On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

The active form of vitamin D, 1,25-dihydroxvitamin D 3 (1,25(OH) 2 D 3 ), is a pleiotropic hormone whose actions include the regulation of calcium homeostasis, control of bone cell differentiation and modification of immune responses. Synthesis of 1,25(OH) 2 D 3 from the major circulating metabolite, 25-hydroxyvitamin D 3 (25(OH)D 3 ), is catalysed by a mitochondrial cytochrome P450 enzyme, 25-hydroxyvitamin D-1 -hydroxylase (1 -OHase). Although 1 -OHase is expressed predominantly in the kidney, extra-renal production of 1,25(OH) 2 D 3 has also been demonstrated in tissues such as lymph nodes and skin. The tight regulation of 1 -OHase which occurs in both renal and peripheral tissues has made studies of the expression and regulation of this enzyme remarkably difficult. However, the recent cloning of mouse, rat and human cDNAs for 1 -OHase (CYP1 /Cyp1 ) has enabled a more thorough characterization of this enzyme. In particular, analysis of the CYP1 gene has identified mutations causing the inherited disorder vitamin D-dependent rickets type 1, also known as pseudo-vitamin D deficiency rickets. Studies from our own group have focused on the distribution of 1 -OHase in both renal and extra-renal tissues. Data indicate that the enzyme is expressed throughout the nephron, suggesting discrete endocrine and paracrine/autocrine functions. Further immunohistochemical analyses have shown that the enzyme is widely distributed in extra-renal tissues, and this appears to be due to the same gene product as the kidney. Collectively, these observations have raised important new questions concerning the role of 1 -OHase in vitamin D signalling at a local level. The relationship between expression of protein for 1 -OHase and enzyme activity has yet to be fully characterized and may be dependent on membrane proteins such as megalin. Similarly, elucidation of the mechanisms involved in differential regulation of renal and extra-renal 1,25(OH) 2 D 3 production will be essential to our understanding of the tissue-specific functions of 1 -OHase. These and other issues are discussed in the current review.

In this, the largest series reported, conventional pituitary irradiation is shown to be an effective and safe means of reducing both serum GH and IGF-I concentrations in patients with acromegaly.

Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. Impaired conversion of cortisone (E) to cortisol (F) by the type 1 isoenzyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in obesity may represent a protective mechanism preventing ongoing weight gain and glucose intolerance. We have studied glucocorticoid metabolism in 33 male subjects with type 2 diabetes mellitus [age, 44.2 +/- 13 yr; body mass index (BMI), 31.1 +/- 7.5 kg/m(2) (mean +/- sd)] and 38 normal controls (age, 41.4 +/- 14 yr; BMI, 38.2 +/- 12.8 kg/m(2)). Circulating F:E ratios were elevated in the diabetic group and correlated with serum cholesterol and homeostasis model assessment-S. There was no difference in 11beta-HSD1 activity between diabetic subjects and controls. In addition, 11beta-HSD1 activity was unaffected by BMI in diabetic subjects. However, in control subjects, increasing BMI was associated with a reduction in the urinary tetrahydrocortisol+5alpha-tetrahydrocortisol:tetrahydrocortisone ratio (P < 0.05) indicative of impaired 11beta-HSD1 activity. The degree of inhibition correlated tightly with visceral fat mass. Changes in 11beta-HSD1 activity could not be explained by circulating levels of adipocytokines. Impaired E to F metabolism in obesity may help preserve insulin sensitivity and prevent diabetes mellitus. Failure to down-regulate 11beta-HSD1 activity in patients with diabetes may potentiate dyslipidemia, insulin resistance, and obesity. Inhibition of 11beta-HSD1 may therefore represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity.