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Biomedical subjects

S R Holman

Publications and source records attributed to S R Holman.

5 recordsLinked to original sources
PubMed1998

Thirty-day monitoring of insulin-like growth factors and their binding proteins in intensive care unit patients.

This study investigates the regulation of the insulin-like growth factors (IGFs) and their regulatory proteins in 14 critically ill patients during the 30-day period following admission to an intensive care unit (ICU). Levels of IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3) and acid-labile subunit (ALS) were low on admission, and in the 8 patients whose serum IGF-I levels failed to increase over 30 days, levels of the other proteins also remained low, while IGFBP-3 proteolytic activity increased. Of these proteins, ALS correlated best with serum levels of nutritional indicators, particularly prealbumin. IGFBP-2 and IGFBP-6 levels tended to be high in critically ill patients, but showed little change over the 30-day period. In contrast, IGFBP-1 levels were high on admission, correlated with early changes in nitrogen balance, and fell rapidly during the first week. By demonstrating that the IGF-I response in ICU patients is related to changes in the IGF regulatory proteins, this study may be of value in planning therapeutic intervention using growth hormone or IGF-I.

Adult↗
PubMed1996

Insulin-like growth factor binding protein-3: factors affecting binary and ternary complex formation.

IGF binding protein-3 (IGFBP-3), the major serum carrier of IGF-I and IGF-II in adults, circulates predominantly in a ternary complex with IGF and the acid-labile subunit (ALS). The affinities of IGF and ALS binding have not previously been determined under conditions of temperature, ionic strength and pH which approximate those in the circulation. IGF-I and -II binding was optimal at pH 4.0-5.5, and relatively poor at pH 7.4. The addition of 0.1 mol/l NaCl to 50 mmol/l phosphate buffer increased the affinity of IGF-II for IGFBP-3 by 2-fold, and of IGF-I by 4-fold. ALS binding peaked at pH 5.5-6.0, and was markedly reduced at pH 7.4, where only approximately 0.4 mol ALS was bound per mol IGFBP-3, with greatly reduced affinity. ALS affinity was further reduced at 37 degrees C compared to 22 degrees C, and in the presence of 0.1 mol/l NaCl compared to its absence. Under 'physiological' conditions, the affinities of ALS binding to IGF-I-IGFBP-3 and IGF-II-IGFBP-3 complexes (2.5 x 10(8) l/mol and 5.8 x 10(7) l/mol, respectively) are 300-fold and 2000-fold lower than the constants for the formation of the corresponding binary complexes. Thus, ALS binding to IGFBP-3 complexes is much weaker than previously recognised, emphasising the importance of ALS dissociation as a controlling factor in the regulation of IGF bioavailability.

Adult↗
PubMed1995

Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumor hypoglycemia.

Hypoglycemia in patients with nonislet cell tumors is often secondary to overexpression of tumor insulin-like growth factor (IGF) II. In these patients the formation of serum complexes between IGFs, IGF binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) is impaired. An 87-yr-old woman with nonislet cell tumor hypoglycemia resulting from a localized fibrous tumor of the pleura was treated for 97 days with graded doses of prednisolone (30, 10, and 5 mg/day) followed by GH (1, 4, 8, 4, and 2 U/day). Both prednisolone and GH alleviated the hypoglycemia, concomitantly with increases in IGF-I, IGFBP-3, and ALS levels. Pretreatment serum IGFBP-2 and IGFBP-6 levels were greatly elevated, but as glucose normalized with treatment, only IGFBP-2 decreased, showing an inverse correlation with glucose (r = 0.716). IGFBP-1 gave a variable pattern not clearly related to blood glucose. Both treatments caused a redistribution of serum IGFBP-3 from binary- to ternary-complexed forms. However, only prednisolone improved the ability of IGFBP-3 to bind ALS in vitro. Prednisolone also suppressed IGF-II, the effect being confined to pro-IGF-II forms. Compared with normal IGF-II, pro-IGF-II inhibited ALS binding to IGFBP-3 in vitro. Although prednisolone and GH reverse hypoglycemia by different mechanisms, with only prednisolone suppressing tumor IGF-II secretion, both increase the formation of ternary IGF-IGFBP-3 complexes. We conclude that the failure of serum IGFBP-3 and tumor IGF-II to complex with ALS is a primary cause of hypoglycemia in nonislet cell tumor hypoglycemia.

Aged↗
PubMed1993

Responses of insulin-like growth factor binding protein-1 (IGFBP-1) and the IGFBP-3 complex to administration of insulin-like growth factor-I.

The importance of insulin-like growth factor binding proteins (IGFBPs) in modulating the bioactivity of administered IGFs is poorly understood. This study examines responses of IGFBP-1 and the IGFBP-3 complex to recombinant human IGF-I. Eight fasted subjects received a single dose of 0.1-0.125 mg/kg IGF-I sc. This caused a 10-fold rise in IGFBP-1 over 6 h, falling rapidly after food intake. Peak (6-h) IGFBP-1 values were highly correlated with peak post-prandial (8-h) glucose values (r = 0.941). IGFBP-3 showed little response, decreasing slightly over the 48-h period following IGF-I. Adaptive changes in IGFBPs were studied in fed adults injected daily for 7 days with IGF-I, 0.1 mg/kg sc. Following the first injection, IGFBP-1 had a markedly blunted response compared to that in fasted subjects. However, after the seventh IGF-I injection, a 3.5-fold greater IGFBP-1 response to the same IGF-I dose was seen. Concomitantly with the increased IGFBP-1 responsiveness, mean immunoreactive IGFBP-3 and acid-labile subunit levels decreased significantly (p < 0.005), whereas IGFBP-2 detected by immunoblotting increased. Thus IGF-I administration causes changes in IGFBPs which may be important in regulating IGF-I bioavailability.

Adult↗