Streptozocin-induced diabetes (STZ-D) in rats is associated with marked hypothyroidism characterized by functional impairment and structural lesions of the pituitary-thyroid axis. Degenerative axonal lesions, which can be prevented by insulin administration, have been reported in the mediobasal hypothalamus (MBH) of STZ-D rats. However, direct evidence connecting anatomic MBH lesions with functional impairment is still missing. We therefore performed a combined functional and morphological investigation in 4-mo-old STZ-D male rats (diabetes lasted 1 mo), applying an in vitro model to study in the same isolated MBH 1) the basal and depolarization-induced thyrotropin-releasing hormone (TRH) release during two successive incubations of 20 min each and 2) morphological and morphometric aspects, including distribution and amount (densitometric evaluation) of immunoreactive TRH in the incubated tissue. In basal conditions, TRH release was much lower in diabetic than control MBH during both incubations (P less than .01 vs. P less than .05). In depolarizing conditions, TRH release was increased during the second incubation in control (P less than .05) and during both incubations in diabetic (P less than .01) rats, the percentage increase of the TRH release due to ionic stimulation being much higher in diabetic than control animals (P less than .01). As determined by light-microscope morphometry, the total area of dilated-axon cross sections was larger in diabetic than control MBH under basal conditions (P less than .01), thus confirming degenerative axonopathy in diabetic rats. By densitometry determination, the amount of immunoreactive TRH was higher in stimulated diabetic MBH compared with both stimulated control and basal diabetic MBH (P less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)