Ziro Suzuoki

Reduction of Insulin Resistance in Obese and/or Diabetic Animals by 5-[4-(1-Methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, Ciglitazone), a New Antidiabetic Agent

Effects of 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63,287, Ciglitazone) on glucose and lipid metabolism were examined in various animal models. ADD-3878, administered as a dietary admixture (30–186 mg/kg/day) to obese-diabetic yellow KK (KK-Ay) mice, markedly suppressed the diabetic syndromes (hyperglycemie, hypertriglyceride-mia, and hyperinsulinemia), accompanied by the reduction of insulin resistance as manifested by improvement of overall insulin sensitivity in either the insulin tolerance test òr the steady-state blood glucose test. Chronic administration of ADD-3878 for as long as 12 wk to young yellow KK mice, which were in the early stage of diabetes and obesity, depressed age-dependent rises in blood glucose, plasma triglyceride, and insulin without exerting any effect on obesity. When orally administered to obese Zucker-fatty rats, ADD-3878 decreased plasma insulin and triglyceride in a dose-dependent manner (5–100 mg/kg/day). The treated rats showed increased tolerance and decreased insulin secretion in response to oral glucose. The glycemie response to insulin and the steady-state plasma glucose were also normalized in the treated rats. Chronic administration of ADD-3878 to young fatty rats for as long as 12 wk decreased the dose-dependent rises in blood glucose, plasma triglyceride, and insulin without exerting any effect on body weight. ADD-3878 had no effect on glucose and lipid metabolism of young Sprague-Dawley rats and mild strepto-zotocin-diabetic rats. However, in old Sprague-Dawley rats that were moderately insulin resistant and hyperli-pidemic compared with young ones, ADD-3878 decreased plasma triglyceride and insulin and improved insulin sensitivity. Five-day administration of ADD-3878 to beagle dogs with slightly impaired glucose tolerance increased glucose tolerance and suppressed postprandial rises in plasma glucose, insulin, and triglyceride. Based on these results, ADD-3878 is effective on abnormal glucose and lipid metabolism associated with insulin resistance or obesity through reduction of peripheral insulin resistance. Therefore, ADD-3878 is expected to be useful in the treatment of hyperglycemie, hyperinsulinemia, and hyperlipemia in obese type II diabetes and Obesity.

A New Genetically Obese-Hyperglycemic Rat (Wistar Fatty)

The fa-gene was transferred from the Zucker rat (13 M strain) to the Wistar Kyoto (WKY) rat. The survey, performed at the 10th generation of backcrossing, showed that Wistar fatty rats (fa/fa), a congenic strain of WKY, developed obesity and obesity-related features, such as hyperinsulinemia and hyperlipemia, in the same manner as Zucker fatty rats. Males, but not females, showed hyperglycemia, glucosuria, and polyuria as early as 8 wk of age. Tolerance and insulin response to oral glucose were decreased with advancing age in males. The diabetic changes appeared to be caused by an interaction between predisposition to develop diabetes in the WKY rat and fa-induced obesity. This is because WKY rats were found to be less sensitive to insulin than Zucker rats by both the glucose tolerance test and the steady-state blood glucose method which estimates overall insulin sensitivity.

Structural changes of pancreatic islets in genetically obese rats.

SummaryLight and electron microscopic observations were performed on pancreatic islets from genetically obese rats, (Zucker, “fatty”), from 5 to 52 weeks of age. At 5 weeks of age, islets were moderately hypertrophied. After that age, hypertrophy of islets became more prominent, until 24 weeks of age, with accompanying degranulation of B cells. The plasma insulin level also continued to increase during this period, but the glucose level was normal. Degranulated B cells contained a highly developed Golgi complex, numerous vesiculated, granular, endoplasmic reticulum and a small number of secretory granules, but no glycogen deposits. Emiocytosis and microtubule formation were very remarkable with these B cells. Frequently, mixed or intermediate cells, such as exocrine-endocrine or ductural-endocrine cell, were observed in pancreas with hypertrophied islets. At 52 weeks of age, both the plasma insulin and triglyceride levels decreased. In the pancreas, there were observed proliferation of fibrous tissue and well granulated B cells in hypertrophied islets. Hence, in fatty rats, pancreatic islets were in an active state during the period of development of obesity and hyperlipaemia (from 5 to 24 weeks of age). These correlates of obesity and hyperinsulinism disappeared at 52 weeks of age.

Biotransformation of Molsidomine (N-Ethoxycarbonyl-3-morpholinosydnonimine), a New Anti-anginal Agent, in Rats

Abstract1. After oral administration of [14C]N-ethoxycarbonyl-3-morpholinosydnon-imine (molsidomine) to rats, 85.0% of the ingested radioactivity was excreted in urine in 24 h. Metabolites found in the urine were molsidomine (0.6% of urinary radioactivity), 3-morpholinosydnonimine (compound A, 8.4%) and N-cyanomethylenaminomorpholine (compound C, 15%). About 48% of urinary radioactivity was accounted for by approximately equal amounts of the two weakly acidic metabolites N-cyanomethylenaminomorpholine-2-one (compound D) and N-cyanomethylenamino-N-(2-hydroxyethyl)-glycine (compound E).2. In 24 h after intraduodenal injection of [14C]molsidomine to rats, 13.3% of the radioactivity was excreted in the gastric juice as molsidomine (95%) and compound C (4.8%). Much of the molsidomine in the gastric juice was present a polar, conjugate-like compound, which on purification by t.l.c. was converted to the parent drug.3. After intravenous injection of [14C]molsidomine to rats, the blood level declined biphasically ...

Metabolism of 8-Chloro-6-phenyl-4H-s-triazolo[4,3-α][1,4]-benzodiazepine (D–40TA), a New Central Depressant. I. Absorption, Distribution and Excretion in Rats

1. [14C]D–40TA was quantitatively absorbed from the rat small intestine by the portal route.2. The blood level of oral D–-40TA reached a peak at 30 min and then declined with a half-life of 60 min. The level after intravenous injection fell off with a half-life of 32 min. D–40TA and its metabolites could enter erythrocytes. The drug was not bound to plasma protein.3. Oral administration of [14C]D–40TA caused a rapid and wide distribution of radioactivity in tissues, with the peak levels at 1 h. T this time, the radioactivity was highest in adrenal, followed by liver and skeletal muscle, and lowest in testis.4. D–40TA was detected in the brain 2 min after oral dosing. Brain levels of D–40TA were the same as, or slightly higher than the blood levels at all times, indicating that the drug easily passed through the blood–brain barrier. A pharmacologically active metabolite B also entered into the brain with ease.5. The oral drug was completely eliminated from the body within 3 days, 18% in urine and 82% in fa...

Congenitally impaired hormone sensitivity of the adipose tissue of spontaneously diabetic mice, KK. Validity of thrifty genotype in KK mice.

SummaryAdipose tissue of KK mice was less sensitive to insulin in its stimulatory action on glucose oxidation or its inhibitory action on lipolysis, and to epinephrine in its stimulatory action on lipolysis as compared to that of C57BL mice. A lack of appreciable increase in plasma NEFA in response to fasting of the KK mice might be caused by the impaired response of lipolysis to the hormones. — Adipose tissue of KK mice was also less sensitive to insulin-like action of concanavalin A, ouabaine or omission of K+ in the medium on glucose oxidation or lipolysis. Lipolysis in response to theophylline and/or DcAMP was less marked in the tissue of KK mice. The mean diameter of the adipocytes was larger in KK than in C57BL mice. In the experiments using adipocytes with the same diameter, however, the cells of KK mice were less sensitive to the hormones than those of C57BL. — With respect to tissue sensitivity to the hormones, the mean diameter of adipocytes and the response of plasma NEFA to fasting, the F1-hybrid mice of KK and C57BL showed values between those of the parental strains. Yellow hybrid (genetically obese F1-hybrid) mice showed higher sensitivity to insulin in the adipose tissue, more remarkable response of plasma NEFA to fasting as compared with KK mice, although hypertrophy of adipocytes was more pronounced in the yellow hybrid mice. — These findings suggest that insulin insensitivity is associated with epinephrine insensitivity in adipocytes of KK mice; both appear to be subjected to genetic factor(s)per se rather than hypertrophy of the adipocytes. Furthermore, insensitivity to both hormones in the KK mice appears to be caused by a common defect in cellular process other than the hormone receptor systems. These genetically determined abnormalities of adipocytes may result in fat-storage metabolism through hyperinsulinemia; this is very similar to the metabolic profile due to thrifty genotype in human diabetes as proposed by Neel.

Metabolism of 6-Chloro-5-cyclohexylindane-1-carboxylic Acid (TAI-284), a New Non-steroidal Anti-inflammatory Agent. I. Absorption, Distribution and Excretion in Rats

Abstract1. In rats, a new non-steroidal anti-inflammatory agent, 6-chloro-5-cyclohexylindane-1-carboxylic acid (TAI-284), labelled with 3H, was almost quantitatively absorbed, mainly from the small intestine. Gastric absorption was also demonstrated.2. The plasma concn. of the orally administered drug reached a peak at 2 h with a half-life of about 7·5 h. The concn. after intravenous injection decreased biphasically with t0·5 values of 20 and 80 min. About half of the plasma radioactivity was the intact drug, of which more than 90% was bound to plasma protein. Plasma metabolites, detected by t.l.c., were the 4′-oxocyclohexyl derivative (I), a mixture of cis-4′- and cis-3′-hydroxycyclohexyl derivatives (IIa and IIb), trans-4′-hydroxycyclohexyl derivative (III) and cis-3′-hydroxycyclohexyl derivative (IV), together with small amounts of unidentified polar metabolites (V and VI). Metabolites IIb and IV are diastereoisomers.3. TAI-284, administered orally or intravenously, was widely distributed, with high co...

INDUCTION OF AORTIC LIPID DEPOSITION IN A HIGH-RESPONSE (ExHC) RAT FED A DIET CONTAINING CHOLESTEROL AND CHOLIC ACID

Male ExHC and Sprague--Dawley rats were fed a diet containing 3% cholesterol, 0.6% sodium cholate and 15% olive oil for 16 weeks. The ExHC rat is highly susceptible to dietary hypercholesterolemia. Aortas of the ExHC rats showed Sudan-stained deposits and cholesterol accumulation in the intima and media, whereas no deposited lipids were seen in those of the Sprague--Dawley rats. In male and female ExHC rats fed diets containing the above supplements at 3 dose levels, plasma cholesterol and aortic lipid deposition were found to be dose-dependent. Lipid deposition was more prominent in female than in males, but aortic intimal proliferation was absent.

The metabolic fate of methyl tetrahydrofurfuryl sulfide and its related compounds in rats

Abstract The metabolic fate of 35S-labelled methyl tetrahydrofurfuryl sulfide (MTFS), methyl tetrahydrofurfuryl sulfoxide (MTFSO), methyl tetrahydrofurfuryl sulfone (MTFSO2) and δ-methylsulfonyl-γ-valerolactone (MSO2VL) was studied in rats. The latter three have already been identified as the urinary metabolites of the 35S-tetrahydrofurfuryl mercaptan moeity of thiamine tetrahydrofurfuryl disulfide (TTFD). Following oral administration of each compound, most of the radioactivity was rapidly excreted into the urine. Urinary metabolites were then quantitatively determined by the combined use of paper electrophoresis and thin-layer chromatography. When MTFS or MTFSO was administered, MSO2VL was the most predominant metabolite and MTFSO was the second predominant one. MTFSO2, MSOVL and inorganic sulfate-35S were also detected in small amounts. When MTFSO2 and MSO2VL was administered, most of the radioactivity was excreted as MSO2VL, and neither the reduction of the sulfones to the sulfoxides nor the formation of inorganic sulfatee-35S was recognized in these cases. The validity of the metabolic pathways which had already been proposed in the biotransformation of the tetrahydrofurfuryl mercaptan moiety of TTFD is discussed on the basis of these results.

The Metabolic Fate of α-Sulphobenzylpenicillin in Rats

1. After intramuscular injection of a new semi-synthetic penicillin, disodium [14C]α-sulphobenzylpenicillin, to rats radioactivity in blood reached a peak at 5 min with a half life of 26 min. Most of the blood radioactivity was not bound to plasma protein and 70% was accounted for as the intact penicillin.2. At 20 min after dosage the radioactivity was distributed mostly in liver, kidney, intestinal contents and blood. About half of the injected radioactivity was excreted into the urine within 8 h. Faecal excretion was much slower but continued for longer duration and amounted to 24% after 3 days.3. In bile-duct cannulated rats, 35% of the dosed radioactivity was excreted into bile and 52% into urine within 24 h.4. In both urine and bile, 50 to 85% of the radioactivity was present as unchanged drug and 10 to 20% as its penicilloic acid.5. Intravenous injection gave similar metabolic patterns as those observed after intramuscular injection except that faecal excretion was increased.6. Autoradiographic stud...