Recurrent hypoglycemia alters hypothalamic expression of the regulatory proteins FosB and synaptophysin

Abstract

A limiting factor to the clinical management of diabetes is iatrogenic hypoglycemia. With multiple hypoglycemic episodes, the collective neuroendocrine response that restores euglycemia is impaired. In our animal model of recurrent hypoglycemia (RH), neuroendocrine deficits are accompanied by a decrease in medial hypothalamic activation. Here we tested the hypothesis that the medial hypothalamus may exhibit unique changes in the expression of regulatory proteins in response to RH. We report that expression of the immediate early gene FosB is increased in medial hypothalamic nuclei, anterior hypothalamus, and posterior paraventricular nucleus of the thalamus (THPVN) of the thalamus following RH. We identified the hypothalamic PVN, a key autonomic output site, among the regions expressing FosB. To identify the subtype(s) of neuronal populations that express FosB, we screened candidate neuropeptides of the PVN for coexpression using dual fluorescence immunohistochemistry. Among the neuropeptides analyzed [including oxytocin, vasopressin, thyrotropin-releasing hormone, and corticotropin-releasing factor (CRF)], FosB was only identified in CRF-positive neurons. Inhibitory gamma-aminobutyric acid-positive processes appear to impinge on these FosB-expressing neurons. Finally, we observed a significant decrease in the presynaptic marker synaptophysin within the PVN of RH-treated vs. saline-treated rats, suggesting that rapid alterations of synaptic morphology may occur in association with RH. Collectively, these data suggest that RH stress triggers cellular changes that support synaptic plasticity, in specific neuroanatomical sites, which may contribute to the development of hypoglycemia-associated autonomic failure.

FOS Proliferating Network Construction in Early Colorectal Cancer (CRC) Based on Integrative Significant Function Cluster and Inferring Analysis

“…FBJ murine osteosarcoma viral oncogene homolog b (FOSB) is relevant to molecular function of transcription factor, other transcription factor, nucleic acid binding and biological process of nucleoside, nucleotide and nucleic acid metabolism, mRNA transcription regulation, protein biosynthesis, proteolysis, vitamin biosynthesis, MHCI-mediated immunity, cell structure, other carbon metabolism, as shown in Table 1 (44)(45)(46)(47)(48).…”

Challenges in Modelling Hypoglycaemia-Associated Autonomic Failure: A Review of Human and Animal Studies

“…A number of studies have performed i.p administration of insulin to induce antecedent hypoglycaemia [30, 33, 34, 38, 61]. Although the most preferred route of administration in many studies is the i.v route [35, 36, 39, 40, 42–44] (see Table 2), some researchers have used a combination of i.p and i.v or s.c and i.v with the i.p or s.c injections used to induce antecedent hypoglycaemia and the i.v administration or continuous i.v infusion used to produce the subsequent hypoglycaemic episode [30, 31, 33, 34, 37, 41]. Intravenous infusions have the advantage of achieving the desired hypoglycaemia levels relatively quickly, but it requires the animals to be surgically fitted with venous catheters to enable researchers to perform repeated i.v administration and thus requires specialised skills which could be challenging.…”

“…The depth of hypoglycaemia achieved in some studies ranged between 2 and 3.2 mmol/L [30, 32–34, 36, 38, 40, 44] during antecedent hypoglycaemic episodes whereas in other studies blood glucose levels have been lowered below 2 mmol/L [28, 35, 37, 39, 42, 43, 61] which may not be relevant to the human condition. During subsequent hypoglycaemic episodes some studies clamped the blood glucose levels at an average of 2.5 mmol/L to avoid excessive hypoglycaemia.…”

“…Flanagan et al [33] have shown diminished plasma adrenaline response to subsequent hypoglycaemia 48 hours after a single antecedent hypoglycaemia. Some researchers have shown diminished response to acute hypoglycaemia after 2 episodes of antecedent hypoglycaemia on the previous day [28, 42–44] whereas some have induced 1 episode of antecedent hypoglycaemia per day for 2 to 4 days [32–35, 37, 39–41, 61] prior to testing the response to subsequent hypoglycaemia (see Table 2). Kudrick et al [38] have tested 1 and 2 antecedent hypoglycaemic episodes a day and reported that the plasma adrenaline response to subsequent hypoglycaemia was significantly reduced only in the rats that had two hypoglycaemic episodes a day, which is contradictory to a number of the abovementioned studies that have successfully achieved a significant reduction in plasma adrenaline response with 1 episode of antecedent hypoglycaemia for 1, 2, or 3 days.…”

“…Analysis of plasma adrenaline was generally performed by HPLC using electrochemical detection [32–35, 37, 39–41], ELISA [30, 36, 38], or radioenzymatic assay [28, 42–44, 61]. Even though most of the studies have reported a significant reduction in plasma adrenaline response to subsequent hypoglycaemia, the levels of plasma adrenaline reported are highly variable between studies.…”