I noticed that Cathy was having trouble accessing the link to the article; so, I tried it and had the same problem. I thought that I had checked the link after I submitted the post, but given my memory anything is possible. I pasted the article below for those of you who want to check it out but can't access it. Sorry for the dead link.
Is the "Metabolic Syndrome" a Mild Form of Cushing's Syndrome?
The Curious Story of 11beta-Hydroxysteroid Dehydrogenase
Ashok Balasubramanyam, MD
Could a Single Defect Trigger Syndrome X?
"Syndrome X," or the "metabolic syndrome," originally described by Gerald Reaven, MD, has now expanded to include a cluster of at least 5 highly prevalent disorders: hypertension, dyslipidemia, diabetes, visceral obesity, and polycystic ovary syndrome (PCOS). Its enormous medical, social, and economic impact has stimulated several fields of research into its causes and treatment.
One intriguing question is: Could a single primary defect trigger a cascade of diverse events leading to these apparently disparate metabolic, cardiovascular, and reproductive defects? Since Cushing's syndrome also encompasses many of these disorders, it is worthwhile considering whether the metabolic syndrome could be a "forme fruste" of Cushing's. Circulating glucocorticoid levels are not elevated in persons with the metabolic syndrome; however, could it be possible that the corticosteroid action occurs at a local level, giving rise to the effects of excess glucocorticoid receptor stimulation in a tissue-restricted manner without elevating plasma levels of glucocorticoids?
From Curiosity to Central Player
About 2 decades ago, Stanley Ulick, MD, described a syndrome characterized by hypertension and hypokalemia and reminiscent of hyperaldosteronism. The cause, however, was not a primary defect in the renin-angiotensin-aldosterone system but an inactivating mutation in the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). This syndrome, which could also be reproduced by the consumption of licorice (the offending ingredient is glycyrrhizic acid), was due to the fact that 11beta-HSD2 normally converts cortisol to its biologically inactive congener cortisone in the kidney and placenta, thus protecting the mineralocorticoid receptor in renal tubules from excess stimulation by cortisol. (The mineralocorticoid receptor can be activated by glucocorticoids as well.) With a nonfunctional 11beta-HSD2 enzyme, patients with the mutation or consumers of potent licorice had excess stimulation of mineralocorticoid receptors by glucocorticoids, resulting in a syndrome of "apparent mineralocorticoid excess (AME)."
For a while, this syndrome and the enzyme at its basis remained in the realm of endocrine exotica. Recent investigations, both in humans and in mice, have returned it and its twin, 11beta-HSD1, to the limelight as possible players in the complex pathophysiology of the metabolic syndrome. A topical symposium at ENDO 2002 entitled "The Adipocyte as a Steroid Factory," as well as numerous abstracts, presented new, intriguing findings in this field.
Knockout Models of 11beta-HSD1 and HSD2
The group led by Professor John Mullins, University of Edinburgh, Scotland, has engineered mice with homozygous deletions of either 11beta-HSD2 or 11beta-HSD1. Professor Mullins presented the physiologic and biochemical phenotypes of these mice. Not surprisingly, the 11beta-HSD2 knockout animal -- being unable to convert potent circulating 11-hydroxy glucocorticoids to their inactive 11-dehydrogenated forms in renal tubular cells -- has hypertension and hypokalemia, together with suppressed plasma renin and aldosterone. Less predictably, it also manifests renal tubular hyperplasia and hypertrophy, as well as aortic dissection (perhaps a manifestation of early-onset, severe hypertension).
The 11beta-HSD1 knockout animal has a different phenotype, reflecting the fact that this enzyme normally functions as the reverse of 11beta-HSD2, converting inactive cortisone to active cortisol within cells in the liver, adipose tissue, and brain. Lacking the ability to perform this localized glucocorticoid "re-activating" biochemical conversion, the 11beta-HSD1 knockout mouse is resistant to glucose intolerance when fed a high-fat diet. It also weighs less than its wild-type littermate despite eating more, and has a higher resting metabolic rate. Interestingly, wild-type mice downregulate 11beta-HSD1 expression in adipose tissues in response to high-fat feeding, indicating that this enzyme is subject to regulatory feedback by alterations in energy balance. Together, these findings suggest that an improperly regulated increase in 11beta-HSD activity or expression in liver, fat cells, or brain might contribute to the tendency to develop several features of the metabolic syndrome, such as visceral adiposity, hypertension, and insulin resistance.
Tissue-Specific Effects in the Liver and Adipose Tissues
Since an increase in 11beta-HSD1 expression or activity would be expected to have "localized" rather than systemic effects, in which of these organs -- liver, adipose tissues, or brain -- does the presence of an abnormal enzyme give rise to more generalized metabolic changes? Professor Mullins' group described the effects of liver-specific overexpression of 11beta-HSD1, while Jeffrey Flier, MD, of the Beth Israel Deaconess Medical Center, Boston, presented his group's data on adipocyte-specific overexpression of 11beta-HSD1.
Overexpression of 11beta-HSD1 in the liver resulted in transgenic mice that had fatty livers and elevations in serum cholesterol and triglycerides, but only mild insulin resistance (normal glucose tolerance with mildly elevated plasma insulin levels). Interestingly, these mice developed hypertension, a key component of the metabolic syndrome. The mechanism likely to be responsible for the development of hypertension is increased intrahepatocyte glucocorticoid activity, which leads to increased expression of the angiotensinogen gene, which would upregulate the activity of the angiotensin-aldosterone system.
Dr. Flier and colleagues reasoned that adipocyte-specific overexpression of 11beta-HSD1 might produce a phenotype that would include additional components of the metabolic syndrome, such as visceral obesity. This hypothesis was based on the knowledge that visceral compartment adipocytes normally have greater expression levels of both 11beta-HSD1 and glucocorticoid receptor than do subcutaneous adipocytes.
The physiology and biochemistry of the adipose-11beta-HSD1 transgenic animals confirmed their hypothesis. As described by Dr. Flier (and reported previously in a paper in Science), their body weight was increased from an early age, and this was associated with a significantly greater increase in mesenteric fat depots compared with subcutaneous or epididymal fat depots. Associated with these changes were increased concentrations of cortisol within adipocytes, but not in the systemic circulation. The blood did, however, contain elevated levels of other markers of the metabolic syndrome: free fatty acids, triglycerides, glucose, and insulin. Notably -- and unlike the liver-specific 11beta-HSD1 transgenic mice -- these animals had a pronounced tendency to develop frank diabetes with advancing age or when fed a high-fat diet. Further evidence that increased adipocyte glucocorticoid signal transduction was occurring was seen in altered patterns of adipose gene expression, as these mice had decreased circulating levels of both adiponectin and resistin. Importantly, from the standpoint of understanding the pathophysiologic cascade leading to these 2 metabolic syndrome components, the adipocyte-specific11beta-HSD1 animals, like the liver-specific 11beta-HSD1 transgenic mice, also developed fatty livers and hypertension. The hypertension appears to be associated with increased expression of the glucocorticoid-dependent angiotensinogen gene in adipocytes, with increased circulating levels of angiotensin II and aldosterone.
These remarkable findings suggest a paradigm whereby tissue-specific "apparent glucocorticoid excess," in the face of a normal hypothalamic-pituitary-adrenal axis, could produce the metabolic syndrome. The HPA axis produces normal levels of serum cortisol, which is normally converted by 11beta-HSD2 into inactive cortisone in adipocytes and the liver. However, abnormally increased activity of 11beta-HSD1 in the liver or adipocytes causes excess reconversion of cortisone to cortisol within these tissues, leading to the inimical tissue-specific and downstream metabolic effects of excessive glucocorticoid activity.
A Hypothesis for the Metabolic Syndrome in Humans?
Dysfunction of 11beta-HSD1 thus provides a persuasive, unifying, even causal hypothesis for the metabolic syndrome. But, except in the situation of a clearly definable gene defect, does this happen in humans, and, if it does, is the dysfunction a cause or an effect of the metabolic syndrome?
It is difficult, as always, to find causal links between putative functional molecular defects and phenotypic outcomes in human pathophysiology, but it is interesting to note that there may be associations between 11beta-HSD activity and expression and some components of the human metabolic syndrome. Professor Paul Stewart of the University of Birmingham, United Kingdom, who first suggested in a provocative paper that the metabolic syndrome might represent "Cushing's disease of the omentum," presented data that suggest that several such associations may exist.
Professor Stewart's group has amassed a large repository of paired human adipose tissue samples from subcutaneous and visceral compartments, together with an extensive clinical and metabolic database. Professor Stewart pointed out that the 11beta-HSD paradigm for the metabolic syndrome may prove to be useful clinically because of the strong correlation between the severity of known mutations in 11beta-HSD and their phenotypic expression. For example, the severity of the enzymatic defects in 11beta-HSD2 determines the severity of illness in patients with the homozygous form of congenital "apparent mineralocorticoid excess"; heterozygotes have a milder disease, and it is possible that persons with salt sensitivity represent an even milder form of the same syndrome. Biochemical studies in the paired human adipose tissue samples confirmed that 11beta-HSD1 activity is higher in adipocytes from the omental region than in adipocytes from subcutaneous sites, both basally and when treated with cortisol. There was also a corresponding increase in lipid accumulation in the omental cells.
The investigators then addressed the hypothesis that 11beta-HSD1 activity might be increased in persons with visceral obesity. As a surrogate for 11beta-HSD1 activity, they measured the ratio of cortisol to cortisone in the urine in subjects with and without visceral obesity. However, the results of this "global" index of 11beta-HSD1 activity did not support the hypothesis, since this ratio fell rather than rose in the obese subjects.
The investigators then attempted to look at tissue-specific effects with assays that indirectly probe the physiologic action of 11beta-HSD1 in the liver or adipocytes. First, they infused subjects with cortisone acetate and measured its conversion to cortisol, a function expected to be carried out by hepatic 11beta-HSD1. The results showed a lower, rather than higher, rate of conversion in the obese. To measure 11beta-HSD1 effects in adipocytes, they quantified the mRNA for 11beta-HSD1 as well as enzyme activity in omental fat samples. Again, these measures were inversely, rather than directly, correlated with fatness.
At face value, the results of these difficult human experiments would appear to refute the "overactive 11beta-HSD1" hypothesis. However, they could also be suggesting the existence of a compensatory downregulation of 11beta-HSD1 enzyme activity as a result of having achieved a critical level of visceral obesity.
Proof of the "overactive 11beta-HSD1" concept in humans is perhaps better tested in persons with congenital defects in 11beta-HSD1 activity. Professor Stewart presented the results of his group's investigations of 8 women with mutations in the 11beta-HSD1 gene who appeared to have a total block in the conversion of cortisone to cortisol. These patients have a syndrome resembling PCOS, with elevated circulating androgens and variable increases in body mass index. The hyperandrogenic polycystic ovary condition could be due to diminished negative feedback to the pituitary by an excess of circulating cortisone compared to cortisol, leading to hyperstimulation of the androgenic steroid synthetic pathway in the adrenal cortex. Since PCOS is one component of the metabolic syndrome, this is at least a partial vindication of 11beta-HSD1 as a candidate initiator of the pathophysiology of the metabolic syndrome. Professor Stewart and colleagues are looking into other potential examples of 11beta-HSD11-related phenotypes, for example, in persons with a cluster of 3 polymorphisms in the intron of the gene for 11beta-HSD1.
A Therapeutic Future?
Whether 11beta-HSD defects hold out as important and common mediators of insulin resistance, visceral obesity, hypertension, and PCOS awaits further investigation, both in humans and in animal models of these conditions. Pharmaceutical companies, however, are not waiting for definitive evidence, as there is much active research already being directed at 11beta-HSD-1 and -2 as key therapeutic targets. The future is clearly exciting for further pathophysiologic, diagnostic, and therapeutic insights arising from the study of these unusual steroid-regulating enzymes.
Mullins J. Insights into steroid production and adipocytes from knockout models of HSD-1 and -2. In: Symposium: The adipocyte as a steroid factory. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California.
Paterson JM, Holmes MC, Morton NM, Seckl JR, Mullins JJ. Liver-specific over-expression of 11beta-HSD1 in transgenic mice produces insulin resistance, hyperlipidaemia and fatty liver. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California. Abstract P2-319.
Flier JS. Overexpression of 11 beta HSD-1 in adipose tissue produces visceral obesity and the metabolic syndrome in mice. In: Symposium: The adipocyte as a steroid factory. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California.
Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001;294:2166-2170.
Bujalska IJ, Kumar S, Stewart PM. Does central obesity reflect "Cushing's disease of the omentum"? Lancet. 1997;349:1210-1213.
Stewart PM. Clinical consequences of 11beta-hydroxysteroid dehydrogenase in humans. In: Symposium: The adipocyte as a steroid factory. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California.
Draper N, Lavery GG, Bujalska IJ, et al. Apparent cortisone reductase deficiency and 11beta hydroxysteroid dehydrogenase type 1: a monogenic cause of polycystic ovary syndrome. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California. Abstract P2-495.
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