Soluble adhesion molecule E-selectin predicts cardiovascular events in Japanese patients with type 2 diabetes mellitus.

Soluble adhesion molecule E-selectin (sE-selectin) is a marker of endothelial activation. To investigate whether high serum concentrations of sE-selectin could predict cardiovascular events, we followed 392 Japanese patients with type 2 diabetes mellitus who had no history of cardiovascular disease for a mean period of 6 years. The cardiovascular end points were defined as fatal and nonfatal myocardial infarction, angina pectoris, stroke, and sudden death. During the follow-up period, 51 patients reached end point. Patients who reached end point were significantly older and had longer duration of diabetes, higher systolic blood pressure, higher hemoglobin A1c, higher plasma glucose, higher sE-selectin, and lower high-density lipoprotein cholesterol compared with those free of such events. The mean serum concentration of sE-selectin was higher in patients who reached end point (81.1 +/- 32.2 ng/mL) than event-free patients (66.7 +/- 33.7 ng/mL, mean +/- SD; P < .01). Multiple logistic regression analysis identified age, systolic blood pressure, total cholesterol, sE-selectin, and low high-density lipoprotein cholesterol as independent factors related to cardiovascular events. The odds ratio for cardiovascular events for 1-SD increase in sE-selectin concentration was 1.45 (95% confidence interval, 1.22-1.71). Kaplan-Meier analysis demonstrated a significantly higher cardiovascular event rate in the highest tertile of sE-selectin compared with the lowest or middle tertile of sE-selectin (P < .01). The results suggest that high serum concentrations of sE-selectin can predict cardiovascular events in Japanese patients with type 2 diabetes mellitus.

Humoral immune response to islet autoantigens in Japanese patients with type 1 diabetes.

In this study, we evaluated autoantibodies to IA-2 (IA-2As), glutamic acid decarboxylase 65 (GADAs), and islet cell antibodies (ICAs) in 233 patients with type 1 diabetes (M:F = 90:143, mean duration 4.0 +/- 6.7 yr) as a cross-sectional study. Of 233 patients with type 1 diabetes, IA-2A was detected in 58% of patients with duration within 2 weeks, 61% of patients with duration <1 yr, 41% of patients with diabetes for 1-3 yr, 29% for 4-9 yr, and 21% for >or=10 yr. These prevalences were similar to those of ICA, while the prevalence of GADA was not influenced by duration of diabetes with positivity of 63-74%. Thus, as the duration of diabetes became longer, the frequency of GADA(+)/IA-2A(-) patients increased and the frequency of GADA(+)/IA-2A(+) patients decreased. However, the frequency of GADA(-)/IA-2A(+) patients was not influenced by duration of diabetes. The prevalence of IA-2A was significantly higher in abrupt-onset group (68%, n= 79) compared to the slowly progressive group (23%, n= 22) in new-onset patients (P= 0.0001). However, there was no difference in the IA-2A frequency between these two groups (abrupt-onset 26%, n= 53 vs. slowly progressive 24%, n= 21) in patients with long-standing disease, suggesting that IA-2A positivity might persist in patients with slowly progressive type 1 diabetes. These results emphasize the heterogeneity of humoral autoimmunity to protein tyrosine phosphatase-like molecules, but not to GAD, in patients with type 1 diabetes.

Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-gamma activation.

Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-gamma, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR-gamma.

Evidence for the role of small ubiquitin-like modifier 4 as a general autoimmunity locus in the Japanese population.

CONTEXT: Recently, an association of a single nucleotide polymorphism, 163A>G encoding M55V, in the gene SUMO4, which has been shown to be a negative feedback regulator for nuclear factor kappaB, has been reported in type 1 diabetes. OBJECTIVE: To establish whether SUMO4 locus contributes to the genetic susceptibility to other autoimmune disorders, a case-control analysis was carried out using genomic DNA from type 1 diabetes, autoimmune thyroid disease (AITD), rheumatoid arthritis (RA), and primary Sjögren's syndrome. SUBJECTS: A total of 1480 samples, including 929 cases (411 patients with type 1 diabetes, 292 AITD, 172 RA, and 54 primary Sjögren's syndrome) and 551 healthy control subjects of Japanese origin participated in the study. METHODS: The 163A>G (rs237025, M55V) polymorphism of SUMO4 was genotyped. RESULTS: SUMO4 M55V variant was associated not only with type 1 diabetes [odds ratio (OR), 1.42; 95% confidence interval (CI), 1.09-1.84; P = 0.0072], but also with increased risk of other autoimmune diseases, AITD (OR, 1.52; 95% CI, 1.14-2.03; P = 0.0041) and RA without amyloidosis (OR, 1.53; 95% CI, 1.65-2.24; P = 0.027), but not primary Sjögren's syndrome. Furthermore, the association of SUMO4 M55V variant was stronger in type 1 diabetic patients complicated with AITD (OR, 1.62; 95% CI, 1.06-2.47; P = 0.023) and in patients who have neither type 1 diabetes-susceptible class II HLA, DRB1*0405 nor DRB1*0901 (OR, 2.28; 95% CI, 1.34-3.87; P = 0.0018). CONCLUSIONS: These results indicate that the SUMO4 is a more common autoimmune disease gene and a supplementary risk factor to type 1 diabetes in conjunction with class II HLA.

Identification of the promoter region required for human adiponectin gene transcription: Association with CCAAT/enhancer binding protein-beta and tumor necrosis factor-alpha.

Adiponectin, an adipose tissue-specific plasma protein, is involved in insulin sensitizing and has anti-atherosclerotic properties. Plasma levels of adiponectin are decreased in obese individuals and patients with type 2 diabetes with insulin resistance. Tumor necrosis factor-alpha (TNF-alpha) decreases the expression of adiponectin in adipocytes. The aims of the present study were: (1) to identify the promoter region responsible for basal transcription of the human adiponectin gene, and (2) to investigate the mechanism by which adiponectin was regulated by TNF-alpha. The human adiponectin promoter (2.1kb) was isolated and used for luciferase reporter analysis by transient transfection into 3T3-L1 adipocytes. Deletion analysis demonstrated that the promoter region from -676 to +41 was sufficient for basal transcriptional activity. Mutation analysis of putative response elements for sterol regulatory element binding protein (SREBP) (-431 to -423) and CCAAT/enhancer binding protein (C/EBP) (-230 to -224) showed that both elements were required for basal promoter activity. Adiponectin transcription was increased 3-fold in cells that over-expressed constitutively active C/EBP-beta. Electrophoretic mobility shift assay, using nuclear extract from 3T3-L1 cells and the -258 to -199 region as a probe, demonstrated specific DNA-protein binding, which was abolished by TNF-alpha treatment. The present data indicate that the putative response elements for SREBP and C/EBP are required for human adiponectin promoter activity, and that suppression by TNF-alpha may, at least in part, be associated with inactivation of C/EBP-beta.