Ataru Taniguchi

Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus.

The aim of the present study was to investigate the association of serum adiponectin concentration with regional adiposity and insulin resistance in subjects with type 2 diabetes mellitus. A total of 73 Japanese men with type 2 diabetes (aged 59 +/- 11 years and body mass index [BMI] 23.8 +/- 3.0 kg/m(2), mean +/- SD) were studied. Fasting serum adiponectin and leptin concentrations were determined by radioimmunoassay. Regional adiposity was measured by abdominal computed tomography (CT) at the umbilical level, and insulin resistance was estimated by homeostasis model assessment (HOMA-R). Univariate regression analysis showed that serum adiponectin levels were negatively correlated with subcutaneous and visceral fat areas. With multivariate regression analysis, visceral fat area was a predominant determinant of serum adiponectin levels. In contrast, subcutaneous fat area was strongly associated with serum leptin concentrations. Among subcutaneous and visceral fat areas, BMI, and serum leptin levels, both subcutaneous and visceral fat areas were independently associated with HOMA-R. In another model incorporating serum adiponectin levels, serum adiponectin levels were selected as an independent determinant of HOMA-R instead of visceral fat area. In conclusion, hypoadiponectinemia was associated with visceral fat accumulation rather than subcutaneous fat depot in Japanese men with type 2 diabetes mellitus. Both subcutaneous and visceral fat accumulation contribute to insulin resistance in these subjects, and the contribution of visceral fat may be mediated, in part, by hypoadiponectinemia.

Pathogenic Factors Responsible for Glucose Intolerance in Patients With NIDDM

To define the pathogenic factors responsible for glucose intolerance in NIDDM, we estimated insulin secretory capacity, SI, and SG in 11 healthy, nondiabetic subjects and 9 NIDDM patients who had no SI impairment. All subjects studied were nonobese and normotensive. Each underwent a 75-g OGTT and a modified FSIGT: glucose was administered (300 mg/kg body weight), and insulin was infused (20 mU/kg over 5 min) from 20 to 25 min after the administration of glucose. SI and SG were estimated by Bergmans minimal-model method. The insulin response to oral glucose was significantly lower in NIDDM patients than in normal control subjects. First-phase insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 20 min was much smaller in NIDDM subjects (214 ±112 pM · min) than in control subjects (4643 ± 885 pM · min, P < 0.01). S, was not statistically different in normal control subjects (1.27 ± 0.18 × 10−4 min−1 · pM−1) versus diabetic patients (1.62 ± 0.33 × 10−4 min−1 · pM−1). However, SG was significantly lower in diabetic subjects (1.11 ± 0.17 × 10−2 min−1) than in control subjects (2.35 ± 0.26 × 10−2 min−1 P < 0.01). These results suggest that impaired insulin secretion and decreased SG are the factors responsible for glucose intolerance of Japanese NIDDM patients with normal insulin sensitivity. Because SI and SG are the factors responsible for glucose intolerance of NIDDM patients with insulin resistance, it is conceivable that decreased SG is common in NIDDM patients regardless of their SI index.

Impaired β-cell function and insulin sensitivity in Japanese subjects with normal glucose tolerance

The development of type 2 diabetes mellitus is characterized by both impaired beta-cell function and increasing insulin resistance. To clarify the roles of them in developing type 2 diabetes, we evaluated insulin resistance by HOMA-IR and insulin secretion by HOMA beta-cell in 453 Japanese subjects whose fasting plasma glucose (FPG) and HbA(1c) levels were within normal range. HOMA beta-cell was found to decrease in the over 30 years groups, while HOMA-IR increased with body mass index (BMI). To analyze the reserve capacity of insulin secretion and insulin sensitivity, the 67 of them, who underwent a standard oral glucose tolerance test and were diagnosed with normal glucose tolerance (NGT), were divided into four degrees of BMI age-adjusted to 50 years. They were compared for insulinogenic index and ISI composite proposed by Matsuda and DeFronzo across the range of BMI. ISI composite was significantly less in the highest BMI group, while insulin secretion did not increase in the higher BMI groups. The subjects with higher BMI had remarkably lower insulinogenic indices than those with lower BMI. These data suggest that insulin secretory reserve is insufficient to compensate for increased insulin resistance in Japanese people with NGT at about 50 years of age.

30 mm regeneration of rat sciatic nerve along collagen filaments.

This paper describes 30 mm regeneration of peripheral nerve axons along collagen filaments; 31-mm-long collagen filaments or collagen tube were grafted to bridge a 30-mm defect of rat sciatic nerve. The mean number and the diameter of regenerated myelinated axons were 330+/-227 and 2.7+/-0.9 microm at the distal end of the collagen-filaments 12 weeks postoperatively; while at the distal end of the tube no axon was found.

Bridging a Spinal Cord Defect Using Collagen Filament

Study Design. A rat model of spinal cord defect was designed to evaluate the effect of collagen filament implant on nerve regeneration in the spinal cord defect. Objectives. To bridge a spinal cord defect and restore the function in adult mammals. Summary of Background Data. Resection of the spinal cord in mammals is always followed by motor paralysis and loss of voluntary function below the lesion. Partial success in bridging the ends of the spinal cord after complete resection was reported. However, restoration of function has not been reported in adult mammalian. Materials and Methods. Four thousand collagen filaments 5-mm-long were grafted to bridge a 5-mm defect of rat spinal cord. Controls had their spinal cord defect left ungrafted after resection. At 1-week intervals, animals were evaluated functionally. After 4 and 12 weeks, animals were evaluated histologically. After 12 weeks, animals were evaluated electrophysiologically. Results. The severed spinal cord axons regenerated along the collagen filament implant crossing the proximal and distal spinal cord implant interfaces at 4 weeks after surgery. The rats with collagen filament grafts could walk, run, and climb with hind forelimb coordination at 12 weeks after surgery. Sensory-evoked potential waveform was found in the rats with collagen filament at 12 weeks after surgery. Conclusions. The collagen filaments support the axonal regeneration of the transected spinal cord and the restoration of function.

Insulin sensitivity, insulin secretion, and glucose effectiveness in anorexia nervosa: A minimal model analysis

The aim of the present study was to estimate insulin secretion, insulin sensitivity (SI), and glucose effectiveness (SG) in subjects with anorexia nervosa. Eight nondiabetic anorectic patients who were dietary restricters and 16 age- and sex-matched healthy control subjects without family history of diabetes were studied. They underwent a modified frequently sampled intravenous glucose tolerance test; glucose (300 mg/kg body weight) was administered and insulin (4 mU/kg body weight/min) was infused from 20 to 25 minutes after administration of glucose. SI and SG were estimated by Bergmans minimal model method. Basal glucose (75.5 +/- 2.1 v 87.1 +/- 1.7 mg/dL) and insulin (3.6 +/- 0.4 v 6.3 +/- 0.5 microU/mL) concentrations were significantly lower in anorectic patients than in control subjects (P < .01). No significant difference was observed in glucose disappearance rate (KG) between the anorectic and control subjects (1.56 +/- 0.5 v 2.26 +/- 0.15%/min). Insulin secretion assessed by the integrated area of plasma insulin above basal level during the first 20 minutes after intravenous stimulation with glucose was significantly decreased in anorectic patients (283 +/- 69 microU.mL-1 x min) compared with control subjects (529 +/- 63 microU.mL-1 x min, P < .05). SI was significantly increased in anorectic patients compared with control subjects (11.2 +/- 1.2 v 7.5 +/- 1.0 x 10(-4) min-1 +/-.[microU/mL]-1, P < .05). However, SG was significantly decreased in anorectic patients (0.015 +/- 0.003 min-1) compared with control subjects (0.023 +/- 0.002 min-1, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Biological activities of angiotensin II-(1-6)-hexapeptide and angiotensin II-(1-7)-heptapeptide in man

Biological activities of angiotensin II-(1-6)-hexapeptide [ANG-(1-6)] and angiotensin II-(1-7)-heptapeptide [ANG-(1-7)] were studied in 5 normal men and 3 patients with Bartters syndrome. The angiotensins were infused iv in each subject from 0900 h to 0915 h at a rate of 21 nmol(16.8 micrograms)/kg X min and 18 nmol(16.2 micrograms)/kg X min for ANG-(1-6) and ANG-(1-7), respectively. In the normal men a significant rise in blood pressure was observed by the infusions of both peptides. Average increments of blood pressure for ANG-(1-6) were 17/14, 23/18, 22/15 and 17/14 mmHg at 2, 5, 10 and 15 min, respectively, and those for ANG-(1-7) were 19/15, 20/17, 13/13 and 15/13 mmHg at 2, 5, 10 and 15 min, respectively. The duration of pressor actions after the cessation of the infusions (T) was 10 min for ANG-(1-6) and 20 (for systolic) and 30 (for diastolic) min for ANG-(1-7). T for ANG-(1-6) was shorter than and T for ANG-(1-7) was similar to T for Ile5-angiotensin II (Ile5-ANG II) reported previously in 7 normal men 5 of whom were the same as examined in the present study. On the other hand, both peptides did not cause a rise in blood pressure in the 3 patients with Bartters syndrome. Both angiotensins did not cause an increase in plasma aldosterone but did cause a significant decrease in plasma renin activity both in the normal men and in the patients. From these results and our previous observations of inactivity of angiotensin II-(5-8)-tetrapeptide, a pressor action of angiotensin II-(4-8)-pentapeptide, and pressor, renin-suppressing and steroidogenic actions of angiotensin II-(3-8)-hexapeptide in normal men, it is thought that ANG-(1-6) and ANG-(1-7) are bound to angiotensin II (ANG II) receptor in the peripheral arterioles and show pressor actions (less than 0.024% and less than 0.028% of Ile5-ANG II, respectively) and suppress renin mainly via short loop feedback and that the shortest biologically active ANG II molecules for pressor, renin-suppressing and steroidogenic actions are Tyr-Ile-His, Val-Tyr-Ile-His and Val-Tyr-Ile-His-Pro-Phe, respectively, in man. It is also evident that ANG-(1-6) is more rapidly metabolized than ANG-(1-7) or Ile5-ANG II in man.

Insulin sensitivity, insulin secretion, and glucose effectiveness in obese subjects: A minimal model analysis

The aim of the present study was to estimate insulin sensitivity (SI), insulin secretion, and glucose effectiveness in 14 obese subjects who were further divided into two groups: one with normal glucose tolerance and the other with impaired glucose tolerance (IGT). Glucose tolerance was determined by criteria of the World Health Organization. All subjects were Japanese. They underwent a modified frequently sampled intravenous glucose tolerance test: glucose (300 mg/kg body weight) was administered, and insulin (20 mU/kg body weight given over 5 minutes) was infused from 20 to 25 minutes after administration of glucose. SI and glucose effectiveness at basal insulin (SG) were estimated by Bergmans minimal model method. Body mass index (33.0 +/- 1.8 v 30.9 +/- 1.5 kg/m2, P > .05) and fasting insulin level (127.9 +/- 30.0 v 107.4 +/- 14.4 pmol/L, P > .05) were higher in obese IGT subjects than in normal obese subjects, but were not statistically significant. With regard to fasting glucose level, obese subjects with IGT (5.9 +/- 0.3 mmol/L) had significantly higher levels than those with normal glucose tolerance (5.1 +/- 0.2 mmol/L, P < .01). There was no significant difference in SI between the two groups (0.53 +/- 0.10 v 0.56 +/- 0.13 x 10(-4).min-1.pmol/L-1, P > .05). Pancreatic insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 19 minutes was significantly lower in obese subjects with IGT (3,366 +/- 1,495 pmol/L.min) than in those with normal glucose tolerance (16,400 +/- 4,509 pmol/L.min, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin sensitivity, insulin secretion, and glucose effectiveness in subjects with impaired glucose tolerance: A minimal model analysis

The aim of the present study was to estimate insulin secretion, insulin sensitivity (SI), and glucose effectiveness (SG) in non-obese Japanese subjects with impaired glucose tolerance (IGT). Ten IGT subjects (five men, five women) and 15 normal-tolerance subjects (seven men, eight women) without a family history of diabetes were studied. They underwent a modified frequently sampled intravenous glucose tolerance test (FSIGT); glucose (300 mg/kg body weight) was administered, and insulin (20 mU/kg over 5 minutes) was infused from 20 to 25 minutes after the administration of glucose. SI and SG were estimated by Bergmans minimal model method. No significant difference was observed in body mass index ([BMI] 22.1 +/- 0.8 v 21.1 +/- 0.5 kg/m2), fasting plasma glucose (5.19 +/- 0.18 v 5.07 +/- 0.11 mmol/L), and insulin levels (50.7 +/- 7.3 v 45.2 +/- 4.5 pmol/L) of subjects with IGT and normal controls. The glucose disappearance rate (KG) was significantly lower in subjects with IGT than in normal-tolerance subjects (1.57 +/- 0.20 v 2.09 +/- 0.15%/min, P < .05). Pancreatic insulin secretion expressed as the integrated area of plasma insulin above the basal level during the first 20 minutes was lower in IGT subjects (2,556 +/- 572 pmol/L x min) than in normal-tolerance subjects (4,957 +/- 800 pmol/L x min, P < .05). SI was not statistically different between the two groups (0.84 +/- 0.13 x 10(-4) v 1.14 +/- 0.15 x 10(-4).min-1.pmol/L-1). However, SG was significantly lower in subjects with IGT than in normal controls (0.013 +/- 0.002 v 0.023 +/- 0.002 min-1, P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Pitavastatin decreases the expression of endothelial lipase both in vitro and in vivo.

AIMS In addition to their cholesterol-lowering effect, statins increase high-density lipoprotein cholesterol (HDL-C) levels. Endothelial lipase (EL) is a regulator of plasma HDL-C levels. In the present study, the effects of statins on EL expression were investigated. METHODS AND RESULTS The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor pitavastatin suppressed basal and cytokine-treated EL expression in endothelial cells. Concomitant treatment with mevalonate or geranylgeranyl pyrophosphate completely reversed the inhibitory effect of pitavastatin, suggesting that geranylgeranylated proteins are involved in the inhibition of EL expression by statins. Inhibition of RhoA activity by overexpression of a dominant-negative mutant of RhoA or a Rho kinase inhibitor decreased EL levels. Pitavastatin reduced phospholipase activities of endothelial cells, and concomitant treatment with mevalonate reversed its inhibitory effect. Pitavastatin reduced RhoA activity and EL expression in mouse tissues. Furthermore, plasma EL concentrations in human subjects were measured by enzyme-linked immunosorbent assays. Plasma EL levels were negatively associated with plasma HDL levels in 237 patients with cardiovascular diseases, and pitavastatin treatment reduced plasma EL levels and increased HDL-C levels in 48 patients with hypercholesterolaemia. CONCLUSION These findings suggest that statins can reduce EL expression in vitro and in vivo via inhibition of RhoA activity. The inhibition of EL expression in the vessel wall may contribute to the anti-atherogenic effects of statins.