San-e Ishikawa

Pathophysiological roles of arginine vasopressin and aquaporin-2 in impaired water excretion

Impaired water excretion occurs in patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), adrenal insufficiency, congestive heart failure and liver cirrhosis with ascites (Bartter & Schwartz, 1967; Schrier, 1988a,b). In these clinical settings, there is hyponatraemia to various extents. Nonsuppressible release of arginine vasopressin (AVP, ADH) is found despite hypoosmolality, which should suppress AVP release to undetectable levels. Reversal of hyponatraemia by specific antagonists of AVP provides conclusive evidence for the role of AVP in pathological states of water retention. In response to AVP, concentrated urine is produced by water reabsorption across renal collecting ducts (Ishikawa, 1993; Knepper & Rector, 1995). The aquaporin-2 (AQP-2) water channel was discovered by Sasaki and colleagues (Fushimi et al ., 1993), and is an AVP-regulated water channel in collecting duct cells. There are two regulatory systems: short-term and long-term regulation. The upregulation of kidney AQP-2 expression is closely related to the nonsuppressible release of AVP in the experimental models of SIADH, liver cirrhosis, congestive heart failure, and adrenal insufficiency (Asahina et al ., 1995; Fujita et al ., 1995; Nielsen et al ., 1997; Xu et al ., 1997; Saito et al ., 2000). Kidney AQP-2 expression has been quantitatively estimated by urinary excretion of AQP-2 (Kanno et al ., 1995; Rai et al ., 1997). Approximately 3% of AQP-2 in the collecting duct cells is excreted into urine (Rai et al ., 1997), and urinary excretion of AQP-2 positively correlates with plasma AVP levels in normal subjects (Saito et al ., 1997c). In this review, we focus on the close association of kidney AQP-2 expression with exaggerated release of AVP in pathological states of impaired water excretion. Furthermore, the diagnostic value of urinary excretion of AQP-2 in disorders of water metabolism dependent on AVP is discussed. Secretion of arginine vasopressin

Circulating betatrophin is elevated in patients with type 1 and type 2 diabetes.

There is evidence that betatrophin, a hormone derived from adipose tissue and liver, affects the proliferation of pancreatic beta cells in mice. The aim of this study was to examine circulating betatrophin concentrations in Japanese healthy controls and patients with type 1 and type 2 diabetes. A total of 76 subjects (12 healthy controls, 34 type 1 diabetes, 30 type 2 diabetes) were enrolled in the study. Circulating betatrophin was measured with an ELISA kit and clinical parameters related to betatrophin were analyzed statistically. Circulating betatrophin (Log transformed) was significantly increased in patients with diabetes compared with healthy subjects (healthy controls, 2.29 ± 0.51; type 1 diabetes, 2.94 ± 0.44; type 2 diabetes, 3.17 ± 0.18; p<0.001, 4.1 to 5.4 times in pg/mL order). Age, HbA1c, fasting plasma glucose and Log triglyceride were strongly associated with Log betatrophin in all subjects (n=76) in correlation analysis. In type 1 diabetes, there was a correlation between Log betatrophin and Log CPR. These results provide the first evidence that circulating betatrophin is significantly elevated in Japanese patients with diabetes. The findings of this pilot study also suggest a possibility of association between the level of betatrophin and the levels of glucose and triglycerides.

Characteristics of diabetic retinopathy in SDT rats.

We previously reported a new diabetic strain of the Sprague‐Dawley rat, named the Spontaneously Diabetic Torii (SDT) rat. The purpose of the present study was to report the histologic and ultrastructural characteristics of diabetic retinopathy (DR) in a new animal model, the SDT rat.

Association of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes

BackgroundOsteoprotegerin is a member of the tumor necrosis factor-related family and inhibits RANK stimulation of osteoclast formation as a soluble decoy receptor. The goal of this study was to determine the relationship of serum osteoprotegerin with vascular calcification in patients with type 2 diabetes.MethodsThe subjects were 124 patients with type 2 diabetes mellitus, including 88 males and 36 females with a mean (± SD) age of 65.6 ± 8.2 years old. Serum levels of osteoprotegerin, osteocalcin, fibroblast growth factor 23 (FGF23), 25-hydroxyvitamin D3 and adiponectin were measured by ELISA. Vascular calcification in the cervical artery was examined by ultrasound sonography. The subjects were divided into 4 quartiles depending on serum osteoprotegerin levels.ResultsVascular calcification was significantly higher in the 4th quartile and significantly lower in the 1st quartile of serum osteoprotegerin levels, compared to other quartiles. There were no differences in serum osteoprotegerin and vascular calcification among patients with different stages of diabetic nephropathy, but serum FGF23 levels were elevated in those with stage 4 diabetic nephropathy. Simple regression analysis showed that serum osteoprotegerin levels had significant positive correlations with age, systolic blood pressure and serum adiponectin levels, and significant negative correlations with BMI and serum 25-hydroxyvitamin D3.ConclusionsThese findings suggest that elevated serum osteoprotegerin may be involved in vascular calcification independently of progression of diabetic nephropathy in patients with type 2 diabetes.

Involvement of cAMP/EPAC/TRPM2 Activation in Glucose- and Incretin-Induced Insulin Secretion

In pancreatic β-cells, closure of the ATP-sensitive K+ (KATP) channel is an initial process triggering glucose-stimulated insulin secretion. In addition, constitutive opening of background nonselective cation channels (NSCCs) is essentially required to effectively evoke depolarization as a consequence of KATP channel closure. Thus, it is hypothesized that further opening of NSCC facilitates membrane excitability. We identified a class of NSCC that was activated by exendin (ex)-4, GLP-1, and its analog liraglutide at picomolar levels. This NSCC was also activated by increasing the glucose concentration. NSCC activation by glucose and GLP-1 was a consequence of the activated cAMP/EPAC-mediated pathway and was attenuated in TRPM2-deficient mice. The NSCC was not activated by protein kinase A (PKA) activators and was activated by ex-4 in the presence of PKA inhibitors. These results suggest that glucose- and incretin-activated NSCC (TRPM2) works in concert with closure of the KATP channel to effectively induce membrane depolarization to initiate insulin secretion. The current study reveals a new mechanism for regulating electrical excitability in β-cells and for mediating the action of glucose and incretin to evoke insulin secretion, thereby providing an innovative target for the treatment of type 2 diabetes.

Efficacy of troglitazone measured by insulin resistance index

Troglitazone is an orally active agent that enhances insulin action. The drug reduces insulin resistance by increasing insulin-mediated glucose disposal and decreasing hepatic glucose output. The results of a double-blind study of troglitazone therapy have revealed that the agent improves glycaemic indices in Japanese and white patients with

Association of the Glu298Asp polymorphism of the eNOS Gene with ischemic heart disease in Japanese diabetic subjects

We analysed the association of the Glu298Asp polymorphism of the endothelial nitric oxide synthase (eNOS) gene with ischemic heart disease (IHD) and albuminuria in 337 Japanese diabetes patients. Restriction fragment length polymorphism analysis of Glu298Asp of the eNOS gene was performed by amplification of genomic DNA isolated from whole blood followed by digestion with the restriction enzyme BanII. Individuals with IHD were identified by review of medical records and were identified based on apparent ischemic change of electrocardiography, significant stenosis of coronary artery, or a history of myocardial infarction, coronary artery bypass surgery, or catheter intervention. Albuminuria was confirmed by a positive test on at least two separate examinations. Of the 337 subjects analysed for polymorphisms of the eNOS gene, 45 with the GluAsp and five with the AspAsp genotype were combined into 1 group (GluAsp or AspAsp group). Among these 50 subjects, 16 (32%) had IHD, and among 287 subjects with the GluGlu genotype, 38 (13.2%) had IHD. The number of subjects with IHD was significantly greater in the GluAsp or AspAsp group than in the GluGlu group (P=0.0006). There was no difference in the frequency of albuminuria among the genotypes. The GluAsp or AspAsp genotype of the Glu298Asp polymorphism was significantly associated with IHD, but not albuminuria in these Japanese diabetic subjects.

Latent associations of low serum amylase with decreased plasma insulin levels and insulin resistance in asymptomatic middle-aged adults.

BackgroundLow serum amylase is likely to be associated with obesity and metabolic abnormalities, which are often accompanied by impaired insulin action. However, it is unclear whether low serum amylase is associated with impaired insulin action in clinical settings. Therefore, we investigated the associations of low serum amylase with plasma insulin levels, and obesity-related parameters, including leptin.Research design and methodsWe measured serum amylase, plasma insulin, obesity-related parameters such as leptin, cardiometabolic risk factors, and anthropometric parameters in a cross-sectional study of 54 asymptomatic subjects (mean age 48.6 ± 7.6 years) who were not being treated for diabetes.ResultsBody mass index (BMI) and plasma glucose at 120 min after a 75-g oral glucose tolerance test (OGTT) were significantly higher in subjects with low serum amylase (< 60 IU/l, n = 21) than in those with normal-to-high serum amylase (n = 33) (P = 0.04 and P = 0.004, respectively). In univariate correlation analysis, serum amylase was significantly correlated with BMI alone (r = –0.39, P = 0.004). By contrast, multivariate logistic analysis showed that each 1-SD increase in quantitative insulin sensitivity check index, and each 1-SD decrease in plasma insulin OGTT at 0 and 60 min, homeostasis model assessment of insulin resistance (HOMA)-R, and HOMA-β were significantly associated with low serum amylase, particularly after adjusting for BMI. When subjects were divided into three groups according to HOMA-R, serum amylase levels were significantly lower in subjects with HOMA-R > 2.5 (n = 23) compared with subjects with HOMA-R 1.6–2.5 (n = 10) (61.1 ± 13.6 U/ml versus 76.9 ± 20.5 U/ml, Bonferroni test, P = 0.02), but not compared with subjects with HOMA-R<1.6 (n = 21; 62.7 ± 17.6 U/ml). Similar trends were observed when subjects were divided according to plasma leptin and fasting plasma insulin levels.ConclusionsThese results suggest that after adjusting for BMI, low serum amylase is associated with decreased basal insulin levels and insulin secretion, as well as high insulin resistance. The nature of these associations remains to be elucidated in further studies.

Association of CTLA-4 polymorphism with positive anti-GAD antibody in Japanese subjects with type 1 diabetes mellitus

CTLA‐4, expressed on activated T cells, is thought to be a negative regulator of T cell function. Its gene (2q33) may confer genetic susceptibility to type 1 diabetes mellitus (IDDM12). The present study was undertaken to clarify the role of CTLA‐4 gene polymorphism in Japanese subjects with type 1 diabetes and its effect on their clinical features.

Association of endogenous insulin secretion and mode of therapy with body fat and serum leptin levels in diabetic subjects

Insulin is one of the hormonal regulators of leptin synthesis and participates in adipose tissue maintenance. The present study was undertaken to clarify the association of endogenous insulin secretion and mode of therapy with body fat and serum leptin levels in diabetic subjects. We measured the fasting serum C-peptide level, as an estimate of endogenous insulin secretion, and the serum leptin level in 176 Japanese diabetic subjects (79 men and 97 women; age, 55.9+/-14.3 years; body mass index [BMI], 23.8+/-4.1 kg/m2 [mean+/-SD]). Thirty-one subjects were treated with diet therapy alone, 66 with sulfonylurea (SU), and 79 with insulin (including 29 with type I diabetes mellitus). Body fat was analyzed by the impedance method. Serum leptin levels significantly correlated with the BMI and body fat and were higher in women, mainly because of their greater body fat. Serum C-peptide concentrations positively correlated with body fat and serum leptin in subjects treated with diet and SU. In insulin-treated type II diabetic subjects, both serum C-peptide and the daily insulin dose were weakly associated with body fat and serum leptin. In those subjects, despite a lower percent body fat and body fat mass, serum leptin concentrations (10.3+/-8.4 ng/mL) were comparable to the levels in subjects treated with diet (8.8+/-8.5 ng/mL). When compared within the same BMI and body fat groups (BMI 20 to 25 and > 25 kg/m2) including the control subjects matched for age and sex, serum leptin levels were higher in insulin-treated type II diabetic subjects versus the control subjects and diabetic patients treated with diet or SU. Stepwise regression analysis for all of the diabetic subjects showed that both the serum C-peptide level and exogenous insulin administration, as well as the BMI, gender, and age, were determinants of the serum leptin level. In conclusion, endogenous insulin secretion is closely associated with body fat and serum leptin in diabetic subjects treated with diet therapy and SU. In Japanese insulin-treated type II diabetic subjects, both endogenous and exogenous insulin are associated with body fat and serum leptin, which is maintained at levels comparable to or somewhat higher than the levels in control subjects and diabetic patients treated without insulin.