Abstract Aims/Introduction There are limited reports on the association between melatonin levels and vascular complications in patients with type 2 diabetes. The aim of this study was to determine the association between urinary 6‐sulfatoxymelatonin, which is a urinary metabolite of melatonin, and diabetic vascular complications or arteriosclerosis in patients with type 2 diabetes. Materials and Methods This retrospective study included patients (167 patients with type 2 diabetes and 27 patients without diabetes adjusted for age and sex) admitted to the hospital who underwent measurement of urinary 6‐sulfatoxymelatonin. The urinary 6‐sulfatoxymelatonin/creatinine ratio (6‐SMT) was calculated. Results The natural logarithmically scaled 6‐SMT level (Ln 6‐SMT) was significantly lower in type 2 diabetes patients (1.9 ± 1.1) compared with patients without diabetes (2.8 ± 1.0, P < 0.001). Multivariate linear regression analysis identified duration of diabetes, smoking status, urinary albumin‐to‐creatinine ratio, retinopathy and coronary heart disease as factors that could influence Ln 6‐SMT levels in type 2 diabetes patients (R2 = 0.232, P < 0.001). Ln 6‐SMT was associated with decreased odds of diabetic retinopathy, even after adjustment for various confounding factors (odds ratio 0.559, 95% confidence interval 0.369–0.846, P = 0.006). Similarly, Ln 6‐SMT was associated with decreased odds of coronary heart disease (odds ratio 0.442, P = 0.030). Conclusions Our results showed the presence of low levels of Ln 6‐SMT in type 2 diabetes patients relative to patients without diabetes. Furthermore, Ln 6‐SMT is an independent risk factor of diabetic retinopathy and coronary heart diseases. These findings suggest that 6‐SMT could be a useful biomarker for the prediction of micro‐ and macrovasculopathies in patients with type 2 diabetes.

It is difficult to detect glycemic excursions using CGM in daily clinical practice. We retrospectively analyzed CGM data in type T2DM to define the correlations between HbA1c and GA levels at admission and the parameters representing glycemic excursions measured by CGM, including the mean amplitude of glycemic excursions (MAGE) and standard deviation (SD). The MAGE correlated significantly with GA and HbA1c, but not with the GA/HbA1c ratio. The SD correlated significantly with GA, HbA1c, and GA/HbA1c. Multivariate analysis identified the GA value to be the most reflective of MAGE. Patients were divided into 2 groups using a MAGE cutoff value of 75 mg/dl, which reflects stable diabetes. There was a significant difference in GA, but not HbA1c, between the groups with low and high mean amplitudes of glycemic excursions. Receiver operating characteristic curve analysis indicated that the cutoff for GA for identifying patients with MAGE of ≤75 mg/dl was 18.1%. Our study identified GA to be the most reflective of glycemic excursions in patients with T2DM. GA can be a useful index of glycemic excursions and treatment optimization to prevent arteriosclerosis.

A 30-year-old female patient had been administered 5-mg/day prednisolone for systemic lupus erythematosus. She developed hypertension, dyslipidemia, moon face, central obesity, hypertrichosis, and impaired glucose tolerance. Although iatrogenic Cushing syndrome was initially suspected, we made a diagnosis of Cushing syndrome caused by a right adrenal adenoma, on the basis of the endocrine function test result and imaging findings. After surgery, the Cushingoid signs disappeared. Autoimmune diseases are often treated with corticosteroids; therefore, a differential diagnosis of primary Cushing syndrome should be made adequately.

Hypoglycemia is associated with cardiovascular diseases, increased risk of death. Therefore, it is important to avoid hypoglycemia. The aim of this study was to characterize hypoglycemia according to glycated hemoglobin (HbA1c) level and determine the contributing factors in type 2 diabetes mellitus (T2DM), using continuous glucose monitoring (CGM).

Objective Type 2 diabetes mellitus (T2DM) and rheumatoid arthritis (RA) are both complicated by arteriosclerosis, resulting in increased rates of cardiovascular events. No previous studies have compared the index between RA and T2DM. We assessed the vascular endothelial function in early-stage arteriosclerosis for each disease to determine the influential factors and compared the extent to which these two diseases cause vascular endothelial dysfunction. Methods This study is a retrospective study based on medical records. Differences in the reactive hyperemia index (RHI) among the groups and factors affecting the RHI in each group was analyzed. The vascular endothelial function was assessed by measuring the RHI using peripheral arterial tonometry. Patients The study subjects were 114 patients with non-functional thyroid tumors (healthy n=14), T2DM (T2DM n=64), and RA (RA n=36). Results The RHI was 2.29 in the control, 1.85 in the T2DM, and 1.83 in the RA group, with values lower in the T2DM and RA groups than in the control group (p=0.033) but not markedly different between the two disease groups. The RHI distribution (<1.68/1.68 to <2.10/≥2.1) was as follows: control group: 14.3%/28.6%/57.1%; T2DM group: 42.2%/39.1%/18.8%; and RA group: 36.1%/44.4%/19.4% (p=0.031), respectively. A multivariate analysis identified the triglyceride level and dyslipidemia in the control group and the Disease Activity Score in 28 joints with the erythrocyte sedimentation rate and fasting plasma glucose level in the RA group to influence the RHI. Conclusion The vascular endothelial function was impaired in approximately 80% of patients with T2DM and RA, with comparable degrees of impairment between the two diseases. No factors affecting the function were identified in the T2DM group, while the function was more impaired in patients with a higher disease activity in the RA group.

The aim of this retrospective study was to elucidate the association between glucose profile using the continuous glucose monitoring system (CGMS) and microvascular complications in patients with type 2 diabetes mellitus (T2DM). The subjects were 160 inpatients with T2DM. The mean blood glucose (MBG) level, percentage of time in a 24-hour period spent with blood glucose level higher than 180 mg/dl (time at >180 mg/dl), standard deviation (SD), and mean amplitude of glycemic excursions (MAGE) were measured continuously over 48 hours using the CGMS. The primary outcome was the association between microvascular complications and glycemic variability. The secondary outcome was the association between microangiopathies and MBG. The SD and MAGE were not associated with presence of microangiopathies or number of complications. There were also no associations between abnormal vibratory sensation in the bilateral lower extremities, coefficient of variation of the R-R interval (CVRR), retinopathy stage, nephropathy stage, or microalbuminuria. MBG was associated, however, with retinopathy, retinopathy stage, and number of complications. Time at >180 mg/dl correlated with abnormal vibratory sensation in the bilateral lower extremities and presence or stage of retinopathy. MBG and time at >180 mg/dl were not associated with presence or stage of nephropathy. Our findings suggest that broad glycemic variability was not associated with microvascular complications, the number of which increased in patients with a high mean glucose level and long time spent with hyperglycemia. It is important, therefore, to reduce the mean glucose level and time spent with hyperglycemia to prevent future microangiopathies.

The purpose of this study was to determine the glycemic profiles of drug-naïve type 2 diabetes patients according to hemoglobin A1c (HbA1c) level using continuous glucose monitoring. We aimed to clarify factors associated with HbA1c and average blood glucose level. Patients were divided into three groups according to their HbA1c level (< 7.0% n=23, 7.0% ≤ HbA1c < 8.0% n=17 and ≥ 8.0% n=31), and the factors associated with HbA1c and average glucose of each group were evaluated. Pre-meal glucose levels were the highest before lunch, and the 2 hour postprandial blood glucose level was the lowest after lunch. The pre-meal and postprandial blood glucose levels increased after each meal with increases in HbA1c. Average glucose level was the most significant determinant of HbA1c, whereas pre-meal glucose level at dinner was the most significant determinant of average glucose level, and the range of increase in glucose from pre-meal at dinner was the most significant determinant of standard deviation (SD) of 24 hour glucose levels. HbA1c subgroup analysis indicated that pre-meal glucose level at lunch significantly correlated with average glucose level in the HbA1c < 8.0% group, while pre-meal glucose level at dinner significantly correlated with average glucose level in the HbA1c ≥ 8.0% group. The range of increase in glucose from pre-meal in the morning significantly correlated with SD of 24 hour glucose levels in the HbA1c < 8.0% group, and the postprandial peak glucose level at lunch significantly correlated with SD of 24 hour glucose levels in the HbA1c ≥ 8.0% group. The results suggest that improvement of the average glucose level is necessary to improve the HbA1c levels. For patients with HbA1c < 7.0%, it is important to improve blood glucose level after breakfast and before lunch to decrease the average glucose level. For patients with 7.0% ≤ HbA1c < 8.0%, it is important to improve blood glucose level before lunch and after dinner to decrease the average glucose level. For patients with HbA1c ≥ 8.0%, it is important to improve blood glucose levels after lunch and before dinner to decrease the average glucose level.

We herein report the case of a young woman who was diagnosed with primary hyperparathyroidism and in whom genetic testing confirmed a diagnosis of hyperparathyroidism-jaw tumor syndrome. Familial hyperparathyroidism was suspected based on the patient's young age at the onset of the disease. Thus, genetic testing was performed. It showed a germline mutation in the HRPT2/CDC73 gene and confirmed the diagnosis of hyperparathyroidism-jaw tumor syndrome. Total parathyroidectomy was performed to prevent recurrence. In patients with early-onset hyperparathyroidism, genetic testing should be considered to facilitate the selection of a proper surgical procedure based on the consideration of future life expectancy.

One adverse effect of methylprednisolone (MP) pulse therapy is an acute dose-dependent increase in the blood glucose level. Five patients with thyroid ophthalmopathy but normal glucose tolerance received MP pulse therapy (3 cycles, 3 days/week) and were assessed by continuous glucose monitoring. Steroid therapy increased the mean sensor glucose level, and all patients developed steroid-induced diabetes. The patients were treated alternately with mitiglinide (30 mg/day) and repaglinide (1.5 mg/day) during the second or third MP pulse therapy. The sensor glucose levels before lunch and dinner were more favorable during treatment with repaglinide than during treatment with mitiglinide. Repaglinide may be more clinically appropriate than mitiglinide.

Objective The use of thiazolidinediones is reported to be associated with an increased frequency of fractures, especially in women; however, the underlying mechanism is not clear. In this prospective study, we compared the effects of pioglitazone and metformin on bone metabolism in Japanese patients with type 2 diabetes mellitus. Methods A total of 58 patients with type 2 diabetes (24 men and 34 women) were randomly assigned to receive either pioglitazone (30 and 15 mg/day for men and women, respectively) or metformin (750 mg/day). The changes in serum and urinary type 1 cross-linked N-telopeptide (NTX), type 1 cross-linked C-telopeptide (CTX), bone alkaline phosphatase (BAP), homocysteine, and serum pentosidine were evaluated before and after three months of treatment. The primary endpoint was changes in bone resorption markers after three months. Patients The subjects of this research were male and female type 2 diabetes patients, less than 80 years of age. Results Pioglitazone significantly increased the serum and urinary NTX and serum and urinary CTX levels. The rates of changes in the serum and urinary NTX and CTX were significantly greater in the pioglitazone group than in the metformin group. Although the BAP levels decreased significantly in the pioglitazone group, the rates of change were similar between the two groups. In the pioglitazone group, the changes in fasting insulin levels correlated significantly with increased bone resorption, independent of age and gender. Conclusion The results demonstrated that pioglitazone increased bone resorption independent of age and gender in Japanese patients with type 2 diabetes.

Aims/IntroductionHigh fluctuations in blood glucose are associated with various complications. The correlation between glycated hemoglobin (HbA1c) level and fluctuations in blood glucose level has not been studied in Japanese patients with type2 diabetes. In the present study, blood glucose profile stratified by HbA1c level was evaluated by continuous glucose monitoring (CGM) in Japanese type2 diabetes patients. Materials and MethodsOur retrospective study included 294 patients with type2 diabetes who were divided by HbA1c level into five groups (6.0 to <7.0%, 7.0 to <8.0%, 8.0 to <9.0%, 9.0 to <10.0% and 10%). The correlation between HbA1c level and CGM data was analyzed. The primary end-point was the difference in blood glucose fluctuations among the HbA1c groups. ResultsThe mean blood glucose level increased significantly with increasing HbA1c (P-trend<0.01). The standard deviation increased with increases in HbA1c (P-trend<0.01). The mean amplitude of glycemic excursions did not vary significantly with HbA1c. The levels of maximum blood glucose, minimum blood glucose, each preprandial blood glucose, each postprandial maximum blood glucose, range of increase in postprandial glucose from pre-meal to after breakfast, the area under the blood concentration-time curve >180mg/dL and percentage of the area under the blood concentration-time curve >180mg/dL were higher with higher HbA1c. Mean glucose level and pre-breakfast blood glucose level were significant and independent determinants of HbA1c. ConclusionsIn Japanese patients treated for type2 diabetes, the mean amplitude of glycemic excursions did not correlate with HbA1c, making it difficult to assess blood glucose fluctuations using HbA1c. Parameters other than HbA1c are required to evaluate fluctuations in blood glucose level in patients receiving treatment for type2 diabetes.

The aim of this 24-week, prospective randomized open-label study was to compare the effects of alogliptin and vildagliptin on glucose control, renal function, and lipid metabolism. In Study 1, DPP-4 inhibitor-naive type 2 diabetes (T2DM) were randomly assigned to alogliptin 25 mg/day or vildagliptin 50 mg twice daily. In Study 2, T2DM on treatment with 50 mg/day sitagliptin were switched to either 25 mg/day alogliptin or 50 mg twice daily vildagliptin. The primary endpoint was change in glycosylated hemoglobin (HbA1c) level at 24 weeks, while the secondary endpoints were changes in urinary albumin excretion and low-density lipoprotein cholesterol (LDL-C) levels at 24 weeks. In Study 1, HbA1c levels changed at 24-week by -0.5±0.7% in the alogliptin group (p=0.002, relative to baseline) and -0.7±0.9% in the vildagliptin group (p=0.001, relative to baseline), and the extent of these changes were comparable between the two groups (p=0.219). The decrease in log urinary albumin excretion was more significant in the vildagliptin group (p=0.008). In Study 2, HbA1c levels at 24-week changed by 0.2±0.7% in the switch-to-alogliptin group (p=0.007) and 0.0±0.6% in the switch-to-vildagliptin group (p=0.188), indicating a significant difference between the groups (p=0.003). In both studies, the changes in LDL-C levels were comparable between the two groups. The two drugs had comparable glucose-lowering effects in DPP-4 inhibitor-naive patients but the effect was more pronounced for vildagliptin in patients switched from sitagliptin. The results may point to subtle yet important differences between the two DPP-4 inhibitors. This trial was registered with UMIN (no. #000019022).

Introduction: The aim of the present study was to determine the actual state of interday glycemic variability and identify the factors that affect glycemic variability in diabetic outpatients on insulin therapy.Materials and Methods: The participants were 45 outpatients with diabetes mellitus receiving insulin therapy. The mean plasma glucose (MPG) levels, intra-day glycemic variability (expressed by standard deviation and mean amplitude of glucose excursion) and inter-day glycemic variability (expressed by mean of daily differences [MODD] in blood glucose levels) were measured continuously over 7 days with iPro2 (R). The primary outcome was the relationship between MODD and the life variability index.Results: MODD values were high in 93.3% of the participants, and significantly higher in patients with lifestyle changes than in those without (higher in patients with high life variability index). MODD values were not associated with age, but significantly higher in women. MODD values correlated significantly with glycated hemoglobin and glycoalbumin levels, and negatively with 1,5-anhydroglucitol levels. MODD values were significantly higher in type 1 diabetes patients and not associated with duration of disease. MODD values correlated significantly with insulin dose. Multivariate analysis identified the life variability index as a significant determinant of MODD.Conclusions: iPro2 (R) provided detailed information on glycemic profile in diabetic outpatients receiving insulin therapy. The results suggest that patients with large inter-day glycemic variability are unlikely to achieve an improvement in their glycated hemoglobin level. Treatment and instructions based on a patient's characteristics, day-to-day glycemic variability and lifestyle are important to achieve good glycemic control.

Purpose To determine trabecular bone analysis values by using tomosynthesis images in determining femoral neck strength in patients with diabetes mellitus and compare its parameters between vertebral compression fracture and nonfracture groups. Materials and Methods The institutional review board approved this study, and written informed consent was obtained from all patients. Forty-nine patients with diabetes mellitus were included. Within 1 week, patients underwent dual x-ray absorptiometry (DXA), tomosynthesis, and computed tomography (CT) covering the T10 vertebral body to the hip joints. The trabecular patterns of tomosynthesis images were extracted, and the total strut length, bone volume per tissue volume, and five textural features (homogeneity, entropy, correlation, contrast, and variance) were obtained as the indices of tomosynthesis images. Failure load of the femoral neck, which was determined with the CT-based finite-element method (FEM), was used as the reference standard for bone strength. A forward stepwise multiple regression analysis for evaluating the availability of the tomosynthesis image indices was performed. The bone mineral density (BMD) at DXA and tomosynthesis image indices were compared between the vertebral compression fracture (n = 16) and nonfracture groups (n = 33) according to Genant semiquantitative morphometry methods by using one-way analysis of variance. Results The combination of BMD with the bone volume per tissue volume at the principal tensile group and the correlation at the principal compressive group showed the highest correlation to the failure load at CT FEM, and the correlation (r2 = 0.83) was higher than that between the failure load and the BMD alone (r2 = 0.76; P < .001). The averages of the bone volume per tissue volume and entropy at the principal tensile group in the vertebral compression fracture group were lower than those in the nonfracture group (P = .017 and P = .029, respectively), but there was no difference in BMD. Conclusion Tomosynthesis-based trabecular bone analysis is technically feasible and, in combination with BMD measurements, can potentially be used to determine bone strength in patients with diabetes mellitus. © RSNA, 2016 Online supplemental material is available for this article.

The older of a pair of sisters experienced hypoglycemia after the start of thiamazole (MMI) treatment. Based on a high insulin antibody level, she was diagnosed with insulin autoimmune syndrome (IAS). HLA-DNA typing identified DRB1*04:06. Although a 75-g oral glucose tolerance test (OGTT) showed biphasic insulin secretion, the secretion pattern became monophasic after discontinuation of the MMI. The younger sister was diagnosed with IAS after the start of MMI treatment. HLA-DNA typing identified DRB1*04:06. The 75-g OGTT showed biphasic insulin secretion, but it became monophasic after discontinuation of the MMI. According to the similar insulin secretion kinetics in the two sisters with IAS, we suspect that a genetic predisposition may be associated with the features of anti-insulin antibodies.

Dapagliflozin, a selective inhibitor of sodium glucose co-transporter 2 (SGLT2), is a novel glucose-lowering agent that has pleiotropic actions on blood pressure and lipids. Its glucose-lowering effect is not mediated by insulin. We report a type 2 diabetic patient whose blood pressure pattern improved from non-dipper to dipper after treatment with dapagliflozin. The 60-year-old man was treated with 5 mg/day dapagliflozin, and the effect of treatment on his blood pressure (BP) was evaluated by ambulatory blood pressure monitoring (ABPM) before and at 8 and 14 days after the start of treatment. The 24-h systolic blood pressure/diastolic blood pressure decreased from 131/87 to 127/83 mmHg at day 14, with a particular decrease in nocturnal blood pressure from 123/84 to 116/75 mmHg (nocturnal blood pressure dip increased from 9.6% to 12.8%), changing from a non-dipper to a dipper blood pressure pattern. Dapagliflozin might potentially improve not only the average blood pressure, but also nighttime blood pressure from non-dipper to dipper in type 2 diabetic patients.

Type 2 diabetes patients complicated by chronic kidney disease (CKD) require restricted use and dose adjustment of orally administered hypoglycemic agents because of renal dysfunction, and treatment is likely to be difficult. Linagliptin and teneligliptin are dipeptidyl-peptidase (DPP)-4 inhibitors that do not require dose adjustment even in type 2 diabetes patients complicated by CKD. The aim of this pilot study was to determine the efficacy of these agents for glycemic control using continuous glucose monitoring (CGM).