Andrew M. Cotterill

Critical illness is associated with low circulating concentrations of insulin-like growth factors-i and -ii, alterations in insulin-like growth factor binding proteins, and induction of an insulin-like growth factor binding protein 3 protease

OBJECTIVESnTo describe the sequential changes in the circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins in critically ill patients. To determine whether critical illness is associated with induction of a specific protease directed against insulin-like growth factor binding protein 3 and to relate these changes to outcome.nnnDESIGNnProspective, descriptive study.nnnSETTINGnIntensive care unit (ICU) of a university hospital.nnnPATIENTSnEighteen heterogeneous critically ill patients, requiring ventilatory support.nnnINTERVENTIONSnSerial daily blood samples were collected until death or discharge from the ICU. In five patients, samples were also obtained on the ward before discharge from the hospital.nnnMEASUREMENTS AND MAIN RESULTSnSerum concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding proteins 1, 2, and 3 were measured by radioimmunoassay. After 5 days, insulin-like growth factor binding protein 3 concentrations were measured on alternate days. Alterations in binding of insulin-like growth factor-I to insulin-like growth factor binding protein 3 and the presence of protease activity directed against insulin-like growth factor binding protein 3 were investigated by Western ligand blotting. Circulating concentrations of insulin-like growth factor-I and insulin-like growth factor-II were low and remained low throughout the 7-day study period. Insulin-like growth factor binding protein 1 concentrations were initially increased to within the fasting range, but subsequently decreased. There was considerable variability in insulin-like growth factor binding protein 2 concentrations, but generally, concentrations were at the upper end of the normal range throughout. Insulin-like growth factor binding protein 3 concentrations were consistently low and Western ligand blotting at the nadir of the insulin-like growth factor-I concentration demonstrated the presence of a protease directed against insulin-like growth factor binding protein 3. The last recorded concentrations of insulin-like growth factor-I and insulin-like growth factor binding protein 3 were higher in survivors than in nonsurvivors (p < .05). Two patients were also studied for a prolonged period. In one patient, a survivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 were low initially, but later increased in association with recovery and cessation of protease activity over a period of 33 days. In another patient, a nonsurvivor, insulin-like growth factor-I and insulin-like growth factor binding protein 3 remained low and protease activity persisted until the patient died 38 days after admission to the ICU.nnnCONCLUSIONSnCritical illness is associated with low circulating concentrations of insulin-like growth factor-I, insulin-like growth factor-II, and insulin-like growth factor binding protein 3 and these low values are associated with induction of protease activity specifically directed against insulin-like growth factor binding protein 3. In survivors, recovery is associated with increasing insulin-like growth factor-I and insulin-like growth factor binding protein 3 concentrations and cessation of protease activity. The therapeutic effects of exogenous growth factors are likely to be influenced by these changes.

Improvement of diagnostic criteria in growth hormone insensitivity syndrome: solutions and pitfalls

A survey to identify children and adolescents with primary growth hormone insensitivity syndrome (GHIS) yielded 38 patients who were positively identified using a scoring system that included five criteria: height, basal growth hormone (GH), GH binding protein, basal insulin‐like growth factor 1 (1GF‐I) and the increase of IGF‐I after 4 days of GH administration (IGF generation test). Because of an overlap of the accepted and excluded groups with respect to points scored, an attempt was made to improve the scoring system. The new criteria were: height below –3 SDS, basal GH 4 mU/I or above, GH binding below 10%, basal IGF‐I and basal IGF binding protein‐3 (IGFBP‐3) below the 0.1 centile for age, an increase of IGF‐I in the IGF generation test less than 15 μg/1, and the increase of IGFBP‐3 less than 0.4 mg/1. With this scoring system, a clear separation between the accepted and the excluded groups was obtained. IGFBP‐3 was included to give the GH‐dependent parameters of the IGF system more weight and because the accuracy of IGFBP‐3 in the IGF generation tests was greater than the accuracy of IGF‐I, when the group of patients with GHIS was compared with a group of patients with GH deficiency. Unexpectedly, the IGF generation test was unable to segregate both cohorts completely. In the GHIS‐positive group, a significant correlation was found between basal IGF‐I or IGFBP‐3 levels corrected for age (SDS) and height SDS (r= 0.49, p < 0.002 and r= 0.61, p < 0.0001, respectively). There was also a significant correlation between the changes of IGF‐I or IGFBP‐3 in the IGF generation test and height SDS. That is, the patients with a slight response to GH were those with the least growth retardation, suggesting the existence of partial GH insensitivity.

The differential regulation of the circulating levels of the insulin-like growth factors and their binding proteins (IGFBP) 1, 2 and 3 after elective abdominal surgery

OBJECTIVESu2003Patients undergoing abdominal surgery often suffer from morbidity associated with increased protein catabolism. Therapeutic recombinant human insulin‐like growth factor (rhIGF)‐I has been proposed as a means of reversing this process. As IGFBPs modulate the bioavailability of the IGFs, we have studied the changes in the circulating levels of these peptides during surgery.

The regulation of insulin‐like growth factor binding protein (IGFBP)‐1 during prolonged fasting

OBJECTIVE Insulin‐like growth factor binding protein (IGFBP)‐1 levels increase overnight, being inversely related to changes in insulin. With prolonged fasting IGFBP‐1 levels increase further. In animal studies high IGFBP‐1 levels increase plasma glucose levels possibly by regulating the insulin‐like actions of ‘bio‐available’ plasma IGF. Following prolonged fasting, there is an increase in insulin requirement. A proportion of this reversible insulin resistance may be due to inhibitory effects of high IGFBP‐1 levels on IGF action. This study examined the regulation of IGFBP‐1 in the presence of reversible insulin resistance.

Changes in serum IGF-I and IGFBP-3 concentrations during the IGF-I generation test performed prospectively in children with short stature.

Genotype and phenotype heterogeneity in patients with GH insensitivity syndrome suggests that partial defects exist in the GH receptor. Children with partial GH resistance would be expected to have short stature, elevated GH levels and relatively low levels of IGF‐I and IGFBP‐3. Provocation tests of the GH–IGF‐I axis may help to identify such children. The IGF‐I generation test in particular may demonstrate impaired secretion of IGF‐I and IGFBP‐3. This prospective study assesses the usefulness of the IGF‐I generation test in the identification of short children with possible GH insensitivity.

Suppression of endogenous insulin secretion regulates the rapid rise of insulin-like growth factor binding protein (IGFBP)-1 levels following acute hypoglycaemia

OBJECTIVES Recent animal studies have suggested that insulin‐like growth factor binding protein (IGFBP)‐1 may regulate the insulin‐like actions of the circulating IGFs. In man, IGFBP‐1 levels change rapidly with nutritional status and are inversely related to changes in insulin. In‐vitro studies have shown that both insulin and glucose independently regulate IGFBP‐1 secretion in an inverse manner. A rapid rise of serum IGFBP‐1 levels following insulin‐induced hypoglycaemia suggested that glucose or glucose availability, rather than insulin, may be the major regulator of IGFBP‐1.

The effect of recombinant human insulin‐like growth factor‐I treatment on growth hormone secretion in two subjects with growth hormone insensitivity (Laron syndrome)

OBJECTIVE Growth hormone (GH) secretion Is increased in conditions of GH insensitivity such as Laron syndrome, with elevation of both basal and peak levels. We have studied the effect of recombinant IGF‐I therapy on the pattern of GH secretion in two subjects with GH insensitivity.

The ‘dawn phenomenon’ in adolescents with insulin dependent diabetes mellitus: possible contribution of insulin-like growth factor binding protein-1

OBJECTIVE Insulin resistance increases during adolescence, and is exaggerated in patients with insulin dependent diabetes mellitus (IDDM). A relative deficiency of insulin‐like growth factor‐I (IGF‐I) may contribute to this increased insulin requirement. Two mechanisms have been proposed: (a) increased GH secretion, caused by failure of IGF feedback control, leading to increased insulin resistance and (b) lack of Insulin‐like action of the IGFs which is reinforced by high plasma levels of IGFBP‐1, an inhibitor of IGF action. The contribution of these two mechanisms to the ‘dawn phenomenon’ is assessed.

The insulin-like growth factor I generation test in the investigation of short stature

Genotypic and phenotypic heterogeneity in patients with growth hormone (GH) insensitivity syndrome suggests that partial defects exist in the GH receptor. The insulin‐like growth factor I (IGF‐I) generation test was assessed as a means of identifying partial GH receptor defects in a heterogeneous group of 22 prepubertal children with short stature. In a subgroup of nine patients with peak GH levels of 63.7 ± 3.7 mU/l during a glucagon tolerance test, the response to the IGF‐I generation test was no different from that for the group as a whole (peak GH, 43.3 ± 4.5 mU/l), despite the fact that this subgroup exhibited a negative relationship between height SDS and peak GH and a positive relationship between height SDS and IGF binding protein‐3. This preliminary study therefore suggests that the IGF‐I generation test in its present form will not be useful as a primary screening test for partial GH insensitivity. Despite this, the IGF‐I generation test has been extremely useful in the confirmation of the diagnosis of GHIS and may therefore also prove useful in the confirmation of partial defects in the GH receptor. A subgroup of short children with peak GH levels above 40 mU/l had some characteristics of partial GH receptor deficiency. These children, to whom GH therapy would not normally be given, may respond better to recombinant human IGF‐I.

Correlation between cortisol and insulin-like growth factor-binding proteins (IGFBPs) under physiological conditions in children

A positive correlation between 24‐h spontaneous growth hormone (GH) and cortisol secretion was previously reported in children. This observation prompted us to examine the relationship between physiological diurnal cortisol variation and the levels of insulin‐like growth factors (IGFs) and IGF‐binding proteins (IGFBPs) under physiological conditions.