Comparison of SGLT2 inhibitors vs. DPP4 inhibitors for patients with metabolic dysfunction associated fatty liver disease and diabetes mellitus.

PURPOSE: This study aimed to examine the potential benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and diabetes mellitus (DM) using a real-world database. METHODS: We analyzed individuals with MAFLD and DM newly initiated on SGLT2 or dipeptidyl peptidase 4 (DPP4) inhibitors from a large-scale administrative claims database. The primary outcome was the change in the fatty liver index (FLI) assessed using a linear mixed-effects model from the initiation of SGLT2 or DPP4 inhibitors. A propensity score-matching algorithm was used to compare the change in FLI among SGLT2 and DPP4 inhibitors. RESULTS: After propensity score matching, 6547 well-balanced pairs of SGLT2 and 6547 DPP4 inhibitor users were created. SGLT2 inhibitor use was associated with a greater decline in FLI than DPP4 inhibitor use (difference at 1-year measurement, - 3.8 [95% CI - 4.7 to - 3.0]). The advantage of SGLT2 inhibitor use over DPP4 inhibitor use for improvement in FLI was consistent across subgroups. The relationship between SGLT2 inhibitors and amelioration of FLI was comparable between individual SGLT2 inhibitors. CONCLUSIONS: Our analysis using large-scale real-world data demonstrated the potential advantage of SGLT2 inhibitors over DPP4 inhibitors in patients with MAFLD and DM.

Association of the Number of HLA-DR Mismatches With Early Post-transplant Acute Cellular Rejection Among Heart Transplantation Recipients: A Cohort Study in Japanese Population.

BACKGROUND: Although many risk factors are reported about graft rejection after heart transplantation (HTx), the effect of HLA mismatch (MM) still remains unknown, especially in the Japanese population. The aim of the present study was to investigate the influence of HLA MM on graft rejection among HTx recipients in Japan. METHODS: We retrospectively investigated the association of the number of HLA MM including class I (A, B) and class II (DR) (for each locus MM: 0 to 2, total MM: 0 to 6) and the incidence of moderate to severe acute cellular rejection (ACR) confirmed by endomyocardial biopsy (International Society for Heart and Lung Transplantation grade ≥ 3A/2R) within 1 year after HTx. RESULTS: Between 2007 and 2014, we had 49 HTx cases in our institute. After excluding those with insufficient data and positive donor-specific antigen, finally 35 patients were enrolled. Moderate to severe ACR was observed in 16 (45.7%) patients. The number of HLA-DR MM was significantly associated with the development of ACR (ACR+: 1.50 ± 0.63, ACR-: 1.11 ± 0.46, P = .029). From univariate analysis, DR MM = 2 was the only independent risk factor for ACR episodes (P = .017). The frequency of ACR within 1 year was significantly higher in those with DR MM = 2 (DR MM = 0 to 1: 0.3 ± 0.47, DR MM = 2: 1.17 ± 1.34 times, P = .007). CONCLUSIONS: The number of HLA-DR MMs was associated with the development and recurrence of ACR episodes among HTx recipients within 1 year after transplantation in Japanese population.

Na(+) /Ca(2+) exchanger 2-heterozygote knockout mice display decreased acetylcholine release and altered colonic motility in vivo.

BACKGROUND: The Na(+) /Ca(2+) exchanger (NCX) is a plasma membrane transporter involved in regulating intracellular Ca(2+) concentrations. NCX is critical for Ca(2+) regulation in cardiac muscle, vascular smooth muscle, and nerve fibers. However, little is known about the physiological role of NCX in the myenteric neurons and smooth muscles of the gastrointestinal tract. METHODS: To determine the role of NCX1 and NCX2 in gastrointestinal tissues, we examined electric field stimulation (EFS)-induced responses in the longitudinal smooth muscle of the distal colon in NCX1- and NCX2-heterozygote knockout mice. KEY RESULTS: We found that the amplitudes of EFS-induced relaxation that persisted during EFS were greater in NCX2 heterozygous mice (HET) than in wild-type mice (WT). Under the nonadrenergic, noncholinergic (NANC) condition, EFS-induced relaxation in NCX2 HET was similar in amplitude to that of WT. In addition, an NCX inhibitor, YM-244769 enhanced EFS-induced relaxation but did not affect EFS-induced relaxation under the NANC condition, as in NCX2 HET. Unlike NCX2 HET, NCX1 HET displayed no marked changes in colonic motility. These results indicate that cholinergic function in the colon is altered in NCX2 HET. The magnitude of acetylcholine (ACh)-induced contraction in NCX2 HET was similar to that in WT. In contrast, EFS-induced ACh release was reduced in NCX2 HET compared with that in WT. CONCLUSIONS & INFERENCES: In this study, we demonstrate that NCX2 regulates colonic motility by altering ACh release onto the myenteric neurons of the distal colon.

Effects of valsartan and amlodipine on home blood pressure and cardiovascular events in Japanese hypertensive patients: a subanalysis of the VART.

The Valsartan Amlodipine Randomized Trial (VART) was performed to compare the beneficial effects of valsartan and amlodipine on cardiovascular events in Japanese hypertensive patients. In this subanalysis of the VART, we assessed the relationship between home blood pressure (HBP) levels and cardiovascular events in the enrolled patients. We enrolled 1021 patients with mild-to-moderate hypertension in the VART. The participants were allocated randomly to either the valsartan group or the amlodipine group. The primary end point was a composite of all-cause death, sudden death, cerebrovascular events, cardiac events, vascular events and renal events. A total of 621 patients (valsartan group: 305 and amlodipine group: 316) completed the measurements of HBP (morning and evening) throughout the trial. Both the agents evenly and significantly lowered morning HBP and evening HBP throughout the trial. There was no significant difference in the primary end point between the two groups. However, we observed significant decreases in the left ventricular mass index and urinary albumin to creatinine ratio in the valsartan group but not in the amlodipine group. There were no significant differences in HBP levels and the main outcome of the cardiovascular events between the valsartan and amlodipine groups. However, in the valsartan group, significant improvements in left ventricular hypertrophy and microalbuminuria were observed.

A Na+/Ca2+ exchanger isoform, NCX1, is involved in retinal cell death after N-methyl-D-aspartate injection and ischemia-reperfusion.

We investigated the expression of Na(+)/Ca(2+) exchanger (NCX) and the functional role of NCX in retinal damage by using NCX1-heterozygous deficient mice (NCX1(+/-)) and SEA0400 (2-[4-[(2,5-difluorophenyl)methoxy] phenoxy]-5-ethoxyaniline), a selective NCX inhibitor in vivo. We also examined the role of NCX in oxygen-glucose deprivation (OGD) stress with a retinal ganglion cell line (RGC-5) cell culture in vitro. The expression of NCX1 was confirmed and entirely localized in retina by immunoblotting and immunohistochemistry, respectively. NCX1(+/-) mice possessed significant protection against retinal damage induced by intravitreal injection of N-methyl-D-aspartate (NMDA). SEA0400 at 3 and 10 mg/kg significantly reduced NMDA- or high intraocular pressure-induced retinal cell damage in mice. Furthermore, SEA0400 reduced the number of TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling)-positive cells and the expression of phosphorylated mitogen-activated protein kinases (ERK1/2, JNK, p38) induced by NMDA injection. In RGC-5, SEA0400 at 0.3 and 1 microM significantly inhibited OGD-induced cell damage. OGD-induced cell damage was aggravated by ouabain (a Na(+),K(+)-ATPase inhibitor) at 100 microM, and this increased damage was significantly reduced by SEA0400 at 1 microM. In conclusion, these results suggest that NCX1 may play a role in retinal cell death induced by NMDA and ischemia-reperfusion.

Oxidative stress induces insulin resistance by activating the nuclear factor-kappa B pathway and disrupting normal subcellular distribution of phosphatidylinositol 3-kinase.

AIMS/HYPOTHESIS: Oxidative stress is associated with diabetes, hypertension and atherosclerosis. Insulin resistance is implicated in the development of these disorders. We tested the hypothesis that oxidative stress induces insulin resistance in rats, and endeavoured to identify mechanisms linking the two. METHODS: Buthionine sulfoximine (BSO), an inhibitor of glutathione synthase, was administered to Sprague-Dawley rats and 3T3-L1 adipocytes. Glucose metabolism and insulin signalling both in vivo and in 3T3-L1 adipocytes were examined. In 3T3-L1 adipocytes, the effects of overexpression of a dominant negative mutant of inhibitory kappa B (I kappa B), one role of which is to block oxidative-stress-induced nuclear factor (NF)-kappa B activation, were investigated. RESULTS: In rats given BSO for 2 weeks, the plasma lipid hydroperoxide level doubled, indicating increased oxidative stress. A hyperinsulinaemic-euglycaemic clamp study and a glucose transport assay using isolated muscle and adipocytes revealed insulin resistance in BSO-treated rats. BSO treatment also impaired insulin-induced glucose uptake and GLUT4 translocation in 3T3-L1 adipocytes. In BSO-treated rat muscle, adipose tissue and 3T3-L1 adipocytes, insulin-induced IRS-1 phosphorylation in the low-density microsome (LDM) fraction was specifically decreased, while that in whole cell lysates was not altered, and subsequent translocation of phosphatidylinositol (PI) 3-kinase from the cytosol and the LDM fraction was disrupted. BSO-induced impairments of insulin action and insulin signalling were reversed by overexpressing the dominant negative mutant of I kappa B, thereby suppressing NF-kappa B activation. CONCLUSIONS/INTERPRETATION: Oxidative stress induces insulin resistance by impairing IRS-1 phosphorylation and PI 3-kinase activation in the LDM fraction, and NF-kappa B activation is likely to be involved in this process.