Insulin-Induced Hypoglycemia Increases Corticotropin- Releasing Factor Messenger Ribonucleic Acid Levels in Rat Hypothalamus*

Suda, Toshio; Tozawa, Fumiko; Yamada, Masakazu; Ushiyama, Tsuyako; Tomori, Naoki; Sumitomo, Takashi; Nakagami, Yuriko; Demura, Hiroshi; Shizume, Kazuo

doi:10.1210/endo-123-3-1371

Cited by 87 publications

(30 citation statements)

References 25 publications

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“…In addition, dramatic changes in tyrosine hydroxylase, dopamine B-hydroxylase and neuropeptide Y mRNA content in the thoracic ganglia of humans have been reported to occur in <1 hr after electrical preganglionic stimulation (24). Pro-opiomelanocortin mRNA in the pituitary increased significantly 60 min after insulin-induced hypoglycemia in rats (25), whereas mRNA for corticotropin-releasing factor in the hypothalamus increased in as little as 30 min after hypoglycemia (26). Similarly, neurotensin mRNA increased within 30 min of haloperidol administration to rats (27).…”

Section: Discussionmentioning

confidence: 99%

Ultradian oscillations in somatostatin and growth hormone-releasing hormone mRNAs in the brains of adult male rats.

Zeitler

Tannenbaum

Clifton

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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In the adult male rat, growth hormone (GH) secretion is characterized by an ultradian rhythin generated by the rhythmic interplay of the stimulatory effects of GHreleasing hormone (GHRH) and the inhibitory effects of somatostatin (Ss). Although considerable evidence indicates that GHRH and Ss are secreted in reciprocal 3-to 4-hr rhythms, the mechanism underlying the rhythmic secretion of these two neuropeptides is unknown. We tested the hypothesis that the rhythmic and reciprocal oscillations in secretion of Ss and GHRH are associated with parallel changes in synthesis and that this would be reflected by coincident oscillations in levels of the respective mRNAs. In the first experiment, Ss mRNA was significantly greater in the periventricular nucleus of animals sacrificed at the time of a presumed peak in the GH rhythm than in animals sacrificed at the time of a presumed trough; this variation was limited to the anterior third of this nucleus. Conversely, GHRH mRNA content throughout the arcuate nucleus was significantly greater at the time of a GH trough. In the second experiment, groups of animals were sacrificed during two consecutive cycles. In this set of animals, Ss mRNA content was 40% greater (P < 0.005) during peak GH concentrations, whereas GBRH mRNA content was 42% greater (P < 0.005) during the GH trough. This difference persisted when the two cycles were analyzed separately. The findings that the cellular nIRNA content for Ss and GHRH varies in a reciprocal manner with the presumed secretion of these neuropeptides suggest that, like secretion, the synthesis of Ss and GHRH also varies rhythmically. The occurrence of this rhythm suggests a model for a transcriptional oscillator that may subserve the generation of this and possibly other neuroendocrine rhythms.In the adult male rat, the secretion of growth hormone (GH) is characterized by an endogenous ultradian rhythm. Highamplitude secretory bursts occur at regular 3.3-hr intervals and are separated by intervening troughs during which basal GH levels are undetectable (1). The patterning of GH secretion is generated by the interplay of the stimulatory effects of GH-releasing hormone (GHRH) and the inhibitory effects of somatostatin (Ss) (for review, see ref.2). In the rat, these two neuropeptides are released in reciprocal 3-to 4-hr cycles and act upon the pituitary somatotropes to generate the ultradian rhythm of GH secretion (3, 4). The primary source of median eminence Ss is from neurons in the periventricular nucleus (PeN) (5), whereas the primary source of GHRH is from neurons in the arcuate nucleus (Arc) (6).Although it is known that the rhythmic oscillation of GH secretion is governed by Ss and GHRH, the mechanisms underlying the rhythmic discharge of Ss and GHRH neurons remain to be elucidated. On the one hand, these discharge patterns could reflect the intrinsic properties of the peptidergic neurons themselves. Alternatively, it is conceivable that the oscillations reflect interactions among the elements of a feedback loop involving G...

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Section: Discussionmentioning

confidence: 99%

Ultradian oscillations in somatostatin and growth hormone-releasing hormone mRNAs in the brains of adult male rats.

Zeitler

Tannenbaum

Clifton

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…Increases in CRH (51,52) and CRH mRNA (53) in response to hypoglycemia were not noticed in some studies. However, others have reported increased hypothalamic CRH mRNA levels in anesthetized rats (11) and after 3 h of hypoglycemia in conscious rats (12). These results indicate the importance of the duration of hypoglycemia and of avoiding anesthesia when analyzing HPA function.…”

Section: Discussionmentioning

confidence: 85%

Diabetes Impairs Hypothalamo-Pituitary-Adrenal (HPA) Responses to Hypoglycemia, and Insulin Treatment Normalizes HPA but not Epinephrine Responses

Chan

Inouye

et al. 2002

Diabetes

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We recently established that in addition to plasma adrenocorticotrophic hormone (ACTH) and corticosterone, hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal type 1 glucocorticoid receptor (GR1) mRNA were also upregulated in uncontrolled streptozotocin-induced diabetes. In the current study, control, diabetic, and insulin-treated diabetic rats underwent a hyperinsulinemic-hypoglycemic glucose clamp to evaluate central mechanisms of hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulininduced hypoglycemia. Increases in plasma ACTH, corticosterone, and epinephrine were significantly lower in diabetic rats versus controls. Insulin treatment restored ACTH and corticosterone but not epinephrine responses to hypoglycemia in diabetic rats. Glucagon and norepinephrine responses to hypoglycemia were not affected by diabetes or insulin treatment. In response to hypoglycemia, hypothalamic CRH mRNA and pituitary proopiomelanocortin mRNA expression increased in control and insulin-treated but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal GR1 mRNA expression in control and insulintreated diabetic rats but not in diabetic rats. In contrast, type 2 glucocortoid receptor (GR2) mRNA was not altered by hypoglycemia. In conclusion, despite increased basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that the defect in CRH response could be related to the defective GR1 response. It is intriguing that insulin treatment restored the HPA response to hypoglycemia but, surprisingly, not the deficient epinephrine response. This is important because during severe hypoglycemia, epinephrine is an important counterregulatory hormone. Diabetes

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“…However, CRH gene expression or release has not been found to increase consistently after stress, and some stimuli have been reported not to change or even to decrease CRH [9, 10]. Although Northern blot and in situ hybridization analysis of CRH mRNA has demonstrated stimulus-induced increases in gene expression only in CRH neurons [11, 12], evidence from portal sampling or median eminence neuropeptide depletion favors a role for vasopressin as a primary mediator of ACTH secretion after hypoglycemia or hypovolemia [2, 8]. It has been argued that in these cases, CRH functions only permissively to maintain adrenocortical axis responsiveness to the other secretagogues [9].…”

Section: Introductionmentioning

confidence: 99%

CRH Deficiency Impairs but Does Not Block Pituitary-Adrenal Responses to Diverse Stressors

et al. 2000

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We have previously observed significant, albeit decreased, corticosterone responses to restraint stress in corticotropin releasing hormone (CRH)-deficient (knockout, CRH KO) mice. Because different stressors have been shown to engage different populations of hypophysiotropic neurons, we have used hypoglycemia and hypovolemia to test whether CRH-independent pituitary-adrenal activation is evoked by stimuli other than restraint. Insulin injection in fasted CRH KO mice elicited increases in corticosterone that were markedly lower than those in wild type but marginally significant relative to corresponding KO controls. Consistent with impaired adrenocortical function, hypoglycemia-induced epinephrine secretion was reduced in female CRH KO mice. Hypovolemia produced by retro-orbital bleeding also significantly elevated corticosterone in CRH KO mice. In contrast to significant stress-induced increases in corticotropin (ACTH) in wild-type mice, those in CRH KO mice were slight, transient and difficult to detect without frequent sampling. Restraint-induced interleukin-6 (IL-6) levels were similar between wild-type and CRH KO mice, arguing against compensatory changes in IL-6 responses to restraint due to CRH deficiency. CRH infusion enhanced adrenocortical responses to restraint independently of effects on basal corticosterone levels, suggesting that pituitary-adrenal activity is augmented by factors besides CRH during stress. We conclude that although stress-induced pituitary-adrenal activity does not require acute increases in CRH, CRH is required to support the normal amplitude of adrenocortical axis responsiveness to other endocrine or neural factors during stress.

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Insulin-Induced Hypoglycemia Increases Corticotropin- Releasing Factor Messenger Ribonucleic Acid Levels in Rat Hypothalamus*

Cited by 87 publications

References 25 publications

Ultradian oscillations in somatostatin and growth hormone-releasing hormone mRNAs in the brains of adult male rats.

Ultradian oscillations in somatostatin and growth hormone-releasing hormone mRNAs in the brains of adult male rats.

Diabetes Impairs Hypothalamo-Pituitary-Adrenal (HPA) Responses to Hypoglycemia, and Insulin Treatment Normalizes HPA but not Epinephrine Responses

CRH Deficiency Impairs but Does Not Block Pituitary-Adrenal Responses to Diverse Stressors

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