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

Abstract

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.

Estradiol regulates effects of hindbrain activator 5-aminoimidazole-4-carboxamide-riboside administration on hypothalamic adenosine 5′-monophosphate-activated protein kinase activity and metabolic neurotransmitter mRNA and protein expression

“…(). CORT concentrations were measured with commercial radioimmunoassay kits (Paranjape and Briski, ; Briski and Nedungadi, ).…”

Hindbrain lactostasis regulates hypothalamic AMPK activity and metabolic neurotransmitter mRNA and protein responses to hypoglycemia

“…Plasma glucagon and corticosterone concentrations were determined by radioimmunoassay, as previously reported (7,44).…”

Role of estradiol in intrinsic hindbrain AMPK regulation of hypothalamic AMPK, metabolic neuropeptide, and norepinephrine activity and food intake in the female rat

“…Immediately after injections, a pre-weighed chow-filled jar was placed in each cage. At 10.00 hr, jars were removed and weighed; measures of consumed food were adjusted by subtracting the weight of food crumbs on underlying paper [Briski and Nedungadi, 2009]. All animals used in this study exhibited cerebrospinal fluid reflex from the cannula tip on day 12; post-mortem histological examination confirmed accuracy of cannula placements within the CV4.…”

“…Evidence that caudal DVC A2 noradrenergic neurons express estrogen receptor-alpha (ERα) and -beta (ERβ) proteins [Ibrahim et al, 2013] as well as biomarkers for metabolic sensing, e.g. glucokinase, K ATP , and AMPK [Briski et al, 2009; Cherian and Briski, 2011; Ibrahim et al, 2013] suggests that these cells are substrates for estrogenic input to neural pathways that control energy homeostasis. Our studies show that estradiol controls A2 hindbrain and hypothalamic AMPK, hypothalamic metabolic neurotransmitter, and physiological and behavioral counter-regulatory responses to intra-caudal fourth ventricular administration of the AMP mimic 5-aminoimidazole-4-carboxamide-riboside (AICAR) in ovariectomized (OVX) female rats [Ibrahim et al, 2013; Alenazi et al, 2014; Ibrahim and Briski, 2014].…”