SummaryBackground: Patients with type 2 diabetes are at high risk of fatal and non-fatal myocardial infarction and stroke. There is indirect evidence that agonists of peroxisome proliferator-activated receptor 7 (PPAR 7) could reduce macrovascular complications. Our aim, therefore, was to ascertain whether pioglitazone reduces macrovascular morbidity and mortality in high-risk patients with type 2 diabetes.

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In this study we tested the use of salivary cortisol and cortisone as alternatives to serum cortisol. Salivary cortisol is often undetectable and contaminated by hydrocortisone. Salivary cortisone strongly reflects serum cortisol.

We have determined the time course of the neuroendocrine response of Piebald-Viral-Glaxo (PVG) rats during the development of mycobacterially induced adjuvant arthritis. Anterior pituitary POMC mRNA increased at the time of onset of mycobacterially induced arthritis, but, paradoxically, coincident with the first signs of arthritis there was a consistent fall in CRF mRNA in the hypothalamic paraventricular nucleus. Coincident with this fall in CRF message, there was a corresponding decrease in CRF-41 peptide release into the hypophysial portal blood (HPB). In contrast, however, vasopressin release into the HPB was increased. There was an increase in adrenal weight associated with the development of arthritis, reflecting chronic activation of the HPA axis, which was reflected by increased circulating corticosterone concentrations. The synthetic adjuvant CP20961, which has different antigenic determinants, also caused an increase in POMC mRNA in the anterior pituitary, a decrease in CRF mRNA in the hypothalamic paraventricular nucleus, and a decrease in CRF-41 peptide release into the HPB in PVG rats 28 days after the induction of the arthritis. The arginine vasopressin level was not significantly different from the control value. In Sprague-Dawley rats, mycobacterial adjuvant resulted in a similar increase in POMC mRNA in the anterior pituitary 28 days after injection of the adjuvant. In this strain of rat there was no corresponding change in CRF mRNA. While there are some strain differences in the degree of change in CRF mRNA, both strains showed a common paradox of a marked increase in adenohypophyseal POMC mRNA not associated with increased CRF mRNA or peptide release. In the PVG strain of rat, CRF actually appears to be inhibited. The mechanisms involved in this disparity are unclear.

Food deprivation in laboratory rats induces profound changes in the neuroendocrine system. We have investigated the hypothalamic and pituitary responses of the hypothalamo-pituitary thyroid axis to 48-h food deprivation in Sprague-Dawley rats. Peripheral T3 and hypophysial portal TRH were measured by RIA, and TSH beta, PRL, and pro-TRH mRNA were measured using in situ hybridization histochemistry. Peripheral total T3 was greatly reduced in food-deprived rats. Hypothalamic portal blood TRH levels declined significantly with time in control animals. The initial level of TRH in the portal blood of food-deprived rats was significantly reduced compared to that in controls, but did not fall further with time. In situ hybridization histochemistry revealed significantly lower pro-TRH mRNA in the paraventricular nucleus of food-deprived animals, while pro-TRH mRNA in the reticular nucleus remained unaltered. Furthermore, in the anterior pituitary, TSH beta mRNA decreased significantly in food-deprived animals, while PRL mRNA was unaltered. We conclude that the reduction in circulating T3 after food deprivation appears to be due primarily to decreased hypothalamic TRH synthesis and release.

1 Adjuvant-induced arthritis (AA) is an experimental inflammation of the joints that results in chronic activation of the hypothalamo-pituitary-adrenal (HPA) axis. 2 In this study the role of hypothalamic corticotrophin-releasing factor (CRF) and arginine vasopressin (AVP) in the regulation of the HPA axis in this condition both in Sprague-Dawley (SD), and PiebaldViral-Glaxo (PVG) rats has been further characterized. 3 The increase in AVP peptide content of portal blood (as early as day 11), just prior to the onset of arthritis is confirmed and further increases, peaking at day 16 are shown, coincident with the progression of inflammation in the PVG rats. 4 The increase in AVP is associated with a significant increase in the expression of AVP but not CRF mRNAs in the medial parvocellular division of the hypothalamic paraventricular nucleus (PVN) of arthritic SD rats. 5 In the presence of maximal inflammation of SD rats there was a significant decrease in the maximum binding of ['251]-Tyr-oCRF to anterior pituitary membranes, whereas AVP receptor concentration in anterior pituitary membranes from both PVG and SD rats showed a significant increase with respect to controls. 6 The basal adrenocorticotrophin (ACTH) secretion in vitro was similar in both control and arthritic SD rats but that from arthritic PVG rat pituitaries was significantly greater than the respective controls (436 + 91 v 167 + 23 pg/tube). The ACTH response of pituitaries of arthritic PVG rats to CRF or the combination of CRF and AVP was significantly higher compared with the controls, although the ACTH response of arthritic SD rat pituitaries was unchanged. 7 The results are consistent with the view that activation of the parvocellular vasopressin system has an important role in the adaptation of the HPA axis to experimentally-induced chronic stress of arthritis.

Twice-daily Chronocort approximates physiologic cortisol secretion, and was well tolerated and effective in controlling androgen excess in adults with CAH. This novel hydrocortisone formulation represents a new treatment approach for patients with CAH.