SynopsisYellow KK mice, carrying the yellow obese gene (Ay), developed marked adiposity and diabetic symptoms in comparison with their control littermates, black KK mice. The blood glucose and circulating insulin levels were increased progressively from 5 weeks of age in yellow KK mice. Age dependent alterlations were also observed in pancreas and kidney. Namely, degranulation and glycogen infiltration of B cells, first observed at 5 weeks of age, were followed by hypertrophy and central cavitation of islets. Renal glomerular changes, which were very similar to diffuse or exudative type of sclerosis in human diabetes, were also recognized in the mice at 16 weeks of age. These changes, though less remarkable, were also noted in their control littermates older than 16 weeks of age. Some metabolic defects were developed, as demonstrated by in vitro experiments. At younger age, lipogenesis by liver and adipose tissue was increased in yellow KK mice, but there was no noticeable difference in glucose oxidation by adipose tissue between both mice. Insulin sensitivity of adipose tissue was decreased with age in both mice, especially in yellow KK mice being reduced more remarkably to its complete loss at 16 weeks of age. These findings indicate that the yellow obese gene not only induces adiposity but also accelerates development of diabetic traits of KK mice. A possible mechanism for the observed diabetogenic action of the gene will be discussed.

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.

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 (hyperglycemia, hypertriglyceridemia, and hyperinsulinemia), accompanied by the reduction of insulin resistance as manifested by improvement of overall insulin sensitivity in either the insulin tolerance test or 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 glycemic 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 streptozotocin-diabetic rats. However, in old Sprague-Dawley rats that were moderately insulin resistant and hyperlipidemic compared with young ones, ADD-3878 decreased plasma triglyceride and insulin and improved insulin sensitivity.(ABSTRACT TRUNCATED AT 250 WORDS)

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111. The similar inhibitory action of phospholipase C (clostridium perfringens and toxin) and of insulin on lipolysis stimulated by Iipolytic hormones and theophylline.