TERTIARY HYPOTHYROIDISM AND HYPERGLYCEMIA IN MICE WITH TARGETED DISRUPTION OF THE THYROTROPIN-RELEASING-HORMONE GENE

Thyrotropin-releasing hormone (TRH) is a brain hypothalamic hormone th at regulates thyrotropin (TSH) secretion from the anterior pituitary a nd 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 develop ment. However, they showed obvious hypothyroidism with characteristic elevation of serum TSI-I level and diminished TSH biological activity, Their anterior pituitaries exhibited an apparent decrease in TSH immu nopositive cells that was not due to hypothyroidism, Furthermore, this decrease could be reversed by TIW, but not thyroid hormone replacemen t, suggesting a direct involvement of TRH in the regulation of thyrotr ophs. The TRH-/- mice also exhibited hyperglycemia, which was accompan ied by impaired insulin secretion in response to glucose. These findin gs indicate that TRH-/- mice provide a model of exploiting tertiary hy pothyroidism, and that TW gene abnormalities cause disturbance of insu lin secretion resulting in marked hyperglycemia.