Tertiary Hypothyroidism and Hyperglycemia in Mice with Targeted Disruption of the Thyrotropin-Releasing Hormone Gene

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 20; pp. 10862 - 10867
• Main Authors: Yamada, Masanobu, Saga, Yumiko, Shibusawa, Nobuyuki, Hirato, Jyunko, Murakami, Masami, Iwasaki, Toshiharu, Hashimoto, Koshi, Satoh, Teturou, Wakabayashi, Katsumi, Taketo, Makoto M., Mori, Masatomo
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 30.09.1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Animal models; Animals; Biological Sciences; Blood glucose; Blood Glucose - metabolism; Body weight; Cell Line; Cellular biology; Chimera; Cloning, Molecular; Endocrinology; Gene Targeting; Genetics; Hormones; Hyperglycemia; Hyperglycemia - genetics; Hyperglycemia - physiopathology; Hypothyroidism; Hypothyroidism - genetics; Hypothyroidism - physiopathology; Insulin; Insulin - metabolism; Insulin Secretion; Islets of Langerhans - metabolism; Islets of Langerhans - ultrastructure; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Microscopy, Electron; Pituitary Gland - physiopathology; Protein Precursors - genetics; Radioimmunoassay; Rodents; Stem Cells - metabolism; Thyrotropin-Releasing Hormone - deficiency; Thyrotropin-Releasing Hormone - genetics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.20.10862

Thyrotropin-releasing hormone (TRH) is a brain hypothalamic hormone that regulates thyrotropin (TSH) secretion from the anterior pituitary and is ubiquitously distributed throughout the brain and other tissues including pancreas. To facilitate studies into the role of endogenous TRH, we have used homologous recombination to generate mice that lack TRH. These TRH-/-mice are viable, fertile, and exhibit normal development. However, they showed obvious hypothyroidism with characteristic elevation of serum TSH level and diminished TSH biological activity. Their anterior pituitaries exhibited an apparent decrease in TSH immunopositive cells that was not due to hypothyroidism. Furthermore, this decrease could be reversed by TRH, but not thyroid hormone replacement, suggesting a direct involvement of TRH in the regulation of thyrotrophs. The TRH-/-mice also exhibited hyperglycemia, which was accompanied by impaired insulin secretion in response to glucose. These findings indicate that TRH-/-mice provide a model of exploiting tertiary hypothyroidism, and that TRH gene abnormalities cause disturbance of insulin secretion resulting in marked hyperglycemia.