Tokutaro Sato

Bezafibrate reduces blood glucose in type 2 diabetes mellitus

The clinical efficacy of bezafibrate was examined with special reference to glucose metabolism in patients with type 2 diabetes mellitus (DM2). In protocol 1, 342 patients with DM2 and hyperlipidemias were randomly divided into 2 groups, 16-week bezafibrate treatment (n = 174) and no bezafibrate treatment (n = 168). In protocol 2, 20 DM2 patients were randomly divided into 2 groups, 8-week bezafibrate treatment (n = 10) and no bezafibrate treatment (n = 10), and a meal tolerance test (MTT) was performed. In protocol 1, bezafibrate treatment significantly reduced the fasting levels of triglyceride (TG) by 50% +/- 1.6%, total cholesterol (TC) by 12% +/- 1.1%, plasma glucose (PG) from 151.3 +/- 3.5 to 128.6 +/- 3.4 mg/dL, and hemoglobin A1c (HbA1c) from 7.2% +/- 0.1% to 6.9% +/- 0.1%, and significantly increased high-density lipoprotein cholesterol (HDL-C) by 20% +/- 0.8%. In protocol 2, fasting TG, PG, and insulin levels were significantly reduced by bezafibrate treatment. Moreover, in the MTT, postprandial increments of TG were significantly blunted after bezafibrate treatment, whereas postprandial PG and insulin levels were not significantly changed. Leptin levels were significantly decreased, while tumor necrosis factor alpha (TNF-alpha) levels were not changed. In conclusion, both hyperglycemia and hyperlipidemia can be improved by bezafibrate treatment in DM2.

Kinin and angiotensin II receptor antagonists in rats with chronic renal failure : chronic effects on cardio- and renoprotection of angiotensin converting enzyme inhibitors

Objective To assess the potential of the kallikrein-kinin and renin-angiotensin systems in mediating the cardio- and renoprotective effects of angiotensin converting enzyme (ACE) inhibitors in rats with chronic renal failure. Materials and methods Spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats subjected to five-sixths nephrectomy were randomly assigned to treatment with vehicle, a kinin antagonist (Hoe 140) or an ACE inhibitor (cilazapril) or both drugs, intraperitoneally via osmotic minipumps for 4 weeks. In addition, the effects of a chronic infusion of a specific angiotensin receptor antagonist (losartan) alone or in combination with an ACE inhibitor (enalapril) were also investigated in nephrectomized SHR for 2 weeks. Results In nephrectomized SHR and WKY rats, cilazapril alone significantly reduced systolic blood pressure, urinary protein excretion, heart weight and serum creatinine. In nephrectomized SHR, Hoe 140 alone or cilazapril in combination with Hoe 140 (7 or 70 μg/kg per day) induced no changes in these parameters, other than those associated with the effects of cilazapril alone. In nephrectomized WKY rats, cilazapril in combination with Hoe 140 (70 μg/kg per day) slightly, but not significantly, attenuated the antihypertensive effect of cilazapril but did not affect the other parameters. These results were confirmed by morphological analysis of kidneys. All the drug regimens provided effective protection against an increase in focal glomerular sclerosis. Enalapril did not modify the antihypertensive and renoprotective effects of losartan in nephrectomized SHR. Conclusions The present results indicate that the kallikrein-kinin system might not be a major factor in the cardio- and renoprotective effects of ACE inhibitors in rats with chronic renal failure.

THE 5-HT2 RECEPTOR ANTAGONIST SARPOGRELATE REDUCES URINARY AND PLASMA LEVELS OF THROMBOXANE A2 AND URINARY ALBUMIN EXCRETION IN NON-INSULIN-DEPENDENT DIABETES MELLITUS PATIENTS†

1. Therapeutic effects of a 5‐HT2 receptor antagonist sarpogrelate on microalbuminuria and thromboxane (TX)A2 biosynthesis were examined in non‐insulin‐dependent diabetes mellitus (NIDDM) patients.

Effects of troglitazone and temocapril in spontaneously hypertensive rats with chronic renal failure.

Objective The insulin resistance state is common in humans and animals with chronic renal failure. We investigated the effects of troglitazone, an insulin sensitizer, on blood pressure and nephropathy in the remnant kidney model of spontaneously hypertensive rats (SHR). Methods Eight-week-old male SHR were subjected to five-sixth nephrectomy. At the age of 10 weeks, the rats were randomly allocated to groups that received troglitazone (70 mg/kg per day); the angiotensin converting enzyme inhibitor temocapril (10 mg/kg per day); troglitazone (70 mg/kg per day) plus temocapril (10 mg/kg per day), or a vehicle alone as an untreated control group. Systolic blood pressure (SBP) and urinary protein excretion were measured every 2 weeks. At the age of 22 weeks, biochemical measurements and histological examination were performed. Results Blood glucose, glycosylated hemoglobin and body weight were similar in the four groups. SBP, serum creatinine and glomerular sclerosis index were significantly reduced in all treated groups compared with those in the control group. Urinary protein excretion, glomerular volume and aortic media thickness were significantly decreased in temocapril-treated rats and troglitazone plus temocapril-treated rats compared with those in control rats. Although antihypertensive effects of troglitazone were minute compared with those of temocapril or troglitazone plus temocapril, there was no significant difference between the glomerular sclerosis indices in these three drug-treated groups. Conclusions The results suggest that troglitazone has renoprotective effects in this rat model. These effects might be due to the inhibition of growth factors rather than to the minute hypotensive effect, although the mechanism remains to be elucidated.

Structure of the carbohydrate moiety of the α1-acid glycoprotein of human plasma

Abstract Periodate oxidation and Smith degradation of the carbohydrate moiety obtained by hydrazinolysis of the α 1 -acid glycoprotein of human plasma have been studied, and an average structure for the polysaccharide has thereby been obtained. The inner core of the polysaccharide appears to be O -(2-acetamido-2-deoxy- d -glucopyranosyl)-(1→3)- O - d -mannopyranosyl)-(1→4)- O -(2-acetamido-2-deoxy- d -glucopyranosyl)- (1→3)- O - d -mannopyranosyl-(1→4)-2-acetamido-2-deoxy- d -glucose, to which several oligosaccharides are attached. To the residue of d -mannose that is linked to the reducting 2-acetamido-2-deoxy- d -glucose residue, equimolar amounts of O -sialyl-(2→3)- O - d -galactopyranosyl-(1→3)- O -(2-acetamido-2-deoxy- d -glucopyranosyl)- and O - l -fucopyranosyl-(1→3)- O - d -galactopyranosyl-(1→4)- O -(2-acetamido-2-deoxy- d -glucopyranosyl)-chains are attached at positions 2, and/or 4, and/or 6. An O -sialyl-(2→6)- d -galactopyranose residue is attached at position 6 of the second residue of 2-acetamido-2-deoxy- d -glucose. An O -sialyl-(2→4)- d -galactose residue is attached at positions 3 or 4 of the third residue of 2-acetamido-2-deoxy- d -glucose, and an O - d -galactopyranosyl-(1→6)- O -(2-acetamido-2-deoxy- d -glucopyranosyl)- (1→6)- O - d -mannopyranosyl chain is attached to the same residue of 2-acetamitado-2-deoxy- d -glucose at position 4 or 3.

DECREASED CONVERSION OF BIG ENDOTHELIN‐1 TO ENDOTHELIN‐1 IN PATIENTS WITH DIABETES MELLITUS

Endothelial cell damage is a primary feature of diabetes mellitus. Endothelin (ET)-1 synthesized by endothelial cells induces vasoconstriction and stimulates endothelial cell growth (Kimura et al. 1988). It is thought that ET-I may be involved in endothelial cell damage in diabetes mellitus. However, some researchers have shown that the plasma-immunoreactive ET concentration in diabetes mellitus is remarkably increased (Takahashi et al. 1990), while others have observed no change in this parameter (Predel et al. 1990). In this study, a highly sensitive and specific sandwich-enzyme immunoassay (EIA) for human ET-1 [l-211 and human big-ET-1 [l-381 was used (Suzuki et al. 1990) to measure simultaneously the plasma concentrations of ET-1 and big-ET-1 in 10 patients aged 32-55 years (43 k 3, x k s.e.m.) with diabetes mellitus type I1 (NIDDM). Their mean blood pressure, haemogloblin A1 and serum creatine concentration were 101.8k3.5 mmHg, 8.1 f 0 . 4 % and 0.75 k 0.03 mg/dL, respectively. Eight age-matched normotensive healthy subjects served as controls. All of the subjects were studied at Tohoku University Hospital. After 30 min of bed rest, blood samples were drawn from the cubital vein into polypropylene tubes containing aprotinin and EDTA-2Na. Plasma immunoreactive (ir)-ET-1 and ir-big-ET-I were extracted with Sep-pak C-18 cartridges and were subjected to sandwich EIA for ir-ET-1 and ir-big-ET-1. These assays consisted of two sets of antibodies that separately recognize the N-terminal and C-terminal portions of ET-1 and big-ET-1. A mouse monoclonal antibody (AwETN40) used as an immobilized antibody in the EIA recognizes the N-terminal loop domain of ET-I and big-ET-1 but does not react with the ET-1 Cterminal heptapeptide [ 15-21]. The Fab’ fragment of rabbit antibodies to C-terminal portions of ET-1 [15-211 or that of big-ET-1 [22-381 was used as the enzyme-labelled antibody after being coupled to horseradish peroxidase. The EIA for ET-1 did not crossreact with big-ET-1 and the EIA for big-ET-1 did not crossreact with ET-1, indicating that each ET-1 can be quantified separately by the EIA. The detection limits of the EIA for ir-ET-1 and ir-big-ET-1 were 0.2 pg per well for both assays. Plasma ir-ET-1 concentration was similar in the patients with diabetes mellitus and the healthy subjects (1.24k0.13 vs 1.45+0.17pg/mL, X+s.e.m., Fig. 1). However, plasma ir-big-ET-1 concentration was markedly elevated in the patients with diabetes mellitus compared with that of the healthy subjects (4.33 & 0.24 vs 3.31 k0.21 pg/mL, P<O.Ol evaluated by Student’s t-test, Fig. 1). Thus, the ratio of plasma ET-1 to plasma big-ET-1 was significantly decreased in the diabetic patients compared with that of the healthy subjects (0.29 + 0.02 vs 0.44 k 0.04, P<O.Ol, Fig. 1).

Relation between natriuresis and urinary excretion of hydrogen peroxide.

Changes in the urinary hydrogen peroxide by exercise or salt load were studied in six healthy male volunteers. Exercise was performed by bicycle ergometer for 30 min at the intensity of 80% of the maximum heart rate predicted by age. Urinary excretion rate of hydrogen peroxide showed a tendency to increase in the salt load experiment, and to decrease by exercise. Correlation coefficient between urinary excretion rate of sodium and hydrogen peroxide one hour after the load was 0.797 (0.1 > p > 0.05) in the exercise experiment, 0.892 (p <0.05) in the salt load experiment and 0.877 (p < 0.001) in both experiments. Correlation coefficient between area under the curve for sodium excretion and hydrogen peroxide excretion was also as high as 0.822 (p < 0.05) in the exercise experiment, 0.909 (p < 0.05) in the salt load experiment and 0.853 (p < 0.001) in both experiments. These results may suggest that urinary excretion rate of hydrogen peroxide is closely related to metabolism of electrolytes and fluid in the renal tubules.

Report on the first annual survey of home parenteral nutrition in Japan

An annual survey of the current national status of home parenteral nutrition (HPN) in Japan was begun in 1991, with a total of 231 registered patients from 142 institutions providing adequate data for evaluation and analysis. HPN was given for an average of 683±764 days to 93 patients with malignant diseases and 138 with benign disease, including 53 with inflammatory bowel disease and 79 with short bowel syndrome, 107 (46.3%) of whom were successfully rehabilitated. By the end of 1990, 61% of the patients investigated were still on HPN, 7% had already completed HPN, and 26% had died, the deceased accounting for 54% of the patients with malignant disease and 7% of those with benign diseases. A total of 321 catheters had been used by all 231 patients, the most common being the subcutaneously implanted type, accounting for 33% of all catheters. By the end of 1990, 32% of these 321 catheters were still in place, 18% had been removed on the termination of HPN and 44% had been removed due to complications of total parenteral nutrition, including 20% for catheter fever. Rehospitalization was required in 62% of the patients, the cause being HPN-related in 21% of the total patients. Metabolic complications were experienced by 60% of the patients, but none of these were severe although 6% required hospitalization. Thus, the total population of HPN patients and the success rate of rehabilitation in Japan were close to those reported in Europe, while the indications for HPN and its outcome were similar to those documented in the USA OASIS report, except that the incidence of rehospitalization from HPN-related causes in the Japanese survey was lower.

Alteration of elastin in aorta from diabetics

The differences in desmosine, isodesmosine (DID), hydroxyproline and cholesterol in the human thoracic aorta from diabetic (n = 16) and non-diabetic (n = 17) autopsy subjects were investigated. DID was analyzed by the use of high performance liquid chromatography. The amount of DID, and total DID (DID+reduced DID) tended to be lower in the diabetic than in non-diabetic subjects. The ratio of DID or total DID to hydroxyproline was significantly decreased in diabetic compared to non-diabetic subjects. Amount of DID, reduced DID and total DID were significantly lower in aorta with plaque formation than that without plaque or ulcer. Multiple regression analysis showed that amount of cholesterol, DID, reduced DID and age were significantly associated with dry weight per area of the aorta. A similar association was not observed in non-diabetic subjects. Compositional changes of aortic cholesterol and elastin have a closer relationship with atherosclerosis in diabetic than in non-diabetic subjects.

Cardiovascular and renal protective effects of losartan in spontaneously hypertensive rats with diabetes mellitus.

1. Cardiovascular and renal benefits of a specific angiotensin II (AII) receptor antagonist, losartan (LOS), were assessed in diabetic rats with renal impairment.