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Atsunori Kashiwagi Shinchi Araki Hiroshi Maegawa 《Journal of diabetes investigation.》2021,12(1):6-20
Recent major clinical trials of the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have shown that they reduce three-point major adverse cardiovascular events, cardiovascular death, hospitalization for heart failure (HF) and a composite renal outcome. These beneficial effects of SGLT2 inhibitors are also evident in type 2 diabetes patients with a previous history of atherosclerotic cardiovascular disease or advanced renal disease. HF is a major determinant of the prognosis of diabetes patients. Although HF with low ejection fraction can be effectively treated with antihypertensive drugs, these treatments do not reduce mortality in HF patients with preserved ejection fraction (HFpEF). HFpEF is clinically characterized by left ventricular diastolic dysfunction, perivascular fibrosis and stiffness of cardiomyocytes, defined as “cardiomyopathy”. Therefore, HFpEF is considered to be an entirely separate entity to HF with low ejection fraction. Recent studies have suggested that HFpEF might be treatable using SGLT2 inhibitors, which ameliorate visceral adiposity, insulin resistance, hyperglycemia, hyperlipidemia, volume overload, hypertension and cardiac inflammation. In the final part of the present review, we discuss the biochemical and molecular mechanisms of the effects of SGLT2 inhibitors in type 2 diabetes patients with HFpEF. These involve amelioration of the low nitric oxide production and oxidative stress, a reduction in cardiac inflammatory cytokine signaling, inhibition of Ca2+ overload, and an improvement in cardiac energy metabolism as a result of ketone body production. Investigations of the beneficial effects of SGLT2 inhibitors on cardiorenal outcomes, including hospitalization for HF, are now being carried out in preclinical and clinical studies. 相似文献
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Matsumoto M Miki T Shibasaki T Kawaguchi M Shinozaki H Nio J Saraya A Koseki H Miyazaki M Iwanaga T Seino S 《Proceedings of the National Academy of Sciences of the United States of America》2004,101(22):8313-8318
Rab3 is a subfamily of the small GTP-binding protein Rab family and plays an important role in exocytosis. Several potential effectors of Rab3, including rabphilin3 and Rims (Rim1 and Rim2), have been isolated and characterized. Noc2 was identified originally in endocrine pancreas as a molecule homologous to rabphilin3, but its role in exocytosis is unclear. To clarify the physiological function of Noc2 directly, we have generated Noc2 knockout (Noc2(-/-)) mice. Glucose intolerance with impaired insulin secretion was induced in vivo by acute stress in Noc2(-/-) mice, but not in wild-type (Noc2(+/+)) mice. Ca(2+)-triggered insulin secretion from pancreatic isles of Noc2(-/-) mice was markedly impaired, but was completely restored by treatment with pertussis toxin, which inhibits inhibitory G protein Gi/o signaling. In addition, the inhibitory effect of clonidine, an alpha(2)-adrenoreceptor agonist, on insulin secretion was significantly greater in Noc2(-/-) islets than in Noc2(+/+) islets. Impaired Ca(2+)-triggered insulin secretion was rescued by adenovirus gene transfer of wild-type Noc2 but not by that of mutant Noc2, which does not bind to Rab3. Accordingly, Noc2 positively regulates insulin secretion from endocrine pancreas by inhibiting Gi/o signaling, and the interaction of Noc2 and Rab3 is required for the effect. Interestingly, we also found a marked accumulation of secretory granules in various exocrine cells of Noc2(-/-) mice, especially in exocrine pancreas with no amylase response to stimuli. Thus, Noc2, a critical effector of Rab3, is essential in normal regulation of exocytosis in both endocrine and exocrine cells. 相似文献
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Keiko Kondo Katsutaro Morino Yoshihiko Nishio Motoyuki Kondo Keiko Nakao Fumiyuki Nakagawa Atsushi Ishikado Osamu Sekine Takeshi Yoshizaki Atsunori Kashiwagi Satoshi Ugi Hiroshi Maegawa 《Metabolism: clinical and experimental》2014
Objective
The beneficial effects of fish and n-3 polyunsaturated fatty acids (PUFAs) consumption on atherosclerosis have been reported in numerous epidemiological studies. However, to the best of our knowledge, the effects of a fish-based diet intervention on endothelial function have not been investigated. Therefore, we studied these effects in postmenopausal women with type 2 diabetes mellitus (T2DM).Materials/Methods
Twenty-three postmenopausal women with T2DM were assigned to two four-week periods of either a fish-based diet (n-3 PUFAs ≧ 3.0 g/day) or a control diet in a randomized crossover design. Endothelial function was measured with reactive hyperemia using strain-gauge plethysmography and compared with the serum levels of fatty acids and their metabolites. Endothelial function was determined with peak forearm blood flow (Peak), duration of reactive hyperemia (Duration) and flow debt repayment (FDR).Results
A fish-based dietary intervention improved Peak by 63.7%, Duration by 27.9% and FDR by 70.7%, compared to the control diet. Serum n-3 PUFA levels increased after the fish-based diet period and decreased after the control diet, compared with the baseline (1.49 vs. 0.97 vs. 1.19 mmol/l, p < 0.0001). There was no correlation between serum n-3 PUFA levels and endothelial function. An increased ratio of epoxyeicosatrienoic acid/dihydroxyeicosatrienoic acid was observed after a fish-based diet intervention, possibly due to the inhibition of the activity of soluble epoxide hydrolase.Conclusions
A fish-based dietary intervention improves endothelial function in postmenopausal women with T2DM. Dissociation between the serum n-3 PUFA concentration and endothelial function suggests that the other factors may contribute to this phenomenon. 相似文献48.
49.
Bone marrow mononuclear cell therapy
limits myocardial infarct size through vascular endothelial
growth factor 总被引:13,自引:0,他引:13
Hiasa K Egashira K Kitamoto S Ishibashi M Inoue S Ni W Zhao Q Nagata S Katoh M Sata M Takeshita A 《Basic research in cardiology》2004,99(3):165-172
Abstract. No prior study has examined the effect of intravenous
injection of bone marrow mononuclear cells (MNCs) on myocardial
infarction size (IS). We tested the hypothesis that
transplantation of MNCs decreases IS through the release of
vascular endothelial growth factor (VEGF). Immediately after
ligation of the left coronary artery of immunodeficient mice,
PBS or MNCs were intravenously administered. Myocardial IS was
significantly less in MNCs-treated mice than in PBS-treated
mice. Trace experiments showed accumulation of exogenously
administered MNCs into the vicinity of infarcted myocardium.
Injection of MNCs did not affect capillary density after
infarction, but did reduced myocardial cell apoptosis. Blockade
of VEGF by a neutralizing antibody or by gene transfer of a
soluble form of Flt-1 VEGF receptor diminished the IS-limiting
effects of MNCs. In conclusion, injection of MNCs can reduce
myocardial IS through the release of VEGF. The MNC therapy for
acute myocardial infarction might improve prognosis of patients
with myocardial infarction. 相似文献
50.
Kazuhiro Hikima Ho Jia Ler Radian Febi Indrawan Hiroyuki Muto Atsunori Matsuda 《RSC advances》2022,12(12):7469
In this study, mechanical milling and liquid-phase shaking are used to synthesise 3Li2S·P2S5 LiI·xLi4SiO4 (Li7P2S8I·xLi4SiO4) solid electrolytes. When mechanical milling is used, the electrolyte samples doped with 10 mol% of Li4SiO4 (Li7P2S8I·10Li4SiO4) have the highest ionic conductivity at ∼25–130 °C. When liquid-phase shaking is used, they exhibit a relatively high conductivity of 0.85 mS cm−1 at ∼20 °C, and low activation energy for conduction of 17 kJ mol−1. A cyclic voltammogram shows that there are no redox peaks between −0.3 and +10 V, other than the main peaks near 0 V (v.s. Li/Li+), indicating a wide electrochemical window. The galvanostatic cycling test results demonstrate that the Li7P2S8I·10Li4SiO4 has excellent long-term cycling stability in excess of 680 cycles (1370 h), indicating that it is highly compatible with Li. Thus, Li7P2S8I solid electrolytes doped with Li4SiO4 are synthesised using the liquid-phase shaking method for the first time and achieve a high ionic conductivity of 0.85 mS cm−1 at 25 °C. This work demonstrates the effects of Li4SiO4 doping, which can be used to improve the ionic conductivity and stability against Li anodes with Li7P2S8I solid electrolytes.The galvanostatic cycling test results demonstrate that the Li7P2S8I·10Li4SiO4 has excellent long-term cycling stability in excess of 680 cycles (1370 h), indicating that it is highly compatible with Li anode. 相似文献