Adaptation of Feeding and Counter-Regulatory Hormone Responses to Intermediate Insulin-Induced Hypoglycaemia in the Ovariectomised Female Rat: Effects of Oestradiol

Oestradiol regulates basal food intake and glucagon and corticosterone secretion, but its influence on these responses to acute and recurring hypoglycaemia remains unclear. The present study utilised an experimental model for repeated intermediate-acting insulin-induced hypoglycaemia that replicates the route of delivery, frequency of administration, and duration of insulin action in the clinical setting. Groups of ovariectomised (OVX) rats were implanted with s.c. capsules containing oestradiol benzoate (EB) or oil, and injected with one or four doses of Humulin neutral protamine Hagedorn (HN), on as many days, or diluent alone. Baseline feeding followed divergent trends in EB- versus oil-implanted animals over a 9-h period after final injections. Recurring HN-induced hypoglycaemia resulted in significantly greater baseline-corrected food intake in OVX + EB and OVX + oil groups, relative to acute hypoglycaemic hyperphagia. Although oestradiol did not modify net food consumption after single or serial HN doses, EB replacement maintained uniform feeding over time in each treatment paradigm. Baseline glucagon and corticosterone secretion was higher in EB- versus oil-treated OVX rats. Oestradiol prolonged acute hypoglycaemic glucagonemia, and increased the magnitude, but shortened the duration, of glucagon secretion during recurring hypoglycaemia. OVX + oil rats responded to both acute and recurring hypoglycaemia with elevated corticosterone secretion at a single time point, which was advanced from +6 to +4 h during recurrent insulin-induced hypoglycemia, whereas OVX + EB animals exhibited increased plasma hormone levels at both +4 and +6 h in response to each paradigm. Area-under-the curve analyses showed that total glucagon and corticosterone release was greater in EB- versus oil-implanted rats after both single and serial dosing with HN. These results demonstrate that repeated HN administration increases food intake in female rats via oestrogen-independent mechanisms, but that oestradiol preserves temporal patterns of hypoglycaemic hyperphagia. The data also reveal that normo- and hypoglyacemic glucagon and corticosterone secretion are enhanced in the presence of oestrogen. Further studies are necessary to identify the sites and cellular substrates that are responsible for this hormonal regulation of behavioural and endocrine responses to prolonged hypoglycaemia.