Impact of recurring intermediate insulin-induced hypoglycemia on hypothalamic paraventricular corticotropin-releasing hormone, oxytocin, vasopressin and glucokinase gene profiles: role of type II glucocorticoid receptors.

Activation of central type II glucocorticoid receptors (GR) during neutral protamine Hagedorn insulin (NPH) administration exacerbates recurring hypoglycemia. The hypothalamic paraventricular nucleus (PVN) integrates metabolic sensory input, controls autonomic and neuroendocrine motor outflow, and is characterized by abundant GR expression. The present studies investigated the hypothesis that PVN GR mediate intensification of hypoglycemia by serial NPH dosing, and that PVN glucokinase (GCK) and glucoregulatory neuropeptide genes acclimate to this treatment paradigm through GR-dependent mechanisms.

Adaptation of glucokinase gene expression in the rat dorsal vagal complex in a model for recurrent intermediate insulin-induced hypoglycemia: impact of gender.

Standard therapeutic management of insulin-dependent diabetes mellitus with intermediate-acting insulin poses a significant risk for iatrogenic hypoglycemia and associated hypoglycemia-associated autonomic failure. Gender differences in preservation of counterregulatory function during recurring hypoglycemia have been documented in the clinical setting. In rats, repeated induction of prolonged hypoglycemia by neutral protamine Hagadorn insulin (NPH) results in diminished neuronal transcriptional activation in several key metabolic loci in male, but not female rat brain, including the hindbrain dorsal vagal complex (DVC).

Effects of caudal fourth ventricular lactate infusion on hypoglycemia-associated MCT2, GLUT3, GLUT4, GCK, and sulfonylurea receptor-1 gene expression in the ovariectomized female rat LHA and VMH: impact of estradiol.

Cellular metabolic stasis is monitored in the lateral hypothalamic area (LHA) and ventromedial hypothalamic nucleus (VMH), the classically defined hypothalamic "anoretic" and "satiety" centers, respectively. Neuronal glucose (GLUT3, GLUT4) and monocarboxylate (MCT2) transporter genes are expressed in both sites, suggesting that glucose and lactate, a product of astrocytic glycolysis, may fuel aerobic respiration in local neurons. Evidence that glucose utilization in the hypothalamus, but not other brain regions, is reported to vary according to cyclic estradiol secretion suggests that this hormone may regulate uptake and/or catabolism of this fuel.

Effects of caudal hindbrain lactate infusion on insulin-induced hypoglycemia and neuronal substrate transporter glucokinase and sulfonylurea receptor-1 gene expression in the ovariectomized female rat dorsal vagal complex: Impact of estradiol.

The monocarboxylate, lactate, is produced by astrocytic glycolysis and is trafficked to neurons as a substrate fuel for aerobic respiration. This molecule is a critical monitored metabolic variable in hindbrain detection of cellular energy imbalance, because diminished uptake and/or oxidative catabolism of lactate in this part of the brain activates neural mechanisms that increase systemic glucose availability. Lactate-sensitive chemosensory neurons occur in the hindbrain dorsal vagal complex (DVC).

Caudal hindbrain lactate infusion alters glucokinase, SUR1, and neuronal substrate fuel transporter gene expression in the dorsal vagal complex, lateral hypothalamic area, and ventromedial nucleus hypothalamus of hypoglycemic male rats.

While in vitro studies show that the oxidizable energy substrate, lactate, is a preferred fuel for CNS neurons during states of energy crisis, and that lactate may regulate neuronal glucose uptake under those conditions, its role in neuronal function in vivo remains controversial. Glucose-excited neurons in hindbrain dorsal vagal complex (DVC) monitor both glucose and lactate, and express both the glucose sensor, glucokinase (GK), and the SUR1 subunit of the plasma membrane energy transducer, K(ATP). Fourth ventricular lactate infusion exacerbates insulin-induced hypoglycemia (IIH) and IIH-associated patterns of DVC neuronal activation.

Testicular regulation of neuronal glucose and monocarboxylate transporter gene expression profiles in CNS metabolic sensing sites during acute and recurrent insulin-induced hypoglycemia.

Recurrent insulin-induced hypoglycemia (RIIH) impairs glucose counter-regulatory function in male humans and rodents and, in the latter, diminishes neuronal activation in CNS structures that monitor metabolic homeostasis, including the lateral hypothalamic area (LHA) and dorsal vagal complex (DVC). We investigated whether habituated neuronal reactivity in CNS sensing sites to hypoglycemia is correlated with modified monocarboxylate and/or glucose uptake by using quantitative real-time RT-PCR to analyze neuronal monocarboxylate transporter (MCT2) and glucose transporter variant (GLUT and GLUT4) gene expression profiles in the microdissected LHA, ventromedial nucleus hypothalamus (VMH), and DVC after one or multiple insulin injections. Because orchidectomy (ORDX) maintains uniform glycemic responses to RIIH in male rats, we also examined whether regional gene response patterns are testes dependent.

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.

Vagal complex monocarboxylate transporter-2 expression during hypoglycemia.

Astrocytic provision of lactate provision to neurons may be a critical indicator of substrate fuel availability in metabolic sensing sites in the brain, including the hindbrain dorsal vagal complex. We examined the hypothesis that vagal complex monocarboxylate transporter protein levels are gender dependent and estrogen dependent, and that estrogen influences adaptation of these protein responses during repeated insulin-induced hypoglycemia. Western blot analyses showed that male and estrogen-treated ovariectomized female rats exhibit opposite changes in monocarboxylate transporter-2 levels after one insulin injection, as well as divergent patterns of adaptation to this metabolic challenge.