A pilot study of ezetimibe vs. atorvastatin for improving peripheral microvascular endothelial function in stable patients with type 2 diabetes mellitus.

BACKGROUND: Elevated cholesterol in type 2 diabetes mellitus (DM) can cause endothelial dysfunction. An effective clinical therapy to improve endothelial dysfunction remains to be established. Different cardiovascular actions between treatments for the inhibition of cholesterol absorption and the suppression of cholesterol synthesis for achieving improvement in endothelial function are unknown in DM. METHODS: Stable patients with type 2 DM and mildly elevated low-density lipoprotein cholesterol were enrolled. We evaluated peripheral microvascular endothelial function using reactive hyperemia peripheral arterial tonometry (RH-PAT) examination and calculated a natural logarithmic transformed value for the RH-PAT index (LnRHI). We randomly assigned 33 patients to each monotherapy: cholesterol synthesis suppression using atorvastatin (5 mg/day, n=16) or cholesterol absorption inhibition using ezetimibe (10 mg/day, n=17). Patients were prospectively followed for 6 months. Serum lipids and LnRHI were repeatedly examined before and after each therapy. RESULTS: LDL significantly decreased in both groups, but the percent changes of LDL showed a greater decrease in the atorvastatin group compared with the ezetimibe group (-34.5±7.8% vs. -21.9±9.6%, p<0.01). Serum levels of non-esterified free fatty acids (NEFA) significantly decreased in the ezetimibe group but not in the atorvastatin group (ezetimibe group: 561.1±236.8 to 429.7±195.9, p<0.01; atorvastatin group: 538.8±319.5 to 520.2±227.3, p=0.75). The percent decrease in NEFA was significantly greater in the ezetimibe group compared with the atorvastatin group (-19.9±27.4% vs. 11.3±44.1%, p<0.05). LnRHI showed a significant increase in the ezetimibe group but not in the atorvastatin group (ezetimibe group: 0.471±0.157 to 0.678±0.187, p<0.01; atorvastatin group: 0.552±0.084 to 0.558±0.202, p=0.64). The percent changes in LnRHI were significantly greater in the ezetimibe group compared with the atorvastatin group (63.3±89.2% vs. 7.4±41.2%, p<0.05). CONCLUSIONS: In patients with type 2 DM, ezetimibe monotherapy significantly reduced LDL and NEFA, and improved peripheral microvascular endothelial dysfunction. Ezetimibe could potentially exhibit beneficial effects on lipid disorders and microvascular endothelial dysfunction in DM.

Severe periodontal disease in Japanese patients with high HbA1c levels: a cross-sectional study.

Objective: This study aimed to investigate the relationship between plasma glucose profiles and periodontal disease (PD) severity in men and women. Methods: We conducted a cross-sectional cohort study, enrolling all eligible patients with type 2 diabetes mellitus (T2DM) who regularly visited the outpatient department. Results: Patients were divided into severe and non-severe PD groups. The severe PD group showed a male predominance and significantly higher hemoglobin A1c (HbA1c) levels than the non-severe PD group. The optimal HbA1c cutoff value on the receiver operating characteristic curve for predicting severe PD was 7.3% [56 mmol/mol] (sensitivity, 52%; specificity, 73%; P = 0.01). Multivariate logistic regression revealed that male sex (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.19-6.34; P = 0.01) and higher HbA1c levels (OR, 3.09; 95% CI, 1.42-6.70; P < 0 .01) were independently and significantly associated with the presence of severe PD. The prevalence rates of severe PD in patients with HbA1c levels < 7.3% [56 mmol/mol] and HbA1c levels ≥ 7.3% [56 mmol/mol] were 17.4% and 53.3% in women, and 50.0% and 66.7% in men, respectively. Conclusions: Men with T2DM had a high risk of severe PD independent of HbA1c levels. Plasma glucose management may be crucial for maintaining periodontal health in T2DM patients, particularly in women.

Reduced Number of Remaining or Healthy Teeth in Patients with Type 2 Diabetes Mellitus: A Cross-sectional Study Assessed by Dentists or Dental Hygienists in Japan.

Objective This study assessed the relationships between oral health (number of remaining and healthy teeth and periodontal disease) and type 2 diabetes mellitus (T2DM) to contribute to improved patient care. Patients We conducted a cross-sectional cohort study of consecutive patients being regularly treated for chronic diseases (T2DM, hypertension, and dyslipidemia). A dentist or dental hygienist accurately evaluated the oral environment. Patients with fewer than 20 teeth were classified as having reduced remaining teeth (RRT). Results A total of 267 patients were enrolled, including 153 patients (57%) with T2DM and 114 without (43%). Patients with T2DM had 3 fewer remaining teeth on average than those without DM [median: 22 (interquartile range (IQR): 11-27) vs. median: 25 (IQR: 17.3-28), p=0.02]. In addition, patients with T2DM had 4 fewer healthy teeth on average than those without DM [median: 8 (IQR: 2.8-15) vs. median: 12 (IQR: 6-16), p=0.02]. The frequency of RRT was higher in the T2DM group (n=63; 41%) than in the non-DM group (n=31; 27%, p=0.02). Multivariable logistic regression for the presence of RRT in the T2DM group found that age [odds ratio (OR), 1.08; 95% confidence interval (CI), 1.03-1.13; p<0.01] and regular dental consultations (OR, 0.28; 95% CI, 0.10-0.76; p=0.01) were independently and significantly associated. Conclusion The number of remaining or healthy teeth was significantly lower in patients with T2DM than in those without T2DM in current Japanese clinical practice. Regular dental consultation is recommended to preserve remaining teeth in patients with T2DM.

Potential Identification of Type 2 Diabetes with Elevated Insulin Clearance.

BACKGROUND: Decreased blood insulin concentrations resulting from reduced pancreatic ß-cell insulin secretion and elevated insulin clearance (IC) could be involved in impaired glucose metabolism in diabetes. Recently, we reported a patient with type 2 diabetes mellitus (T2DM) who had decreased blood insulin concentrations and elevated IC. METHODS: For this study, we recruited patients with newly diagnosed, treatment-naïve T2DM and measured the metabolic clearance rate of insulin (MCRI) determined by a hyperinsulinemic-euglycemic clamp examination. We defined elevated IC as an MCRI of more than 700 ml/min/m2. Using this tentative cutoff, we identified patients with T2DM with elevated IC and investigated their clinical characteristics. RESULTS: We enrolled 101 patients in this study; 78.2% were men. Patients had a mean age of 54.1 years, a median body-mass index (BMI) of 25.1 kg/m2 (interquartile range [IQR], 22.9 to 28.4 kg/m2), a median hemoglobin A1c of 10.0% (IQR, 8.0 to 12.3%), and a median MCRI of 655 ml/min/m2 (IQR, 562 to 810 ml/min/m2). Our case definition for elevated IC was met by 44 patients whose median MCRI was 842 ml/min/m2 (IQR, 747 to 975 ml/min/m2) compared with those without elevated IC (570 ml/min/m2; IQR, 500 to 628 ml/min/m2). On the basis of this division, fasting blood glucose and insulin levels were 178 mg/dl (IQR, 140 to 218 mg/dl) and 4.2 mU/l (IQR, 2.7 to 5.5 mU/l), respectively, in patients with elevated IC compared with 146 mg/dl (IQR, 128 to 188 mg/dl) and 9.6 mU/l (IQR, 6.6 to 14.9 mU/l), respectively, in patients without elevated IC. The BMI of patients with elevated IC was 22.9 kg/m2 (IQR, 20.7 to 24.2 kg/m2) compared with 27.3 kg/m2 (IQR, 25.2 to 29.4 kg/m2) in patients who did not have elevated IC. There were no clinically significant differences in renal or hepatic function test results. CONCLUSIONS: Our data suggest that there is a group of patients with T2DM with elevated IC, and that they are nonobese and have decreased blood insulin concentrations. If confirmed, this novel form of T2DM could affect the treatment of such patients. (UMIN Clinical Trials Registry number, UMIN000032014.)

c-Maf suppresses human T-cell leukemia virus type 1 Tax by competing for CREB-binding protein.

Latent infection of human T-cell leukemia virus type 1 (HTLV-1) is considered to be preferentially associated with CCR4(+) CD4(+) T cells. Here we report that c-Maf, one of the critical transcription factors for Th2 differentiation, suppresses the transcriptional activity of HTLV-1 Tax by competing for CREB-binding protein. Notably, c-maf expression is selectively induced in a fraction of CCR4(+) CD4(+) T cells upon activation. Furthermore, c-Maf significantly decreases Tax-induced HTLV-1 envelope gp46 gene expression from an infectious HTLV-1 molecular clone and tax expression in a cell-free HTLV-1 infection system. Collectively, c-Maf may play a role in latent infection of HTLV-1 in CCR4(+) CD4(+) T cells by negatively regulating Tax activity.

A Non-obese, Treatment-Naive Japanese Diabetic Patient With Elevated Insulin Clearance and Hyperglycemia Under Enhanced Insulin Sensitivity and Increased Insulin Secretion: Elevated Insulin Clearance as Type 2 Japanese Diabetes Mellitus (T2JDM).

Diabetes mellitus is a heterogeneous and complex metabolic disorder characterized by hyperglycemia secondary to either resistance to insulin actions on the liver and peripheral tissues, insufficient insulin secretion from pancreatic ß-cells, or both. An integrated balance between blood insulin levels and whole-body insulin sensitivity could theoretically provide the clinical effectiveness of insulin action. Peripheral blood insulin concentrations might be determined by the capacity of endogenous pancreatic ß-cell insulin secretion and the degree of the whole body insulin clearance. Here, we report a non-obese normoinsulinemic Japanese diabetic patient with elevated insulin clearance assessed by a hyperinsulinemic-euglycemic clamp examination and increased insulin secretion measured by daily urinary excretion of C-peptide immunoreactivity. We propose this unique pathogenic condition of diabetes with normoinsulinemia and elevated insulin clearance as "type 2 Japanese diabetes mellitus (T2JDM)."

Body Muscle-to-Fat Ratio, Rather Than Fat-to-Muscle Ratio, Significantly Correlates With Measured Insulin Resistance in Patients With Type 2 Diabetes Mellitus.

BACKGROUND: Insulin resistance (IR) assessment is important in treating type 2 diabetes mellitus (T2DM). We thus compared body muscle-to-fat ratio (BMFR) and fat-to-muscle ratio (FMR) values against M/I values as clinical index of IR. METHODS: Subject included 118 untreated T2DM patients. Hyperinsulinemic-euglycemic clamp examination was performed to calculate the M/I as index of IR. Body composition was measured by impedance analysis using InBody770. RESULTS: Simple linear regression analyses confirmed correlations between M/I and BMFR (B: 0.756 (P < 0.01), coefficients of determination (R2): 0.572, mean absolute error (MAE): 3.19, and root mean squared error (RMSE): 4.14), and between M/I and FMR (B: -0.601 (P < 0.01), R2: 0.362, MAE: 3.97, and RMSE: 5.05). Against the M/I values, BMFR also showed better goodness-of-fit than did FMR. In comparing correlation coefficients, the BMFR absolute B value was significantly larger than that of FMR (P = 0.027). CONCLUSIONS: BMFR is more useful than FMR in quantifying IR in patients with T2DM because the correlation between BMFR and the insulin sensitivity index M/I is significantly greater than that between FMR and M/I.

Changes in urinary glucose concentration and body weight in patients treated with the selective SGLT2 inhibitor luseogliflozin.

AIMS: We investigated the effects of the SGLT2 inhibitor luseogliflozin on blood and urinary glucose and body weight. METHODS: Luseogliflozin 2.5 mg was administered once daily for 24 weeks to 30 outpatients with type 2 diabetes. Urinary glucose concentration, continuous glucose monitoring values, HbA1c, fasting glucose, and body weight were evaluated. Correlations with urinary glucose, subcutaneous/visceral fat mass, insulin, EPA/AA ratio, plasma free fatty acids, ghrelin, blood ketones, plasma 1,5-anhydro-D-glucitol were evaluated. RESULTS: Urinary glucose significantly increased from 11.1 ± 11.8 g at Week -4 to 84.5 ± 46.8 g at Week 24. HbA1c significantly declined from 7.88 ± 0.88% to 7.36 ± 1.13% at Week 24. Mean blood glucose significantly decreased from 149.6 ± 41.8 to 131.6 ± 31.1 mg/dL at Week 24. Subcutaneous and visceral fat mass was also significantly decreased, as were AST and ALT (P < 0.01). Blood urea nitrogen was significantly increased, and urate significantly decreased from 5.04 ± 1.07 to 4.53 ± 0.94 mg/dL. The homeostasis model assessment ratio remained significantly improved throughout the treatment period. Acyl ghrelin levels remained constant but des-acyl ghrelin increased significantly. CONCLUSIONS: Luseogliflozin monotherapy resulted in an improvement in blood glucose, a decrease in body weight, and decreased insulin resistance. Luseogliflozin appears to be an effective therapy for obese diabetics.

CCR7 signals are essential for cortex-medulla migration of developing thymocytes.

Upon TCR-mediated positive selection, developing thymocytes relocate within the thymus from the cortex to the medulla for further differentiation and selection. However, it is unknown how this cortex-medulla migration of thymocytes is controlled and how it controls T cell development. Here we show that in mice deficient for CCR7 or its ligands mature single-positive thymocytes are arrested in the cortex and do not accumulate in the medulla. These mutant mice are defective in forming the medullary region of the thymus. Thymic export of T cells in these mice is compromised during the neonatal period but not in adulthood. Thymocytes in these mice show no defects in maturation, survival, and negative selection to ubiquitous antigens. TCR engagement of immature cortical thymocytes elevates the cell surface expression of CCR7. These results indicate that CCR7 signals are essential for the migration of positively selected thymocytes from the cortex to the medulla. CCR7-dependent cortex-medulla migration of thymocytes plays a crucial role in medulla formation and neonatal T cell export but is not essential for maturation, survival, negative selection, and adult export of thymocytes.

RANKL-induced DC-STAMP is essential for osteoclastogenesis.

Osteoclasts are bone-resorbing, multinucleated giant cells that are essential for bone remodeling and are formed through cell fusion of mononuclear precursor cells. Although receptor activator of nuclear factor-kappaB ligand (RANKL) has been demonstrated to be an important osteoclastogenic cytokine, the cell surface molecules involved in osteoclastogenesis are mostly unknown. Here, we report that the seven-transmembrane receptor-like molecule, dendritic cell-specific transmembrane protein (DC-STAMP) is involved in osteoclastogenesis. Expression of DC-STAMP is rapidly induced in osteoclast precursor cells by RANKL and other osteoclastogenic stimulations. Targeted inhibition of DC-STAMP by small interfering RNAs and specific antibody markedly suppressed the formation of multinucleated osteoclast-like cells. Overexpression of DC-STAMP enhanced osteoclastogenesis in the presence of RANKL. Furthermore, DC-STAMP directly induced the expression of the osteoclast marker tartrate-resistant acid phosphatase. These data demonstrate for the first time that DC-STAMP has an essential role in osteoclastogenesis.

Differential regulatory function of resting and preactivated allergen-specific CD4+ CD25+ regulatory T cells in Th2-type airway inflammation.

Although CD4(+)CD25(+) regulatory T (Treg) cells are known to suppress Th1 cell-mediated immune responses, their effect on Th2-type immune responses remains unclear. In this study we examined the role of Treg cells in Th2-type airway inflammation in mice. Depletion and reconstitution experiments demonstrated that the Treg cells of naive mice effectively suppressed the initiation and development of Th2-driven airway inflammation. Despite effective suppression of Th2-type airway inflammation in naive mice, adoptively transferred, allergen-specific Treg cells were unable to suppress airway inflammation in allergen-presensitized mice. Preactivated allergen-specific Treg cells, however, could suppress airway inflammation even in allergen-presensitized mice by accumulating in the lung, where they reduced the accumulation and proliferation of Th2 cells. Upon activation, allergen-specific Treg cells up-regulated CCR4, exhibited enhanced chemotactic responses to CCR4 ligands, and suppressed the proliferation of and cytokine production by polarized Th2 cells. Collectively, these results demonstrated that Treg cells are capable of suppressing Th2-driven airway inflammation even in allergen-presensitized mice in a manner dependent on their efficient migration into the inflammatory site and their regulation of Th2 cell activation and proliferation.

Type 2 Diabetes Remission and Substantial Body Weight Reduction Achieved with Metformin and a Sodium-Glucose Cotransporter 2 Inhibitor.

The overall goal in the treatment of type 2 diabetes mellitus (T2DM) is remission. However, the effects of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) on remission of T2DM are unknown. We herein report a case involving an overweight 43-year-old man who completely recovered from T2DM after SGLT2i therapy (dapagliflozin at 5 mg/day). In the pretreatment period, he had a body mass index (BMI) of 26.0 kg/m2, hemoglobin A1c (HbA1c) concentration of 10.3%, advanced insulin resistance, pancreatic ß-cell dysfunction, and fatty liver. Eighteen months after comprehensive therapy, including the administration of an SGLT2i and metformin, his BMI had decreased to 21.3 kg/m2 and his glycemic control was almost normal (HbA1c of 5.3%) despite discontinuation of all hypoglycemic medications. This report is the first to propose the usefulness of the combination therapy of SGLT2i and metformin for achieving normal body weight and remission of newly diagnosed T2DM in a real-world clinical situation.

Initial Acute Decline in Estimated Glomerular Filtration Rate After Sodium-Glucose Cotransporter-2 Inhibitor in Patients With Chronic Kidney Disease.

BACKGROUND: Renal function deterioration accompanied by an acute decrease in estimated glomerular filtration rate (eGFR) was observed early after starting sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy. It is unclear how much and how frequently the initial acute decline in eGFR (IAD-eGFR) would occur after SGLT2i administration, and the effects of IAD-eGFR on subsequent renal function are unknown in type 2 diabetes mellitus (T2DM) patients with chronic kidney disease (CKD). METHODS: We retrospectively recruited T2DM patients with CKD (stage 3b; 30 ≤ eGFR < 45 mL/min/1.73 m2) and who were newly treated with add-on SGLT2i. We further investigated the effects of SGLT2i therapy on eGFR early after starting treatment (1 - 3 months) and after 6 months of treatment. We examined the factors associated with a large IAD-eGFR (≥ 10%) using logistic regression analyses. RESULTS: Eighty-seven patients (male, 74.7%; mean age, 69.8 years; median hemoglobin A1c, 7.3%; mean eGFR, 37.8 mL/min/1.73 m2) were analyzed. The mean minimum eGFR early after SGLT2i administration was 34.9 mL/min/1.73 m2, which was significantly lower than before treatment (mean, -7.7%). Seventy patients (80.5%) had IAD-eGFR, and 36 patients (41.4%) had a large IAD-eGFR (≥ 10%). Overall, the mean eGFR was 38.2 at 6 months after starting SGLT2i administration. In patients with a large IAD-eGFR (≥ 10%), the eGFR decreased by 72.2% at 6 months to 35.5 mL/min/1.73 m2, showing a significant decline from the pretreatment value. In patients without a large IAD-eGFR, eGFR increased by 66.7% at 6 months to 40.0 mL/min/1.73 m2. Multiple logistic regression analysis showed that patients with a large IAD-eGFR had a significant association with a high estimated daily salt intake. CONCLUSIONS: SGLT2i treatment frequently induced a significant decrease in eGFR early after starting therapy, but eGFR tended to recover after 6 months in T2DM patients with CKD stage 3b. A large IAD-eGFR (≥ 10%) caused by SGLT2i may lead to subsequent deterioration in renal function, and it was significantly associated with a higher estimated daily salt intake. These results suggest that a more effective renoprotective therapeutic strategy using SGLT2i may be implemented by avoiding the occurrence of a large IAD-eGFR. Further prospective studies are warranted.

Characteristics of nephropathy in severely obese Japanese patients complicated with type 2 diabetes mellitus: a cross-sectional cohort study.

PURPOSE: We aimed to investigate the characteristics of kidney disease in severely obese Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: This was a cross-sectional study of severely obese patients (body mass index ≥35 kg/m2) with T2DM treated at Jinnouchi Hospital, Kumamoto, Japan. RESULTS: A total of 3128 T2DM patients visited the hospital during the survey period, of whom 55 patients (1.7%) were severely obese and 50 patients were enrolled. In terms of diabetic nephropathy (DN), twenty-five patients were stage 1 (non-DN, 50.0%), sixteen were stage 2 (32.0%), five were stage 3 (10.0%), and four were stage 4 (8.0%). There were significant differences in the presence of urinary occult blood (P = 0.01) and history of cardiovascular disease (CVD) (P = 0.04) between patients with DN (stages 2-4) and those without DN (stage 1). The presence of urinary occult blood (odds ratio [OR], 4.96; 95% confidence interval, 1.32-18.6; P = 0.02) was significantly associated with the presence of DN according to multivariate logistic regression analysis with forced inclusion of age, sex, and CVD history. CONCLUSIONS: Urinary occult blood may be a significant independent factor associated with the presence of nephropathy in severely obese Japanese patients with T2DM. The presence of urinary occult blood could thus be an important pathogenic factor in obesity-related nephropathy in patients with T2DM.

Elevation of the renal threshold for glucose is associated with insulin resistance and higher glycated hemoglobin levels.

AIMS/INTRODUCTION: The renal threshold for glucose (RTg) corresponds to a blood glucose level of ~180 mg/dL; however, in hospitals, patients are often encountered who are hyperglycemic, but urine glucose test strip-negative, who remain negative for urine glucose even at blood glucose concentrations >180 mg/dL, implying a high RTg value. In this study, we aimed to identify factors determining high RTg in Japanese patients with type 2 diabetes mellitus. MATERIALS AND METHODS: We estimated RTg (eRTg) using urinalysis data from 67 type 2 diabetes mellitus patients for whom the glucose infusion rate (GIR) was determined by hyperinsulinemic-euglycemic clamp. After allocating patients to two groups according to their baseline eRTg (<180 mg/dL or ≥180 mg/dL), we identified the factors affecting eRTg using simple and multiple linear regression analyses. RESULTS: GIR, glycated hemoglobin (HbA1c), insulin use and dyslipidemia differed significantly between the groups. In simple regression analysis, GIR, HbA1c, body muscle-to-fat ratio and insulin use were significantly correlated with eRTg; and in multiple regression analysis, GIR and HbA1c remained independent negative and positive determinants, respectively, with the contribution of GIR being substantial. In receiver operating characteristic curve analysis, when GIR <5.7 was used as the insulin resistance threshold, the cut-off value of eRTg was 189 mg/dL (P = 0.0001). Furthermore, in receiver operating characteristic analysis using eRTg ≥189 mg/dL, the cut-off value for HbA1c was 8.0% (P = 0.0006). CONCLUSIONS: High eRTg is associated with low GIR and high HbA1c, with GIR making a substantial contribution.

CXCR7 is inducible by HTLV-1 Tax and promotes growth and survival of HTLV-1-infected T cells.

Human T-lymphotropic virus type 1 (HTLV-1), the etiological agent of adult T-cell leukemia (ATL), encodes the potent transcriptional activator Tax, which is required for HTLV-1-induced immortalization of T cells. CXCR7 is an atypical chemokine receptor frequently expressed by tumor cells and known to promote cell growth and survival. We found that HTLV-1-immortalized T cells expressing Tax consistently expressed CXCR7. Induction of Tax in JPX-9 upregulated CXCR7. Wild-type Tax efficiently activated the CXCR7 promoter via a proximal NF-kappaB site, while a mutant Tax selectively defective in NF-kappaB activation did not. CCX754, a synthetic CXCR7 antagonist, inhibited cell growth and increased apoptosis of HTLV-1-immortalized T cells. Knockdown of CXCR7 by small interfering RNA also reduced cell growth. Stable expression of CXCR7 in a CXCR7-negative ATL cell line promoted cell growth and survival. Taken together, CXCR7 is inducible by Tax and may play an important role in HTLV-1-induced immortalization of T cells by promoting growth and survival of HTLV-1-infected T cells.

Body muscle-to-fat ratio gender-specific cut-off values for impaired insulin sensitivity in patients with treatment-naïve type 2 diabetes mellitus.

PURPOSE: We previously reported that the body muscle-to-fat ratio (BMFR), measured using bioelectrical impedance, significantly correlated with whole-body insulin sensitivity. We examined BMFR gender-specific cut-off values for impaired insulin sensitivity in treatment-naïve type 2 diabetes mellitus (T2DM) patients. METHODS: Subjects included 101 untreated T2DM patients (male, 66; female, 35). We performed a hyperinsulinemic-euglycemic clamp examination to measure the steady-state glucose infusion rate (M value) as an indicator of whole-body insulin resistance. We defined the M value divided by the steady-state serum insulin value as the M/I value. We defined the existence of insulin resistance using an M/I ratio <9.0. The optimal cut-off value for BMFR was calculated by receiver operating characteristics (ROC) analysis. RESULTS: The cut-off value of the BMFR for insulin resistance was 2.75 (area under the curve [AUC] = 0.83, sensitivity 75%, and specificity 76%, P < 0.001) for males and 1.65 (AUC = 0.87, sensitivity 84%, and specificity 81%, P < 0.001) for females. Simple linear regression analysis showed that BMFR was significantly correlated with the M/I value in both genders (males, B = 0.77, P< 0.01; females, B = 0.83, P< 0.01). CONCLUSIONS: BMFR cut-off values for impaired insulin sensitivity in treatment-naïve T2DM patients were 2.75 for males and 1.65 for females.

Renoprotective Effects of Additional SGLT2 inhibitor Therapy in Patients With Type 2 Diabetes Mellitus and Chronic Kidney Disease Stages 3b-4: A Real World Report From A Japanese Specialized Diabetes Care Center.

BACKGROUND: Large randomized clinical trials of patients with type 2 diabetes mellitus (T2DM) and at high risk for cardiovascular disease revealed that sodium-glucose cotransporter 2 (SGLT2) inhibitors significantly reduced renal events. However, the trials included small numbers of patients with moderate-to-severe chronic kidney disease (CKD). Therefore, the renoprotective effects of SGLT2 inhibitors remain unknown in T2DM patients complicated with impaired renal function. We examined if SGLT2 inhibitors conferred beneficial effects on kidney function in T2DM patients with CKD. METHODS: We retrospectively recruited T2DM patients who were newly treated with add-on of SGLT2 inhibitors and suffered from moderate-to-severe renal impairment with CKD stages 3b-4 (15 < estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2), at initiation of SGLT2 inhibitor therapy. We analyzed T2DM patients with moderate-to-severe renal impairment who continued to use SGLT2 inhibitors for at least 1 year. We investigated the effects of SGLT2 inhibitor therapy on 1-year changes in eGFR and urinary protein excretion before and after the treatment. RESULTS: We analyzed 42 T2DM patients with median eGFR of 40.4 mL/min/1.73 m2. One-year SGLT2 inhibitor therapy lowered median hemoglobin A1c (HbA1c) levels from 7.6% to 7.5% (not significant). Body weight and blood pressure were significantly decreased, and hemoglobin was significantly increased. The median value of eGFR after 1 year of SGLT2 inhibitor therapy was 41.0 mL/min/1.73 m2, with no significant difference compared with baseline. The annual decline in eGFR improved significantly after SGLT2 inhibitor therapy (eGFR: (median), pre: -3.8, vs. post: 0.1 mL/min/1.73 m2 per year, P < 0.01). We also found a significant decrease in urinary protein excretion after SGLT2 inhibitor therapy (urinary protein-to-creatinine ratio: (median), pre: 0.36, vs. post: 0.23 g/g creatinine, n = 35, P < 0.01). CONCLUSIONS: This study revealed the promising observations that add-on treatment with SGLT2 inhibitors exerted significant renoprotective effects, culminating in improvements in annual decline in eGFR and urinary protein excretion in T2DM patients with CKD stages 3b-4, but did not significantly reduce HbA1c. Further prospective clinical trials are warranted to fully elucidate the effects of SGLT2 inhibitors on glycemic control and renal function in T2DM patients with moderate-to-severe renal impairment.

Extensive expansion and diversification of the chemokine gene family in zebrafish: identification of a novel chemokine subfamily CX.

BACKGROUND: The chemokine family plays important roles in cell migration and activation. In humans, at least 44 members are known. Based on the arrangement of the four conserved cysteine residues, chemokines are now classified into four subfamilies, CXC, CC, XC and CX3C. Given that zebrafish is an important experimental model and teleost fishes constitute an evolutionarily diverse group that forms half the vertebrate species, it would be useful to compare the zebrafish chemokine system with those of mammals. Prior to this study, however, only incomplete lists of the zebrafish chemokine genes were reported. RESULTS: We systematically searched chemokine genes in the zebrafish genome and EST databases, and identified more than 100 chemokine genes. These genes were CXC, CC and XC subfamily members, while no CX3C gene was identified. We also searched chemokine genes in pufferfish fugu and Tetraodon, and found only 18 chemokine genes in each species. The majority of the identified chemokine genes are unique to zebrafish or teleost fishes. However, several groups of chemokines are moderately similar to human chemokines, and some chemokines are orthologous to human homeostatic chemokines CXCL12 and CXCL14. Zebrafish also possesses a novel species-specific subfamily consisting of five members, which we term the CX subfamily. The CX chemokines lack one of the two N-terminus conserved cysteine residues but retain the third and the fourth ones. (Note that the XC subfamily only retains the second and fourth of the signature cysteines residues.) Phylogenetic analysis and genome organization of the chemokine genes showed that successive tandem duplication events generated the CX genes from the CC subfamily. Recombinant CXL-chr24a, one of the CX subfamily members on chromosome 24, showed marked chemotactic activity for carp leukocytes. The mRNA was expressed mainly during a certain period of the embryogenesis, suggesting its role in the zebrafish development. CONCLUSION: The phylogenic and genomic organization analyses suggest that a substantial number of chemokine genes in zebrafish were generated by zebrafish-specific tandem duplication events. During such duplications, a novel chemokine subfamily termed CX was generated in zebrafish. Only two human chemokines CXCL12 and CXCL14 have the orthologous chemokines in zebrafish. The diversification observed in the numbers and sequences of chemokines in the fish may reflect the adaptation of the individual species to their respective biological environment.

Expression of CCL17 and CCL22 by latent membrane protein 1-positive tumor cells in age-related Epstein-Barr virus-associated B-cell lymphoproliferative disorder.

Age-related Epstein-Barr virus-positive (EBV(+)) B-cell lymphoproliferative disorder (ALPD) is a disease entity identified from a large-scale re-survey of cases diagnosed as diffuse large B-cell lymphoma. ALPD is a group of EBV(+) polymorphic B-cell lymphoma typically seen in elderly patients. An age-associated decline in host immunity against EBV might be partly responsible for the pathogenesis of ALPD. Histologically, ALPD is often characterized by a minor proportion of EBV-encoded RNA-positive tumor cells in a background of extensive cellular infiltration, similar to that of classical Hodgkin's lymphoma. In contrast to Hodgkin and Reed-Sternberg cells, ALPD tumor cells are clearly positive for B cell markers CD20 and/or CD79a. Hodgkin and Reed-Sternberg cells produce various chemokines, including CCL17 and CCL22, that attract chemokine receptor CCR4-expressing Th2 cells and regulatory T cells. Previously, we have shown that EBV-immortalized B cells also produce CCL17 and CCL22 through latent membrane protein 1 (LMP1)-mediated activation of nuclear factor kappaB. Here we examined expression of CCL17 and CCL22 in ALPD. ALPD tumor cells were often heterogeneous in size in accordance with the differential expression of EBV latent genes at the single cell level. LMP1-expressing tumor cells were typically large in size and selectively positive for CCL17 and CCL22. CCR4(+) cells and forkhead box protein 3(+) regulatory T cells were abundantly present, and the majority of forkhead box protein 3(+) cells were CCR4(+). Collectively, our data show production of CCL17 and CCL22 by LMP1(+) large-sized tumor cells and accumulation of CCR4-expressing cells including regulatory T cells in ALPD.