Takeshi Matsumura

Aims: Obesity, a risk factor for atherosclerosis development and progression, is marked by excessive reactive oxygen species (ROS) production. We previously demonstrated that high-glucose (HG) conditions induce mitochondrial ROS (mtROS) production in aortic endothelial cells (ECs). However, the link between elevated mtROS levels in obesity and atherosclerosis progression remains unclear. This study aimed to investigate whether endothelial-specific mtROS suppression by overexpressing manganese superoxide dismutase (MnSOD) could attenuate atherosclerosis progression in high-fat diet (HFD)-induced obese apolipoprotein E-deficient (ApoE KO) mice. Results: Atherosclerotic lesion formation did not differ significantly between normal chow-fed control ApoE KO mice and endothelial cell-specific MnSOD-overexpressing ApoE KO (eMnSOD-Tg/ApoE KO) mice. However, in HFD-fed groups, eMnSOD-Tg/ApoE KO mice exhibited reduced atherosclerotic lesion size, decreased relative ROS levels, and lower Icam1 and Ccl2 expression compared to HFD-fed control ApoE KO mice. In obese ApoE KO mice, serum glucose, lipopolysaccharide (LPS), and low-density lipoprotein (LDL) levels were elevated. In human aortic endothelial cells, exposure to LPS, oxidized LDL, and high glucose increased relative mtROS levels, which was effectively attenuated by MnSOD overexpression. MnSOD also suppressed intercellular adhesion molecule-1 and monocyte chemoattractant protein-1 expression under these conditions. Innovation: Our findings demonstrate that endothelial-specific MnSOD overexpression suppresses obesity-related atherosclerosis in ApoE KO mice. Conclusion: mtROS plays a pivotal role in obesity-associated atherosclerosis, and targeting endothelial mtROS may offer a therapeutic strategy for preventing vascular complications in obesity. Antioxid. Redox Signal. 45, 63–77.

Aims/Introduction: This study aimed to investigate whether non‐invasive fingertip autofluorescence can evaluate micro‐ and macrovascular complications in patients with type 2 diabetes. Materials and Methods: This multicenter cross‐sectional study recruited 452 patients with type 2 diabetes between August 2017 and January 2023. Fingertip autofluorescence levels were measured using AGEs Sensor (Air Water Biodesign, Kobe, Japan). Results: Fingertip autofluorescence correlated with body mass index, glycated hemoglobin, estimated glomerular filtration rate, and duration of diabetes. Fingertip autofluorescence was increased in parallel with the number of micro‐ and macrovascular complications. A significant relationship was noted between fingertip autofluorescence as a dependent variable and sex, serum albumin, history of diabetic nephropathy, and coronary arterial disease as independent variables. Logistic regression analysis indicated the association of fingertip autofluorescence as a dichotomous variable with diabetic nephropathy as a significant predictor variable adjusted for age, sex, duration of diabetes, smoking status, and serum albumin. The receiver operating characteristic curve revealed that fingertip autofluorescence could be used to identify the presence of macrovascular complications (area under the curve: 0.65, 95% confidence interval: 0.585–0.707, P < 0.001). Conclusions: Fingertip autofluorescence may be a convenient and non‐invasive potential marker for evaluating micro‐ and macrovascular complications in patients with type 2 diabetes.

Remnant lipoproteins (RLs), which are typically present at high concentrations in patients with type 2 diabetes mellitus (T2DM), are associated with cardiovascular disease (CVD). Although an RL cholesterol homogeneous assay (RemL-C) is available for the measurement of RL concentrations, there have been no studies of the relationship between RemL-C and clinical parameters in T2DM. Therefore, we evaluated the relationships between RemL-C and CVD-related parameters in patients with T2DM. We performed a cross-sectional study of 169 patients with T2DM who were hospitalized at Kumamoto University Hospital. Compared with those with low RemL-C, those with higher RemL-C had higher fasting plasma glucose, homeostasis model assessment for insulin resistance (HOMA-R), total cholesterol, triglyceride, small dense low-density lipoprotein cholesterol (sdLDL-C), and urinary albumin-creatinine ratio; and lower high-density lipoprotein cholesterol, adiponectin, and ankle brachial pressure index (ABI). Multivariate logistic regression analysis showed that sdLDL-C and ABI were significantly and independently associated with high RemL-C. Although LDL-C was lower in participants with CVD, there was no difference in RemL-C between participants with or without CVD. Thus, RemL-C may represent a useful index of lipid and glucose metabolism, and that may be a marker of peripheral atherosclerotic disease (PAD) in male patients with T2DM.

Aim: Risk of cardiovascular disease is increased in patients with diabetes mellitus (DM). Cholesterol metabolism (hepatic synthesis and intestinal absorption) is known to be associated with cardiovascular risk. Next, we examined the association of DM with cholesterol absorption/synthesis. Methods: The CACHE Consortium, which is comprised of 13 research groups in Japan possessing data of lathosterol (Latho, synthesis marker) and campesterol (Campe, absorption marker) measured by gas chromatography, compiled the clinical data using the REDCap system. Among the 3597 records, data from 2944 individuals were used for several analyses including this study. Results: This study analyzed data from eligible 2182 individuals including 830 patients with DM; 42.2% were female, median age was 59 years, and median HbA1c of patients with DM was 7.0%. There was no difference in Latho between DM and non-DM individuals. Campe and Campe/Latho ratio were significantly lower in DM individuals than in non-DM individuals. When the associations of glycemic control markers with these markers were analyzed with multivariable-adjusted regression model using restricted cubic splines, Campe and Campe/Latho ratio showed inverse associations with glucose levels and HbA1c. However, Latho showed an inverted U-shaped association with plasma glucose, whereas Latho showed a U-shaped association with HbA1c. These associations remained even after excluding statin and/or ezetimibe users. Conclusion: We demonstrated that DM and hyperglycemia were independent factors for lower cholesterol absorption marker levels regardless of statin/ezetimibe use.

Introduction Sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors ameliorate blood glucose levels in patients with type 2 diabetes mellitus (T2DM) by inhibiting the reabsorption of glucose from the kidneys, thus increasing urinary glucose excretion. Most SGLT2 inhibitors have been reported to exert dose-dependent effects. However, little is known about the benefits of increasing the dose of SGLT2 inhibitors in clinical use. The aim of the present study was to investigate the effect of increasing the dose of the SGLT2 inhibitor empagliflozin in T2DM. Methods We collected 52 subjects with T2DM with inadequate glycemic control. The dose of empagliflozin was increased from 10 to 25 mg, taken once daily, and the alterations in glycemic control and several other clinical parameters were evaluated. Results The increased dose of empagliflozin significantly ameliorated glycemic control. In addition, body weight (BW), body mass index (BMI), triglyceride (TG), and γ-glutamyltranspeptidase (GGT) were significantly decreased and hematocrit (Hct) was increased. Multivariate logistic regression analyses revealed that baseline diastolic blood pressure (DBP) (odds ratio 1.093, 95% CI 1.019–1.156, P = 0.012) and baseline TG (odds ratio 1.012, 95% CI 1.001–1.023, P = 0.026) were retained as independent predictors for the improvement of hemoglobin A1c (HbA1c) levels. Moreover, multivariate stepwise regression analyses revealed that changes in high-density lipoprotein cholesterol (β − 0.264, 95% CI − 1.217 to 0.000, P = 0.049) and HbA1c (β 0.302, 95% CI 0.077–1.096, P = 0.025) were retained as independent predictors for changes in BMI. Conclusion Increasing the dose of empagliflozin significantly ameliorated BW, BMI, GGT, TG, fasting plasma glucose and HbA1c and increased Hct in patients with T2DM. Moreover, baseline DBP and TG were independent predictors for the improvement of HbA1c. These findings may provide useful information when considering increasing the dosage of SGLT2 inhibitors in patients with T2DM who have inadequate glycemic control. Trial Registration UMIN Clinical Trials Registry (UMIN000041543).

Because the renin-angiotensin-aldosterone system influences glucose homeostasis, the mineralocorticoid receptor (MR) signal in pancreatic islets may regulate insulin response upon glucose load. Glucagon-like peptide-1 (GLP-1) production is stimulated by interleukin-6 (IL-6) in pancreatic α-cells. To determine how glucose homeostasis is regulated by interactions of MR, IL-6 and GLP-1 in islets, we performed glucose tolerance and histological analysis of islets in primary aldosteronism (PA) model rodents and conducted in vitro experiments using α-cell lines. We measured active GLP-1 concentration in primary aldosteronism (PA) patients before and after the administration of MR antagonist eplerenone. In PA model rodents, aldosterone decreased insulin-secretion and the islet/pancreas area ratio and eplerenone added on aldosterone (E+A) restored those with induction of IL-6 in α-cells. In α-cells treated with E+A, IL-6 and GLP-1 concentrations were increased, and anti-apoptotic signals were enhanced. The E+A-treatment also significantly increased MR and IL-6 mRNA and these upregulations were blunted by MR silencing using small interfering RNA (siRNA). Transcriptional activation of the IL-6 gene promoter by E+A-treatment required an intact MR binding element in the promoter. Active GLP-1 concentration was significantly increased in PA patients after eplerenone treatment. MR signal in α-cells may stimulate IL-6 production and increase GLP-1 secretion, thus protecting pancreatic β-cells and improving glucose homeostasis.