Evidence that elevated plasma corticosterone levels are the cause of reduced hypothalamic corticotrophin-releasing hormone gene expression in diabetes.
Abstract
Uncontrolled diabetes mellitus causes both a sustained activation of the hypothalamic-pituitary-adrenal (HPA) axis and reduced expression of corticotrophin-releasing hormone (CRH) mRNA in the hypothalamic paraventricular nucleus (PVN). To investigate the role of glucocorticoids in the regulation of CRH mRNA expression in the PVN of diabetic rats, we studied surgically adrenalectomized (ADX) and sham-operated male Sprague-Dawley rats 4 days after i.v. injection of streptozotocin (STZ; 65 mg/kg i.v.) or vehicle. Among sham-operated animals, AM plasma corticosterone levels were significantly increased in diabetic as compared to nondiabetic animals (1.46+/-0.54 vs. 0.22+/-0.05 microg/dl; P <0.05), and were positively correlated to both plasma ACTH levels (r = 0.74; P = 0.015) and adrenal gland weight (r = 0.70; P = 0.025). In contrast, CRH mRNA levels measured in the PVN by in situ hybridization were inversely related to the plasma corticosterone level (r = -0.68; P = 0.045). In a second experiment, both diabetic and nondiabetic ADX rats received a continuous subcutaneous infusion of either corticosterone at one of two doses or its vehicle for 4 days. Among vehicle-treated ADX animals, STZ diabetes raised hypothalamic CRH mRNA levels, in contrast to the tendency for diabetes to lower CRH mRNA in intact rats in the first experiment. Corticosterone administration lowered CRH mRNA comparably in both diabetic and nondiabetic ADX rats. In contrast, diabetes reduced arginine vasopressin (AVP) mRNA levels in the PVN of ADX rats and blunted the inhibitory effect of glucocorticoids on AVP mRNA levels in this setting. We conclude (1) glucocorticoids are necessary for the effect of diabetes to reduce hypothalamic CRH gene expression, since diabetes causes a paradoxical increase in CRH mRNA levels in adrenalectomized animals; (2) glucocorticoid inhibition of hypothalamic CRH gene expression is intact in diabetic rats; and (3) the activation of the HPA axis by diabetes is associated with a proportionate decrease in PVN CRH gene expression. These findings support a model in which hypothalamic factors additional to CRH activate the HPA axis in uncontrolled diabetes, and inhibit CRH gene expression indirectly by negative glucocorticoid feedback.
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Circulating corticosterone levels are elevated in STZ-diabetic rats.
“circulating levels of corticosterone were elevated in STZ-diabetic rats (44)”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [44]
Conditions associated with leptin deficiency, such as fasting and uDM, raise corticosterone levels via a mechanism that can be reversed with leptin treatment.
“conditions associated with leptin deficiency, such as fasting and uDM, clearly raise corticosterone levels via a mechanism that can be reversed with leptin treatment (44,45,49).”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [44]
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- Authors
- Schwartz, M. W., Strack, A. M., & Dallman, M. F.
- Affiliations
- United States Department of Veterans Affairs (US)
- University of California, San Francisco (US)
- Corresponding author
- Schwartz, Michael W
- ORCID
- Schwartz, Michael W
- Venue
- Regulatory Peptides
- Publisher
- Elsevier BV
- Published
- 1997-10
- Volume
- 72
- Issue
- 2-3
- Pages
- 105-112
- ISSN
- 0167-0115 (ISSN-L)
- OpenAlex
- W2053027732
- Cited by
- 57
- References
- 28
- Citations by year
- 2022: 1 · 2019: 1 · 2017: 2 · 2016: 1 · 2015: 4 · 2014: 5 · 2013: 2
- FWCI
- 1.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Regulatory Peptides (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK17844, DK28172)
- National Institute of Neurological Disorders and Stroke (NS-32273)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- diabetes mellitus, corticosterone, glucocorticoids, corticotropin-releasing factor, CRH gene expression, hypothalamic paraventricular nucleus, hypothalamic-pituitary-adrenal axis, adrenalectomy, streptozotocin-induced diabetes, vasopressin, ACTH, glucocorticoid feedback inhibition
- MeSH terms
- Adrenal Glands, Adrenalectomy, Animals, Arginine Vasopressin, Corticosterone, Corticotropin-Releasing Hormone, Diabetes Mellitus, Experimental, Gene Expression Regulation, Hypothalamus, Male, Neuropeptides, Organ Size, Paraventricular Hypothalamic Nucleus, Pituitary-Adrenal System, RNA, Messenger, Streptozocin, Rats, Sprague-Dawley, In Situ Hybridization, Rats
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