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Background In animal studies, a meal containing Alaska pollack protein (APP) induces fast-twitch muscle hypertrophy. To our knowledge, no interventional studies have examined the benefits of APP intake on muscle mass and muscle weakness and the prevention of sarcopenia in older individuals. Objectives We evaluated the effects of APP intake on skeletal muscle mass, muscle strength, and physical performance among healthy community-dwelling older Japanese women. Methods In this double-blind randomized controlled trial, healthy women ≥ 65 y old were allocated to an APP or whey protein control (CON) group. Participants ingested test protein meals (5.0–5.1 g protein/serving) daily for 24 wk. Between-group differences in the change of skeletal muscle mass index (SMI) as the primary outcome and muscle strength as a secondary outcome were tested using multifrequency BIA and a handheld dynamometer, respectively, at baseline, and 4, 12, and 24 wk. The mean changes in the measured primary and secondary outcome variables from baseline to 4, 12, and 24 wk were compared using unpaired t tests. Results There were no between-group differences in nutritional status, food intake, or total energy and protein intakes at baseline, 12 wk, or 24 wk. The change in SMI was 0.12 kg/m2 (95% CI: 0.01, 0.23 kg/m2) and 0.11 kg/m2 (95% CI: 0.03, 0.19 kg/m2) greater in the APP group than in the CON group at 12 wk and 24 wk (P  ≤ 0.03) and knee extension strength was 0.07 Nm/kg BW (95% CI: 0.02, 0.12 Nm/kg BW) and 0.05 Nm/kg BW (95% CI: 0.00, 0.09 Nm/kg BW) higher in the APP group than in the CON group at these times (P  ≤ 0.015), respectively. The groups did not differ at 4 wk. Conclusions Daily intake of a meal containing APP compared with whey protein increases skeletal muscle mass and lower-extremity muscle strength in healthy older women, suggesting that an APP-containing meal may be useful in the prevention of sarcopenia in this group. This trial was registered at as UMIN000035718. [ABSTRACT FROM AUTHOR]

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: Objective: Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) system plays an important role in the development of atherosclerosis. It has been recently reported that endogenous secretory RAGE (esRAGE) and total soluble RAGE (sRAGE) levels are associated with diabetic complications. The aim of the present study is to longitudinally evaluate the association between esRAGE and sRAGE levels and the progression of carotid intima-media thickness (IMT), a surrogate marker of atherosclerosis. Methods and results: Japanese type 1 diabetic patients (n =47, aged 24.0±3.1 years) were enrolled into a 4-year follow-up study and annual measurements of serum esRAGE and sRAGE levels and IMTs were performed. At baseline, mean-IMT was inversely correlated with circulating esRAGE levels (r =−0.317, p =0.0292), whereas there was not statistical significance between mean-IMT and sRAGE levels. Mean-IMT significantly increased during the follow-up period (from 0.63±0.10 to 0.67±0.10mm, p =0.0022). Annual increase in mean-IMT (=(mean-IMT after 4 years−mean-IMT at baseline)/4) was positively correlated with the arithmetic average of systolic blood pressure (r =0.310, p =0.0332) and triglyceride (r =0.337, p =0.0201), and inversely correlated with circulating esRAGE levels (r =−0.360, p =0.0124) and sRAGE levels (r =−0.406, p =0.0042) during the follow-up period. Furthermore, stepwise multivariate regression analyses revealed that continuous low levels of circulating esRAGE and sRAGE were determinants of the progression of mean-IMT independently of conventional risk factors. Conclusions: Circulating esRAGE level as well as sRAGE level was an independent risk factor for the progression of carotid IMT in type 1 diabetic subjects. [Copyright &y& Elsevier]

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: Integrated backscatter (IBS) signal obtained by extracranial ultrasound examination of the carotid artery can be used to evaluate the tissue characteristics of arterial plaque. To examine whether clustering of several cardiovascular risk factors, metabolic syndrome (MetS), affects the tissue characteristics of the carotid artery, we measured Calibrated-IBS values of the intima–media complex in the carotid artery for 142 patients (61.6±9.5 years old) with at least one component of MetS. Calibrated-IBS values were inversely correlated with the number of MetS components (r =−0.224, p =0.0073). Furthermore, the number of MetS components was an independent risk factor for a low Calibrated-IBS. The subjects with coronary heart disease (CHD) (n =20) showed significantly lower Calibrated-IBS than those without it (n =122) (−17.8±5.1 vs. −21.7±5.5dB, p =0.0020), and the logistic regression analysis showed that the presence of CHD was associated with Calibrated-IBS (RR=0.898, 95%CI: 0.811–0.994, p =0.0374). These results suggest that clustering of the cardiovascular risk factors affects the Calibrated-IBS, an acoustic parameter of tissue characteristics of the intima–media complex in the carotid artery. [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: 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: Objective: Adiponectin has anti-atherogenic properties and reduced serum adiponectin levels are associated with cardiovascular disease (CVD). In this study, we examined the relationship between CVD and adiponectin (ADIPOQ) gene G276T polymorphism that is associated with serum adiponectin level in a large cohort of type 2 diabetic patients. Research design and methods: We enrolled 2637 Japanese type 2 diabetic subjects (males, 61.1%; age, 54.9±7.9 years old), determined their genotypes regarding ADIPOQ G276T polymorphisms, and evaluated the association between this polymorphism and the prevalence of CVD (myocardial infarction and/or cerebral infarction). Results: The prevalence of CVD tended to be higher as the number of G alleles increased [GG (9.5%), GT (6.8%), TT (5.6%), p value for trend=0.0059] and was significantly higher in the subjects with GG genotype compared to those with GT or TT genotype (9.5% vs. 6.6%, p =0.0060). Multiple logistic regression analyses revealed that the number of G alleles (Odds ratio (OR)=1.49 with 95%CI 1.09–2.05, p =0.0125) and GG genotype (OR=1.66 with 95%CI 1.13–2.43, p =0.0098) were significantly associated with CVD even after adjustment for conventional risk factors. Interestingly, the presence of obesity further and significantly increased the risk of CVD in the subjects with GG genotype (OR=1.67 with 95%CI 1.14–2.44, p =0.0090) but not in the subjects with TT or GT genotype (OR=1.17 with 95%CI 0.73–1.89, NS). Conclusions: It is likely that the G allele of the ADIPOQ G276T polymorphism is a susceptibility allele for CVD in Japanese type 2 diabetic patients, especially when they accompany obesity. [Copyright &y& Elsevier]

Abstract: Objective: It is indicated that total/HDL cholesterol and LDL/HDL cholesterol ratios have more predictive power for cardiovascular disease compared to classic lipid parameters. However, there have been few reports about the usefulness of these indices for the assessment of early stage atherosclerosis in Japanese type 2 diabetic subjects. Methods: We examined the relation between various lipid parameters and carotid atherosclerosis in 934 type 2 diabetic subjects without apparent atherosclerotic diseases (males, 71.7%; age, 59.6±10.5 years (mean±SD)). Serum concentrations of total cholesterol (TC), HDL cholesterol (HDL-C), and triglyceride were measured. LDL cholesterol (LDL-C) level was calculated using the Friedewald formula. The presence of carotid plaque and intima-media thickness (IMT) were evaluated by ultrasonography. Results: A stepwise multivariate regression analysis demonstrated that HDL-C (β =−0.110, p <0.001), TC/HDL-C (β =0.132, p <0.001) and LDL-C/HDL-C ratios (β =0.132, p <0.001) were independent determinants of IMT even after adjustment of other conventional risk factors. However, there was no significant correlation between IMT and TC, triglyceride, LDL-C, and non-HDL-C levels. TC/HDL-C and LDL-C/HDL-C ratios and non-HDL-C levels were significantly higher, but HDL-C levels were significantly lower in patients with carotid plaque than those without it (p <0.05). There was no significant difference between the groups regarding TC, LDL-C, and triglyceride levels. Furthermore, TC/HDL-C (OR; 1.34, p <0.001) and LDL-C/HDL-C (OR; 1.54, p <0.001) ratios showed a positive and linear relationship with the prevalence of carotid plaque, whether covariates were adjusted or not. Conclusions: TC/HDL-C and LDL-C/HDL-C ratios are useful as a tool to assess the risk of early stage atherosclerosis in Japanese type 2 diabetic patients. [Copyright &y& Elsevier]

Abstract: Objective: It is believed that oxidative stress, which is provoked in patients with diabetes, plays critical roles in the pathogenesis of myocardial infarction (MI). We simultaneously determined 5 relatively common genetic variants related to oxidative stress and evaluated the combined effect on MI. Methods: We enrolled 3819 Japanese type 2 diabetic subjects (males 60.8%, 60.6±10.0 years old) and determined their genotypes regarding glutamate-cysteine ligase modifier subunit (GCLM) C-588T, manganese superoxide dismutase (SOD2) Val16Ala, endothelial nitric oxide synthase (NOS3) G894T, NAD(P)H oxidase p22phox (CYBA) C242T, and myeloperoxidase (MPO) G-463A polymorphisms. The diagnosis of the occurrence of MI was based on the clinical records, characteristic ECG changes, and the findings in coronary angiography and echocardiography. Results: The single association analysis revealed that there were no statistically significant associations between each polymorphism and the prevalence of MI. Interestingly, the prevalence of MI was higher with the increase of the total number of 5 concomitant unfavorable “pro-oxidant alleles” in each subject (p value for linear trend=0.018). Furthermore, a multiple logistic regression analysis showed that the number of pro-oxidant alleles was a risk factor for MI independently of conventional risk factors (odds ratio for 1-point increase in the number of pro-oxidant allele=1.16 with 95% CI 1.01–1.34, p =0.034). Conclusions: Accumulation of gene polymorphisms related to oxidative stress is likely associated with the prevalence of MI in type 2 diabetic patients, suggesting that the combined information about these variants is useful to assess the risk of MI. [ABSTRACT FROM AUTHOR]

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]

Abstract: Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic β-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Normal β-cells can compensate for insulin resistance by increasing insulin secretion and/or β-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, β-cell function gradually deteriorates and insulin resistance aggravates. Under diabetic conditions, oxidative stress and endoplasmic reticulum stress are induced in various tissues, leading to activation of the c-Jun N-terminal kinase pathway. The activation of c-Jun N-terminal kinase suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of c-Jun N-terminal kinase in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the c-Jun N-terminal kinase pathway plays a central role in pathogenesis of type 2 diabetes and could be a potential target for diabetes therapy. [Copyright &y& Elsevier]

It has been shown that oxidative stress and activation of the c-Jun N-terminal kinase (JNK) pathway induce the nucleocytoplasmic translocation of the pancreatic transcription factor PDX-1, which leads to pancreatic β-cell dysfunction. In this study, we have shown that the forkhead transcription factor Foxo1/FKHR plays a role as a mediator between the JNK pathway and PDX-1. Under oxidative stress conditions, Foxo1 changed its intracellular localization from the cytoplasm to the nucleus in the pancreatic β-cell line HIT-T15. The overexpression of JNK also induced the nuclear localization of Foxo1, but in contrast, suppression of JNK reduced the oxidative stress-induced nuclear localization of Foxo1, suggesting the involvement of the JNK pathway in Foxo1 translocation. In addition, oxidative stress or activation of the JNK pathway decreased the activity of Akt in HIT cells, leading to the decreased phosphorylation of Foxo1 following nuclear localization. Furthermore, adenovirus-mediated Foxo1 overexpression reduced the nuclear expression of PDX-1, whereas repression of Foxo1 by Foxo1-specific small interfering RNA retained the nuclear expression of PDX-1 under oxidative stress conditions. Taken together, Foxo1 is involved in the nucleocytoplasmic translocation of PDX-1 by oxidative stress and the JNK pathway. [ABSTRACT FROM AUTHOR]

Abstract: Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic β-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Normal β-cells can compensate for insulin resistance by increasing insulin secretion and/or β-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, β-cell function gradually deteriorates and insulin resistance aggravates. Under diabetic conditions, oxidative stress and endoplasmic reticulum stress are induced in various tissues, leading to activation of the c-Jun N-terminal kinase pathway. The activation of c-Jun N-terminal kinase suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of c-Jun N-terminal kinase in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the c-Jun N-terminal kinase pathway plays a central role in pathogenesis of type 2 diabetes and could be a potential target for diabetes therapy. [Copyright &y& Elsevier]

MafA, a recently isolated pancreatic β-cell-specific transcription factor, is a potent activator of insulin gene transcription. In this study, we show that MafA overexpression, together with PDX-1 (pancreatic and duodenal homeobox factor-1) and NeuroD, markedly increases insulin gene expression in the liver. Consequently, substantial amounts of insulin protein were induced by such combination. Furthermore, in streptozotocin-induced diabetic mice, MafA overexpression in the liver, together with PDX-1 and NeuroD, dramatically ameliorated glucose tolerance, while combination of PDX-1 and NeuroD was much less effective. These results suggest a crucial role of MafA as a novel therapeutic target for diabetes. [ABSTRACT FROM AUTHOR]

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]

Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic β-cell dysfunction are the hallmarks of the disease. In this study, we have shown that endoplasmic reticulum (ER) stress, which is provoked under diabetic conditions, plays a crucial role in the insulin resistance found in diabetes by modifying the expression of oxygen-regulated protein 150 (ORP150), a molecular chaperone that protects cells from ER stress. Sense ORP overexpression in the liver of obese diabetic mice significantly improved insulin resistance and markedly ameliorated glucose tolerance. Conversely, expression of antisense ORP150 in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of IRS-1 and Akt, which are key molecules for insulin signaling, and the expression levels of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase, key enzymes of gluconeogenesis, were also altered by ORP150 overexpression. This is the first report showing that ER stress plays a crucial role in the insulin resistance found in diabetes and thus could be a potential therapeutic target for diabetes. [ABSTRACT FROM AUTHOR]

The proliferation of vascular smooth muscle cells (VSMCs) and alterations of their phenotype are implicated in the pathogenesis of atherosclerosis. Arterial wall injury induces the expression of proto-oncogenes, leading to the proliferation of VSMCs. In particular, c- Myc and c-Myb play a central role in cell cycle progression and are essential for VSMC replication. The proto-oncogene Pim-1 cooperates with c-Myc and enhances the transcriptional activity of c-Myb in hematopoietic cells, suggesting that Pim-1 is involved in cell cycle regulation. The aim of this study was to examine the possible involvement of Pim-1 in VSMC proliferation. Pim-1 was substantially induced in neointimal VSMCs of balloon-injured rat carotid arteries, and in vivo infection with a dominant negative Pim-l-expressing adenovirus (Ad-DN-Pim-1) markedly suppressed neointima formation and cell cycle progression in the balloon-injured arteries. In cultured VSMCs, treatment with serum or H2O2 induced Pim-1 expression, and H2O2- or serum-stimulated cell cycle progression and DNA synthesis were almost completely inhibited by DN-Pim-1 overexpression. Furthermore, we performed immunohistochemical staining for Pim-1 in human thoracic aortas and coronary arteries obtained from six individuals at autopsy and found that Pim-l-positive cells are observed predominantly in the thickened intima of the aortas and coronary arteries. To the best of our knowledge, this is the first report showing Pim-1 expression in rodent and human arterial walls. To summarize, Pim-1 expression was observed in the neointima of balloon- injured rat carotid arteries and in human thoracic aortas and coronary arteries showing intimal thickening, and the specific inhibition of Pim-1 function markedly suppressed neointima formation after balloon injury and the proliferation of cultured VSMCs, suggesting that Pim-1 plays a role in VSMC proliferation. [ABSTRACT FROM AUTHOR]

The c-Jun N-terminal kinase (JNK) pathway is known to be activated under diabetic conditions and to possibly be involved in the progression of insulin resistance. In this study, we examined the effects of modulation of the JNK pathway in liver on insulin resistance and glucose tolerance. Overexpression of dominant-negative type JNK in the liver of obese diabetic mice dramatically improved insulin resistance and markedly decreased blood glucose levels. Conversely, expression of wild type JNK in the liver of normal mice decreased insulin sensitivity. The phosphorylation state of crucial molecules for insulin signaling was altered upon modification of the JNK pathway. Furthermore, suppression of the JNK pathway resulted in a dramatic decrease in the expression levels of the key gluconeogenic enzymes, and endogenous hepatic glucose production was also greatly reduced. Similar effects were observed in high fat, high sucrose diet-induced diabetic mice. Taken together, these findings suggest that suppression of the JNK pathway in liver exerts greatly beneficial effects on insulin resistance status and glucose tolerance in both genetic and dietary models of diabetes. [ABSTRACT FROM AUTHOR]

We previously reported that insulin receptor substrate-2 (IRS-2)-deficient mice develop diabetes as a re. suit of insulin resistance in the liver and failure of β-cell hyperplasia. In this study we introduced the IRS-2 gene specifically into the liver of Irs2-1- mice with adenovirus vectors. Glucose tolerance tests revealed that the IRS-2 restoration in the liver ameliorated the hyperglycemia, but the improvement in hyperinsulinemia was only partial. Endogenous glucose production (EGP) and the rate of glucose disappearance (Rd) were measured during hyperinsulinemic-euglycemic clamp studies: EGP was increased 2-fold in the Irs2-1- mice, while Rd decreased by 50%. Restoration of IRS-2 in the liver suppressed EGP to a level similar to that in wild-type mice, but Rd remained decreased in the Adeno-IRS-2-infected Irs2-1- mice. Irs2-1- mice also exhibit obesity and hyperleptinemia associated with impairment of hypothalamic phosphatidylinositol 3-kinase activation. Continuous intracerebroventricular leptin infusion or caloric restriction yielded Irs2-1- mice whose adiposity was comparable to that of Irs2+/+ mice, and both the hyperglycemia and the hyperinsulinemia of these mice improved with increased Rd albeit partially. Finally combination treatment consisting of adenovirus-mediated gene transfer of IRS-2 and continuous intracerebroventricular leptin infusion completely reversed the hyperglycemia and hyperinsulinemia in Irs2-/- mice. EGP and Rd also became normal in these mice as well as in mice treated by caloric restriction plus adenoviral gene transfer. We therefore concluded that a combination of increased EGP due to insulin signaling defects in the liver and reduced Rd due to obesity accounts for the systemic insulin resistance in Irs2-/- mice. [ABSTRACT FROM AUTHOR]

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]

Aims: Since diabetes-associated kidney complication changes from diabetic nephropathy to diabetic kidney disease (DKD), more suitable biomarkers than urinary albumin are required. It has been hypothesized that urinary adiponectin (u-ADPN) is associated with the progression of DKD. We therefore evaluated the effectiveness of u-ADPN in predicting the decline of the renal function in patients with diabetes prior to end-stage renal disease.Methods: An ultrasensitive immune complex transfer enzyme immunoassay (ICT-EIA) was used to measure total and high molecular weight (HMW) adiponectin separately. We evaluated the relationships between the creatinine-adjusted urinary total-ADPN and HMW-ADPN, albumin (UACR) and liver-type fatty acid binding protein (L-FABP) at baseline and the 2-year change of the estimated glomerular filtration rate (ΔeGFR).Results: This 2-year prospective observational study included 201 patients with diabetes. These patients were divided into three groups according to their ΔeGFR: ≤-10 mL/min/1.73m2, >-10 and ≤0 mL/min/1.73m2, and >0 mL/min/1.73m2. Jonckheere-Terpstra test showed that lower ΔeGFR was associated with higher u-HMW-ADPN (p = 0.045). In logistic regression analysis, u-HMW-ADPN was associated with ΔeGFR after adjusted age, sex, and basal eGFR.Conclusion: Urinary HMW-ADPN could predict a declining renal function in patients with diabetes. [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]