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Regulation of Insulin-Like Growth Factor Binding Protein-I During the 24-Hour Metabolic Clock and in Response to Hypoinsulinemia Induced by Fasting and Sandostatin in Normal Women

Tarja L. Butzow, MD

Gail A. Laughlin

Minh Ho, MD

Arlene J. Morales, MD

Samuel C. Yen, MD, DSc

Department of Reproductive Medicine, University of California, San Diego School of Medicine, La Jolla, California

Objective: To establish the relation of insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) with 24-hour metabolic excursions in normal healthy women and in response to acute interruption of metabolic homeostasis by hypoinsulinemia.

Methods: Hourly blood samples during the 24-hour metabolic clock were obtained from seven normally cyclin women. Uniform dietary composition (50% carbohydrate, 35% fat, and 15% protein) and timing of meals (8 AM, 12 PM, and 6 PM) were prescribed. Daytime hypoinsulinemia was induced by omitting meals and by Sandostain (100 µg) administration. Changes in serum levels of glucose, insulin, cortisol, IGF-I, and IGFBP-1 were measured.

Results: The diurnal pattern of serum IGFBP-1 levels during the 24-hour metabolic clock was characterized by a rapid fall during the feeding phase of the day and a progressive 3.5-fold rise during nocturnal fasting; IGF-I levels were unchanged. Changes in IGFBP-1 levels were in parallel to those of cortisol and were inversely related to increases in glucose (80%) and insulin (tenfold) levels after each meal and to their decline during nocturnal fasting. Daytime fasting and administration of Sandostatin were accompanied by rapid and sustained increases in IGFBP-1 when insulin levels declined to 54 ± 20 pmol/L.

Conclusions: With constant levels of IGF-I, the diurnal rhythm of IGFBP-1 may subserve a physiologic function by coordinating insulin and IGF-I action with substrate availability. Fluctuations of insulin levels during the 24-hour metabolic clock in normal women appear to sere as a signal, with an inhibitory effect on IGFBP-1 production when levels are above 70 pmol/L and a stimulatory effect at levels below 70 pmol/L. These findings provide a basis for future investigations in woman with nutritionally related reproductive disorders.

Key Words: IGFBP-1 • diurnal rhythm • metabolic clock • insulin

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