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Type 2 diabetes is frequently complicated by nonalcoholic fatty liver disease (NAFLD) , which is mainly caused by high-fat and high-calorie diets, and obesity. In this regard, both the quantity and quality of fat accumulating in the liver are important, and in particular, the proportion of each fatty acid may be an important biomarker for NAFLD. We investigated whether serum fatty acid composition, especially n-6 polyunsaturated fatty acid (PUFA) and, saturated fatty acid (MUFA) and desaturase activity are associated with NAFLD in type 2 diabetes patients. Eighty-five type 2 diabetes patients (age: 60.3±13.9 years, BMI 27.5±5.8 kg/m2) who had no history of alcohol drinking, and had a negative result for hepatitis viruses were included as study subjects. Fatty liver (FL) was diagnosed based on liver ultrasonographic findings. Patients with FL were included in the FL group (n=51) , whereas those without FL included in the non-FL group (n=34) . Serum fatty acid levels were measured using gas chromatography. Desaturase activity for n-6 PUFAs was calculated as the ratio of arachidonic acid to dihomo-gamma-linolenic acid (DGLA) for Δ5 desaturase (D5D) . Waist circumference, BMI, serum triglyceride (TG) concentration, and ALT level were significantly higher in the FL group than in the non-FL group. The FL group also demonstrated higher levels of palmitic acid (PAL) and stearic acid (STA) , PAL/STA ratio, and DGLA than the non-FL group. In the FL group D5D activity was significantly lower than that in the non-FL group. PAL level, DGLA, and PAL/STA ratio showed a significant positive correlation with TG and ALT levels. Multiple regression analysis showed that DGLA was independently associated with FL development. These results suggest that type 2 diabetes patients with NAFLD have changes in their blood fatty acid profile, especially increased DGLA and PAL levels. The high levels of blood DGLA indicate downregulation of n-6 PUFA metabolism, probably caused by the decreased activity of D5D. Disclosure M.Higa: None. T.Ichijo: None.

BACKGROUND It is well established that primary aldosteronism (PA) and aldosterone-to-renin ratio (ARR) are associated with kidney disease. The aim of this study was to retrospectively investigate the relationship between ARR, urinary albumin excretion (UAE), and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes from a single center. MATERIAL AND METHODS We included 70 patients with type 2 diabetes, UAE ≤100 mg/day, not taking renin-aldosterone system inhibitors, did not meet the diagnostic criteria for PA, and had an ARR20. The patients were divided into 3 groups: the normal low (NL) group (33 patients) with a UAE10 mg/day, the normal (N) group (22 patients) with a UAE of 10-29 mg/day, and the microalbuminuria (M) group (15 patients) with a UAE of 30-100 mg/day. The ARR, plasma renin activity (PRA), and plasma aldosterone (PAC) were compared among groups. RESULTS The ARR was highest in group M (10.1±4.6), 6.5±0.3 in group NL, and 7.0±2.7 in group N. The PRA and PAC were significantly lower in group M (P0.001). The ARR showed a significant positive correlation with log UAE (r=0.37, P0.001) and a significant negative correlation with eGFR (r=-0.33, P0.01). CONCLUSIONS High levels of aldosterone relative to renin, which did not fulfill confirmatory criteria for PA, may be one of the risk factors for the development of diabetic nephropathy in patients with diabetes. The present results are supported by previous research showing that an increased ARR without PA was a risk factor for kidney disease.

In superior vena cava occlusion, multiple collateral pathways develop to maintain venous drainage. Major patterns and pathways of venous collateral blood flow are well described, but rarely in complete chronic superior vena cava occlusion secondary to malignancy. A 59-year-old man with facial and upper extremity edema had a severely compressed superior vena cava at the initial diagnosis of stage IV mediastinal lung adenocarcinoma. The occlusion of superior vena cava progressed. After 10 months of treatment, the complete occlusion led to mild symptoms of hoarseness, muscle weakness, cough, and slight upper extremity edema. Venography clearly illustrated well-developed venous collateral blood flow through lateral thoracic, azygos-hemiazygos, and vertebral collateral venous pathways classified as Stanford type IV. The patient survived for a total of 20 months. He maintained Eastern Cooperative Oncology Group performance status of 1-2 until 2 months before death without severe symptoms of superior vena cava occlusion. This case described a rarely occurring venographic demonstration of well-developed Stanford type IV collateral pathway. Moreover, even with complete superior vena cava occlusion, well-developed Stanford type IV lateral thoracic collateral pathway can compensate for the venous flow without deterioration of performance status for a long period in certain cases. Keywords: Collateral, Complete occlusion, Lateral thoracic pathway, Lung cancer, Stanford type IV, Superior vena cava syndrome

Aim: A close association between primary aldosteronism (PA) and atherosclerosis has been well established. We aimed to determine the association between plasma renin activity (PRA) and aldosterone levels (PAC) as well as their ratios (PAC-to-PRA ratio: ARR) with urinary albumin excretion (UAE) in type 2 diabetic patients who did not fulfill PA confirmatory criteria. Methods: The subjects were 70 type2 diabetic patients (age: 53.3±11.0 years, male: 51, female: 19) with UAE ≤100 mg/gCr. They did not take ACE inhibitors, angiotensin receptor blockers (ARB) or diuretic agents. Patients were selected for this study based on various criteria: PRA level ˂10 ng/ml/hr, PAC ˂20 ng/dl, and ARR ˂20 (ng/dl per ng/ml/hr). They were divided into three groups according to UAE levels: NL group (N=33) ˂ 10mg/gCr, N group (N=22) 10-29 mg/gCr, and M group (N=15) 30-100 mg/gCr. Results: There were no significant differences in age, BMI, HbA1c, and eGFR levels among the three groups. The systolic blood pressure in the M group was significantly higher than those in the NL and N groups. The ARR in the M group was 10.1±4.6, which was significantly higher than those in NL (6.5±0.3) or N (7.0±2.7) groups. In the M group, the levels of PRA and PAC were significantly lower than those in NL or N groups. Log UAE was positively correlated with ARR (r=0.34, p Conclusion: These results suggest that a high ARR level, which did not fulfill confirmatory criteria for PA, was associated with diabetic nephropathy. The relative increase in PAC to PRA might contribute to the development of diabetic nephropathy, even if PAC remains normal level. Disclosure M. Higa: None. T. Suzuki: None. T. Kido: None. M. Zenri: None. K. Nao: None. M. Hijikata: None. K. Yamashita: None. K. Ikehara: None. T. Ichijo: None.

Objective: We investigated whether barley with a high β-glucan content (7.2 g per 100 g) improves postprandial plasma glucose levels and fluctuations using a meal tolerance test and Continuous Glucose Monitoring (CGM) in patients with type 2 diabetes. Methods: A meal tolerance test (500 kcal) was conducted using two types of test meals: one with white rice (WR diet) and one with white rice mixed 1:1 with high β-glucan-containing barley (BR diet). Both meals included the same side dish. Plasma glucose changes over 180 minutes were compared after ingestion of the test meals. In addition, participants wore a CGM device for the 2 study days, to measure the daily variations in glucose levels when the WR or BR diet as staple food was provided 3 times a day with the same side dish in both meals. Results: Twenty-nine patients with type 2 diabetes (age 52.5 ± 15.1 years, BMI 27.5 ± 4.7 kg/m2, HbA1c 8.1 ±1.8 %) were included in this study. The incremental area under the curve of plasma glucose levels after BR diet ingestion was significantly lower than that after WR diet ingestion (7934.0 ± 4151.2 vs 9434.0 ± 4701.2 mg·min/dL). CGM showed a 24-hour standard deviation of blood glucose after the BR diet was significantly lower than that after the WR diet. Conclusion: These results suggest that postprandial plasma glucose elevation and fluctuation in patients with type 2 diabetes are suppressed by adding high-β-glucan barley to white rice in meals.

Aims To identify factors predicting a need for insulin therapy in gestational diabetes mellitus (GDM) by comparing plasma glucose (PG) levels in a 75-g oral glucose tolerance test (75-g OGTT) with those in a 500-kcal meal tolerance test (MTT) containing 75 g of carbohydrate. Subjects and methods The MTT was performed in 61 patients who diagnosed with GDM by a 75-g OGTT (age, 33.2 ± 4.5 years; prepregnancy body mass index, 22.6 ± 4.7 kg/m2; number of gestational weeks, 25.1 ± 6.4 weeks). PG and serum insulin levels were measured before the meal and up to 180 min after the meal. The insulin secretion capacity and resistance index were calculated. Results PG levels increased from 86.8 ± 8.8 mg/dL at fasting to 132.7 ± 20.1 mg/dL at 30 min, and 137.8 ± 27.7 mg/dL at 60 min after MTT in the 35 patients with needed insulin therapy; these levels were significantly higher than those in the 26 patients, who only needed diet therapy. The patients with needed insulin therapy had significantly higher fasting PG levels in the 75-g OGTT, PG levels at fasting and 30 min after the MTT, and homeostasis model assessment of insulin resistance (HOMA-IR), and a significantly lower disposition index (DI) and insulin index than patients treated by diet alone. Receiver operating characteristic curve analysis was performed for factors involved in insulin therapy, with the following cutoff values: fasting PG in the 75-g OGTT, 92 mg/dL; PG 30 min after MTT, 129 mg/dL; HOMA-IR, 1.51; DI, 3.9; HbA1c, 5.4%. Multivariate analysis revealed that the 30-min PG level after MTT and HOMA-IR predicted insulin therapy. Conclusion PG levels at 30 min after MTT may be useful for identifying patients with GDM, who need insulin therapy.

IntroductionGiven an increasing use of dipeptidyl peptidase-4 (DPP-4) inhibitors to treat patients with type 2 diabetes mellitus in the real-world setting, we conducted a prospective observational study (Japan-based Clinical Research Network for Diabetes Registry: J-BRAND Registry) to elucidate the safety and efficacy profile of long-term usage of alogliptin.Research design and methodsWe registered 5969 patients from April 2012 through September 2014, who started receiving alogliptin (group A) or other classes of oral hypoglycemic agents (OHAs; group B), and were followed for 3 years at 239 sites nationwide. Safety was the primary outcome. Symptomatic hypoglycemia, pancreatitis, skin disorders of non-extrinsic origin, severe infections, and cancer were collected as major adverse events (AEs). Efficacy assessment was the secondary outcome and included changes in hemoglobin A1c (HbA1c), fasting blood glucose, fasting insulin and urinary albumin.ResultsOf the registered, 5150 (group A: 3395 and group B: 1755) and 5096 (3358 and 1738) were included for safety and efficacy analysis, respectively. Group A patients mostly (>90%) continued to use alogliptin. In group B, biguanides were the primary agents, while DPP-4 inhibitors were added in up to ~36% of patients. The overall incidence of AEs was similar between the two groups (42.7% vs 42.2%). Kaplan-Meier analysis revealed the incidence of cancer was significantly higher in group A than in group B (7.4% vs 4.8%, p=0.040), while no significant incidence difference was observed in the individual cancer. Multivariate Cox regression analysis revealed that the imbalanced patient distribution (more elderly patients in group A than in group B), but not alogliptin usage per se, contributed to cancer development. The incidence of other major AE categories was with no between-group difference. Between-group difference was not detected, either, in the incidence of microvascular and macrovascular complications. HbA1c and fasting glucose decreased significantly at the 0.5-year visit and nearly plateaued thereafter in both groups.ConclusionsAlogliptin as a representative of DPP-4 inhibitors was safe and durably efficacious when used alone or with other OHAs for patients with type 2 diabetes in the real world setting.

Polyunsaturated fatty acid (PUFA) is an essential class of dietary fatty acids, because of the lack of endogenous enzymes for desaturation in humans. Previous research on n-3 PUFA has demonstrated several health benefits and antiatherogenic actions, but n-6 PUFA have not received much research attention. We investigated whether serum fatty acid composition, especially n-6 PUFAs and desaturase activity, is associated with obesity in type 2 diabetic patients. Subjects were 80 type 2 diabetic patients (age: 60.3±13.9 years) who had no EPA agent intake. They were divided into two groups: obese group (n=52) with a BMI more than 25 kg/m2 and non-obese group (n=28) with a BMI less than 25 kg/m2. Fatty acid levels in serum were measured using gas chromatography. The desaturase activity for n-6 PUFAs was calculated as the arachidonic acid/dihomo-gamma-linolenic acid (DGLA) ratio for Δ5 desaturase (D5D). The obese group revealed a higher saturated fatty acid (SFA) and DGLA levels than those in the non-obese group. No significant difference was observed in the serum n-3 PUFA levels between the two groups. The D5D index of the obese group was significantly lower than that of the non-obese group. Serum DGLA levels showed significant positive correlations with waist circumference, BMI, triglyceride, and hepatic AST and ALT levels. Moreover, SFA showed a significant positive correlation with BMI. The levels of D5D index showed a significant negative correlation with BMI. Increase in serum DGLA levels was related to the number of metabolic factors. These results suggest that type 2 diabetic patients with obesity had changes in their blood fatty acid profile, especially increased DGLA levels. The high levels of blood DGLA indicate downregulation of n-6 metabolism, probably caused by the decreased activity of D5D. The fat quality in the diet and changes in desaturase activity might contribute to the development of obesity. Disclosure M. Saito: None. M. Higa: None. T. Suzuki: None. M. Michishita: None. M. Hijikata: None. K. Yamashita: None. K. Ikehara: None. T. Ichijo: None.

Nonalcoholic fatty liver disease (NAFLD), which is currently the most prevalent liver disorder, not only leads to chronic liver disease but is also associated with cardiovascular mortality. Several studies have conclusively established that increased arterial stiffness is an independent risk factor for cardiovascular events and that the brachial-ankle pulse velocity (baPWV) is a useful clinical indicator of arterial stiffness for early evaluation of functional and structural changes in vessel walls. The aim of this study was to assess whether ultrasonographically diagnosed fatty liver disease is associated with arterial stiffness and carotid intima-media thickness (CIMT) in type 2 diabetic patients. The subjects were 294 type 2 diabetic patients (age: 66.4±10.3 years). Patients with and without fatty liver (FL) were categorized into the FL group (n=155), and non-FL group (n=139), respectively. The baPWV was measured as an index of arterial stiffness, and structural changes in vessel walls were assessed using the CIMT obtained with B-mode ultrasonography. BMI, waist circumference, blood pressure, serum LDL-C, triglyceride (TG), and HbA1c levels, as well as the baPWV and CIMT levels were significantly higher in the FL than in the non-FL group. Serum levels of TG, hepatic AST, age, waist circumference and systolic blood pressure showed significant positive correlations with baPWV, respectively. However, no significant association was observed between the CIMT and serum hepatic AST levels. Multiple regression analysis showed that serum hepatic AST and ALT were independently associated with increased baPWV. Our findings suggest that NAFLD is associated with increased arterial stiffness. This is a clinically significant observation because it implicates arterial stiffness in the pathogenesis of NAFLD, suggesting that abdominal obesity and low-grade inflammation might be key etiopathogenetic contributors to both hepatic steatosis and macrovascular disease in type 2 diabetic patients. Disclosure M. Higa: None. M. Hijikata: None. K. Yamashita: None. T. Suzuki: None. M. Saito: None. M. Michishita: None. K. Ikehara: None. T. Ichijo: None.

Osimertinib has demonstrated efficacy against stable or asymptomatic central nervous system (CNS) metastases of epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) in phase 2 and 3 clinical trials that allowed prior CNS radiotherapy. However, the efficacy of osimertinib only or the optimal treatment combination or sequence of radiotherapy has not been investigated. A 74-year-old woman diagnosed with T4N1M1c Stage IVB lung adenocarcinoma with EGFR mutation presented with a left upper lobe mass and multiple bilateral lung metastases. A total of more than 20 asymptomatic multiple brain metastases with a maximum diameter of 12 mm were diagnosed simultaneously. Osimertinib was administered as first-line treatment. Whole brain radiotherapy was deferred because she had no neurological symptoms. After 5 weeks, the multiple brain metastases disappeared completely, together with the response in the lung lesions. This case demonstrated that first-line treatment with osimertinib could even achieve complete remission of multiple brain metastases comprising as many as twenty lesions of EGFR-mutated NSCLC without radiation therapy. Radiation therapy for brain metastases can be deferred or even withheld. A new treatment strategy for EGFR mutated NSCLC with CNS metastases should be investigated using osimertinib, especially regarding optimal combination or sequence of radiotherapy.

Background Few prospective studies have compared the cardiovascular benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors. We aimed to clarify the efficacy of dapagliflozin versus sitagliptin for modulating cardiometabolic risk factors including high glycated hemoglobin (HbA1c) levels, hypoglycemia, and body weight. Methods This prospective, randomized, open-label, blinded-endpoint, parallel-group trial enrolled 340 Japanese patients with early-stage type 2 diabetes receiving metformin alone or no glucose-lowering agents, who were randomized to receive dapagliflozin or sitagliptin for 24 weeks. The primary endpoint was the proportion of patients who achieved the composite endpoint of HbA1c level maintenance Results Clinical characteristics of patients were age, 58.1 ± 12.2 years; known duration of diabetes, 5.8 ± 6.1 years; body weight, 74.7 ± 14.2 kg; body mass index, 27.9 ± 4.1 kg/m2; and HbA1c level, 7.8 ± 0.8% at baseline. The achievement ratio of primary endpoint was significantly higher in the dapagliflozin group than in the sitagliptin group (24.4% vs. 13.8%, P P Conclusions Compared to sitagliptin, dapagliflozin was significantly more effective at improving cardiometabolic risk factors, suggesting that SGLT2 inhibitors might be more suitable than DPP-4 inhibitors for preventing cardiovascular events in patients with early-stage but inadequately controlled type 2 diabetes. Trial registration Trial number, UMIN000028014; registered on June 30, 2017

Introduction It is unclear whether adding basal insulin or enhancing incretin signaling with a glucagon-like peptide-1 receptor agonist (GLP-1RA) is more effective as an up-titration strategy after dipeptidyl peptidase-4 inhibitor (DPP-4i)-based oral antidiabetic drug (OAD) therapy. GLP-1RAs can be injected without dose adjustment, unlike basal insulin. Our objective was to examine the efficacy of changing patients inadequately controlled with oral DPP-4i-based OAD therapy to injectable GLP-1RA and discontinuing the DPP4i versus adding basal insulin glargine (IGlar) with the continuation of the oral DPP4i. Methods Sixty patients with type 2 diabetes (T2DM) and glycated hemoglobin (HbA1c) between 7.0% and 10.0% on DPP-4i-based OAD therapy were randomized to either adding IGlar and remaining on the DPP-4i or liraglutide and discontinuing the DPP-4i for 24 weeks. Patients in the IGlar group started with 0.1 unit/kg and were titrated according to the algorithm. In the liraglutide group, the DPP-4i was replaced with liraglutide 0.9 mg/day, the maximum dose in Japan. We evaluated HbA1c, glycated albumin (GA), and anthropometrics. Results HbA1c was significantly lower at week 24 (− 1.0 ± 0.9% in the IGlar group and − 0.6 ± 0.8% in the liraglutide group), but the difference between groups was not significant. Changes in GA were similar (− 2.9 ± 3.2% vs. − 2.6 ± 3.2%) in both groups. Body weight (BW) was significantly lower only in the liraglutide group (+ 0.5 ± 2.6 kg vs. − 2.2 ± 2.0 kg). The rate of minor hypoglycemic episodes was similar for both groups. Conclusion For poorly controlled T2DM on DPP-4i-based OAD therapy, switching to single-dose liraglutide to enhance incretin signaling is as effective as dose-titrated basal IGlar, but significant BW reduction was only seen in the liraglutide group. These results suggest that enhancing incretin signaling with a single-dose injectable GLP-1 RA might be an alternative to dose-titrated basal insulin therapy in patients with T2DM poorly controlled with DPP-4i-based OAD therapy. These findings should be confirmed in a longer and larger trial. Trial Registration Trial Registry (UMIN-CTR) as UMIN000012224. Electronic supplementary material The online version of this article (10.1007/s13300-018-0486-1) contains supplementary material, which is available to authorized users.

The aim of our study was to investigate whether high β-glucan-containing barley (7.2 g per 100 g) improves postprandial plasma glucose levels and suppresses postprandial insulin levels during a meal tolerance test in type 2 diabetic patients. A meal tolerance test (500 kcal) was conducted using two types of test meals: a test meal with white rice (WR) alone (WR diet) and a test meal with WR mixed with 50% barley (BR diet) as staple food. The side dish was the same in the both meals. The changes in plasma glucose and serum C-peptide immunoreactivity (CPR) levels for 180 minutes after ingestion of the test meals were compared. Ten patients with type 2 diabetes (age 52.5 ± 15.1 years, and 7 males and 3 females) were included in this study. The mean HbA1c level and body mass index were 8.8 ± 1.4%, and 29.7 ± 4.5 kg/m2, respectively. Plasma glucose levels after ingestion of the WR diet or BR diet peaked at 60 minutes, which showed no significant differences between the two types of test meals. However, the incremental area under the curve (IAUC) of plasma glucose levels after ingestion of BR diet was significantly lower than that of WR diet. The serum CPR levels at 180 min and their IAUC over 180 minutes after ingestion of BR diet were significantly lower than those of WR diet. Conclusion: Increase in postprandial plasma glucose and insulin levels was suppressed by mixing high-β-glucan barley with WR in type 2 diabetic patients.

Aim: Polyunsaturated fatty acids (PUFAs) are essential fatty acids, because they cannot be synthesized in the body and must be taken from food, but excessive intake may cause obesity. Therefore, the measurement of serum fatty acid composition is useful for monitoring the fat composition of the diet. In recent years, accumulating evidence has indicated the importance of gut microbiota in maintaining human health. The aim of our study was to evaluate the relationship between fatty acid composition and gut microbiota in obese patients with type 2 diabetes. Research Design and Method: The subjects included 100 patients (age: 60.3±13.9 years, BMI 27.5±5.8 kg/m2) who were not taking EPA agents. They were divided into two groups, i.e., obese group (n=64) with a BMI of greater than 25 kg/m2 and non-obese group (n=36) with a BMI less than 25 kg/m2. Serum levels of fatty acids were measured using gas chromatography. In 45 of 100 patients, gut microbiota profiles were measured using T-RFLP methods. Results: The serum levels of dihomo-gamma-linolenic acid (DGLA), which is an n-6 PUFA, and palmitic acid, a saturated fatty acid (SFA), were significantly higher in the obese group than in the non-obese group. No significant differences were observed in the serum levels of n-3 PUFA. The ratio of Firmicutes/Bacteroidetes in the fecal microbiota was significantly lower in the patients with high serum levels of DGLA. The rate of Bacteroidetes showed a significant positive correlation with serum DGLA and palmitic acid. Conclusion: These results suggest that high levels of serum DGLA may play an important role in the development of not only obesity but also gut microbiota in type 2 diabetes patients. The fat quality in the diet might contribute to the development of obesity. Disclosure M. Higa: None. M. Kawai: None. R. Eto: None. F. Ayako: None. G. Sato: None. M. Hijikata: None. K. Yamashita: None. T. Ichijo: None.

Aim: Elevated saturated fatty acid (SFA) and decreased polyunsaturated fatty acid (PUFA) levels, especially n-3 PUFAs levels are important in the development of obesity and metabolic syndrome, but there are few accounts of the relationship between fatty acid composition and diabetic kidney disease. We investigated whether serum fatty acid composition, especially SFA and PUFA, are associated with urine albumin excretion (UAE) and estimated glomerular filtration rate (eGFR) in obese type 2 diabetic patients. Research Design and Method: The subjects were 85 patients (age: 60.3±13.9 years old, 47 male and 38 female) who were not taking EPA agents. They were divided into two groups, i.e., Obese group (n=54) with a BMI of more than 25 kg/m2 and non-Obese group (n=31) with a BMI below 25 kg/m2. Serum levels of fatty acids were measured by gas chromatography. Results: In the Obese group, the serum levels of palmitic acids and stearic acids, which belong to SFA, and dihomo-gamma-linolenic acid (DGLA), which is an n-6 PUFA, were significantly higher than those in the non-Obese group. No significant differences were seen in the serum levels of n-3 PUFA. UAE in the Obese group was 218.8±88.9 mg/gCr, which tended to be higher than that in the non-Obese group (135.9±49.0 mg/gCr), but there were no significant differences in eGFR between the two groups. The serum levels of palmitic acids, stearic acids, and DGLA showed significant positive correlations with UAE and eGFR in the Obese group, while no significant correlation was seen in the non-Obese group. Palmitic acids and DGLA were correlated with serum adiponectin and leptin levels. Conclusion: These results suggest that an excessive lipid intake may play an important role in the development of not only obesity but also diabetic kidney disease. The high levels of blood SFA and n-6 PUFA might contribute to the diabetic kidney disease progression via hyperfiltration and inflammatory effects in type 2 diabetes patients with obesity. Disclosure M. Kawai: None. R. Eto: None. F. Ayako: None. G. Sato: None. M. Hijikata: None. K. Yamashita: None. T. Ichijo: None. M. Higa: None.

Background: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have attracted attention by the recently reported improved cardiovascular (CV) outcomes in patients with T2DM. In contrast, dipeptidyl peptidase 4 inhibitors (DPP-4i) were reported neutral on CV outcomes. However, there are few prospective studies that have compared the efficacy of SGLT2i and DPP-4i on the prevention of CV disease risks. Therefore, we planned this prospective, randomized, parallel-group trial aimed to compare the therapeutic benefits of dapagliflozin (Dapa) and sitagliptin (Sita) on CV disease risks, with special focus on HbA1c, body weight (BW), and hypoglycemia. Methods: A total of 340 T2DM patients treated with metformin alone or with no glucose-lowering agents (20-80 years of age, HbA1c ≥ 7.1% and < 10.0%) were equally randomized to Dapa 5 mg/day or Sita 50 mg/day add-on group, and treated for 24 weeks. After the 8 weeks, if HbA1c is 7.0% or higher, Dapa and Sita were increased to 10 mg/day and 100 mg/day, respectively. The primary endpoint was the ratio of achieving composite endpoints of the following all 3 items; 1) HbA1c below 7.0%; 2) 3.0% BW loss from baseline; 3) avoidance of hypoglycemia {< 3.0 mmol/L (< 54 mg/dL)}. Hypoglycemia was monitored by flash glucose monitoring system. Results: The achievement ratio of HbA1c below 7.0% was comparable between the groups (49.4 vs. 50.0%, p=1.00, Dapa vs. Sita, respectively). However, 3.0% BW loss was preferably achieved in Dapa group (54.4 vs. 19.6%, p In summary, Dapa treatment for 24 weeks improved CV risk factors in patients with inadequately controlled T2DM. This study provides the evidence on ideal therapeutic choice for preventing CV events in T2DM. Disclosure A. Fuchigami: None. F. Shigiyama: None. T. Kitazawa: Speaker’s Bureau; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Y. Okada: None. T. Ichijo: None. M. Higa: None. T. Hiyoshi: Other Relationship; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly Japan K.K., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. I. Inoue: None. K. Iso: Research Support; Spouse/Partner; AstraZeneca. H. Yoshii: None. T. Hirose: None. N. Kumashiro: Speaker’s Bureau; Self; Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Funding AstraZeneca K.K.

It is well known the primary aldosteronism (PA) is most common endocrinological hypertension and accounted for 10% among all hypertension population, and it develops cardiovascular disease more frequently than blood pressure matched essential hypertension. Many literatures have been reported patients with obesity often shows hyperaldosteronism by hyperactivation of sympathetic nerves, over secretion from adipocytes themselves, or aldosterone-secreting factors from adipocytes. Thus, we investigated the impact of BMI on diagnosis of PA in this study. We investigated 328 cases of adrenal venous sampling performed patients with PA in our hospital since 2007, including 125 males and 203 females, and their mean age was 56.1 ± 11.8 years old. We evaluated the relationship of those patients’ body mass index (BMI) with gender, systolic and diastolic blood pressure (SBP and DBP, respectively), serum sodium, serum potassium, plasma renin activity (PRA), plasma aldosterone concentration (PAC), aldosterone-renin ratio (ARR), ACTH, cortisol, and the ratio of patients who showed 1 mg dexamethasone suppression test positive, and none of each showed statistical relationship with BMI. In confirmatory tests, we evaluated those values of PRA at 120 min. in upright furosemide test, either higher values of ARR at 60min. or 90 min. in captopril challenge test, and PAC at 4 hours in saline infusion test (SIT), also positive ratio of those test considered by PRA 20, and PAC>6.0 in those tests, respectively. In adrenal venous sampling (AVS), we evaluated lateralized ratio (LR) and contralateral ratio (CR) and those positive ratios considered by LR >4 or CR4 and CR

The effect of white rice (WR) mixed with high β-glucan-containing barley at 50% on improvement of postprandial blood glucose levels was assessed by meal tolerance test and continuous glucose monitoring (CGM) in 15 healthy subjects with normal glucose tolerance (age 31.6 ± 12.9 years old, 4 males and 11 females). A meal tolerance test (500 kcal) was conducted using 2 types of test meals: a test meal only with WR and a test meal WR mixed 50% barley, and the side dish was the same in both meals. Blood glucose levels of the subjects 180 minutes after ingestion of the test meals were compared. In addition, a CGM device was attached to the subjects for 2 days when the WR or barley as a staple food was provided 3 times a day for consecutive days, and the daily variation of glucose was investigated. The glucose levels 30 minutes after dietary loads and the area under the blood concentration-time curve over 180 minutes were significantly decreased in the barley consumption group. In CGM, 24-hour mean blood glucose and 24-hour standard deviation of blood glucose were also significantly decreased after ingestion of the barley. Postprandial glucose level elevation was suppressed by mixing high-β-glucan barley with WR in subjects with normal glucose tolerance.

Increasing evidence supports a more prominent role for postprandial glucose (PPG) regulation in the management of type 2 diabetes. Viscous dietary fibers including oat and barley β-glucan are one of the most effective classes of functional food ingredients for reducing PPG. We investigated the effect of high β-glucan barley on postprandial plasma glucose and C-peptide levels using a meal tolerance test and continuous glucose monitoring (CGM) in 15 subjects with normal glucose tolerance (NGT) and 29 type 2 diabetic patients. A 500-kcal meal tolerance test, using white rice alone (white rice) or white rice mixed with 50% of barley (Kirari-mochi®) containing 1.5-times β-glucan higher than usual barley (barley), was performed, and plasma glucose and C-peptide levels were measured every 30 minutes for 180 minutes. Daily glucose variability was measured using CGM over two days, while subjects consumed 1600-kcal or 1800-kcal test meals consisting of white rice or barley. Subsequently, a meal tolerance test with identical carbohydrate quantity (52g carbohydrate) with or without 1.8g of β-glucan, was performed in 7 diabetic patients. In NGT subjects and diabetic patients, the incremental area under the curve (AUC) of plasma glucose and C-peptide levels for 180 minutes after the meal tolerance test were significantly decreased following the consumption of barley compared to the consumption of white rice alone. The studies using CGM have demonstrated that the consumption of barley lead to a significant decrease in the 24-h standard deviation of blood glucose (24-h SDBG) and mean amplitude of glycemic excursion (MAGE) in diabetic patients. Similar results were obtained in subsequent tests with identical carbohydrate quantity but with β-glucan. In conclusion, these results suggest that high-β-glucan barley may contribute to decreased PPG levels and endogenous insulin secretion in both patients with type 2 diabetes and the subjects with NGT. Disclosure M. Higa: None. A. Hashimoto: None. M. Hayasaka: None. M. Hijikata: None. A. Ueda: None. K. Oda: None. D. Kato: None. K. Yamashita: None. T. Ichijo: None.

Protein S (PS) deficiency, an autosomal dominant hereditary thrombophilia, is more prevalent in East Asian populations than in Caucasians. PS-deficient patients have historically been administered a heparin product followed by warfarin for the treatment and secondary prevention of venous thromboembolism (VTE). However, warfarin can be ineffective or causes detrimental effects in rare cases. While direct oral anticoagulants (DOACs) are being increasingly used for the treatment and prevention of VTE, their efficacy in PS-deficient patients has not been established. We describe a 91-year-old woman who presented with chronic bilateral lower leg swelling with VTE that was refractory to warfarin anticoagulation therapy for over 1 year. Her recurrent VTE was diagnosed as quantitative hereditary PS deficiency. Rivaroxaban was administered as maintenance therapy instead of warfarin; after 8 weeks, the severities of the patient’s leg swelling and venous ulcerations were significantly reduced with rivaroxaban compared to warfarin, thus demonstrating the efficacy of rivaroxaban for warfarin-refractory chronic VTE associated with hereditary PS deficiency. This case illustrates that rivaroxaban can potentially serve as therapeutic agents to treat warfarin-refractory VTE in PS-deficient patients. Further investigations are required to confirm the efficacy of rivaroxaban on the long term in this regard.

Background: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is widely used in patients with type 2 diabetes. However, the pleiotropic effects of sitagliptin is not well understood. Objective: To assess the clinical efficacy and safety of sitagliptin on atherosclerosis, β-cell function, and glycemic control in Japanese patients with type 2 diabetes. Methods: A prospective observational study of 270 patients with type 2 diabetes mellitus was carried out. Patients (aged 64.3 [12.4] years, body mas index 25.2 [4.3]) with glycated hemoglobin >6.9% (52 mmol/mol) or fasting plasma glucose >130 mg/dL were treated with sitagliptin for 12 months. The primary end point was glycated hemoglobin level changes from baseline to 3 months. The secondary end points included changes in several biomarkers related to inflammation and β-cell function from baseline to 3 months, as well as changes in glycated hemoglobin level from baseline to 12 months. Results: Glycated hemoglobin levels were significantly lower in patients treated with sitagliptin for 3 months than at baseline (8.1% [1.4%]–7.3% [1.2%]) (65 [16.9]–56 [13.1] mmol/mol]) (P < 0.0001), which continued after 12 months (7.4% [1.3%]) (56 [15.2] mmol/mol) (P < 0.0001). In addition, a marker of vascular-specific inflammation, pentraxin-3, and a marker of β-cell function (proinsulin/insulin ratio), respectively, were lower after treatment with sitagliptin for 3 months than at baseline (1.88 [0.78]–1.65 [0.63] ng/mL [P = 0.0038] and 0.20 [0.14]–0.17 [0.11] [P = 0.01], respectively). On the other hand, a biomarker reflecting whole body inflammation; that is, high-sensitivity C-reactive protein level, was unchanged. Adverse events occurred in 14 patients (5.18%). Conclusions: Sitagliptin may have beneficial effects on vascular inflammation and β-cell function in Japanese patients with type 2 diabetes. Pentraxin-3 may be an early predictive marker for detecting the antiatherosclerotic effects of dipeptidyl peptidase-4.

We examined the correlation between blood levels of dihomo-gamma-linolenic acid (DGLA), which belongs to the n-6 polyunsaturated fatty acids (PUFAs), and obesity in type 2 diabetic patients. The subjects were 62 type 2 diabetic patients (age 63.3 ± 9.3 years; 35 males and 27 females) who were not taking eicosapentaenoic acid (EPA) agents and were divided into two groups, i.e., an obese group (n = 29) with BMIs >25 kg/m2 and non-obese group (n = 33) with BMIs

We report a rare case of diabetic mastopathy in man with type 2 diabetes. The patient was a 64-year-old man who had suffered from type 2 diabetes for 18 years. He had poor glycemic control, and also had retinopathy and nephropathy. Seven years ago, he had undergone a mastectomy on the left side because of a breast mass. However, pathogenesis of the resected mass was not known. He developed a hard and mobile mass (diameter 4 cm) under the nipple of his right breast and complained of slight pain. Mammography revealed a dense mass without calcification, and ultrasonography revealed a hypoechoic lesion with unclear boundaries, acoustic shadows, and Doppler color flow. When a core needle aspiration biopsy was performed to exclude breast cancer the mass was diagnosed as diabetic mastopathy. As far as we know, this was the second case of diabetic mastopathy involving a man to occur in Japan.

Objective To analyse the efficacy of low-dose rosuvastatin for treating hypo high-density lipoprotein (HDL) cholesterolaemia in patients with type 2 diabetes and dyslipidaemia. Methods Patients with HDL-cholesterol (C) Results Out of 49 patients, all lipid parameters other than TG were significantly improved at 3 and 6 months. At 3 months, 83.3% of patients had achieved the target LDL-C level. Among nonlipid parameters, no changes were observed except for estimated glomerular filtration rate, which was improved by + 5.2% and + 9.6% at 3 and 6 months, respectively. Conclusions Low-dose rosuvastatin was effective in improving hypo-HDL cholesterolaemia and may have renoprotective effects.

Helicobacter cinaedi infection is recognized as an increasingly important emerging disease in humans. Although H. cinaedi -like strains have been isolated from a variety of animals, it is difficult to identify particular isolates due to their unusual phenotypic profiles and the limited number of biochemical tests for detecting helicobacters. Moreover, analyses of the 16S rRNA gene sequences are also limited due to the high levels of similarity among closely related helicobacters. This study was conducted to evaluate intact-cell mass spectrometry (ICMS) profiling using matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) as a tool for the identification of H. cinaedi . A total of 68 strains of H. cinaedi isolated from humans, dogs, a cat, and hamsters were examined in addition to other Helicobacter species. The major ICMS profiles of H. cinaedi were identical and differed from those of Helicobacter bilis , which show >98% sequence similarity at the 16S rRNA sequence level. A phyloproteomic analysis of the H. cinaedi strains examined in this work revealed that human isolates formed a single cluster that was distinct from that of the animal isolates, with the exception of two strains from dogs. These phyloproteomic results agreed with those of the phylogenetic analysis based on the nucleotide sequences of the hsp60 gene. Because they formed a distinct cluster in both analyses, our data suggest that animal strains may not be a major source of infection in humans. In conclusion, the ICMS profiles obtained using a MALDI-TOF MS approach may be useful for the identification and subtyping of H. cinaedi .

Hemoglobin A1c (HbA1c) is used routinely to monitor long-term glycemic control in diabetic patients, but its accuracy can be affected adversely by the presence of Hb variants. More than 20 methods for determination of HbA1c are commercially available to clinical laboratories. We report a diabetic patient with Hb variant Hb Mito that was discovered incidentally following the use of a different method of HbA1c measurement. A 66-year-old Japanese woman with an 11-year history of type 2 diabetes was referred to our hospital with hyperglycemia diagnosed from a HbA1c level of 12.2 % measured by immunonephlometry method. Her HbA1c could not be measured by high-performance liquid chromatography (HPLC) in our hospital. Her blood glucose level was 273 mg/dl, and her glycosylated albumin was 33.9 %. She was diagnosed as having Hb Mito (β144 Lys → Glu) by mutation sequence analysis. This was the second case in Japan since the first case was reported in 1985 according of our survey of the literature.

We report a 48-year-old man with thrombosis of the portal and superior mesenteric vein and inferior vena cava associated with primary antiphospholipid syndrome (APS). Primary APS was diagnosed by a positive reaction with anticardiolipin antibody (aCL) and the absence of any evidence suggesting the presence of other disease states known to be associated with aCL. A coeliac angiography showed obstruction of the portal and superior mesenteric vein with prominent collaterals and cavernous transformation. Femoral vein angiography showed total obstruction of the external iliac vein and inferior vena cava, and dilation of the pelvic veins, with contrast medium in the lumbar vein. This case is noteworthy as a report of primary APS accompanied by extensive abdominal and pelvic venous thrombosis.

We report a 70-year-old woman with hypothyroidism and severe hyponatremia. Her plasma antidiuretic hormone (ADH) level was inappropriately high for her low plasma osmolality. Her low serum sodium level was gradually corrected by water restriction and sodium supplementation prior to the initiation of thyroid hormone replacement. After a diagnosis of Hashimoto's thyroiditis had been made, the patient was treated with levothyroxine. Following this treatment, the patient's serum sodium level increased drastically. It is suggested that the elevated plasma ADH level played an important role in the development of hyponatremia in this case.

The crystal structure of a novel component of the mannan biodegradation system, 4-O-β- d -mannosyl- d -glucose phosphorylase (MGP), was determined to a 1.68-A resolution. The structure of the enzyme revealed a unique homohexameric structure, which was formed by using two helices attached to the N-terminus and C-terminus as a tab for sticking between subunits. The structures of MGP complexes with genuine substrates, 4-O-β- d -mannosyl- d -glucose and phosphate, and the product d -mannose-1-phosphate were also determined. The complex structures revealed that the invariant residue Asp131, which is supposed to be the general acid/base, did not exist close to the glycosidic Glc-O4 atom, which should be protonated in the catalytic reaction. Also, no solvent molecule that might mediate a proton transfer from Asp131 was observed in the substrate complex structure, suggesting that the catalytic mechanism of MGP is different from those of known disaccharide phosphorylases.

The consecutive genes BF0771–BF0774 in the genome of Bacteroides fragilis NCTC 9343 were found to constitute an operon. The functional analysis of BF0772 showed that the gene encoded a novel enzyme, mannosylglucose phosphorylase that catalyzes the reaction, 4-O-β- d -mannopyranosyl- d -glucose + Pi → mannose-1-phosphate + glucose. Here we propose a new mannan catabolic pathway in the anaerobe, which involves 1,4-β-mannanase (BF0771), a mannobiose and/or sugar transporter (BF0773), mannobiose 2-epimerase (BF0774), and mannosylglucose phosphorylase (BF0772), finally progressing to glycolysis. This pathway is distributed in microbes such as Bacteroides, Parabacteroides, Flavobacterium, and Cellvibrio.

Introduction To date, there have been no reports on the prevalence of adrenal masses in type 2 diabetic patients. The present study aimed to evaluate the prevalence of adrenal incidentaloma in type 2 diabetic patients in Japan. Subjects We retrospectively evaluated the presence of adrenal masses using abdominal CT scans in 304 type 2 diabetic patients. In those with adrenal masses, we examined the hormone production capacity of the adrenal mass. Results Fourteen patients (4.6%) had an adrenal mass. Hormonal analysis identified one case as having subclinical Cushing's syndrome, two with primary aldosteronism. Eleven cases had non-functioning masses. Discussion The reported prevalence of adrenal incidentaloma in normal subjects is 0.6-4.0% in abdominal CT scan series. Our results show a relatively high prevalence of adrenal tumors in diabetic patients. On the other hand, the frequency of functional adenoma in diabetic patients is 21.4%, which is similar to that of normal subjects. Conclusion Although further studies are needed to evaluate the prevalence of adrenal tumors in diabetic patients, our data suggest that evaluation of the presence of adrenal masses may be needed in patients with type 2 diabetes mellitus.