Troglitazone stimulates pancreatic growth in congenitally CCK-A receptor-deficient OLETF rats.

We examined the effect of troglitazone treatment on pancreatic growth in the CCK-A receptor-deficient Otsuka Long-Evans Tokushima fatty (OLETF) rat, an animal model for type 2 diabetes mellitus. A troglitazone-rich diet (0.2%) was given from 12 to 28 wk of age or from 12 or 28 wk of age to 72 wk of age. Fasting serum glucose concentrations in control OLETF rats increased progressively with age, which was almost completely prevented by troglitazone treatment. Insulin levels in serum and pancreatic content in the control rat markedly increased at 28 wk of age but significantly decreased at 72 wk of age compared with those at 12 wk of age, whereas those in troglitazone-treated rats were nearly the same at all ages and were similar to those in control rats at 12 wk of age. Pancreatic wet weight in control rats decreased with age irrespective of whether they were hyperinsulinemic (28 wk old) or hypoinsulinemic (72 wk old). Troglitazone treatment significantly increased pancreatic wet weight and protein, DNA, and enzyme contents compared with those in the control rats. Moreover, troglitazone treatment completely prevented or reversed histological alterations such as fibrosis, fatty replacement, and inflammatory cell infiltration. Our results indicate that troglitazone stimulates pancreatic growth in the congenitally CCK-A receptor-deficient OLETF rat not only by reducing insulin resistance and potentiating insulin action but also by suppressing inflammatory changes in the pancreas.

Troglitazone prevents and reverses dyslipidemia, insulin secretory defects, and histologic abnormalities in a rat model of naturally occurring obese diabetes.

Troglitazone has been shown to improve insulin sensitivity and thereby exert hypoglycemic effects in various animal models and humans with insulin resistance and diabetes. The recently established animal model of naturally occurring obese diabetes, the Otsuka Long-Evans Tokushima fatty (OLETF) rat, has many similarities with human type 2 diabetes mellitus and is characterized by a high degree of insulin resistance. In the present study, we examined the effect of pharmacologic intervention with troglitazone on metabolic and histopathologic changes in OLETF rats. Two groups of rats received a troglitazone-rich diet (200 mg/100 g normal chow) from age 12 weeks (ie, before the onset of diabetes) or 28 weeks (ie, after the onset of diabetes) to age 70 weeks, while a third group received standard rat chow. The addition of troglitazone to the diet did not alter food intake or body weight gain. Troglitazone had no influence on visceral adipose depots, but it significantly reduced fasting glucose, insulin, cholesterol, triglyceride (TG), and free fatty acid (FFA) levels. Troglitazone reduced the insulin resistance and maintained the postglycemic insulin response at a normal level, and thus inhibited the development of insulin insensitivity and frank diabetes in OLETF rats up to 70 weeks of age. The pancreatic wet weight and insulin content were significantly higher in the treated rat groups versus the control rats. The morphologic changes observed in the control rats, such as fibrosis and structural disarrangement of islets, were minimal in the troglitazone-treated rats. Our study demonstrates that troglitazone, albeit at a dosage 10 to 15 times higher than that in humans, not only prevents but also reverses the metabolic derangement and histopathologic changes in genetically determined obese diabetes.

Metabolic abnormalities in the genetically obese and diabetic Otsuka Long-Evans Tokushima Fatty rat can be prevented and reversed by alpha-glucosidase inhibitor.

The recently developed Otsuka Long-Evans Tokushima Fatty (OLETF) rat is known to develop insulinopenic diabetes after a prolonged period in a condition resembling non-insulin-dependent diabetes mellitus (NIDDM). We examined the effect of pharmacological intervention with a potent intestinal alpha-glucosidase inhibitor, acarbose, on the metabolic and histopathologic changes in this rat model. The first two groups of rats received an acarbose-rich diet (150 mg/100 g normal chow) from 12 weeks of age (ie, before the onset of diabetes) or from 28 weeks of age (ie, after the onset of diabetes), while a third group received the acarbose-rich diet for the initial 16 weeks only (from 12 to 28 weeks of age). A control group received standard rat chow. Acarbose-fed rats gained less weight or lost weight despite increased food intake when switched to the acarbose-rich diet. Acarbose also reduced visceral adipose depots and fasting triglyceride (TG), glucose, and insulin levels. At the end of the study at 72 weeks, the pancreatic wet weight and insulin content were significantly higher in the treated groups versus control rats. The morphological changes observed in control rats, such as atrophy of the pancreas and reduced number and size of islets, were not present in acarbose-treated rats. Rats fed acarbose from 12 to 28 weeks of age gradually gained weight after switching to standard chow, and hyperinsulinemia, hyperglycemia, and hyperlipidemia appeared (in that order). The pancreatic insulin content in these rats was significantly higher and the visceral adipose depot was significantly smaller than in control rats. Our study demonstrates that acarbose prevented and reversed the metabolic derangement and histopathological changes in genetically diabetic rats. Moreover, treatment with acarbose even for a short period produced a marked delay in the development of insulin insensitivity and frank diabetes.