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Letter to the Editor |
Department of Medical Sciences, Endocrinology Unit, The University of Edinburgh, Western General Hospital, EH4 2XU Edinburgh, United Kingdom
Address correspondence to: Brian R. Walker, M.D., Department of Medical Sciences, Endocrinology Unit, The University of Edinburgh, Western General Hospital, EH4 2XU Edinburgh, United Kingdom.
To the editor:
The comments from Drs. Kerstens and Dullaart are pertinent, and we apologize for our misrepresentation of their previous important study of the effects of insulin therapy on cortisol metabolite excretion. Their major comment is in keeping with the widely held presumption that dysregulation of 11HSD1 is specifically associated with visceral, rather than generalized, obesity in humans. This has been inferred from circumstantial evidence: glucocorticoid excess in Cushing’s syndrome causes visceral obesity; mice with adipose-selective overexpression of 11HSD1 exhibit visceral obesity (1); obese Zucker rats have greater up-regulation of 11HSD1 in omental than in sc adipose tissue (2); and in human adipose cells in primary culture, 11HSD1 activity is greater in cells from omental than sc biopsies (3).
However, this presumption is not supported by direct evidence in humans. A series of studies have assessed 11HSD1 activity in obesity using urinary cortisol to cortisone metabolic ratios (4, 5, 6, 7), measuring in vivo conversion of cortisone to cortisol on first pass through the liver (8, 9, 10), or directly measuring 11HSD1 activity and/or mRNA in adipose biopsies (9, 10, 11, 12). These show that obesity is associated with impaired 11HSD1 activity in the liver and enhanced expression and activity in sc adipose tissue. Omental adipose 11HSD1 may not be altered in human obesity (13), although these biopsies can only be obtained during surgery and cells were then cultured in vitro, which may have confounding effects. Crucially, the associations with 11HSD1 indices are equally strong for measurements of generalized (body mass index, percentage body fat) and central (waist circumference, waist to hip ratio) obesity; in none of these studies could the influence of body mass index be distinguished statistically from the influence of waist to hip ratio.
Unfortunately, we cannot address this question directly in our case-control study of patients with impaired glucose tolerance (14) because waist and hip circumferences were not measured in 25 of the 50 participants, but there is no reason to suppose that these subjects will differ from other groups. Detailing the relationship of body fat distribution and cortisol metabolism is, as Kerstens and Dullaart suggest, a crucial research objective, but we think it unlikely that this will explain the differences we described in glucose-intolerant subjects compared with normal subjects with matched body mass indices.
Received March 13, 2003.
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