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J. R. BLAIR-WEST, A. BRODIE, J. P. COGHLAN, D. A. DENTON, C. FLOOD, J. R. GODING, B. A. SCOGGINS, J. F. TAIT, S. A. S. TAIT, E M. WINTOUR, and R. D. WRIGHT

SUMMARY

The effect of sodium depletion on the conversion of corticosterone to aldosterone has been examined in vivo using the adrenal transplants of two sheep. [3H]Corticosterone was infused continuously directly into the adrenal gland via the carotid artery over a period of 30 min. and the total adrenal effluent was collected via the jugular vein in six consecutive 5-min. samples. The conversion of [3H]corticosterone to [3H]aldosterone and the endogenous output of aldosterone was measured in each sample using a double isotope derivative method and the specific activity of the aldosterone calculated. Radioactive conversion of B → aldosterone reached equilibrium within 10 min. of the start of infusion and remained constant over a period of 10–25 min. Aldosterone secretion was also constant during the first 25 min. of infusion.

In the same sheep the mean percentage conversion increased as aldosterone secretion rose over a range of 2–12 μg./hr. With more severe sodium depletion, i.e. with aldosterone secretion rates of 12–16 μg./hr., conversion decreased to that found in the sodium replete state. The specific activity of the aldosterone was constant throughout the mildly deplete range (2–12 μg./hr.) but fell with severe sodium depletion. In the sodium replete range (0–2 μg./hr.) before the introduction of a parotid fistula, the specific activity was the same as in the mildly deplete state. After the introduction of a parotid fistula the specific activity increased as the secretion decreased from 2 to 0 μg.

The validity of the approach and interpretation of the results in terms of the biosynthetic pathways involved are discussed.

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L Lundholm, G Bryzgalova, H Gao, N Portwood, S Fält, K D Berndt, A Dicker, D Galuska, J R Zierath, J-Å Gustafsson, S Efendic, K Dahlman-Wright, and A Khan

The aim of this study was to validate the role of estrogen receptor α (ERα) signaling in the regulation of glucose metabolism, and to compare the molecular events upon treatment with the ERα-selective agonist propyl pyrazole triol (PPT) or 17β-estradiol (E2) in ob/ob mice. Female ob/ob mice were treated with PPT, E2 or vehicle for 7 or 30 days. Intraperitoneal glucose and insulin tolerance tests were performed, and insulin secretion was determined from isolated islets. Glucose uptake was assayed in isolated skeletal muscle and adipocytes. Gene expression profiling in the liver was performed using Affymetrix microarrays, and the expression of selected genes was studied by real-time PCR analysis. PPT and E2 treatment improved glucose tolerance and insulin sensitivity. Fasting blood glucose levels decreased after 30 days of PPT and E2 treatment. However, PPT and E2 had no effect on insulin secretion from isolated islets. Basal and insulin-stimulated glucose uptake in skeletal muscle and adipose tissue were similar in PPT and vehicle-treated ob/ob mice. Hepatic lipid content was decreased after E2 treatment. In the liver, treatment with E2 and PPT increased and decreased the respective expression levels of the transcription factor signal transducer and activator of transcription 3, and of glucose-6-phosphatase. In summary, our data demonstrate that PPT exerts anti-diabetic effects, and these effects are mediated via ERα.

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L Lundholm, G Bryzgalova, H Gao, N Portwood, S Fält, K D Berndt, A Dicker, D Galuska, J R Zierath, J-Å Gustafsson, S Efendic, K Dahlman-Wright, and A Khan