A phase 3 multicenter open-label maintenance study to investigate the long-term safety of sodium zirconium cyclosilicate in Japanese subjects with hyperkalemia.

BACKGROUND: Hyperkalemia is associated with many chronic diseases and renin-angiotensin-aldosterone system inhibitor therapy. Sodium zirconium cyclosilicate (SZC), an oral, highly selective cation-exchanger, is approved for the treatment of hyperkalemia. METHODS: This phase 3, multicenter, open-label, single-arm, flexible-dose study assessed the safety and efficacy of SZC in Japanese patients with hyperkalemia during a correction phase of up to 3 days and long-term (1 year) maintenance phase (NCT03172702). RESULTS: Overall, 150 patients received treatment during both study phases; the study population was generally representative of hyperkalemic Japanese patients in clinical practice. Most patients (78.7%) had three doses of SZC during the correction phase. All but one patient received SZC for ≤ 48 h before transitioning to the maintenance phase. In the maintenance phase, mean (standard deviation; SD) exposure to the study drug was 319.4 (98.1) days and mean (SD) dose was 7.38 (2.85) g/day. Adverse events (AEs) were reported in 131 patients (87.3%); most were mild. The most common treatment-related AEs as evaluated by investigators were constipation (6.7%), peripheral edema (4.0%), and hypertension (2.7%). In the correction phase, 78.7% of patients were normokalemic at 24 h and 98.7% within 48 h; ≥ 65.5% maintained normokalemia throughout the maintenance phase. CONCLUSION: After a year of exposure, SZC treatment was well tolerated by Japanese patients and potassium levels were well controlled.

Clinical utility of brachial-ankle pulse wave velocity in the prediction of cardiovascular events in diabetic patients.

BACKGROUND: Brachial-ankle pulse wave velocity (baPWV) is a method to estimate arterial stiffness, which reflects the stiffness of both the aorta and peripheral artery; it would be applicable to general practice, since its measurementis automated. The aim of this study was to evaluate whether baPWV can be predictors of future cardiovascular events (CVE) in diabetic patients. METHODS: We prospectively evaluated the association between baPWV or carotid intima-media thickness (carotid IMT) at baseline and new onset of CVE in 1040 type 2 diabetic patients without CVE. The predictability of baPWV and/or carotid IMT for identifying patients at high risk for CVE was evaluated by time-dependent receiver-operating-characteristic (ROC) curve analysis. RESULTS: During a median follow-up of 7.5 years, 113 had new CVD events. The cumulative incidence rates of CVE were significantly higher in patients with high baPWV values (≥1550 cm/s) as compared to those with low baPWV values (<1550 cm/s) (p < 0.001, log-rank test). Similarly, the cumulative incidence rate of CVE was significantly higher in patients with higher maximum carotid IMT (maxIMT) values (≥1.0 mm) as compared to those with lower maxIMT values (<1.0 mm) (p < 0.001, log-rank test). Subjects with both "high PWV" and "high IMT" had a significantly higher risk of developing CVE as compared to those with either "high PWV" or "high IMT," as well as those with neither. A multivariate Cox proportional hazards regression model revealed that both baPWV (HR = 1.30, [95%CI: 1.07-1.57]; p = 0.009) and maxIMT (HR = 1.20, [95%CI: 1.01-1.41]; p = 0.033) were independent predictors for CVE, even after adjustment for the conventional risk factors. Time-dependent ROC curve analyses revealed that the addition of maxIMT to the Framingham risk score resulted in significant increase in AUC (from 0.60 [95%CI: 0.54-0.67] to 0.63 [95%CI: 0.60-0.82]; p = 0.01). Notably, the addition of baPWV to the Framingham risk score and maxIMT resulted in further and significant (p = 0.02) increase in AUC (0.72 [95%CI: 0.67-0.78]). CONCLUSIONS: Evaluation of baPWV, in addition to carotid IMT and conventional risk factors, improved the ability to identify the diabetic individuals with high risk for CVE.

Oral administration of cysteine peptides attenuates UV-B-induced skin erythema and pigmentation in humans.

The oral administration of antioxidants may suppress UV-B-induced skin damage. HITHION YH-15, the extract of Torula yeast (Cyberlindnera jadinii), is rich in cysteine-containing peptides such as reduced and oxidized glutathione (GSH and GSSG), γ-glutamylcysteine (γ-Glu-Cys), and cysteinylglycine (Cys-Gly). These four constituents are termed cysteine peptides. In this study, we investigated the protective effects of cysteine peptides against UV-B in a randomized, placebo-controlled, double-blind, parallel-group study. A total of 90 healthy males and females aged 30-59 years were enrolled and randomized into two groups of 45 individuals each (cysteine peptides (48 mg/day) and placebo). Changes in UV-B-induced erythema and pigmentation were compared between groups after 5 weeks of test food intake. The minimal erythema dose (MED) significantly increased (*p = 0.019) in the cysteine peptides group compared to that in the placebo group, indicating suppression of UV-B-induced erythema. ΔL* value significantly increased (***p < 0.0001) in the cysteine peptides group compared to that in the placebo, indicating pigmentation suppression. We demonstrated that oral administration of cysteine peptides suppresses UV-B-induced erythema and pigmentation through multiple mechanisms. Thus, cysteine peptides may find use as nutricosmetics for maintaining skin health and well-being.UMIN Clinical Trials Registry ID: UMIN 000050157.

Metabolic syndrome is not a predictor for cardiovascular events in Japanese patients with diabetes mellitus asymptomatic for coronary artery disease: a retrospective analysis of the J-ACCESS-2 study.

PURPOSE: Patients with metabolic syndrome (MetS) have potentially higher risk for cardiovascular events. The aim of this study was to evaluate the effect of MetS on cardiac events in type-2 diabetic patients asymptomatic for coronary artery disease (CAD) in a Japanese population. METHODS: A total of 485 patients from a J-ACCESS-2 investigation with stress-gated myocardial perfusion imaging (MPI) and quantitative-gated MPI analysis were examined. Cardiovascular hard events (cardiac death and acute coronary syndrome) and total events during a 3-year follow-up were analyzed. RESULTS: The MetS group (n = 229) had higher incidence of hypertension, dyslipidemia, and ventricular dilatation than the non-MetS group (n = 256). The hard events were 8 and 12 for the MetS and non-MetS groups (P = n.s.), and total events were 31 and 31 for each of these groups, respectively (P = n.s.). Significant variables related to total cardiovascular events included age, current smoking, insulin use, total cholesterol, ejection fraction, summed stress score ≥ 9, and summed difference score ≥ 2. Cox proportional hazard analysis and Kaplan-Meier survival analysis showed that only the summed stress score was related to total events (P = .01), and the presence and the number of items for MetS criteria were not. CONCLUSION: In patients with type 2 diabetes asymptomatic for CAD, cardiovascular events and ischemia are as common in diabetic patients without MetS as in those with MetS. A high MPI defect score is related to total events including cardiac and cerebrovascular events.

Association of myeloperoxidase G-463A gene polymorphism with diabetic nephropathy in Japanese type 2 diabetic subjects.

It is possible that myeloperoxidase (MPO) contributes to the pathogenesis of diabetic nephropathy through the production of reactive oxygen species and HOCl/OCl⁻. In this study, we examined the relationship between renal damage and MPO G-463A gene polymorphism that is associated with its transcription activity in diabetic patients. We evaluated the association between MPO G-463A polymorphism and the prevalence of proteinuria and estimated GFR (eGFR) in 1448 Japanese type 2 diabetic subjects. The prevalence of macroalbuminuria was higher as the number of G alleles increased (GG (7.6%), GA (3.8%), AA (0.0%), p for trend=0.0269). The number of G alleles was significantly associated with macroalbuminuria (odds ratio 2.12, 95%CI 1.06-4.24, p=0.0344) even after adjustment for conventional risk factors. Inversely, eGFR was lower as the number of G alleles increased (GG (76.7±20.7 mL/min/1.73m²), GA (81.0±22.8 mL/min/1.73m²), AA (92.0±23.1 mL/min/1.73m²), p for trend=0.0025) and the number of G allele was an independent risk factor for a low eGFR (ß=-0.072, p=0.003). We also examined the association between MPO expression and several stages of renal damage in a high-fat diet-induced diabetic mouse model. The proteinuria-induced increase in MPO expression was markedly enhanced in diabetic mice, and MPO expression was significantly correlated with the severity of kidney damage. In conclusion, it is likely that the G allele of the MPO G-476T polymorphism is a susceptibility allele for renal injury in type 2 diabetic patients.

Association of serum copper levels and glycemic control in patients with type 2 diabetes.

It has been suggested that copper ion is involved in the pathogenesis of various diseases. The aim of this study is to examine the association of serum copper levels and glycemic control in patients with type 2 diabetes. We recruited a total of 132 patients with type 2 diabetes, and measured their serum copper levels by atomic absorption spectrometry. Serum copper levels were positively correlated with HbA1c levels (r=0.176, p=0 .044). In addition, after 3-month glycemic control, we evaluated whether the improvement of glycemic control influenced serum copper levels. As hemoglobin A1c (HbA1c) levels were decreased (from 8.7% to 6.8%, p<0.001), copper levels tended to be decreased (from 105.7 µg/dL to 101.8 µg/dL, p=0.069). In conclusion, it is likely that serum copper levels are associated with glycemic control in patients with type 2 diabetes.

A candidate gene approach to genetic contributors to the development of IgA nephropathy.

BACKGROUND: Genetic factors contributing to the development of IgA nephropathy remain to be elucidated. METHODS: The present multicenter cross-sectional case-control study measured genotype frequencies of 65 atherosclerotic disease-related gene polymorphisms in 230 Japanese patients with IgA nephropathy and 262 apparently healthy volunteers with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m(2) and negative or trace proteinuria and hematuria by dipstick test [non-chronic kidney disease (CKD) participants]. Clinical characteristics at kidney biopsy of patients with IgA nephropathy and those at the study recruitment of non-CKD participants were included as covariates in multivariate logistic regression models. RESULTS: Among 31 gene polymorphisms with ≥5% of minor genotype in non-CKD participants, methionine synthase MTR A2756G (D919G) was significantly associated with IgA nephropathy using χ(2) test even after controlling for family-wise error rate by the method of Bonferroni (P = 0.044). A multivariate nonconditional logistic regression model identified MTR A2756G as a significant contributor of IgA nephropathy [2756AG and GG versus AA, odds ratio 0.42 (95% confidence interval 0.25-0.69) and 0.21 (95% confidence interval 0.06-0.68), P(trend) < 0.001]. After each patient with IgA nephropathy was randomly matched to a non-CKD participant on age (±5 years), gender, mean arterial pressure (±5 mmHg) and eGFR (±5 mL/min/1.73 m(2)), a multivariate conditional logistic regression model also verified their significant association [odds ratio 0.42 (95% confidence interval 0.18-1.00) and odds ratio 0.09 (95% confidence interval 0.01-0.73), P(trend) = 0.004]. MTR A2756G was not associated with slope of eGFR (mL/min/1.73 m(2)/year) in 230 patients with IgA nephropathy. CONCLUSION: MTR A2756G was associated with the development, but not progression, of IgA nephropathy.

Different impacts of metabolic profiles on future risk of cardiovascular disease between diabetes with and without established cardiovascular disease: the Japan diabetes complication and its prevention prospective study 7 (JDCP study 7).

AIMS: Most risk calculators that predict future cardiovascular disease (CVD) by baseline profiles are originally developed for primary prevention, but some studies applied the calculators to secondary prevention. We compared the impact of baseline profiles on the future CVD risk between patients with diabetes with and without a CVD history. METHODS: We analyzed a multicenter prospective cohort of 6338 Japanese patients with diabetes aged 40-74 years, including those with (n = 634) and without a CVD history (n = 5704). The future risk of CVD was investigated using the competing risk model, with adjustment for non-cardiovascular mortality. RESULTS: During the median follow-up of 6.9 years, 413 CVD events were observed. The 8-year cumulative incidence rates of CVD were 21.5% and 7.2% in patients with and without a CVD history, respectively. A higher systolic blood pressure and lower high-density lipoprotein cholesterol levels were independently associated with a future CVD risk in patients without a CVD history (both P < 0.05), whereas they were not associated in those with a CVD history. The P values for interaction were 0.040 and 0.005, respectively. The male sex, an older age, a longer duration of diabetes, higher hemoglobin A1c levels, and higher low-density lipoprotein cholesterol levels were common independent risk factors regardless of CVD history (all P < 0.05). CONCLUSIONS: The prognostic impact of metabolic profiles on CVD risk would not be identical between patients with and without a CVD history, suggesting that it might be inappropriate to apply CVD risk calculators developed for primary prevention to patients with a CVD history.

The phosphodiesterase inhibitor cilostazol induces regression of carotid atherosclerosis in subjects with type 2 diabetes mellitus: principal results of the Diabetic Atherosclerosis Prevention by Cilostazol (DAPC) study: a randomized trial.

BACKGROUND: Antiplatelet drugs are effective in preventing recurrence of atherosclerosis in type 2 diabetic patients. However, the efficacy and usefulness of 2 different antiplatelet drugs, aspirin and cilostazol, in the progression of carotid intima-media thickening are unknown. METHODS AND RESULTS: To compare prevention by cilostazol and aspirin of progression of atherosclerosis, we conducted a prospective, randomized, open, blinded end point study in 4 East Asian countries. A total of 329 type 2 diabetic patients suspected of peripheral artery disease were allocated to either an aspirin-treated (81 to 100 mg/d) group or a cilostazol-treated (100 to 200 mg/d) group. The changes in intima-media thickness of the common carotid artery during a 2-year observation period were examined as the primary end point. The regression in maximum left, maximum right, mean left, and mean right common carotid artery intima-media thickness was significantly greater with cilostazol compared with aspirin (-0.088 + or - 0.260 versus 0.059 + or - 0.275 mm, P<0.001; -0.042 + or - 0.274 versus 0.045 + or - 0.216 mm, P=0.003; -0.043 + or - 0.182 versus 0.028 + or - 0.202 mm, P=0.004; and -0.024 + or - 0.182 versus 0.048 + or - 0.169 mm, P<0.001). In a regression analysis adjusted for possible confounding factors such as lipid levels and hemoglobin A(1c), the improvements in common carotid artery intima-media thickness with cilostazol treatment over aspirin treatment remained significant. CONCLUSIONS: Compared with aspirin, cilostazol potently inhibited progression of carotid intima-media thickness, an established surrogate marker of cardiovascular events, in patients with type 2 diabetes mellitus. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: C000000215.

Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide.

The JNK pathway is known to be activated in several tissues in the diabetic state, and is possibly involved in the development of insulin resistance and suppression of insulin biosynthesis. Here we show a potential new therapy for diabetes using cell-permeable JNK-inhibitory peptide. Intraperitoneal administration of the peptide led to its transduction into various tissues in vivo, and this treatment markedly improved insulin resistance and ameliorated glucose tolerance in diabetic mice. These data indicate that the JNK pathway is critically involved in diabetes and that the cell-permeable JNK-inhibitory peptide may have promise as a new therapeutic agent for diabetes.

Prognostic value of normal stress myocardial perfusion imaging and ventricular function in Japanese asymptomatic patients with type 2 diabetes--a study based on the J-ACCESS-2 database.

BACKGROUND: This study was designed to determine the clinical risk for hard events after normal single-photon emission computed tomography (SPECT) and to identify the predictors of increased risk in asymptomatic patients with diabetes mellitus, based on a Japanese Assessment of Cardiac Events and Survival Studies by quantitative gated SPECT (J-ACCESS)-2 study. METHODS AND RESULTS: A total of 513 consecutive asymptomatic patients who underwent stress (99m)Tc-tetrofosmin SPECT in Japan were included in this study. Based on SPECT image and QGS data, 319 had a summed stress score < or =3, a summed difference score <2 and normal cardiac function (end-systolic volume < or =60 ml, males, < or =40 ml, females; left ventricular ejection fraction > or =49%, males, > or =50%, females). Myocardial perfusion was normal in 62% of this study population. During a 3-year follow-up, there were a total of 8 cardiac major events (2.5%): 2 cases of sudden death, 5 of acute coronary syndrome, and 1 of hospitalization because of congestive heart failure. The annual major event rate was 0.8%. Subjects undergoing coronary angiography had significantly more major events than those who did not among normal SPECT subjects (P=0.01). Kaplan-Meier analysis showed that the cardiac major events rate was very low, and subjects with normal SPECT can be considered as low risk among asymptomatic patients with diabetes. CONCLUSIONS: An excellent prognosis was associated with a normal SPECT in asymptomatic patients with diabetes, so these patients can be exempted from further invasive procedure.

[Recent advance in genetic marker for diabetic macroangiopathy].

Because of Westernized life style, diabetes and its complications become one of the most popular diseases in Asian countries as well as Westernized countries. Compared with diabetic microvascular complications, several risk factors such as postprandial hyperglycemia, increased coagulability, chronic inflammation, and genetic risk factors may lead to augment atherosclerosis, are shown to result in diabetic macroangiopathies (acute coronary syndrome, brain infarction, and ASO). Addition to candidate gene approach, genome wide association study (GWAS) successfully elucidated several novel single nuclear polymorphisms (SNP), contributing atherosclerosis. However, these genetic risk factors are still shown to contribute a relatively small part of atherosclerosis. Recently we have determined more than 100 atherosclerosis-related SNPs of around 2,000 subjects with type 2 diabetes. We have shown the combination of two atherosclerosis-prone SNPs highly significantly contribute to carotid atherosclerosis and coronary artery disease in subjects with type 2 diabetes. Also, accumulation of oxygen stress-prone alleles of some SNPs are proven to relate with serum level of 8-OHdG, as oxidative stress marker, carotid IMT, and prevalence of old myocardial infarction. These data clearly indicate that several genetic risk factors as well as conventional risk factors additively or synergistically contribute to diabetic macroangiopathy.

Cardiovascular events in Japanese asymptomatic patients with type 2 diabetes: a 1-year interim report of a J-ACCESS 2 investigation using myocardial perfusion imaging.

PURPOSE: Diabetic patients have a high risk for cardiovascular events. The role of myocardial perfusion imaging was investigated in asymptomatic diabetic patients to evaluate short-term prognosis in a Japanese population. METHODS: A total of 506 asymptomatic patients ≥ 50 years of age who had carotid artery maximum intima-media thickness ≥ 1.1 mm, urinary albumin excretion of ≥ 30 mg/g creatinine, with additional criteria of abdominal obesity, low HDL cholesterol, high triglyceride level, and hypertension were enrolled and followed up over a 3-year period. Gated SPECT with stress-rest protocol was performed and analyzed by summed defect scores and QGS software. One-year cardiovascular events were analyzed. RESULTS: Myocardial ischemia was observed in 17% of patients, and abnormal perfusion findings of ischemia and/or scar were observed in 32% of patients. By the end of the 1-year follow-up, 33 (6.5%) cardiovascular events occurred including 6 all-cause deaths. Patients with summed stress score (SSS) >8 had a higher incidence of either death or cardiovascular events. Event-free survival rates for SSS 0-3, 4-8, 9-13, and ≥ 14 were 0.96, 0.95, 0.82, and 0.76, respectively. Multivariate Cox regression analysis showed that significant variables were SSS, history of cerebrovascular accident, and electrocardiographic abnormality at rest. CONCLUSION: The 1-year interim summary showed that cardiovascular events were significantly higher in patients with SPECT abnormality, although hard cardiac event rate was relatively low. Targeted treatment strategy is required for asymptomatic but potentially high-risk diabetic patients.

Role of copper ion in the pathogenesis of type 2 diabetes.

Reactive oxygen species (ROS) are induced under diabetic conditions and are likely associated with the development of type 2 diabetes. It is also known that ROS production is facilitated in the presence of copper ion through the Fenton reaction. The aim of this study was to examine the involvement of copper ion in the pathogenesis of type 2 diabetes and to evaluate the potential usefulness of a copper chelating agent for the treatment of type 2 diabetes. First, both serum copper ion and ROS levels in diabetic C57BL/KsJ-db/db mice were significantly higher compared to those in nondiabetic mice. Second, we treated diabetic db/db mice with a copper chelating agent tetrathiomolybdate and examined the effects on the development of type 2 diabetes. As the results, both serum copper ion and ROS levels were significantly decreased by the treatment, which were equivalent to those in non-diabetic mice. Consequently, the treatment with a copper chelating agent reduced insulin resistance and ameliorated glucose intolerance in diabetic db/db mice. In addition, serum triglyceride levels were also decreased by the treatment. In conclusion, our present results suggest that copper ion is involved in the development of type 2 diabetes and thereby a potential therapeutic target for diabetes.

Pioglitazone reduces ER stress in the liver: direct monitoring of in vivo ER stress using ER stress-activated indicator transgenic mice.

It is known that endoplasmic reticulum (ER) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. In this study, using ER stress-activated indicator (ERAI) transgenic mice which express green fluorescent protein under ER stress conditions, we directly evaluated the effects of a diabetic agent pioglitazone on in vivo ER stress under diabetic conditions. In high fat and high sucrose diet-induced diabetic ERAI transgenic mice, 8 weeks of pioglitazone treatment reduced the accumulation of fat droplets in the liver and attenuated the development of insulin resistance. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly reduced as early as after 4 weeks of pioglitazone treatment, preceding the improvement of insulin resistance. In addition, after the pioglitazone treatment, serum free fatty acid and triglyceride levels were decreased, and serum adiponectin levels were increased. These data indicate that pioglitazone treatment suppresses ER stress in the liver which may explain, at least in part, the pharmacological effects of pioglitazone to reduce insulin resistance.

Direct monitoring of in vivo ER stress during the development of insulin resistance with ER stress-activated indicator transgenic mice.

Type 2 diabetes is one of the most prevalent and serious metabolic diseases in the world, and insulin resistance and pancreatic beta-cell dysfunction are the hallmarks of the disease. It has been suggested that endoplasmic reticulum (ER) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. In this study, using ER stress-activated indicator (ERAI) transgenic mice which express green fluorescent protein (GFP) under ER stress conditions, we directly monitored in vivo ER stress in various insulin target tissues such as liver, fat, and muscle in diabetic mice with insulin resistance induced by high fat and high sucrose (HF/HS) diet treatment. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly observed as early as after 4 weeks of HF/HS diet treatment, whereas it was not detected at all in the fat and muscle even after 12 weeks of HF/HS diet treatment. These results suggest that induction of ER stress is associated with the development of insulin resistance and that ER stress in the liver may facilitate the development of insulin resistance in the whole body. This is the first report to directly monitor in vivo ER stress in various insulin target tissues during the development of insulin resistance. In addition, our present results suggest that ERAI transgenic mice are very useful for evaluating in vivo ER stress, especially in the liver, during the development of insulin resistance.

PDX-1 functions as a master factor in the pancreas.

Various pancreatic transcription factors are involved in pancreas development and beta-cell differentiation. Among them, pancreatic and duodenal homeobox factor-1 (PDX-1) plays a crucial role in pancreas development and beta-cell differentiation, and maintaining mature beta-cell function. MafA is a recently isolated beta-cell-specific transcription factor and functions as a potent activator of insulin gene transcription. These pancreatic transcription factors also play a crucial role in inducing surrogate beta-cells from non-beta-cells and thus could be therapeutic targets for diabetes. On the other hand, under diabetic conditions, expression and/or activities of PDX-1 and MafA in beta-cells are reduced, which leads to suppression of insulin biosynthesis and secretion. Thus, it is likely that alteration of such transcription factors explains, at least in part, the molecular mechanism for beta-cell glucose toxicity found in diabetes.

Endogenous secretory RAGE but not soluble RAGE is associated with carotid atherosclerosis in type 1 diabetes patients.

Advanced glycation end-products (AGEs) and the receptor for AGEs (RAGE) system play an important role in the development of diabetic complications. The soluble form of RAGE (sRAGE) that potentially counteracts AGEs consists of several forms, including endogenous secretory RAGE (esRAGE; a splice variant of RAGE) and cleaved-type soluble RAGE derived from cell-surface RAGE. The aim of this study was to compare sRAGE and esRAGE directly in patients with type 1 diabetes. The associations of both total sRAGE and esRAGE with markers of glycaemic control and with carotid intima-media thickness (IMT) as a marker of atherosclerosis were examined in 130 type 1 diabetes patients (aged 23.6+/-4.9 years) and 22 age-matched non-diabetic subjects. IMT was inversely correlated with esRAGE (r=-0.254, p=0.0015) but neither with sRAGE nor subtracted soluble RAGE values (that is, circulating total sRAGE values - circulating esRAGE values). Furthermore, a stepwise multivariate regression analysis revealed that esRAGE (F=7.3), but not sRAGE, was a variable that interacted independently of IMT. It is likely that circulating sRAGE and esRAGE are distinct markers and that circulating esRAGE levels, but not sRAGE levels, are associated with the status of early-stage atherosclerosis.

MafA regulates expression of genes important to islet beta-cell function.

Insulin transcription factor MafA is unique in being exclusively expressed at the secondary and principal phase of insulin-expressing cell production during pancreas organogenesis and is the only transcriptional activator present exclusively in islet beta-cells. Here we show that ectopic expression of MafA is sufficient to induce a small amount of endogenous insulin expression in a variety of non-beta-cell lines. Insulin mRNA and protein expression was induced to a much higher level when MafA was provided with two other key insulin activators, pancreatic and duodenal homeobox (PDX-1) and BETA2. Potentiation by PDX-1 and BETA2 was entirely dependent upon MafA, and MafA binding to the insulin enhancer region was increased by PDX-1 and BETA2. Treatment with activin A and hepatocyte growth factor induced even larger amounts of insulin in AR42J pancreatic acinar cells, compared with other non-beta endodermal cells. The combination of PDX-1, BETA2, and MafA also induced the expression of other important regulators of islet beta-cell activity. These results support a critical role of MafA in islet beta-cell function.

Glycated albumin is a better indicator for glucose excursion than glycated hemoglobin in type 1 and type 2 diabetes.

To determine the impact of blood glucose profile, involving fluctuation and excursion of blood glucose levels, on glycated proteins, we evaluated the association among the daily profile of blood glucose, and glycated albumin (GA) and HbA1c levels in patients with type 1 diabetes (n = 93) and type 2 diabetes (n = 75). GA levels were strongly correlated with HbA1c levels in type 1 (r = 0.85, P<0.0001) and type 2 diabetes (r = 0.61, P<0.0001), respectively. HbA1c levels were similar between patients with type 1 and type 2 diabetes, while GA levels were significantly higher in type 1 diabetes. Thus the ratio of GA levels to HbA1c levels was significantly higher in type 1 diabetes than that in type 2 diabetes (3.32 0.36 vs. 2.89 0.44, p<0.001). The degrees of GA levels and HbA1c levels correlated with maximum and mean blood glucose levels in patients with type 1 and type 2 diabetes. Stepwise multivariate analysis revealed that GA levels independently correlated with maximum blood glucose levels in type 1 diabetes (F = 43.34, P<0.001) and type 2 diabetes (F = 41.57, P<0.001). HbA1c levels also independently correlated with maximum blood glucose levels in type 1 diabetes (F = 34.78, P<0.001), as well as being correlated with mean blood glucose levels in type 2 diabetes (F = 11.28, P<0.001). In summary, GA could be a better marker for glycemic control than glycated hemoglobin in diabetic patients, especially for evaluating glycemic excursion, which is considered to be a major cause of diabetic angiopathy.