PREVENTION OF DIABETES DOES NOT COMPLETELY PREVENT INSULIN SECRETORY DEFECTS IN THE ZDF RAT

The rapid insulin secretory pulses that occur in the perfused rat pancreas can be entrained by an oscillatory glucose concentration in pancreata from nondiabetic rats but not from X diabetic Zucker diabetic fatty (ZDF) rats. To investigate whether this defect is present in prediabetic ZDF rats and whether treatment with either pioglitazone or acarbose can prevent or reverse this defect, 39 ZDF and 5 lean ZDF control rats were studied. The ZDF rats were divided into six groups depending on age, form of therapy used, and the time at which pioglitazone was started in relation to the onset of diabetes. The pancreas was isolated and perfused using a sine wave-shaped glucose concentration (mean 7 mM, period 10 min, amplitude 10%). The results, assessed by spectral analysis, revealed that in prediabetic animals and in controls, entrainment of pulsatile insulin secretion was normal. Initiation of pioglitazone therapy in ZDF rats at the time of weaning or before diabetes onset prevented hyperglycemia. However, entrainment was only partially retained. Thus, in these two groups, the spectral power at 10 min was greater than in untreated animals but lower than in prediabetic and control animals. Treatment with acarbose before or with pioglitazone after diabetes onset improved but did not normalize glucose levels, and it did not improve entrainment. The results demonstrate the presence of insulin secretory defects in 13-wk-old ZDF rats in which hyperglycemia was prevented.