genetic, pharmacological gain and loss of KLF5 function approaches and AAV (adeno-associated virus)-mediated Klf5 delivery in mice showed that KLF5 induces DbCM. Accordingly, the protective effect of cardiomyocyte FOXO1 ablation in DbCM was abolished when KLF5 expression was rescued. Similarly, constitutive cardiomyocyte-specific KLF5 overexpression caused cardiac dysfunction. KLF5 caused oxidative stress via direct binding on NADPH oxidase (NOX)4 promoter and induction of NOX4 (NADPH oxidase 4) expression. This was accompanied by accumulation of cardiac ceramides. Pharmacological or genetic KLF5 inhibition alleviated superoxide formation, prevented ceramide accumulation, and improved cardiac function in diabetic mice. CONCLUSIONS: Diabetes-mediated activation of cardiomyocyte FOXO1 increases KLF5 expression, which stimulates NOX4 expression, ceramide accumulation, and causes DbCM.

The Role of Pediatric BCG Vaccine in Type 1 Diabetes Onset.

INTRODUCTION: Bacille Calmette-Guérin (BCG) vaccination has shown promising therapeutic effects for type 1 diabetes (T1D). According to recent studies, immunometabolism modification and regulation of T lymphocytes constitute the proposed mechanisms by which BCG vaccination may delay T1D onset. Clinical trial evidence from Turkey supports that two to three doses of the BCG vaccine in childhood, with the first dose administered in the first year of life, may prevent T1D. In the same study, one or zero vaccinations appeared to have no effect in T1D onset prevention. In Greece, the BCG vaccine was administered in a single dose at the age of 9 years in elementary school. BCG vaccination was not performed on a mandatory basis, creating one BCG vaccinated and one non-vaccinated population. The aim of our study was to investigate the possible effect of a single dose of BCG vaccine, at the age of 9 years, on the time of T1D onset, in a population of BCG vaccinated and non-vaccinated patients with diagnosed T1D. METHODS: To test this hypothesis, a survey through the Pan-Hellenic Federation of People with Diabetes (PFPD) was performed. In this observational, retrospective study, participating patients provided information regarding age, gender, time of diagnosis, and BCG vaccination status. Patients diagnosed with T1D before the age of 9 years were excluded from the analysis. RESULTS: The final sample included 196 patients (73 male and 123 female) with a mean age of 42.2 ± 14.3 years and a mean duration of diabetes of 16.8 ± 12.9 years. Mean age of T1D diagnosis in the BCG vaccinated group was 24.0 ± 19.0 years, while the mean age of T1D diagnosis in the BCG non-vaccinated group was 21.5 ± 14.3 years (p = 0.03). No interaction was found between gender and the age of diagnosis for BCG vaccinated and unvaccinated patients (p = 0.86). CONCLUSION: The results of our study suggest that a single dose of BCG vaccine, performed at the age of 9 years, may delay the onset of T1D by 2.5 years. Additional studies of children receiving multiple doses of BCG should be conducted to possibly prove prolongation of the disease-free interval.