AIMS:The aim of this study was to investigate the association between serum total bilirubin concentration and complicated macrovascular diseases, such as cerebrovascular disease (CBVD), cardiovascular disease (CAD), and peripheral arterial disease (PAD), in patients with type 2 diabetes.METHODS:We performed a retrospective cross-sectional study in 674 patients with type 2 diabetes. Serum total bilirubin concentration was compared between patients with and without CBVD, CAD, and PAD. Logistic regression analyses were performed to identify risk factors for CBVD, CAD, and PAD. Associations between total bilirubin concentration and the number of complicated macrovascular diseases were analyzed.RESULTS:Patients with CBVD and PAD showed significantly lower serum total bilirubin concentrations than did those patients without those diseases. However, the bilirubin concentration did not differ between patients with and without CAD. Total bilirubin concentration was an independent predictor of CBVD, but not of CAD or PAD. There was a statistically significant trend for a decrease in bilirubin concentration in the presence of an increasing number of macrovascular diseases.CONCLUSION:The presence of more than one macrovascular disease, called polyvascular disease, carries a high risk for cardiovascular mortality. Serum total bilirubin concentration may be useful as a clinical biomarker of polyvascular disease.

This cross-sectional study was conducted to assess the association between serum albumin concentration (SAC) and microvascular complications in hypertensive patients complicated by type 2 diabetes mellitus (T2DM).Four hundred and ninety five hypertensive patients (331 men) with T2DM were investigated. SAC was compared between patients with and without microvascular complications (retinopathy, nephropathy, and neuropathy). Then, logistic regression analyses were performed to examine the effects of various factors on microvascular diseases, and the following factors were considered as independent variables: SAC, gender, age, duration of diabetes, body mass index (BMI), systolic blood pressure (SBP), HbA1c, eGFR, LDL-cholesterol, and triglyceride.The age, duration of diabetes, BMI, HbA1c, and SAC of 495 patients were 65.7 ± 13.2 years, 14.7 ± 10.8 years, 26.3 ± 6.5 kg/m, 8.9 ± 2.0 %, and 3.8 ± 0.6 g/dl. Two hundred and fifteen (43%) patients had retinopathy, 284 (57%) had nephropathy, and 345 (70%) had neuropathy. SAC was significantly lower in patients with retinopathy (3.55 ± 0.67 vs. 3.92 ± 0.58 g/dl, p < 0.01), nephropathy (3.53 ± 0.66 vs. 4.04 ± 0.50 g/dl, p < 0.01), and neuropathy (3.68 ± 0.65 vs. 3.95 ± 0.61 g/dl, p < 0.01) than in those without complications. The results of logistic regression analyses were as follows. SAC, age, duration of DM, SBP, HbA1c, and eGFR were independent explanatory factors for retinopathy. SAC, duration of DM, and SBP were independent factors for nephropathy. SAC, duration of DM, and SBP were independent factors for neuropathy.In hypertensive patients with T2DM, SAC was lower in those with retinopathy, nephropathy, and neuropathy. The results of multivariate analyses showed that SAC was a common explanatory factor for three microvascular complications. Therefore, low SAC in hypertensive and diabetic patients might have pathophysiological significance in the onset of microvascular complications.

Objective: This cross-sectional study was conducted to assess the association between serum albumin concentration (SAC) and microvascular complications in hypertensive patients complicated by type 2 diabetes mellitus (T2DM). Design and Method: Four hundred and ninety five hypertensive patients (331 men) with T2DM were investigated. SAC was compared between patients with and without microvascular complications (retinopathy, nephropathy, and neuropathy). Then, logistic regression analyses were performed to examine the effects of various factors on microvascular diseases, and the following factors were considered as independent variables: SAC, gender, age, duration of diabetes, body mass index (BMI), systolic blood pressure (SBP), HbA1c, eGFR, LDL-cholesterol, and triglyceride. Results: The age, duration of diabetes, BMI, HbA1c, and SAC of 495 patients were 65.7 ± 13.2 years, 14.7 ± 10.8 years, 26.3 ± 6.5 kg/m2, 8.9 ± 2.0 %, and 3.8 ± 0.6 g/dl. Two hundred and fifteen (43%) patients had retinopathy, 284 (57%) had nephropathy, and 345 (70%) had neuropathy. SAC was significantly lower in patients with retinopathy (3.55 ± 0.67 vs. 3.92 ± 0.58 g/dl, p < 0.01), nephropathy (3.53 ± 0.66 vs. 4.04 ± 0.50 g/dl, p < 0.01), and neuropathy (3.68 ± 0.65 vs. 3.95 ± 0.61 g/dl, p < 0.01) than in those without complications. The results of logistic regression analyses were as follows. SAC, age, duration of DM, SBP, HbA1c, and eGFR were independent explanatory factors for retinopathy. SAC, duration of DM, and SBP were independent factors for nephropathy. SAC, duration of DM, and SBP were independent factors for neuropathy. Conclusions: In hypertensive patients with T2DM, SAC was lower in those with retinopathy, nephropathy, and neuropathy. The results of multivariate analyses showed that SAC was a common explanatory factor for three microvascular complications. Therefore, low SAC in hypertensive and diabetic patients might have pathophysiological significance in the onset of microvascular complications.

Objective: This retrospective study was undertaken to compare hemoglobin A1c and glycoalbumin levels as glycemic control indicators during linagliptin treatment in diabetic patients with or without nephropathy. The efficacy and safety of linagliptin were also examined. Methods: The subjects were 127 outpatients with type 2 diabetes, including 69 patients with nephropathy. The hypoglycemic effect of linagliptin and the factors contributing to its hypoglycemic effect were examined. Several clinical parameters were compared before and after the initiation of linagliptin to evaluate the drug’s safety. Results: Linagliptin significantly decreased hemoglobin A1c and glycoalbumin levels at 3 and 6 months after treatment initiation. At 6 months, changes in hemoglobin A1c levels from baseline were strongly correlated with changes in glycoalbumin levels in diabetic patients with and without nephropathy. Changes in hemoglobin A1c and glycoalbumin at 6 months were significantly greater in patients with higher baseline values and shorter diabetes duration. Linagliptin decreased both hemoglobin A1c and glycoalbumin levels, irrespective of the baseline estimated glomerular filtration rate. No changes in clinical parameters thought to indicate adverse events were noted. Conclusions: Glycoalbumin is an equivalent glycemic control indicator and predictor to hemoglobin A1c during linagliptin treatment. Linagliptin is safe and effective in diabetic patients with or without nephropathy.

Objective: This retrospective cohort study aimed to investigate the significance of dipeptidyl peptidase-4 (DPP- 4) inhibitor switch therapy, which is currently not recommended by major diabetes guidelines. Methods: The subjects were 238 outpatients with type 2 diabetes who had been prescribed sitagliptin 50 mg daily, which was subsequently changed in one of three ways. Patients whose sitagliptin was switched to vildagliptin 50 mg twice daily were defined as the switched group. Patients whose sitagliptin was increased to 100 mg once daily were defined as the increased group. Patients who received an additional alfa-glucosidase inhibitor (α-GI) three times daily prior to meals and sitagliptin 50 mg once daily were defined as the added group. The primary endpoint was the glycated hemoglobin (HbA1c) value at 6 months after the medication change. Patients whose oral hypoglycemic agents were changed within 6 months after switching to vildagliptin, increasing sitagliptin, or adding α-GI were excluded from the full analysis set and the remaining patients were included in the per protocol analysis. Results: The per protocol analysis revealed that the HbA1c level decreased significantly in the switched group (n=71) and the added group (n=18) but did not change significantly in the increased group (n=69). Analysis of the full set showed that the HbA1c level decreased significantly in all three groups (switched [n=92], increased [n=88], and added [n=25]). Conclusion: Switching DPP-4 inhibitors can adequately reduce HbA1c compared with increasing original DPP- 4 inhibitor dose or adding an α-GI. When the original DPP-4 inhibitor did not significantly improve glycemic control, making a DPP-4 inhibitor switch, which is not recommended by major diabetes guidelines, can be an alternative strategy.

Objective: Recently, we reported that total bilirubin concentration (TBC) is an important risk factor for diabetic retinopathy. On the other hand, hypertension is reported to be a risk factor for diabetic retinopathy. Therefore, we compared systolic blood pressure (SBP) and TBC in terms of risk factor for retinopathy. Design and Method: Six hundred and sixty six patients (440 men) with type 2 diabetes mellitus were investigated in this cross-sectional study. SBP and TBC were compared between the patients with and without retinopathy by unpaired t-test. Correlation between SBP and TBC was tested using Pearson's correlation coefficients. Logistic regression analysis was performed to examine the effects of various factors on retinopathy, and the following factors were considered as independent variables: SBP, TBC, gender, age, diabetes duration, BMI, HbA1c, eGFR, LDL-cholesterol, and triglyceride. Results: The age, diabetes duration, HbA1c, SBP, and TBC of 666 patients were 64.7 ± 13.9 years, 13.9 + 10.9 years, 9.1 + 2.1 %, 133.7 + 22.4 mmHg, and 0.74 + 0.36 mg/dl. Two hundred and seventy five (41%) patients had retinopathy. SBP was higher in patients with retinopathy (137.8 + 24.5 vs. 130.8 + 24.5 mmHg, p < 0.01) than in those without retinopathy. TBC was significantly lower in patients with retinopathy (0.65 + 0.30 vs. 0.80 + 0.39 mg/dl, p < 0.01) than in those without retinopathy. SBP and TBC did not correlate (r = -0.046, p = 0.23). The results of logistic regression analysis showed that SBP (p < 0.01), TBC (p < 0.05), age (p < 0.05), diabetes duration (p < 0.01), HbA1c (p < 0.05), and eGFR (p < 0.01) were independent explanatory factors for retinopathy. Conclusions: In diabetic patients, SBP was higher and TBC was lower in those with retinopathy. High SBP and low TBC in diabetic patients might have pathophysiological significance in the onset of retinopathy.

Aims Although a relationship between serum bilirubin concentration and diabetic microangiopathy in patients with type 2 diabetes has been reported, whether such a relationship exists in patients with type 1 diabetes is unknown. This study assessed the relationships between serum total bilirubin concentration and retinopathy/nephropathy in patients with type 1 diabetes. Methods A total of 126 patients with type 1 diabetes were investigated in this cross-sectional study. Serum total bilirubin concentration was compared between patients with and without diabetic retinopathy/nephropathy, and among the categories stratified according to the severity of retinopathy/nephropathy. A logistic regression model was used to assess the association of retinopathy/nephropathy with total bilirubin. Finally, total bilirubin concentration was compared among patients with none, either, or both diabetic retinopathy and nephropathy. Results Serum total bilirubin concentration was significantly lower in patients with retinopathy/nephropathy than in those without complications. Receiver operating characteristic analysis indicated that a bilirubin concentration of 0.55 mg/dl might be the appropriate threshold for the detection of retinopathy/nephropathy. Total bilirubin concentration differed significantly according to the severity of microangiopathy. In logistic regression analyses, total bilirubin level was significantly inversely associated with retinopathy/nephropathy. Moreover, bilirubin level in patients with either retinopathy or nephropathy was significantly higher than that in patients with both of them, and significantly lower than that in patients with neither of them. Conclusions Total bilirubin concentration was shown to be lower in patients with type 1 diabetes complicated by retinopathy/nephropathy. Bilirubin might function protectively against microangiopathy in patients with type 1 diabetes.

Aims: This retrospective study aimed to determine the hypoglycaemic effect of 2 years of sitagliptin administration in terms of changes in HbA1c and C-peptide immunoreactivity (CPR) index (plasma CPR [ng/mL]/glucose [mg/dL] x 100).Methods: The inclusion criteria for DPP-4 inhibitor-naive outpatients with type 2 diabetes (n = 285) were: continuation of sitagliptin for >= 700 days from initial administration and measurement of HbA1c, serum CPR, and plasma glucose levels at 0, 3, 6, 12, 18, and 24 months after sitagliptin initiation. Logistic regression analyses determined the factors contributing to the response to sitagliptin, based on responder (Delta HbA1c <=-0.4% [<=-4 mmol/mol]) and non-responder (DHbA1c >-0.4% [>- 4 mmol/mol]) groups.Results: The HbA1c level decreased and CPR index increased from baseline to 3, 6, 12, 18, and 24 months after the start of sitagliptin administration (HbA1c: 7.4 perpendicular to 0.8% [57 perpendicular to 9 mmol/mol], 7.3 +/- 0.9% [57 +/- 9 mmol/mol], 7.4 +/- 0.9% [58 +/- 10 mmol/mol], 7.1 +/- 0.8% [55 +/- 9 mmol/mol], and 7.3 +/- 0.9% [57 +/- 10 mmol/mol], respectively, all P < 0.001 vs. baseline [8.0 +/- 1.0%, 64 +/- 11 mmol/mol] and CPR index: 1.69 +/- 0.96, 1.71 +/- 1.10, 1.62 +/- 0.96, 1.64 +/- 0.92, and 1.66 +/- 0.96, respectively, all P < 0.05 vs. baseline [1.47 +/- 0.81]). Higher baseline HbA1c level, shorter diabetes duration, and greater CPR index increase after sitagliptin administration were associated with the response to sitagliptin.Conclusions: Our results suggest that sitagliptin improves glycaemic control via an improved intrinsic insulin response. (c) 2015 Elsevier Ireland Ltd. All rights reserved.

Aims: Serum bilirubin concentration is associated with diabetic retinopathy in patients with type 2 diabetes. This study investigated the relationships between serum bilirubin concentration and the severity of diabetic retinopathy. In addition, the importance of bilirubin was compared with factors that were previously shown to be associated with the incidence of diabetic retinopathy.Methods: A total of 674 patients with type 2 diabetes were investigated in this cross-sectional study. Serum total bilirubin concentration was compared between patients with and without diabetic retinopathy, and according to the severity of retinopathy. Univariate and multivariate analyses were performed to evaluate the association of retinopathy with total bilirubin concentration, duration of diabetes, body mass index, systolic blood pressure, and haemoglobin A1c.Results: Serum total bilirubin concentration was significantly lower in patients with retinopathy than in those without Patients with severer retinopathy showed lower total bilirubin concentration, longer diabetes duration, and higher systolic blood pressure. These three parameters were independent explanatory factors for diabetic retinopathy.Conclusions: Total bilirubin concentration is lower in patients with type 2 diabetes complicated with severer retinopathy. Thus, bilirubin might protect against retinopathy in patients with type 2 diabetes. (C) 2015 Elsevier Inc. All rights reserved.

Aims: Although relationships of serum bilirubin concentration with estimated glomerular filtration rate (eGFR) and urinary albumin excretion (UAE) in patients with type 2 diabetes have been reported, whether such relationships exist in patients with type 1 diabetes is unknown.Methods: A total of 123 patients with type 1 diabetes were investigated in this cross-sectional study. The relationship between bilirubin (total and indirect) concentrations and log(UAE) as well as eGFR was examined by Pearson's correlation analyses. Multivariate regression analyses were used to assess the association of bilirubin (total and indirect) with eGFR as well as log(UAE).Results: A positive correlation was found between serum bilirubin concentration and eGFR; total bilirubin (r = 0.223, p = 0.013), indirect bilirubin (r = 0.244, p = 0.007). A negative correlation was found between serum bilirubin concentration and log(UAE); total bilirubin (r = 0.258, p = 0.005), indirect bilirubin (r = 0.271, p = 0.003). Multivariate regression analyses showed that indirect bilirubin concentration was an independent determinant of eGFR and log(UAE).Conclusions: Bilirubin concentration is associated with both eGFR and log(UAE) in patients with type 1 diabetes. Bilirubin might have a protective role in the progression of type 1 diabetic nephropathy. (C) 2015 Elsevier Inc. All rights reserved.

OBJECTIVE:This retrospective study evaluated the long-term efficacy of sitagliptin and the factors contributing to its glucose-lowering effect.METHODS:Six hundred and sixteen dipeptidyl peptidase-4 inhibitor-naïve outpatients with type 2 diabetes who began sitagliptin treatment between December 1, 2009 and December 31, 2011 were included in this study. The inclusion criteria were that the patient had regularly visited our hospital for a period of ≥700 days from the initiation of sitagliptin treatment and the measurement of hemoglobin A1c (HbA1c) had been performed at 0, 3, 6, 12, 18, and 24 months after the initiation of treatment. From the population of 616 patients, 447 and 169 had received sitagliptin for ≥700 and <700 days, respectively. The primary endpoint was ΔHbA1c at 24 months. The factors associated with the hypoglycemic effect of sitagliptin were also investigated.RESULTS:Sitagliptin treatment significantly decreased the level of HbA1c, and the hypoglycemic effect was sustained for at least 2 years. The baseline HbA1c level, duration of diabetes, Δbody weight value, and ΔHbA1c value at 3 months were independently associated with the hypoglycemic effect of sitagliptin.CONCLUSION:Sitagliptin has a long-term hypoglycemic effect in type 2 diabetes patients. A patient's ΔHbA1c at 3 months may be a predictor of their ΔHbA1c at 24 months.

This retrospective study was undertaken to clarify the characteristics of patients in whom vildagliptin exerts its HbA1c-lowering effect fully. The safety of vildagliptin was also examined.

AIMS:Hypertension stimulates the sympathetic nervous system and this phenomenon is exacerbated by diabetes mellitus. We investigated the effects of cilnidipine, an N/L-type calcium channel blocker, on aspects of this system in patients with type 2 diabetes mellitus. METHODS:In 33 hypertensive patients with type 2 diabetes mellitus treated with a calcium channel blocker other than cilnidipine, we evaluated the influence of switching to cilnidipine on blood pressure, heart rate, catecholamine, plasma renin and aldosterone concentration, brain natriuretic peptide, urine liver-type fatty acid binding protein, and urinary albumin excretion ratio in the same patients by a cross-over design. Other biochemical parameters were also evaluated. RESULTS:Switching to cilnidipine did not change blood pressure but caused reduction in catecholamine concentrations in blood and urine and plasma aldosterone concentration, accompanied by significant reduction in brain natriuretic peptide, urine liver-type fatty acid binding protein, and albumin excretion ratio. These parameters other than brain natriuretic peptide were significantly increased after cilnidipine was changed to the original calcium channel blocker. CONCLUSIONS:In 33 hypertensive patients with type 2 diabetes mellitus, compared to other calcium channel blockers, cilnidipine suppressed sympathetic nerve activity and aldosterone, and significantly improved markers of cardiorenal disorders. Therefore, cilnidipine may be an important calcium channel blocker for use in combination with renin-angiotensin-aldosterone system inhibitors when dealing with hypertension complicated with diabetes mellitus.

Chronic inflammation in adipose tissue contributes to obesity-related insulin resistance. The 3-phosphoinositide-dependent protein kinase 1 (Pdk1)/forkhead transcription factor (Foxo1) pathway is important in regulating glucose and energy homeostasis, but little is known about this pathway in adipose tissue macrophages (ATMs). To investigate this, we generated transgenic mice that carried macrophage/granulocyte-specific mutations, including a Pdk1 knockout (LysMPdk1(-/-)), a Pdk1 knockout with transactivation-defective Foxo1 (Δ256LysMPdk1(-/-)), a constitutively active nuclear (CN) Foxo1 (CNFoxo1(LysM)), or a transactivation-defective Foxo1 (Δ256Foxo1(LysM)). We analyzed glucose metabolism and gene expression in ATM populations isolated with fluorescence-activated cell sorting. The LysMPdk1(-/-) mice exhibited elevated M1 macrophages in adipose tissue and insulin resistance. Overexpression of transactivation-defective Foxo1 rescued these phenotypes. CNFoxo1(LysM) promoted transcription of the C-C motif chemokine receptor 2 (Ccr2) in ATMs and increased M1 macrophages in adipose tissue. On a high-fat diet, CNFoxo1(LysM) mice exhibited insulin resistance. Pdk1 deletion or Foxo1 activation in bone marrow-derived macrophages abolished insulin and interleukin-4 induction of genes involved in alternative macrophage activation. Thus, Pdk1 regulated macrophage infiltration by inhibiting Foxo1-induced Ccr2 expression. This shows that the macrophage Pdk1/Foxo1 pathway is important in regulating insulin sensitivity in vivo.

Forkhead box‐containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a Foxo1‐CoRepressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3‐F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo‐target genes and adipocyte size and increased insulin sensitivity in Leprdb/db mice and in mice fed a high‐fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo‐target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine‐tune Foxo1 activity. This study characterizes a novel Foxo1 CoRepressor (FCoR) that regulates insulin sensitivity and energy metabolism as revealed by whole‐body knockout. As target of PKA phosphorylation, FCoR modulates Foxo's acetylation known to control Foxo's biological activity.