Jeffrey M P Holly

Circadian variation of GH-independent IGF-binding protein in diabetes mellitus and its relationship to insulin. A new role for insulin?

Evidence is accumulating that a non‐GH dependent insulin‐like growth factor‐binding protein (IGF‐BP) is not only a carrier protein but also has an active role in the growth process.

Effects of luteinizing hormone, insulin, insulin-like growth factor-I and insulin-like growth factor small binding protein 1 in the polycystic ovary syndrome

This study explores the clinical and endocrine implications of hyperinsulinae‐mia in the polycystic ovary syndrome (PCOS). Oral glucose tolerance tests were performed on 34 lean and 19 obese women with PCOS and on 13 lean women with normal ovaries. Insulin measurements were compared with basal gonado‐trophins, androgens, insulin‐like growth factor‐I (IGF‐I) and insulin‐like growth factor binding protein 1 (IGFBP‐1). Unselected lean women with PCOS were found to have fasting hyperinsulinaemia and the raised serum insulin concentrations were associated with menstrual disturbance and hyperandro‐genaemia. In addition, serum insulin concentrations in lean women with PCOS correlated positively with serum IGF‐I and negatively with serum IGFBP‐I concentrations. Ovarian stimulation by insulin appears to be independent of luteinizing hormone (LH) and is an important feature in 30% of lean women with PCOS.

The growth hormone independent insulin-like growth factor-I binding protein BP-28 is associated with serum insulin-like growth factor-I inhibitory bioactivity in adolescent insulin-dependent diabetics.

The relationship between the growth hormone independent insulin‐like growth factor binding protein (BP‐28) and serum insulin‐like growth factor‐I (IGF‐I) inhibitory bioactivity observed in diabetic serum was investigated in five poorly controlled adolescent type I diabetics. We have measured the in‐vitro effects of purified BP‐28 from amniotic fluid on serum IGF‐I stimulated and basal cartilage sulphation and compared serum IGF‐I bioactivity obtained from 24‐h serum profiles from each diabetic subject with serum concentrations of BP‐28 and IGF‐I measured by specific radioimmunoassays. Purified BP‐28 inhibited serum IGF‐I stimulated and basal cartilage sulphation in vitro, in a dose‐dependent manner. Serum IGF‐I bioactivity of diabetic sera showed a change in activity over the 24‐h period, with peak inhibitory bioactivity observed in each subject between 0800 and 1000 h. BP‐28 concentrations in each individual showed a marked circadian rhythm with maximum peak levels occurring at 0800 h. Long‐acting insulin administered in the evening in two of the diabetic subjects blunted the maximum peak level attained compared to the three diabetics who had long‐acting insulin administered in the morning. IGF‐I concentrations did not change over the 24‐h period in each individual. The data shows that BP‐28 inhibits serum IGF‐bioactivity on cartilage in vitro. The changes in inhibitory bioactivity observed in diabetic serum are associated with similar changes in serum concentrations of BP‐28. We propose that BP‐28 is one of the IGF‐I inhibitors observed in diabetic serum and that it may play a role in retarded growth and delayed puberty often seen in the adolescent diabetic.

Levels of GH binding activity, IGFBP-1, insulin, blood glucose and cortisol in intensive care patients

Summary. objective To Investigate levels of serum GH binding activity, Insulin‐like growth factor binding protein‐1 (IGFBP‐1), blood glucose, serum insulin, and cortisol in patients on the Intensive Therapy Unit.

The effects of recombinant insulin-like growth factor I administration on growth hormone levels and insulin requirements in adolescents with type 1 (insulin-dependent) diabetes mellitus

SummaryType 1 (insulin-dependent) diabetes mellitus in adolescence is associated with reduced levels of insulin-like growth factor I, elevated growth hormone concentrations and insulin resistance. In order to determine whether restoring insulin-like growth factor I levels to normal might lead to a reduction in growth hormone levels and insulin requirements, we undertook a double-blind placebo controlled study of a single s. c. dose of recombinant insulin-like growth factor I (40 μg/kg body weight) in nine late pubertal subjects with Type 1 diabetes. After administration of placebo or insulin-like growth factor I at 18.00 hours, a variable rate insulin infusion was used to maintain euglycaemia overnight. Plasma insulin-like growth factor I, growth hormone, free insulin, and intermediate metabolite concentrations were monitored throughout the study. Recombinant insulin-like growth factor I led to a rise in plasma concentrations which reached a peak at 5.5 h (413.1±28.2 ng/ml, mean±SEM). Mean growth hormone levels between 20.00 and 08.00 hours were significantly reduced after recombinant insulin-like growth factor I (19.4±4.0 compared with 33.6±5.8 mU/l; p=0.01), as were the insulin requirements for euglycaemia (0.25±0.02 compared with 0.31±0.04 mU · kg−1 · min−1; p=0.03). Plasma free insulin levels were lower after recombinant insulin-like growth factor I administration (31.9±2.7 compared with 67.9±16.0 mU/l; p=0.001) but no significant differences in ketone or lactate levels were detected. Recombinant insulin-like growth factor I in a s. c. dose of 40 μg/kg body weight leads to a significant reduction in overnight growth hormone levels and insulin requirements in adolescents with Type 1 diabetes.

Relationship between the pubertal fall in sex hormone binding globulin and insulin-like growth factor binding protein-I. A synchronized approach to pubertal development?

In a cross‐sectional study of 69 normal adolescents we have found sex hormone‐binding globulin (SHBG) levels to fall in both males and females throughout the pubertal period. Multiple regression analysis revealed a close negative correlation with insulin in both sexes. Weaker correlations were also found between SHBG and circulating androgen concentrations, in both males and females. Similar results were also obtained for a second circulating binding protein of primarily hepatic origin. This low molecular weight insulin‐like growth factor (IGF) binding protein I (IBP‐I) is one of two distinct classes of IGF binding proteins which bind IGF‐I and IGF‐II. IGF‐I in turn mediates, at least in part, the actions of growth hormone. IBP‐I also fell throughout puberty, correlating with the increasing insulin levels. In addition IBP‐I correlated with androgen levels in both sexes. These similarities between SHBG and IBP‐I, together with a strong correlation across puberty between the levels of the two binding proteins themselves (r= 0.737, P < 0.001), suggest common mechanisms of control over the circulating levels of these two binding proteins. The association with insulin raises the possibility of a synchronized modulation of the actions of sex steroids and IGFs by nutritional intake. Thus pubertal growth and sexual development may occur over the same time with both modulated according to nutritional intake, linked through pancreatic insulin release, to hepatic production of SHBG and IBP‐I.

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.

Menstrual irregularities are more common in adolescents with type 1 diabetes: association with poor glycaemic control and weight gain.

Ovarian function in post‐menarchal girls with Type 1 diabetes was evaluated. Menstrual histories from 24 adolescents with Type 1 diabetes were compared with those from 24 age and sex matched controls. A fasting blood sample was obtained from subjects with Type 1 diabetes for the measurement of ovarian and adrenal sex hormones, LH and FSH, glucose and insulin, insulin‐like growth factor‐l (IGF‐I), and insulin‐like growth factor binding protein‐1 (IGFBP‐1); and an ovarian ultrasound scan was performed. Menstrual irregularity was more prevalent in patients with Type 1 diabetes than controls (54% vs 21%, p < 0.01) and their mean body mass index (BMI) was greater (22.3 ± 0.5 (± SEM) vs 20.7 ± 0.6 kg m−2, p < 0.05). Subjects with Type 1 diabetes with irregular menses (when compared with diabetic subjects with a regular cycle) had a significantly higher HbA***1 (12.8 ± 0.4 vs 10.5 ± 0.5%, p < 0.01) and BMI (23.2 ± 0.6 vs 21.4 ± 0.6 kg m−2, p < 0.05) associated with a lower sex hormone binding globulin (SHBG) (37.2 ± 4.0 vs 52.6 ± 4.0 nmol I−1, p < 0.025) and IGF‐I (1.4 ± 0.2 vs 2.2 ± 0.2 ***mUI−1, p < 0.025) and a higher LH:FSH ratio (2.6 ± 0.5 vs 1.4 ± 0.2, p < 0.05). Polycystic ovarian changes were identified in 10/13 (77%) of these patients with an irregular cycle. Menstrual irregularity is common in post‐menarchal girls with Type 1 diabetes and is associated with poor glycaemic control and weight gain. The apparent high incidence of polycystic ovarian change requires further investigation.

Inhibitory effects of insulin-like growth factor-binding proteins on steroidogenesis by human granulosa cells in culture

The effects of insulin-like growth factor-binding proteins (IGFBPs) 1 and 3 on steroidogenesis by human granulosa cells has been examined. Both IGFBP-1 and IGFBP-3 produced a dose-related inhibition of IGF-I-stimulated oestradiol accumulation in granulosa cell-conditioned medium with complete reversal of the effects of IGF-I in the presence of a molar excess of binding protein. IGFBPs 1 and 3 also exerted a small (25-40%) but significant and consistent inhibition of oestradiol secretion in response to follicle-stimulating hormone (FSH) alone. The progesterone response to IGF-I was inhibited by IGFBPs 1 and 3 but there was no effect on FSH-stimulated progesterone production. These data support the concept of a physiologically important intraovarian IGF system in the human ovary and demonstrate an unequivocally inhibitory effect of IGFBPs 1 and 3 on IGF-I-stimulated granulosa cell steroidogenesis.

INSULIN‐LIKE GROWTH FACTOR BINDING PROTEINS IN FOLLICULAR FLUID FROM NORMAL DOMINANT AND COHORT FOLLICLES, POLYCYSTIC AND MULTICYSTIC OVARIES

There is now considerable evidence that the insulin‐like growth factors (IGFs) IGFs in ovarian physiology, the presence and functions of these IGFBPs will need to be characterized play an important role in the human ovary. It has also recently become apparent that the physiological activity of the IGFs is modulated by a number of specific binding proteins (IGFBPs). In order to understand the role of the. As an initial step towards this we have investigated the presence of the various binding proteins by Western ligand blotting and have measured the levels of one of them, IGFBP‐1, in follicular fluid (FF) obtained from unstimulated dominant and cohort follicles in 19 normal women and in eight patients with polycystic and one with multicystic ovaries. In normal women, IGFBP‐1 levels in dominant follicles were similar to matched serum levels but were significantly lower in cohort follicles. IGFBP‐1 levels correlated with FF‐volume (r= 0.58, P < 0.001) and with paired serum levels (r= 0.63, P < 0.001). In post‐LH surge dominant follicles this relationship with serum levels no longer held and in three out of nine subjects FF levels were higher than in serum. Thus IGFBP‐1 in normal human FF appears to be partly derived from the circulation but with additional local production in the larger developing dominant follicles. Western ligand blotting revealed five IGF‐binding proteins in FF running parallel with those identified in serum, suggesting that the IGFBP species previously identified in serum may also be present in FF. The two bands in positions corresponding to the components of the large (150kDa) binding complex were, as in serum, the predominant forms and in most FF samples these were even more prominent than in the accompanying serum sample. This contrasts with previous studies in lymph which suggested that the 150kDa complex was largely retained in the circulation. All three small IGFBPs varied considerably between FF samples even within an individual; each IGFBP varied independently of the other IGFBPs. Our results demonstrate that at least four discrete IGFBPs are present in FF and suggest that each may be produced independently within the ovary.