Naloxone, but Not Valsartan, Preserves Responses to Hypoglycemia After Antecedent Hypoglycemia

Abstract

OBJECTIVEHypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of type 1 diabetes. Neurons in the ventromedial hypothalamus are thought to mediate counterregulatory responses to hypoglycemia. We have previously hypothesized that hypoglycemia-induced hypothalamic angiotensin might contribute to HAAF, suggesting that the angiotensin blocker valsartan might prevent HAAF. On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF. The goal of this study was to generate novel hypothalamic markers of hypoglycemia and use them to assess mechanisms mediating HAAF and its reversal.RESEARCH DESIGN AND METHODSQuantitative PCR was used to validate a novel panel of hypothalamic genes regulated by hypoglycemia. Mice were exposed to one or five episodes of insulin-induced hypoglycemia, with or without concurrent exposure to valsartan or naloxone. Corticosterone, glucagon, epinephrine, and hypothalamic gene expression were assessed after the final episode of hypoglycemia.RESULTSA subset of hypothalamic genes regulated acutely by hypoglycemia failed to respond after repetitive hypoglycemia. Responsiveness of a subset of these genes was preserved by naloxone but not valsartan. Notably, hypothalamic expression of four genes, including pyruvate dehydrogenase kinase 4 and glycerol 3-phosphate dehydrogenase 1, was acutely induced by a single episode of hypoglycemia, but not after antecedent hypoglycemia; naloxone treatment prevented this failure. Similarly, carnitine palmitoyltransferase-1 was inhibited after repetitive hypoglycemia, and this inhibition was prevented by naloxone. Repetitive hypoglycemia also caused a loss of hypoglycemia-induced elevation of glucocorticoid secretion, a failure prevented by naloxone but not valsartan.CONCLUSIONSBased on these observations we speculate that acute hypoglycemia induces reprogramming of hypothalamic metabolism away from glycolysis toward β-oxidation, HAAF is associated with a reversal of this reprogramming, and naloxone preserves some responses to hypoglycemia by preventing this reversal.

Regulation of Peripheral Metabolism by Substrate Partitioning in the Brain

“…While assessing molecular mechanisms mediating the suppression of counterregulation by estradiol, we observed that estradiol inhibited hypothalamic Cpt1a, plausibly contributing to counterregulatory failure by increasing reliance on glycolysis [94]. Similarly we observed that repetitive hypoglycemia also reduced hypothalamic expression of Cpt1a in association with counterregulatory failure [95]. We also confirmed the induction of Cpt1a by fasting in the hypothalamus, but not the cortex [34].…”

“…As suggested above, hypoglycemia produces similar metabolic [31] and molecular [95] effects as produced by fasting [34, 100]. In turn, metabolic responses to fasting require Ppar-alpha [100-103].…”

“…Likewise, many responses to fasting are mediated by hypothalamic neurons through leptin signaling [30] which in turn depends on glucose metabolism [34, 106]. We have recently reported that acute hypoglycemia induces many genes in the hypothalamus that are targets of the transcription factor Ppar-alpha, and the induction of these genes is correlated with endocrine responses [95]. These observations led us to hypothesize that many whole-body responses to hypoglycemia and fasting are mediated by Ppar-alpha in the VMH [95].…”

Metabolic mystery: aging, obesity, diabetes, and the ventromedial hypothalamus

“…A single episode of hypoglycemia induces several Ppar-alpha target genes in the VMH, and the induction of these genes is preferentially lost after antecedent hypoglycemia which impairs counterregulatory responses to hypoglycemia [49]. Furthermore, Ppar-alpha knockout mice exhibit elevated whole-body glucose metabolism that is not reversed by replacing Ppar-alpha in the liver, but is reversed by activating Ppar-alpha in the brain [50].…”

The Response to Hypoglycemia: A Role for the Opioid System?

“…Opioid receptors are expressed within the VMH and a number of other hypothalamic and thalamic regions where they might conceivably modulate glucose sensing during hypoglycemia (15). However, evidence for a direct role for opioids in the hypothalamus is limited to studies showing reversal of hypoglycemia-induced changes in gene expression (16), and there are as yet no in vivo animal studies that have examined the effect of hypothalamic manipulation of opioid action on perturbations of glucose homeostasis such as hypoglycemia.…”