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Aims/Introduction Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate (GFR). We analyzed secular changes in the prevalence of albuminuria and reduced estimated GFR (eGFR) in Japanese patients with type 2 diabetes, and identified factors associated with these changes. Materials and Methods Using 1996, 2001, 2006 and 2014 cohort data from the Japanese serial cross‐sectional studies conducted at Shiga University of Medical Science, secular changes in the prevalence of diabetic kidney disease (albuminuria and/or reduced eGFR), patient characteristics and their associations were analyzed. Results The prevalence of microalbuminuria and macroalbuminuria decreased over time, whereas the prevalence of moderately reduced eGFR (30–60 mL/min/1.73 m2) and severely reduced eGFR (<30 mL/min/1.73 m2) increased. Severely reduced eGFR was observed mainly in the patients with macroalbuminuria, regardless of year. Conversely, the prevalence of moderately reduced eGFR increased in the patients without macroalbuminuria. Both macroalbuminuria and moderately reduced eGFR without macroalbuminuria in the 2014 cohort were refractory to the recently recommended intensive therapy. Finally, we showed that obesity accompanied by vascular dysfunction was a risk factor for the development of albuminuria, and that age‐dependent arterial stiffness was associated with reduced eGFR without macroalbuminuria in the 2014 cohort. Conclusions During the past 20 years in Japan, the prevalence of albuminuria declined, whereas that of reduced eGFR increased. Additionally, obesity‐ and high age‐related vascular damage seems to be associated with macroalbuminuria and reduced eGFR without macroalbuminuria, respectively. Diabetic kidney disease is characterized by increased albuminuria and/or a reduced glomerular filtration rate. During the past 20 years in Japan, the prevalence of albuminuria declined, whereas that of reduced estimated glomerular filtration rate increased. Additionally, obesity‐ and high age‐related vascular damage seems to be associated with macroalbuminuria and reduced estimated glomerular filtration rate without macroalbuminuria, respectively.

Aims/Introduction Sodium–glucose cotransporter 2 inhibitors reduce bodyweight (BW) by creating a negative energy balance. Previous reports have suggested that this BW reduction is mainly loss of body fat and that ~20% of the reduction is lean mass. However, the effects of sodium–glucose cotransporter 2 inhibitors on BW and body composition remain unclear. We examined these effects in Japanese patients with type 2 diabetes mellitus treated with insulin. Materials and Methods In this open‐label, randomized controlled trial, 49 overweight patients (body mass index ≥23 kg/m2) with inadequate glycemic control (hemoglobin A1c >7.0%) receiving insulin treatment were randomly assigned to receive add‐on ipragliflozin or no additional treatment (control group). Patients were followed for 24 weeks. The goal for all patients was to achieve glycated hemoglobin <7.0% without hypoglycemia. The primary end‐point was a change in BW from baseline to week 24. Body composition was assessed with dual‐energy X‐ray absorptiometry and bioelectrical impedance analysis. Results BW change was significantly larger in the ipragliflozin group than in the control group (−2.78 vs −0.22 kg, P < 0.0001). Total fat mass was reduced evenly in the arms, lower limbs and trunk in the ipragliflozin group. Total muscle mass and bone mineral content were maintained, but muscle mass in the arms might have been affected by ipragliflozin treatment. Conclusions Ipragliflozin treatment for 24 weeks resulted in reduced BW, mainly from fat mass loss. Muscle mass and bone mineral content were maintained. Further study is necessary to elucidate the long‐term effects of ipragliflozin. The administration of ipragliflozin for 24 weeks to insulin‐treated patients significantly reduced their bodyweight compared with the control group. Total muscle mass and bone mineral content were maintained, but the arms might have been affected by treatment with ipragliflozin.

A fiber-rich diet has a cardioprotective effect, but the mechanism for this remains unclear. We hypothesized that a fiber-rich diet with brown rice improves endothelial function in patients with type 2 diabetes mellitus. Twenty-eight patients with type 2 diabetes mellitus at a single general hospital in Japan were randomly assigned to a brown rice (n = 14) or white rice (n = 14) diet and were followed for 8 weeks. The primary outcome was changes in endothelial function determined from flow debt repayment by reactive hyperemia using strain-gauge plethysmography in the fasting state. Secondary outcomes were changes in HbA1c, postprandial glucose excursions, and markers of oxidative stress and inflammation. The area under the curve for glucose after ingesting 250 kcal of assigned rice was compared between baseline (T0) and at the end of the intervention (T1) to estimate glucose excursions in each group. Improvement in endothelial function, assessed by fasting flow debt repayment (20.4% vs. -5.8%, p = 0.004), was significantly greater in the brown rice diet group than the white rice diet group, although the between-group difference in change of fiber intake was small (5.6 g/day vs. -1.2 g/day, p<0.0001). Changes in total, HDL-, and LDL-cholesterol, and urine 8-isoprostane levels did not differ between the two groups. The high-sensitivity C-reactive protein level tended to improve in the brown rice diet group compared with the white rice diet group (0.01 μg/L vs. -0.04 μg/L, p = 0.063). The area under the curve for glucose was subtly but consistently lower in the brown rice diet group (T0: 21.4 mmol/L*h vs. 24.0 mmol/L*h, p = 0.043, T1: 20.4 mmol/L*h vs. 23.3 mmol/L*h, p = 0.046) without changes in HbA1c. Intervention with a fiber-rich diet with brown rice effectively improved endothelial function, without changes in HbA1c levels, possibly through reducing glucose excursions.

Background The size of the remnant stomach with respect to weight loss failure after laparoscopic sleeve gastrectomy (LSG) remains controversial. This study aimed to evaluate the impact of the actual size and volume of the remnant stomach, as measured by three-dimensional computed tomography (3D-CT) volumetry, on weight loss after LSG. Methods The clinical outcomes of 52 patients who underwent LSG between October 2008 and February 2019 were assessed. Weight metrics were recorded at 1, 3, and 6 months and 1 year postoperatively. 3D-CT volumetry was performed 1 year postoperatively, and the total remnant stomach volume (TSV), proximal stomach volume (PSV), antral stomach volume (ASV), and the distance between the pylorus and the distal edge of staple line (DPS) were measured. The relationship between the weight metrics and aforementioned factors was analyzed. Results Of the 52 patients who underwent LSG, 40 patients participated in this study. The average body mass index preoperatively was 38.3 ± 5.1 kg/m 2 , and the average percentage of total weight loss (%TWL) 1 year after LSG was 26.6 ± 9.3%. The average TSV, PSV, ASV, and DPS were 123.2 ± 60.3 ml, 73.4 ± 37.2 ml, 49.8 ± 30.3 ml, and 59.9 ± 18.5 mm, respectively. The DPS ( r  = − 0.394, p  = 0.012) and ASV ( r  = − 0.356, p  = 0.024) were correlated with %TWL 1 year postoperatively. Conclusions The actual DPS and ASV measured by 3D-CT affected weight loss after LSG. 3D-CT may be useful for the immediate identification of factors affecting insufficient weight loss in patients; this may, in turn, aid in the implementation of early intervention treatments.

Aims/hypothesis O- GlcNAcylation is characterised by the addition of N -acetylglucosamine to various proteins by O -GlcNAc transferase (OGT) and serves in sensing intracellular nutrients by modulating various cellular processes. Although it has been speculated that O -GlcNAcylation is associated with glucose metabolism, its exact role in whole body glucose metabolism has not been fully elucidated. Here, we investigated whether loss of O -GlcNAcylation globally and in specific organs affected glucose metabolism in mammals under physiological conditions. Methods Tamoxifen-inducible global Ogt -knockout ( Ogt -KO) mice were generated by crossbreeding Ogt -flox mice with R26 -Cre-ER T2 mice. Liver, skeletal muscle, adipose tissue and pancreatic beta cell-specific Ogt -KO mice were generated by crossbreeding Ogt -flox mice with Alb -Cre, Mlc1f -Cre, Adipoq -Cre and Pdx1 PB -CreER™ mice, respectively. Glucose metabolism was evaluated by i.p. glucose and insulin tolerance tests. Results Tamoxifen-inducible global Ogt -KO mice exhibited a lethal phenotype from 4 weeks post injection, suggesting that O -GlcNAcylation is essential for survival in adult mice. Tissue-specific Ogt deletion from insulin-sensitive organs, including liver, skeletal muscle and adipose tissue, had little impact on glucose metabolism under physiological conditions. However, pancreatic beta cell-specific Ogt -KO mice displayed transient hypoglycaemia ( Ogt -flox 5.46 ± 0.41 vs Ogt -βKO 3.88 ± 0.26 mmol/l) associated with about twofold higher insulin secretion and accelerated adiposity, followed by subsequent hyperglycaemia ( Ogt -flox 6.34 ± 0.32 vs Ogt -βKO 26.4 ± 2.37 mmol/l) with insulin depletion accompanied by beta cell apoptosis. Conclusions/interpretation These findings suggest that O -GlcNAcylation has little effect on glucose metabolism in insulin-sensitive tissues but plays a crucial role in pancreatic beta cell function and survival under physiological conditions. Our results provide novel insight into O -GlcNAc biology and physiology in glucose metabolism.

Teff is a staple food in Ethiopia that is rich in dietary fiber. Although gaining popularity in Western countries because it is gluten-free, the effects of teff on glucose metabolism remain unknown. To evaluate the effects of teff on body weight and glucose metabolism compared with an isocaloric diet containing wheat. Mice fed teff weighed approximately 13% less than mice fed wheat (p < 0.05). The teff-based diet improved glucose tolerance compared with the wheat group with normal chow but not with a high-fat diet. Reduced adipose inflammation characterized by lower expression of TNFα, Mcp1, and CD11c, together with higher levels of cecal short chain fatty acids such as acetate, compared with the control diet containing wheat after 14 weeks of dietary treatment. In addition, beige adipocyte formation, characterized by increased expression of Ucp-1 (~7-fold) and Cidea (~3-fold), was observed in the teff groups compared with the wheat group. Moreover, a body-weight matched experiment revealed that teff improved glucose tolerance in a manner independent of body weight reduction after 6 weeks of dietary treatment. Enhanced beige adipocyte formation without improved adipose inflammation in a body-weight matched experiment suggests that the improved glucose metabolism was a consequence of beige adipocyte formation, but not solely through adipose inflammation. However, these differences between teff- and wheat-containing diets were not observed in the high-fat diet group. Teff improved glucose tolerance likely by promoting beige adipocyte formation and improved adipose inflammation.

Recent studies have proposed that n-3 polyunsaturated fatty acids (n-3 PUFAs) have direct antioxidant and anti-inflammatory effects in vascular tissue, explaining their cardioprotective effects. However, the molecular mechanisms are not yet fully understood. We tested whether n-3 PUFAs showed antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a master transcriptional factor for antioxidant genes. C57BL/6 or Nrf2(-/-) mice were fed a fish-oil diet for 3 weeks. Fish-oil diet significantly increased the expression of heme oxygenase-1 (HO-1), and endothelium-dependent vasodilation in the aorta of C57BL/6 mice, but not in the Nrf2(-/-) mice. Furthermore, we observed that 4-hydroxy hexenal (4-HHE), an end-product of n-3 PUFA peroxidation, was significantly increased in the aorta of C57BL/6 mice, accompanied by intra-aortic predominant increase in docosahexaenoic acid (DHA) rather than that in eicosapentaenoic acid (EPA). Human umbilical vein endothelial cells were incubated with DHA or EPA. We found that DHA, but not EPA, markedly increased intracellular 4-HHE, and nuclear expression and DNA binding of Nrf2. Both DHA and 4-HHE also increased the expressions of Nrf2 target genes including HO-1, and the siRNA of Nrf2 abolished these effects. Furthermore, DHA prevented oxidant-induced cellular damage or reactive oxygen species production, and these effects were disappeared by an HO-1 inhibitor or the siRNA of Nrf2. Thus, we found protective effects of DHA through Nrf2 activation in vascular tissue, accompanied by intra-vascular increases in 4-HHE, which may explain the mechanism of the cardioprotective effects of DHA.

To investigate the effect of weight loss and metabolic improvement after laparoscopic sleeve gastrectomy (LSG) in older adults aged 65 years or over compared with younger adults in a retrospective analysis. The J-SMART study database of 322 Japanese individuals with body mass index (BMI) ≥32 kg/m who underwent LSG between 2011 and 2014 at 10 centers accredited by the Japanese Society for Treatment of Obesity were analyzed. The subjects were classified into two groups: ≥65 age group (range, 65-76 years; n = 25) and <65 age group (range, 22-64 years; n = 297). Clinical parameters were compared between the groups. Baseline data for the ≥65 vs. <65 age groups were: median age 67 years vs. 45 years; weight 92.7 kg vs. 114.4 kg; BMI 40.0 kg/m vs. 41.9 kg/m ; and HbA1c 6.8% vs. 6.5%. The ≥65 age group had significantly lower preoperative weight, BMI, estimated glomerular filtration rate, and ABCD score, but higher visceral fat area and prevalence of diabetes, hypertension, and obstructive sleep apnea (OSAS). Weight was significantly reduced in both groups throughout 5 years post-LSG, though total weight loss at 2 years was lower in the ≥65 age group (28.0%) than in the <65 group (30.0%). Remission rates of diabetes, hypertension, OSAS, and joint disorders 2 years after LSG showed no significant differences, except for dyslipidemia. LSG may be an efficacious option for improving obesity-related health problems in older adults. However, postoperative safety and complications were not evaluated in this study and further research is needed. The online version contains supplementary material available at 10.1007/s13340-024-00767-w.

Purpose To quantitatively evaluate the efficacy of methylprednisolone pulse therapy for extraocular muscle inflammation in thyroid-associated ophthalmopathy (TAO) using the short-tau inversion-recovery (STIR) technique of magnetic resonance imaging (MRI). Methods The signal intensities of the superior rectus (SR), inferior rectus (IR), lateral rectus (LR), medial rectus (MR), and superior oblique (SO) muscles were measured using the STIR images from 34 eyes of 17 patients with TAO before and after methylprednisolone pulse therapy and 19 eyes of 19 controls. The signal intensity ratio (SIR) of the signal intensity in muscles to that in brain white matter was calculated. Results The mean SIRs of the controls were 1.08 ± 0.26 in the SR, 1.32 ± 0.29 in the IR, 1.34 ± 0.19 in the LR, 1.47 ± 0.25 in the MR, and 1.28 ± 0.22 in the SO muscles. SIRs exceeding 2.0 were out of the normal range. The SIRs of the patients with TAO before treatment were 2.19 ± 0.64, 2.44 ± 0.58, 1.96 ± 0.43, 2.24 ± 0.47, and 1.91 ± 0.42, respectively, which was significantly ( P  < 0.001) higher than those of the controls; after treatment, the mean SIRs were 1.82 ± 0.57, 1.81 ± 0.49, 1.64 ± 0.35, 1.88 ± 0.43, and 1.54 ± 0.33, respectively, significantly ( P  < 0.001) lower in all muscles than those before treatment. However, the SIRs of some muscles remained over 2.0. Moreover, all cases that had deterioration of TAO had one or more muscles with a SIR exceeding 2.5 after treatment. Conclusion Extraocular muscle inflammation in TAO improved with treatment. However, inflammation in some muscles persisted after treatment, and a high SIR in the muscle after treatment suggested the risk of deterioration of TAO.

Aims/Introduction Preprandial metformin administration significantly reduces postprandial plasma triglyceride levels in animal studies by reducing intestinal absorption through delayed gastric emptying. However, this effect has not been shown in a clinical study. Therefore, we planned to investigate the efficacy of preprandial metformin administration on postprandial hypertriglyceridemia and the related gastrointestinal effects in patients with type 2 diabetes mellitus. Materials and Methods A total of 11 patients taking single‐dose metformin at 500–1,000 mg, with non‐fasting plasma triglyceride levels of 150–1,000 mg/dL, were recruited at a single university hospital. The difference between preprandial and postprandial metformin administration on postprandial hypertriglyceridemia was examined by a meal test. The gastrointestinal effects of metformin, including stomach heaviness, heartburn and satiety, were also assessed using a visual analog scale. Results The mean bodyweight of patients was 80.6 kg (body mass index 27.9 kg/m2), and the mean non‐fasting plasma triglyceride level was 275.9 ± 57.0 mg/dL. The area under the curve of triglyceride during the meal test was significantly lower in the preprandial protocol than in the postprandial protocol (P < 0.05). Compared with postprandial administration, preprandial administration of metformin increased satiety (P = 0.036) without stomach heaviness or heartburn. Conclusions Preprandial metformin administration significantly reduced plasma triglyceride level during meal testing without marked exacerbation of gastrointestinal adverse effects. The present results suggest that a simple change in the timing of metformin administration represents a novel approach for enhancing triglyceride‐lowering strategies in patients with type 2 diabetes mellitus and postprandial hypertriglyceridemia. Preprandial metformin administration significantly reduced postprandial plasma triglyceride levels compared with postprandial administration. Filled circle: pre‐Met protocol; open circle: post‐Met protocol.