Hisashi Iwatsuka

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.

Emeriamine, an antidiabetic β-aminobetaine derived from a novel fungal metabolite

Abstract Emeriamine [(R)-3-amino-4-trimethylaminobutyric acid], derived from a novel fungal metabolite “emericedin” [(R)-3-acetylamino-4-trimethylaminobutyric acid], was proved to be a strong and specific inhibitor of carnitine-dependent oxidation of long chain fatty acid (IC 50 ; 3.2 × 10 −6 M) and its main inhibition site was shown to be carnitine palmitoyltransferase I located on the outer-surface of the mitochondrial inner membrane. Emeriamine also showed hypoglycemic and antiketogenic activities in a dose-dependent manner (1–10 mg/kg) when administered orally to fasted normal and diabetic animals.

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.

Increased renal vascular reactivity to norepinephrine in stroke-prone spontaneously hypertensive rat (SHR).

Abstract Vascular responses of isolated perfused kidneys to norepinephrine, angiotensin II and KCl were examined in stroke-prone spontaneously hypertensive rats (SHR-SP), stroke-resistant SHR (SHR-SR) and control Wistar Kyoto rats (WKR) at 8 to 10 weeks of age. Average values of systolic blood pressure were 181, 155 and 122 mmHg in the SHR-SP, SHR-SR and WKR, respectively. Basal renal vascular resistance was identical among these rats. In response to norepinephrine, the SHR-SP demonstrated shift in the dose-response curve to the left and lower vasoconstrictor threshold than the controls. The SHR-SR was intermediate between the SHR-SP and the controls in the response to norepinephrine. For angiostein II, the SHR-SP but not SHR-SR displayed a slightly greater response than the controls. However, response to KCl was not significantly different among these three strains of rats. The results suggest that the SHR-SP rats have an intrinsic augmentation of renal vascular reactivity to norepinephrine, which in turn leads to rapid elevation of blood pressure at the early hypertensive stage.

Streptozotocin resistance of the genetically diabetic KK mouse.

Intraperitoneally administered streptozotocin (100 mg. per kilogram) produced hyperglycemia (higher than 200 mg. per 100 ml.) in 100 per cent of C57BL, but in none of KK mice. Pretreat-ment with phentolamine (50 mg. per kilogram), an α-adrenergic blocking agent, decreased resistance of KK mice to the diabetogenic action of streptozotocin. On the other hand, pre-treatment with propranolol (10 mg. per kilogram), a β-adrenergic blocking agent, induced resistance to streptozotocin in C57BL mice. This effect of propranolol was potentiated by administration of epinephrine (1 mg. per kilogram). These findings suggest that the α-adrenergic system protects pancreatic β cells from cytotoxic action by streptozotocin, indicating a predominance of the α-adrenergic system in diabetic mice of the KK strain.

Accelerating effects of dexamethasone and thyroxine on hypertension without accompanying stroke in stroke-prone spontaneously hypertensive rats

Abstract Effect of glucocorticoid (dexamethasone) and thyroid hormone (thyroxine) on the development of cerebrovascular lesions (stroke) was investigated in stroke-prone spontaneously hypertensive rats, which were already hypertensive at the start of experiments. Either administration of dexamethasone (0.1 mg/kg) or thyroxine (0.001% in diet), as well as salt-loading, significantly accelerated the rising pace of blood pressure, and induced a severe hypertension. Renal vascular changes such as fibrinoid necrosis and proliferative arteriolosclerosis, and the incidence of stroke were more remarkable in the salt-loaded group compared with the control group. However, the vascular changes in the kidneys and brain were not aggravated in the hormone treated groups. The results suggest that dexamethasone and thyroxine exert an accelerating effect on the elevation of blood pressure but not on the development of stroke.