Rosiglitazone prevents the onset of hyperglycaemia and proteinuria in the Zucker diabetic fatty rat

Aim: To investigate the potential of rosiglitazone, a highly potent agonist at the nuclear peroxisome proliferator activated receptor-gamma (PPAR-gamma), to prevent the development of diabetes in the Zucker diabetic fatty (ZDF) rat or to ameliorate the condition at a later stage of the disease. Methods: Rosiglitazone (10 mu mol/kg body weight daily) was given via the diet to ZDF rats from aged 6 weeks, before the onset of hyperglycaemia (Prevention group), or from aged 21 weeks after hyperglycaemia and proteinuria were established (Intervention group). Untreated ZDF rats and age-matched Zucker lean rats (ZL) served as controls and the experiment was terminated when the animals were aged 28 weeks. Results: Whilst the combined ZDF control and Intervention groups were already hyperglycaemic (14.6 +/- 1.6 vs. ZL 5.7 +/- 0.1 mmol/l, mean +/- s.e.m.; p < 0.05), glycosuric and polydipsic at aged 11 weeks, and thereafter had a declining plasma insulin concentration, rosiglitazone Prevention treatment maintained normoglycaemia even at aged 27 weeks (3.7 +/- 0.3 mmol/l vs. ZL 3.0 +/- 0.3 mmol/l; NS). Intervention treatment at aged 21 weeks, however, failed to ameliorate the diabetes. These functional data were supported by determinations of pancreatic insulin content (mug/mg tissue as follows: ZL, 43.1 +/- 3.9; ZDF control (28 weeks) + ZDF Intervention control (21 weeks), 6.0 +/- 0.8; Prevention, 63.6 +/- 15.8; Intervention, 6.2 +/- 0.9) and by morphological, immunohistochemical and electron microscopical examination of pancreata at the end of the study. Thus, islets from rosiglitazone Prevention rats were similar to ZL rats, whereas ZDF controls and Intervention rats exhibited islets depleted of insulin, with a disorganized architecture and an ultrastructure indicative of work hypertrophy. ZDF control rats and Intervention rats, though not rosiglitazone Prevention rats, also exhibited marked proteinuria, indicative of renal glomerular damage. Conclusions: Our results demonstrate that in ZDF rats, rosiglitazone prevents the progression from insulin resistance to overt diabetes. These data provide a rationale for investigating whether treatment with rosiglitazone of patients with early signs of perturbed glucose metabolism (e.g. impaired fasting glucose (IGT)) may prevent the progression to type 2 diabetes and its associated complications.