Effects of acute and chronic insulin-induced hypoglycemia on type II glucocorticoid receptor (GR) gene expression in characterized CNS metabolic loci.
The metabolic stressor, hypoglycemia, elicits integrated counterregulatory responses, including activation of the hypothalamic-pituitary-adrenal axis. Type II glucocorticoid receptors (GR) occur in multiple components of the central autonomic circuitry that regulates glucostasis, and antecedent GR stimulation is implicated in impaired glucagon and counterregulatory dysfunction during recurrent insulin-induced hypoglycemia (RIIH). To examine the hypothesis that this chronic stress may alter basal and/or hypoglycemic patterns of GR gene expression in a site-specific manner, real-time RT-PCR techniques were utilized to evaluate tissue GR mRNA levels in the microdissected lateral hypothalamic area (LHA) and paraventricular (PVH), dorsomedial (DMH), ventromedial (VMH), and arcuate (ARH) hypothalamic nuclei, before and after one or four injections, on as many days, of the intermediate-acting insulin formulation, Humulin NPH (NPH), while controls were treated with diluent alone. Rats injected with four doses of NPH were pretreated by intracerebroventricular (icv) administration of the selective nonsteroidal GR antagonist, CP-472555, or vehicle alone prior to insulin injections on days 1-3. The results show that acute hypoglycemia had no impact on GR mRNA levels in each structure evaluated. Basal GR gene expression was not altered by antecedent hypoglycemia, but tissue transcript levels were elevated in the DMH, PVH, VMH, and ARH during RIIH. Icv CP-472555 administration prior to antecedent hypoglycemia prevented RIIH-associated increases in GR mRNA in each of these sites. These data show that GR gene transcripts are increased in discrete CNS metabolic loci during RIIH, and that these local responses are attenuated by pharmacological blockade of central GR activation. The present studies demonstrate that hypoglycemic hypercorticosteronemia causes upregulated GR gene expression during RIIH, and implicate GR in mechanisms underlying this action.
Kale
Ajay Y
AY
Department of Basic Pharmaceutical Sciences, College of Pharmacy, The University of Louisiana at Monroe, 71209, USA.
Vavaiya
Kamlesh V
KV
Briski
Karen P
KP
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage*; D007328:Insulin / Q000008:administration & dosage*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid