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Aims: To evaluate the efficacy and safety of insulin glargine 300U/mL (Gla-300) versus glargine 100U/mL (Gla-100) in adults with type 1 diabetes in Japan over 12months.Methods: EDITION JP 1 was a multicentre, randomised, open-label phase 3 study. Following a 6-month on-treatment period, participants continued to receive Gla-300 or Gla-100 once daily, plus mealtime insulin, over a 6-month open-label extension phase. HbA1c, hypoglycaemia, body weight and adverse events were assessed.Results: Overall, 114/122 (93%) and 114/121 (94%) of participants in the Gla-300 and Gla-100 group, respectively, completed the 6-month extension phase. Glycaemic control was sustained in both groups up to month 12 (mean HbA1c: Gla-300, 7.9% [62mmol/mol]; Gla-100, 7.8% [62mmol/mol]). Annualised rates of hypoglycaemia were lower with Gla-300 versus Gla-100; significantly for nocturnal confirmed (<3.0mmol/L [<54mg/dL]) or severe hypoglycaemia (2.39 and 3.85 events per participant-year; rate ratio: 0.62 [0.39-0.97]). No between-treatment differences in mean body weight change or adverse events were observed.Conclusion: Over 12months' treatment, participants with type 1 diabetes receiving Gla-300 achieved sustained glycaemic control and experienced less nocturnal hypoglycaemia that was confirmed (<3.0mmol/L [<54mg/dL]) or severe compared with Gla-100, supporting the 6-month results. [ABSTRACT FROM AUTHOR]

Abstract: Insulin resistance is the principal cause of glucose intolerance and type 2 diabetes and induces progression of severe atherosclerosis in these patients. Adiponectin, the adipose-specific proteins, is known to correlate negatively with insulin resistance in patients with obesity and type 2 diabetes. The purpose of this study was to evaluate the potential of using serum adiponectin levels as a marker of insulin resistance in various states of insulin resistance. Furthermore, we attempted to establish a modified index of the homeostasis model assessment index (HOMA-IR), calculated from the product of serum insulin and plasma glucose levels divided by serum adiponectin levels (HOMA-AD). We recruited 117 Japanese subjects with various degrees of glucose tolerance and determined serum adiponectin levels and insulin sensitivity (M-value) by using the euglycemic hyperinsulinemic clamp technique. M-value, the gold standard index of insulin resistance, correlates significantly and independently with fasting insulin (r =−0.313, P <0.001), glucose (r =−0.319, P <0.001), and adiponectin (r =0.241, P <0.002) levels. M-values were more significantly correlated with HOMA-AD (r =−0.643, P <0.001) than HOMA-IR values (r =−0.591, P <0.001). In subjects with moderate hyperglycemia (fasting glucose levels>8.0mmol/L, n =30), HOMA-AD showed a more significant correlation with the M-value than HOMA-IR (r =−0.535, P =0.005 versus r =−0.461, P =0.010). We would therefore like to propose a novel index, HOMA-AD, as a simple and adequate index for determining insulin resistance even in diabetic patients with overt hyperglycemia. [Copyright &y& Elsevier]

Abstract: Nateglinide, a rapid insulin secretagogue, is known to facilitate the early phase of insulin secretion and has been used for the treatment of type 2 diabetic patients with postprandial hyperglycemia. The aim of this study is to evaluate the effect of nateglinide on insulin resistance as well as insulin secretory defects in type 2 diabetic patients. Insulin secretion ability was evaluated by the hyperglycemic clamp test, and insulin sensitivity was evaluated by the euglycemic hyperinsulinemic clamp test, using an artificial pancreas. The hyperglycemic clamp test showed that a 7-day treatment with nateglinide significantly increased insulin secretion in response to high glucose. Interestingly, although nateglinide is known to facilitate insulin secretion, daily urinary C-peptide excretion was decreased after nateglinide treatment. Moreover, in the euglycemic hyperinsulinemic clamp test, glucose infusion rate was significantly increased by nateglinide treatment, indicating that nateglinide functions to decrease insulin resistance. Nateglinide ameliorates insulin resistance as well as insulin secretory defects in type 2 diabetic patients. [Copyright &y& Elsevier]

Abstract: Peripheral vascular disease (PVD) has been reported to cause deterioration in insulin sensitivity. The precise mechanism of insulin resistance induced by PVD has not been clarified. To elucidate the mechanism causing impaired insulin action and glucose metabolism under peripheral ischemic conditions, we determined glucose turnover and glucose tolerance in hindlimb-ischemic (FAL) rats. The right femoral artery was ligated in hindlimb-ischemic (FAL) rats, while the artery was only exposed in the Sham operated (Sham) rats used as a control. Two weeks after the ligation, glucose tolerance was impaired and plasma insulin levels were significantly increased in FAL rats compared with Sham rats after intraperitoneal glucose loading (2gkg−1). Under euglycemic hyperinsulinemic clamp conditions, the glucose infusion rate was significantly lower in FAL rats compared with Sham rats, but there was no significant difference in the glucose disappearance rate between the two groups. Hyperinsulinemia suppressed endogenous glucose production by 50% in Sham rats, while the suppression was 20% in FAL rats, indicating hepatic insulin resistance in FAL rats. mRNA analysis of isolated liver after the clamp experiment revealed that glucokinase mRNA, but not PEPCK and glucose-6-phosphatase mRNA, was significantly lower in FAL rats compared with Sham rats. In conclusion, chronic hindlimb ischemia impaired glucose tolerance associated with insulin resistance in the liver rather than the peripheral tissues. [Copyright &y& Elsevier]

To investigate the dose-dependent effect of free fatty acid (FFA) on the hepatic glucose uptake (HGU), we determined hepatic glucose fluxes by a dual tracer technique during the basal state and euglycemic hyperinsulinemic clamp combined with a portal glucose load in three groups of rats given saline (saline), low-dose lipid (lipid-L), or high-dose lipid infusion (lipid-H).In the basal state, lipid infusion dose-dependently increased plasma FFA (saline, 400±50; lipid-L, 550±30; lipid-H, 1700±270 μmol l-1; mean±S.E). Endogenous glucose production (EGP) in lipid-H was 63.5±5.5 μmol kg-1 min-1 and significantly higher than in the saline and lipid-L (40.2±2.9, 47.6±3.1 μmol kg-1 min-1, respectively). During euglycemic hyperinsulinemic clamp, plasma FFA decreased to 130±30 μmol l-1 in saline, but remained at basal levels in lipid-L and lipid-H (470±30 and 1110±180 μmol l-1, respectively). Insulin-suppressed EGP was complete in saline and lipid-L, but impaired in lipid-H (38.0±6.4 μmol kg-1 min-1). Elevated FFA dose-dependently reduced HGU (saline, 12.2±0.9; lipid-L, 8.6±0.6; lipid-H, 4.7±1.4 μmol kg-1 min-1). In conclusion, acutely elevated FFA impairs HGU as well as insulin-mediated suppression of EGP during hyperinsulinemic clamp with portal glucose loading. Impaired hepatic glucose uptake associated with elevated FFA may contribute to the development of insulin resistance in obesity and type 2 diabetes. [Copyright &y& Elsevier]

Abstract: We examined the association between diabetic retinopathy and monocyte chemoattractant protein (MCP)-1 A-2518G polymorphism in 3802 Japanese type 2 diabetic subjects. The prevalence of diabetic retinopathy was higher as the number of G alleles increased, suggesting that the G allele of this polymorphism is a susceptibility allele for diabetic retinopathy. [Copyright &y& Elsevier]

Abstract: The hallmark of type 2 diabetes is insulin resistance and insufficient insulin secretion, and appropriate therapy should be selected for each patient. In this study, to establish some index to select suitable therapy for each patient, we evaluated insulin sensitivity and insulin secretion with euglycemic hyperinsulinemic clamp and hyperglycemic clamp tests, respectively, and found that specific GIR index (GIR×IRI (90)) could be a useful marker to select suitable therapy for each type 2 diabetic patient (GIR: glucose infusion rate in euglycemic hyperinsulinemic clamp test; IRI (90): plasma insulin level 90 min after starting the hyperglycemic clamp test). [Copyright &y& Elsevier]

Aims: This study investigated the hypoglycemia risk in people with type 2 diabetes (T2D) who initiated or switched to insulin glargine 300 U/mL (Gla-300) by stratifying them by age and renal function.Methods: We examined data from 4621 people with T2D (1227 insulin-naïve and 3394 insulin-experienced) of the X-STAR study, a prospective, observational, 12-month study conducted from December 2015 to August 2018 in Japan. Participants were stratified by age (<65, 65 to <75, and ≥75 years) and estimated glomerular filtration rate (eGFR) (≥90, 60 to <90, 30 to <60, and <30 mL/min/1.73 m2). Hypoglycemia was defined according to the Ministry of Health, Labour and Welfare manual of Japan.Results: No apparent increase in the proportion of people who experienced hypoglycemia was found in all subgroups. The proportions were 2.9-3.5% and 2.7-5.2% of insulin-naïve and insulin-experienced people, respectively, for age subgroups, and 2.4-4.7% and 4.6-4.8%, respectively, for eGFR subgroups. The result was similar for HbA1c levels below and at or above 7.0% in all age subgroups.Conclusions: Our study found no apparent increase in the hypoglycemia risk in people with older age and renal impairment who were administered Gla-300. These results would provide reassuring information on Gla-300 use. [ABSTRACT FROM AUTHOR]

Aims: Currently, inhibition of dipeptidyl peptidase-4 (DPP-4) is widely used in the treatment of type 2 diabetes. Application of this strategy is awaited as a new therapeutic approach for type 1 diabetes, but the scientific basis is still lacking. This report describes the evaluation of serum DPP-4 activity in type 1 diabetes compared with control subjects, and assessment of relationships between DPP-4 activity and diabetic complication markers and metabolic variables in type 1 diabetes.Methods: We examined serum DPP-4 activity in Japanese young-adult type 1 diabetes (n=76, females 69.7%, age 30.9 ± 6.2 years, duration of diabetes 16.5 ± 11.1 years; mean ± SD) and healthy controls (n=22). Association of the enzymatic activity with diabetic micro- and macro- vascular complication markers and clinical parameters was also assessed.Results: Subjects with type 1 diabetes displayed significantly higher serum DPP-4 activity than healthy controls (relative value, control: 1.00 ± 0.28, T1D, 1.29 ± 0.38; p=0.0011) independent of other clinical parameters. In type 1 diabetes, DPP-4 activity was positively correlated with duration of diabetes (r=0.248, p=0.031), while not correlated with HbA1c level. In univariate correlation analysis of diabetic complication markers and other metabolic parameters, coefficient of variation of R-R intervals (CVR-R) and gamma (γ)-glutamyltransferase (GGT) levels were correlated with DPP-4 activity. GGT was extracted as an independent variable of DPP-4 activity in multivariate analysis (β=0.213, p=0.035).Conclusions: Serum DPP-4 activity is significantly elevated in Japanese type 1 diabetes, suggesting pathophysiological significance of the enzyme in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Abstract: Aims: Pentraxin3 (PTX3), a recently discovered inflammatory mediator, is produced abundantly in various cells in atherosclerotic lesions, and therefore, its plasma level could reflect local inflammation at the site of atherosclerotic lesion. The present study evaluated whether plasma PTX3 levels are associated with subclinical atherosclerosis in young subjects with type 1 diabetes. Methods: Plasma PTX3 levels, urinary albumin excretion, diabetic retinopathy, and carotid intima-media thickness (IMT) were examined in 78 Japanese type 1 diabetic patients (30 men and 48 women, aged 28.5±5.3 years (±SD), duration of diabetes 19.7±6.5 years). Results: There was statistically significant association between plasma PTX3 levels and Max-IMT (r =0.363, p =0.001). A stepwise multivariate regression analysis including conventional coronary risk factors as independent variables revealed that plasma PTX3 levels (β =0.389, p <0.001), duration of diabetes (β =0.256, p =0.035), and serum triglyceride levels (β =0.371, p <0.001) were independent determinants of Max-IMT. In addition, plasma PTX3 levels was an independent determinant of urinary albumin excretion, an indicator of diabetic nephropathy (β =0.258, p =0.018). However, there was no significant association between plasma PTX3 levels and diabetic retinopathy. Conclusions: Increased levels of plasma PTX3 are associated with accelerated atherosclerotic change and increased albuminuria in young patients with type 1 diabetes. [Copyright &y& Elsevier]

Abstract: We performed a 3-year observation study of type 2 diabetic patients treated with glibenclamide or glimepiride and found that the annual progression of the maximum carotid intima-media thickness was significantly attenuated in the subjects treated with glimepiride (n =20) as compared with those treated with glibenclamide (n =20) (−0.044±0.171mm/year vs. 0.077±0.203mm/year, p =0.0474). [Copyright &y& Elsevier]

Abstract: To clarify factors determining the preference for a self-monitoring blood glucose (SMBG) system in patients with diabetes mellitus. A total of 52 Japanese inpatients with diabetes mellitus were recruited into a single-center trial. After the patients got used to one SMBG system, the SMBG system was substituted with another one of the three, and the subjects were given questionnaires. The following parameters were identified as independent factors associated with the preference of SMBG: display (P <0.0001), operation for inserting strips (P =0.0004), and lancing-device operation (P <0.05). When the subjects were divided according to age, the independent variables associated with overall preference in the older group (≥60 years) were display (P =0.001) and procedure for detaching a used needle (P =0.01), whereas those in the younger group (age<60 years) were operation of the lancing device (P <0.0001), operation to apply blood to strip (P =0.001), and amount of blood (P =0.04). These data suggest that in elderly patients with diabetes, display and detachment of the needle are important factors affecting the choice of SMBG system, whereas younger subjects give weight to skin puncture-related issues in choosing an SMBG system. [Copyright &y& Elsevier]

Objective: An open randomized prospective study was performed to elucidate the effect of an alpha-glucosidase inhibitor, voglibose, on the progression of atherosclerosis in subjects with type 2 diabetes. Research Design and Methods: Voglibose at a dose of 0.4-0.6 mg/day was added on 51 subjects out of 101 type 2 diabetic patients being treated with diet, sulphonylurea (SU) or insulin injections, and the average (AveIMT) and maximum intima-media thickness (MaxIMT) of their carotid arteries were examined for 3 years. Results: Irrespective of the differences in treatments, addition of voglibose reduced the progression of AveIMT and MaxIMT to -0.024 +/- 0.047 (+/-S.D.) and -0.021 +/- 0.144 mm/year, respectively. Without voglibose, diabetic patients showed significant (P < 0.0001) progression of AveIMT and MaxIMT (0.056 +/- 0.046 and 0.098 +/- 0.122 mm/year, respectively). The administration of voglibose resulted in a significant reduction of hemoglobin A1c (HbA1c), total cholesterol and triglyceride concentrations, as well as an increase in HDL cholesterol concentration. Multivariate regression analysis showed that administration of voglibose independently reduced the progression of AveIMT by 0.069 mm/year (P < 0.0001). Conclusions: These results suggest that voglibose reduces the progression of IMT and may be a candidate for an anti-atherosclerotic drug for type 2 diabetic patients. [ABSTRACT FROM AUTHOR]

Abstract: Objective:: An open randomized prospective study was performed to elucidate the effect of an α-glucosidase inhibitor, voglibose, on the progression of atherosclerosis in subjects with type 2 diabetes. Research design and methods:: Voglibose at a dose of 0.4–0.6mg/day was added on 51 subjects out of 101 type 2 diabetic patients being treated with diet, sulphonylurea (SU) or insulin injections, and the average (AveIMT) and maximum intima-media thickness (MaxIMT) of their carotid arteries were examined for 3 years. Results:: Irrespective of the differences in treatments, addition of voglibose reduced the progression of AveIMT and MaxIMT to -0.024 ± 0.047 (±S.D.) and -0.021 ± 0.144mm/year, respectively. Without voglibose, diabetic patients showed significant (P < 0.0001) progression of AveIMT and MaxIMT (0.056 ± 0.046 and 0.098 ± 0.122mm/year, respectively). The administration of voglibose resulted in a significant reduction of hemoglobin A1c (HbA1c), total cholesterol and triglyceride concentrations, as well as an increase in HDL cholesterol concentration. Multivariate regression analysis showed that administration of voglibose independently reduced the progression of AveIMT by 0.069mm/year (P < 0.0001). Conclusions:: These results suggest that voglibose reduces the progression of IMT and may be a candidate for an anti-atherosclerotic drug for type 2 diabetic patients. [Copyright &y& Elsevier]

Objective: This study was conducted to examine whether tissue characterization of the carotid artery wall by determining integrated backscatter (IBS) can identify subjects with a recent history of acute coronary syndrome (ACS) or atherothrombotic infarction (ATI). Research design and methods: The maximum thickness (Max-IMT) and IBS value (corrected-IBS) of the carotid artery intima–media complex were measured ultrasonographically for 132 type 2 diabetic subjects (62.9±8.5 (±S.D.) years old, 87 men and 45 women) with or without cardiovascular diseases. Results: The diabetic patients with recent ACS or ATI had a significantly lower corrected-IBS and higher Max-IMT than those with Max-IMT ≧ 1.1 mm but without cardiovascular diseases. The product of Max-IMT and corrected-IBS (IMT-IBS product) of the patients with recent ACS was significantly lower than that of the patients with chronic stable angina. The multiple logistic model showed that only the IMT-IBS product was associated with a recent history of ACS (odds ratio 0.94, P<0.05) and ATI (odds ratio 0.90, P<0.005). Conclusions: Diabetic patients who had a recent history of ACS or ATI showed a lower IBS value and higher IMT for their carotid artery. Both the size and tissue characteristics of the carotid plaque may identify subjects with a high risk of cardiovascular disease. [Copyright &y& Elsevier]

Oxidative stress is induced under diabetic conditions and causes various forms of tissue damage in patients with diabetes. Recently, pancreatic β-cells have emerged as a putative target of oxidative stress-induced tissue damage and this seems to explain in part the progressive deterioration of β-cell function in type 2 diabetes. As a step toward clinical trial of antioxidant for type 2 diabetes, we investigated the possible anti-diabetic effects of probucol, an antioxidant widely used as an anti-hyperlipidemic agent, on preservation of β-cell function in diabetic C57BL/KsJ-db/db mice. Probucol-containing diet was given to mice from 6 to 16 weeks of age. Immunostaining for oxidative stress markers such as 4-hydroxy-2-nonenal (HNE)-modified proteins and heme oxygenase-1 revealed that probucol treatment decreased reactive oxygen species (ROS) in pancreatic islets of diabetic animals. Oxidative stress is known to enhance apoptosis of β-cells and to suppress insulin biosynthesis, but probucol treatment led to preservation of β-cell mass and the insulin content. According to intraperitoneal glucose tolerance tests, the probucol treatment preserved glucose-stimulated insulin secretion and improved glucose tolerance at 10 and 16 weeks: insulin, 280±82 vs. 914±238 pmol/l (120 min, at 16 weeks; P<0.05); glucose, 44.6±2.4 vs. 35.2±2.6 mmol/l (120 min, at 16 weeks; P<0.05). Thus, our present observations demonstrate the potential usefulness of probucol for treatment of type 2 diabetes. [Copyright &y& Elsevier]

Aim: Our previous study revealed that sarcopenia was frequently observed in subjects with type 1 diabetes mellitus (T1DM). However, the factors associated with sarcopenia that are related to T1DM have not yet been clarified. Insulin-like growth factor-1 (IGF-1) has been shown to play a role in skeletal muscle growth, differentiation, and regeneration. The present study, therefore, investigated the association between the serum IGF-1 level and sarcopenia and low skeletal muscle mass in subjects with T1DM.Methods: This cross-sectional study enrolled subjects with T1DM (n = 168) and without diabetes (n = 59) who had had their clinical data on serum IGF-1 collected in the iDIAMOND study.Results: The z-score of serum IGF-1 was significantly lower in the subjects with T1DM than that in those without diabetes (p < 0.001). Among subjects with T1DM, the z-score of serum IGF-1 was significantly lower in sarcopenic subjects than in non-sarcopenic subjects. The multivariable logistic regression analysis showed that the serum IGF-1 z-score was an independent determinant of sarcopenia and a low skeletal muscle mass index, but not low grip strength nor slow gait speed in subjects with T1DM.Conclusions: A low serum IGF-1 level is correlated with sarcopenia and low skeletal muscle mass in subjects with T1DM. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the possible association of vitamin D deficiency with diabetic retinopathy in 75 young Japanese type 1 diabetic patients. A multivariate regression analysis, duration of diabetes and vitamin D deficiency were independent determinants of diabetic retinopathy. [ABSTRACT FROM AUTHOR]

Abstract: The aim of this study was to examine the possible association between YKL-40, a new biomarker of endothelial dysfunction, and albuminuria in 180 type 2 diabetic patients. Multivariate logistic regression analyses demonstrated that serum YKL-40 level was a determinant of albuminuria independently of conventional risk factors. [Copyright &y& Elsevier]

Abstract: Serum pigment epithelium-derived factor (PEDF) levels were significantly higher in type 1 diabetic patients with retinopathy (n =20, 10.38±3.87μg/ml) compared to the patients without it (n =57, 7.68±2.80μg/ml) (p =0.0013). Elevated PEDF levels may be related to the progression of diabetic retinopathy. [Copyright &y& Elsevier]