CCN Proteins Are Distinct from, and Should Not Be Considered Members of, the Insulin-Like Growth Factor-Binding Protein Superfamily

Thomas Remer

Research Institute of Child Nutrition 44225 Dortmund, Germany

To the editor:

Recently, Longcope et al. (1) reported findings on the importance of dietary components in regulating the circulating levels of sex hormone-binding globulin (SHBG). The authors analyzed a large cross-sectional sample of data from the Massachusetts Male Aging Study. After controlling for a number of confounding variables (e.g. sex steroids, age, BMI) fiber intake was found to be significantly positively correlated to serum SHBG concentration, whereas protein intake showed a clear negative association with SHBG. Longcope et al. (1) proposed the following plausible mechanism by which protein intake can be a controlling factor on SHBG concentration: protein ingestion is known to increase insulin secretion, and insulin in turn has been shown to inhibit hepatic SHBG production. However, dietary carbohydrate intake, another stimulus for insulin release, did not show a significant association with SHBG. Therefore, the authors argued that the relationship of protein intake to SHBG levels probably involves more than only an effect on insulin. But from their data it was not possible to identify what that could be.

Recently, we have shown in a controlled experimental diet study that a lactovegetarian low protein diet, which is characterized by a diminished overall insulin secretion, can reduce adrenocortical activity as reflected in a reduced urinary dehydroepiandrosterone sulfate and free cortisol excretion (2). Because glucocorticoids have an independent potential to suppress circulating SHBG levels (3, 4), the reduction in adrenocortical activity with low protein intake could be an additional causal factor involved in the regulation of SHBG. With regard to the role of insulin as a regulator of circulating SHBG, it is of interest that apart from dietary protein also dietary fiber intake affects the insulin secretory dynamics. Not only low protein diets but also high fiber intakes attenuate postmeal insulin secretory peaks (5, 6). Thus, it is intelligible why a vegetarian nutrition, although providing very high carbohydrate intakes, can result in very low overall insulin secretion rates (2). Our corresponding diet study (comprising 5-day diet periods) proved, indeed, long enough to detect clear effects of nutrition on adrenal corticosteroid output but not long enough to see clear changes in SHBG levels (2). Therefore, controlled dietary long-term intervention studies are required to validate whether the discussed diet effects represent sustained changes in insulin secretion, adrenocortical activity, and, finally, hepatic SHBG production.

Taken together, the increase in circulating SHBG with low protein and high fiber intakes observed by Longcope et al. (Ref. 1 and other authors) could be a result of the combined effects of reduced insulin secretion and reduced glucocorticoid secretion. With regard to practice, reductions in serum SHBG levels will lead to elevated bioavailable testosterone (and vice versa). However, recommendations to decrease SHBG with high protein diets in elderly men (who have age-related low levels of bioavailable testosterone) are problematic because high protein diets can induce marked increases in renal acid loads (7) and renal net acid excretion capacity is reduced in aging subjects (8).

Received February 29, 2000.

References

  1. Longcope C, Feldman HA, McKinlay JB, Araujo AB. 2000 Diet and sex hormone-binding globulin. J Clin Endocrinol Metab. 85:293–296.[Abstract/Free Full Text]
  2. Remer T, Pietrzik K, Manz F. 1998 Short-term impact of a lactovegetarian diet on adrenocortical activity and adrenal androgens. J Clin Endocrinol Metab. 83:2132–2137.[Abstract/Free Full Text]
  3. Davis SR, Burger HG. 1996 Androgens and the postmenopausal woman. J Clin Endocrinol Metab. 81:2759–2763.[Medline]
  4. Hautanen A, Sarna S, Pelkonen R, Adlercreutz H. 1993 Serum sex hormone-binding globulin, cardiovascular risk factors, and adrenal cortisol responses to dexamethasone and corticotropin: Metabolism. 42:870–874.
  5. Ranganathan S, Champ M, Pechard C, et al. 1994 Comparative study of the acute effects of resistant starch and dietary fibers on metabolic indexes in men. Am J Clin Nutr. 59:879–883.[Abstract]
  6. Reiser S. 1987 Metabolic effects of dietary pectins related to human health. Food Technol. 41:91–99.
  7. Remer T, Manz F. 1995 Potential renal acid load of foods and its influence on urine pH. J Am Diet Assoc. 95:791–797.[CrossRef][Medline]
  8. Frassetto LA, Morris RC, Sebastian A. 1996 Effect of age on blood acid-base composition in adult humans: role of age-related renal functional decline. Am J Physiol. 271:F1114–F1122.




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