Pioglitazone is more potent in prevention than treatment of hyperglycaemia in Zucker diabetic fatty (ZDF) rats

Aims: The use of thiazolidinediones (TZDs) not only for therapy, but also for prevention of type 2 diabetes is under discussion. Here we describe the therapeutic vs. preventive potential of pioglitazone (PIO) in an obese-hyperglycaemic animal model.

Methods: Male ZDF rats, which were at different stages of the development of their diabetes-like syndrome, received PIO for at least 2.5 weeks (12mg/kg/d; initiation of treatment at 7, 10.5, or 15.5 weeks of age, when plasma glucose was 112±7, 387±11, and 404±12mg/dl, respectively). Body weight and blood glucose were monitored regularly, further parameters were measured at the end of treatment.

Results: Independent of the age of intervention, PIO stimulated growth of the epididymal fat pad and body weight gain (weight gain during 1st 10 days in g/d, PIO vs. vehicle: 7 weeks-old: 9.1±0.1 vs. 6.6±0.1; 10.5 weeks-old: 2.4±0.3 vs. 0.3±0.1; 15.5 weeks-old: 2.0±0.4 vs. 0.1±0.1; p<0.01 each). In contrast to persistent adipogenic action, the antihyperglycaemic effect of PIO was highly dependent on the age of intervention. PIO entirely prevented a sharp rise in glycaemia between 7 and 11.5 weeks of age (PIO, from 112±7 to 111±4mg/dl; vs. vehicle, from 112±13 to 304±29mg/dl; p<0.0001). When treatment was initiated at an age of 10.5 weeks, PIO ameliorated the prevailing hyperglycaemia (after 10 days of treatment: PIO, 323±20; vs. vehicle, 401±15mg/dl; p=0.007), but this effect was transient and almost faded after 24 days of treatment (PIO, 405±14; vs. vehicle, 434±18mg/dl; ns). In 15.5 weeks-old ZDF rats, PIO utterly failed to reduce plasma glucose (e.g., after 10 days of treatment: PIO 404±28; vs. vehicle, 411±10mg/dl; ns).

Conclusion: The potential of PIO to prevent hyperglycaemia outranges its potential to ameliorate established hyperglycaemia. However, the exploitation of this preventive potential in humans requires risk/benefit considerations and raises the question, if pharmacological intervention that anticipates reluctance to life style changes is in principle appropriate.