Caloric restriction in obese pre-diabetic rats prevents beta-cell depletion, loss of beta-cell GLUT 2 and glucose incompetence

Abstract

Pre-diabetic male Zucker diabetic fatty rats (ZDF) become diabetic between 8 and 10 weeks of age. At that time their beta cells exhibit high basal insulin secretion, absent insulin response to glucose and loss of GLUT 2 glucose transporter. Beta-cell volume, which is increased at the onset of non-insulin-dependent diabetes, declines precipitously by age 18 weeks. To determine if expression of this diabetic phenotype was dependent upon the increased food intake of these rats, they were diet-matched to lean littermates for 12 weeks beginning at 6 weeks of age. Untreated control ZDF rats received an unrestricted diet for 3 months. All of the controls became hyperglycaemic by 8 weeks of age, whereas all diet-matched rats remained euglycaemic throughout the 3 months, despite the fact that at 18 weeks of age their mean body weight equaled that of obese rats on an unrestricted diet. In the former rats glucose-stimulated insulin secretion was absent at 12 weeks of age and GLUT-2-positive beta cells had fallen below 30%. The volume fraction of their beta cells was 2.6 times normal at this age but by 18 weeks of age it had declined by 75%. Diet restriction for 3 months prevented the loss of glucose-stimulated insulin secretion and the reduction of beta-cell GLUT-2 and beta-cell volume fraction. However, neither the elevated basal insulin secretion nor the exaggerated arginine-stimulated insulin secretion of the obese rats was reversed or prevented by caloric restriction.(ABSTRACT TRUNCATED AT 250 WORDS)

Leptinomimetic effects of the AMP kinase activator AICAR in leptin-resistant rats: prevention of diabetes and ectopic lipid deposition

“…Obese male ZDF (fa/fa) rats given free access to food typically develop severe type 2 diabetes by the age of 14 weeks [11]. Accordingly, in the present study, hyperglycaemia (20 mmol/l) developed in these rats between 3 to 5 weeks of the study (age 10-12 weeks), whereas the AICAR-treated rats remained normoglycaemic (Fig.…”

“…Because of their method of selection, these rats were not a true control group either for the AICAR or the groups with free access to food (see Discussion). Instead, they provide a comparison with an earlier study, in which the effect of more severe calorie restriction was assessed in the ZDF rat [11]. Non-esterified fatty acid levels were not significantly different in the three groups (data not shown).…”

“…In the present study, similar findings were obtained in functionally leptin-receptor-deficient fa/fa rats and leptin-deficient ob/ob mice, both of which are obese and have ectopic lipid deposition in liver and muscle. The effect of thiazolidinedione therapy was not examined here; however, one of the investigators of this study (R.H. Unger) has previously shown that treatment with troglitazone decreases ectopic lipid accumulation in multiple tissues and prevents the development of diabetes in the ZDF rat [10,11]. In addition, we have recently demonstrated that pioglitazone treatment increases AMPK activity and lowers malonyl CoA levels in livers both of the Dahlsalt-sensitive rat and of rats infused with glucose and insulin [31].…”

“…These abnormalities in the ZDF rat are prevented by treatment with the thiazolidinedione troglitazone [10] or severe caloric restriction [11], both of which we have found to activate AMPK in rat tissues [31,32]. In the present study we assessed whether AMPK activity is diminished in tissues of rodents deficient in either leptin or the leptin receptor.…”

“…First, obese humans have increased intramyocellular triglycerides in heart [8], skeletal muscle [9] and liver [5]; second, thiazolidinediones appear to prevent or retard the development of overt type 2 diabetes and other manifestations of the metabolic syndrome in humans [9] and obese rodents [10], as does caloric restriction [11]; and third, the beneficial effects of thiazolidinediones and caloric restriction have been associated in humans and rats with a reduction in lipid overload in non-adipose tissues.…”