Comment—Do Glucocorticoids Mediate the Hypoglycemia-Induced Rise in Insulin-Like Growth Factor Binding Protein-1?

Robert C. Baxter

Kolling Institute of Medical Research Royal North Shore Hospital St Leonards, NSW 2065, Australia

Insulin-like growth factor binding protein-1 (IGFBP-1) is distinct among the members of the IGFBP family in being acutely regulated by metabolic stimuli (1). Studies with cultured human liver explants suggest that the major regulatory influences on IGFBP-1 production are insulin, which is inhibitory, and hepatic substrate deprivation, which is stimulatory, acting through a cyclic AMP-dependent mechanism (2, 3). Dexamethasone is also markedly inhibitory to IGFBP-1 production by human liver in explant culture (2).

Metabolic influences appear to account for the marked diurnal variation in serum IGFBP-1 levels seen in healthy subjects, which can be attributed to changing nutritional status throughout the day (4, 5, 6, 7, 8). The peak and the nadir of daily serum IGFBP-1 levels correspond temporally to the maximal and minimal serum cortisol levels, respectively (9), suggestive of a functional link in their regulation. However, in hypercortisolism due to Cushing’s disease, serum IGFBP-1 is markedly suppressed, and the diurnal variation is lost (9).

While the apparent suppression of IGFBP-1 in hypercortisolism is consistent with the inhibitory effect of dexamethasone in human liver explants, it is contrary to the well-established role of corticosteroids in the rat, where dexamethasone has been shown to increase IGFBP-1 serum levels and gene transcription (10, 11). Expression of the human IGFBP-1 gene is also stimulated by glucocorticoids (12), so that the likely explanation for the suppressive effect of hypercortisolism on serum IGFBP-1 levels is that it occurs secondarily to cortisol-induced hyperinsulinemia (13). The inhibitory effect of dexamethasone in human liver explants remains unexplained.

Insulin-induced hypoglycemia provokes a sharp rise in serum IGFBP-1, commencing an hour after the glucose nadir (1). IGFBP-1 can inhibit the effect of IGF-I on tissue glucose uptake (14). A high serum level of IGFBP-1, whether introduced by infusion or by transgenesis, is associated with hyperglycemia, and reverses the hypoglycemic action of IGF-1 (15, 16). These observations suggest that the hypoglycemia-induced rise in IGFBP-1 could serve a counterregulatory role in glucose homeostasis, as first proposed in 1988 (1). The 1-hr delay in IGFBP-1 response might render it ineffective as a counter to acute, pharmacologically-induced hypoglycemia; this delay might be caused in part by the residual suppressive effect of the administered insulin. Nevertheless, a prolonged IGFBP-1 increase in response to the gradual hypoglycemia associated with extended fasting (7) might effectively block the unwanted hypoglycemic activity of free IGFs in this more physiological situation, so that IGFBP-1 could play a true counterregulatory role.

Katz et al. (17) have recently described the increase of IGFBP-1 in 21 children in response to hypoglycemia associated with prolonged fasting. A positive association between serum cortisol and IGFBP-1 levels led the authors to conclude that the IGFBP-1 rise was "cortisol-induced." However, it is possible that the association was coincidental rather than causal, and other data suggest that the IGFBP-1 rise can occur independently of glucocorticoids. For example, in adrenalectomized rats with undetectably low serum corticosterone levels, iv insulin still induced a rise in IGFBP-1, though less than that seen in adrenal-intact animals (18). Similarly, increases in IGFBP-1 during fasting studies in a limited number of cortisol-deficient children led Cotterill et al. (7) to conclude that IGFBP-1 rose independently of cortisol levels.

In the original study on insulin-induced hypoglycemia (1), we also reported in the text that the IGFBP-1 rise occurred independently of the cortisol response to hypoglycemia. Figure 1iGollustrates the IGFBP-1 responses in 14 subjects who, after an overnight fast, were treated at 0900 h with a single injection containing GnRH (100 µg), TRH (200 µg), and insulin (0.1 U/Kg), as part of an investigation of pituitary function (1). In 11 subjects, a mean cortisol peak of 680 ± 54 nmol/L (SEM) was achieved at 60 min, a rise of some 250 nmol/L above initial values. The other 3 subjects, defined as failing to show a cortisol response, peaked at a mean cortisol level of 321 ± 126 nmol/L, less than 50 nmol/L above initial values. As seen in the figure, initial IGFBP-1 in the cortisol-responsive group (n=11) was 60.1 ± 12.6 µg/L, compared with 142.0 ± 17.2 µg/L in the cortisol-nonresponsive group (n=3). Despite the higher baseline IGFBP-1 levels in the latter group, both groups showed a marked IGFBP-1 rise commencing 90 min after insulin administration. At 180 min, IGFBP-1 in the cortisol-responsive group was 168.0 ± 31.6 µg/L, a comparable increment above baseline to that seen in the cortisol-nonresponsive group (277.7 ± 6.7 µg/L at 180 min).



View larger version (24K):
[in this window]
[in a new window]
 
Figure 1. Changes in serum levels of IGFBP-1 and cortisol in overnight-fasted adults undergoing an evaluation of pituitary function. They received a single injection at time zero containing GnRH (100 µg), TRH (200 µg), and insulin (0.1 U/kg). All subjects achieved a hypoglycemia of 2.5 mmol/L or lower. Mean values ± SEM.

 
Thus in these subject groups a lower fasting cortisol is associated with, if anything, a higher fasting IGFBP-1 level; and both the timing and magnitude of the IGFBP-1 response to hypoglycemia are independent of the cortisol response. We suggest, therefore, notwithstanding animal studies suggesting some involvement of an adrenal factor in the IGFBP-1 response to hypoglycemia, that the balance of evidence does not support the view that this factor is cortisol.

Footnotes

Received February 16, 1999. Address correspondence to: Robert C. Baxter, Department of Molecular Medicine, University of Sydney (E25), Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia.

References

  1. Yeoh SI, Baxter RC. 1988 Metabolic regulation of the growth hormone independent insulin-like growth factor binding protein in human plasma. Acta Endocrinol. 119:465–473.[Medline]
  2. Lewitt MS, Baxter RC. 1989 Regulation of growth hormone-independent insulin-like growth factor-binding protein (BP-28) in cultured human fetal liver explants. J Clin Endocrinol Metab. 69:246–252.[Abstract]
  3. Lewitt MS, Baxter RC. 1990 Inhibitors of glucose uptake stimulate the production of insulin-like growth factor binding protein (IGFBP-1) by human fetal liver. Endocrinology. 126:1527–1533.[Abstract]
  4. Rutanen E-M, Seppälä M, Pietilä R, Bohn H. 1984 Placental protein 12 (PP12): Factors affecting levels in late pregnancy. Placenta. 5:243–248.[Medline]
  5. Baxter RC, Cowell CT. 1987 Diurnal rhythm of growth hormone-independent binding protein for insulin-like growth factors in human plasma. J Clin Endocrinol Metab. 65:432–440.[Abstract]
  6. Busby WH, Snyder DK, Clemmons DR. 1988 Radioimmunoassay of a 26,000-Dalton plasma insulin-like growth factor-binding protein: Control by nutritional variables. J Clin Endocrinol Metab. 67:1225–1230.[Abstract]
  7. Cotterill AM, Cowell CT, Baxter RC, McNeil D, Silink M. 1988 Regulation of the growth hormone-independent growth factor-binding protein in children. J Clin Endocrinol Metab. 67:882–997.[Abstract]
  8. Suikkari A-M, Koivisto VA, Rutanen E-M, et al. 1988 Insulin regulates the serum levels of low molecular weight insulin-like growth factor-binding protein. J Clin Endocrinol Metab. 66:266–272.[Abstract]
  9. Degerblad M, Pòvoa G, Thorèn M, Wivall I-L, Hall K. 1989 Lack of diurnal rhythm of low molecular weight insulin-like growth factor binding protein in patients with Cushing’s disease. Acta Endocrinol. 120:195–200.[Medline]
  10. Luo J, Reid RE, Murphy LJ. 1990 Dexamethasone increases hepatic insulin-like growth factor binding protein-1 (IGFBP-1) mRNA and serum IGFBP-1 concentrations in the rat. Endocrinology. 127:1456–1462.[Abstract]
  11. Suh D-S, Ooi GT, Rechler MM. 1994 Identification of cis-elements mediating the stimulation of rat insulin-like growth factor-binding protein-1 promoter activity by dexamethasone, cyclic adenosine 3',5'-monophosphate, and phorbol esters, and inhibition by insulin. Mol Endocrinol. 8:794–805.[Abstract]
  12. Suwanichkul A, Allander SV, Morris SL, Powell DR. 1994 Glucocorticoids and insulin regulate expression of the human gene for insulin-like growth factor-binding protein-1 through proximal promoter elements. J Biol Chem. 269:30835–30841.[Abstract/Free Full Text]
  13. Lee PDK, Conover CA, Powell DR. 1993 Regulation and function of insulin-like growth factor-binding protein-1. Proc Soc Exptl Biol Med. 204:4–29.[Abstract]
  14. Lewitt MS, Saunders H, Cooney GJ, Baxter RC. 1993 Effect of human insulin-like growth factor-binding protein-1 on the half-life and action of administered insulin-like growth factor-I in rats. J Endocrinol. 136:253–260.[Abstract]
  15. Lewitt MS, Denyer GS, Cooney GJ, Baxter RC. 1991 Insulin-like growth factor-binding protein-1 modulates blood glucose levels. Endocrinology. 129:2254–2256.[Abstract]
  16. Rajkumar K, Barron D, Lewitt MS, Murphy LJ. 1995 Growth retardation and hyperglycemia in insulin-like growth factor binding protein-1 transgenic mice. Endocrinology. 136:4029–4034.[Abstract]
  17. Katz LEL, Satin-Smith MS, Collett-Solberg P, et al. 1998 Dual regulation of insulin-like growth factor binding protein-1 levels by insulin and cortisol during fasting. J Clin Endocrinol Metab. 83:4426–4430.[Abstract/Free Full Text]
  18. Lewitt MS, Saunders H, Baxter RC. 1992 regulation of rat insulin-like growth factor-binding protein-1: The effect of insulin-induced hypoglycemia. Endocrinology. 131:2357–2364.[Abstract]




This Article
Full Text (PDF)
Submit a related Letter to the Editor
Purchase Article
View Shopping Cart
Alert me when this article is cited
Alert me when eLetters are posted
Alert me if a correction is posted
Citation Map
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the journal
Download to citation manager
Request Copyright Permission
Google Scholar
Articles by Baxter, R. C.
Articles citing this Article
PubMed
PubMed Citation
Articles by Baxter, R. C.


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals